heparitin-sulfate and Thrombosis

In the context of inpatient and increasingly ambulatory thrombosis prophylaxis, heparins have been recognised as standard therapy for decades. In addition to the therapeutic benefit, therapy with heparins also entails the risk of undesirable side effects, such as bleeding and thrombocytopenia. Heparin-induced thrombocytopenia (HIT II) is deemed a serious side effect.. In the following work, HIT II is subjected to a medico-economic consideration (treatment, pharmaceuticals, subsequent costs due to possible complications) and, with regard to a possible HIT II prophylaxis, aspects of increasingly respected patient safety are also considered.. In the context of a literature search the active ingredients argatroban and danaparoid, which are approved for HIT II treatment, were evaluated.. HIT II - especially in combination with thromboembolic complications - represents a medical-economic burden for the hospital. Although this is only an orientation guide, it shows that HIT II syndrome is not adequately cost-covered by the G‑DRG system. An early thrombosis prophylaxis with argatroban/danaparoid for HIT II risk patients should therefore be taken into account for medical-related as well as patient safety-relevant aspects. According to experience, the pharmaceutical supply for these medically needed products (anticoagulants) should be ensured for reasons of patient safety.. The risk of an immunological response to heparin therapy is known. Within the context of increased patient safety, thrombosis prophylaxis should be issued with a risk-adjusted prophylaxis.

Topics: Arginine; Chondroitin Sulfates; Costs and Cost Analysis; Dermatan Sulfate; Germany; Hemorrhage; Heparin; Heparitin Sulfate; Hospitalization; Humans; Pipecolic Acids; Risk Factors; Sulfonamides; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparanase, the sole mammalian endoglycosidase degrading heparan sulfate, is causally involved in cancer metastasis, angiogenesis, inflammation and kidney dysfunction. Despite the wide occurrence and impact of heparan sulfate proteoglycans in vascular biology, the significance of heparanase in vessel wall disorders is underestimated. Blood vessels are highly active structures whose morphology rapidly adapts to maintain vascular function under altered systemic and local conditions. In some pathologies (restenosis, thrombosis, atherosclerosis) this normally beneficial adaptation may be detrimental to overall function. Enzymatic dependent and independent effects of heparanase on arterial structure mechanics and repair closely regulate arterial compliance and neointimal proliferation following endovascular stenting. Additionally, heparanase promotes thrombosis after vascular injury and contributes to a pro-coagulant state in human carotid atherosclerosis. Importantly, heparanase is closely associated with development and progression of atherosclerotic plaques, including stable to unstable plaque transition. Consequently, heparanase levels are markedly increased in the plasma of patients with acute myocardial infarction. Noteworthy, heparanase activates macrophages, resulting in marked induction of cytokine expression associated with plaque progression towards vulnerability. Together, heparanase emerges as a regulator of vulnerable lesion development and potential target for therapeutic intervention in atherosclerosis and related vessel wall complications.

Topics: Animals; Atherosclerosis; Carotid Arteries; Extracellular Matrix; Glucuronidase; Heparitin Sulfate; Humans; Macrophage Activation; Macrophages; Mice; Neoplasms; Plaque, Atherosclerotic; Thrombosis

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

Topics: Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Evidence-Based Medicine; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Infusions, Intravenous; Peptide Fragments; Pipecolic Acids; Polysaccharides; Practice Guidelines as Topic; Recombinant Proteins; Societies, Medical; Sulfonamides; Thrombin; Thrombosis; United States

Danaparoid case reports of 91 pregnancies in 83 patients with a history of thrombophilia and/or intra-uterine growth retardation have been analysed. All had intolerance to the heparins including HIT and acute or past thromboses or a history of repeated pregnancy loss (RPL). Danaparoid was started in the first, second and third trimesters in 60.2%, 19.3% and 20.5% pregnancies respectively at a dosing intensity of 1000 to 7500 U/day. Subcutaneous and/or intravenous administration was continued for a median 105 days (range 1-252) during pregnancy and 7 days (range 2 to 56) post-partum. The live birth rate was 90.4% (75/81) and danaparoid was restarted after 37 deliveries. Maternal adverse events in 46.2% of the pregnancies included 2 post cesarean deaths (a failed post-operative resuscitation and a major bleed in a patient refusing transfusion), 3 non-fatal major bleeds (associated with cesarean section and faulty placental implantation), 3 thrombo-embolic events unresponsive to danaparoid dose increase and 10 recurrent rashes. Seven early miscarriages, 1 therapeutic termination and 1 neonatal death occurred. In 13 reports a maternal, but no fetal, adverse event was attributed to danaparoid. Anti-Xa activity levels in maternal plasma were between 0.1 and 1.2 U/mL, absent from 6 fetal cord blood samples and 0 - 0.07 U/mL in the 5 maternal breast milk samples tested.. The successful birth rate and adverse event profile indicates that danaparoid can be an effective and safe alternative anti-thrombotic in pregnancies complicated by HIT or intolerance or resistance to (LMW)heparins.

Topics: Abortion, Spontaneous; Chondroitin Sulfates; Dermatan Sulfate; Exanthema; Female; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Infant, Newborn; Infusions, Intravenous; Injections, Subcutaneous; Pregnancy; Research; Thrombosis; Treatment Outcome

One hundred and twenty-two case reports of treatment outcomes of danaparoid use for intermittent haemodialysis (HD) in severely ill patients with heparin intolerance (including 97 HIT patients) have been analysed. HD sessions of 4 - 6 hours were successfully conducted daily to 3 times/week for periods of up to 4 years (median 7 sessions/patient (range 1 - >650). In these patients danaparoid use was relatively safe (4 unprovoked non-fatal major bleeds) and efficacious in protecting the circuit (95% no clotting problem) or patient (6 thromboses: 4 fatal or leading to danaparoid discontinuation). HIT diagnosis was improved if recurrent platelet count reduction with each HD and circuit/AV graft clotting were included. Alternative reasons for and very low nadirs of the platelet count undermined the usefulness of the 4 T pre-test HIT predictability scores, but a positive functional serological test confirmed HIT in most patients. Deaths (15.6%) and thrombosis only occurred in HIT cases. Possible reasons are discussed. Replacing the standard intermittent pre-HD dose regimen with the therapeutic infusion regimen to provide continuous daily systemic antithrombotic protection, should further improve efficacy.. Danaparoid appears to be a useful alternative antithrombotic for patients with heparin intolerance and renal failure requiring haemodialysis.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Platelet Count; Pregnancy; Recurrence; Renal Dialysis; Thrombosis; Treatment Outcome

Topics: Anticoagulants; Arginine; Autoantibodies; Chondroitin Sulfates; Dermatan Sulfate; Drug Monitoring; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Count; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Warfarin

Thrombocytopenia following heparin administration can be associated with an immune reaction, now referred to as heparin-induced thrombocytopenia (HIT). HIT is essentially a prothrombotic disorder mediated by an IgG antiplatelet factor 4/heparin antibody, which induces platelet, endothelial cell, monocyte, and other cellular activation, leading to thrombin generation and thrombotic complications. Indeed, HIT can also be regarded as a serious adverse drug effect. Importantly, HIT can be a life-threatening and limb-threatening condition frequently associated with characteristically severe and extensive thromboembolism (both venous and arterial) rather than with bleeding. This article provides an overview of HIT, with an emphasis on the clinical diagnosis and management.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Hirudins; Humans; Male; Monitoring, Physiologic; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Count; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Safety Management; Severity of Illness Index; Sulfonamides; Survival Rate; Thrombocytopenia; Thrombosis; Time Factors

Malignant tumor cells invade normal tissues in the vicinity of cancer through devastating the extracelluar matrix and blood vessel wall of the tissues. An important step in this process is degradation of heparan sulfate proteoglycan, a carbohydrate-protein complex. Heparan sulfate proteoglycan is a major component of the extracellular matrix, and is essential for the self-assembly, insolubility and barrier properties of basement membranes. Heparanase is an endoglucuronidase that cleaves heparan sulfate and expression level of this enzyme correlates with metastatic potential of tumor cells. Treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. Heparin, a widely used anticoagulant, is structurally related to heparan sulfate and a natural substrate of heparanase. Long-term treatment of cancer patients having venous thromboembolism with low molecular weight heparin showed improved survival rate. Understanding the functional roles and the corresponding molecular mechanisms of heparin, heparan sulfate and heparanase in cancer development may pave the way for exploring remedies against tumor metastasis.

Topics: Animals; Anticoagulants; Extracellular Matrix; Heparin; Heparin Lyase; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Substrate Specificity; Thrombosis

To summarize new information on frequency of heparin-induced thrombocytopenia (HIT) in patients treated in intensive care units (ICU), developments in the interpretation of assays for detecting anti-PF4/heparin antibodies, and treatment of HIT patients.. All data on the frequency of laboratory-confirmed HIT in ICU patients were included; for laboratory testing of HIT and treatment of patients, this review focuses on recent data that became available in 2005 and 2006.. HIT is a potentially life-threatening adverse effect of heparin treatment caused by platelet-activating antibodies of immunoglobulin G class usually recognizing complexes of platelet factor 4 and heparin. HIT is more often caused by unfractionated heparin than low-molecular-weight heparin and is more common in postsurgical than in medical patients. In the ICU setting, HIT is uncommon (0.3-0.5%), whereas thrombocytopenia from other causes is very common (30-50%). For laboratory diagnosis of HIT antibodies, both antigen assays and functional (platelet activation) assays are available. Both tests are very sensitive (high negative predictive value) but specificity is problematic, especially for the antigen assays, which also detect nonpathogenic immunoglobulin M and immunoglobulin A class antibodies. Detection of immunoglobulin M or immunoglobulin A antibodies could potentially lead to adverse events such as bleeding if a false diagnosis of HIT prompts replacement of heparin by an alternative anticoagulant. For treatment of HIT, three alternative anticoagulants are approved: the direct thrombin inhibitors, lepirudin and argatroban, and the heparinoid, danaparoid (not approved in the United States). Recent data indicate that the approved dosing regimens of the direct thrombin inhibitors are too high, especially in ICU patients.. HIT affects <1% of ICU patients even though 30-50% develop thrombocytopenia. The choice of the optimal alternative anticoagulant depends on patient characteristics. Many ICU patients require lower doses of alternative anticoagulant than those recommended by the manufacturer.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Extracorporeal Circulation; Heparin; Heparitin Sulfate; Hirudins; Humans; Intensive Care Units; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) and heparin induced thrombocytopenia with thrombosis (HITT) ar rare complications associated with use of unfractionate heparin (UFH) or low-molecular-weight heparin (LMWH) HIT is a benign clinical condition characterized by a mil drop in platelet count with no clinical significance. HIT is an immune-mediated reaction associated with a wide spread "hypercoagulable" state resulting in arterial an venous thrombosis. There is a higher incidence of HIT with UFH use than with LMWH use. Orthopedic surger patients are at higher risk for developing HITT than are patients who receive prophylactic heparin for cardiovascular surgery or medical reasons. Therapy for patients suspected of having HITT should begin with immedi ate discontinuation of heparin in any form followed by pharmacologic inhibition with thrombin (e.g., recombinant hirudin [lepirudin], argatroban, danaparoid sodium).

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Arginine; Cardiac Surgical Procedures; Cardiovascular Diseases; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sensitivity and Specificity; Sulfonamides; Thrombocytopenia; Thrombosis

Pregnant patients with acute venous thrombosis or a history of thrombosis may need alternative anticoagulation, when heparin intolerance occurs. Only limited data on the use of the heparinoid danaparoid are available in literature. We reviewed the use of danaparoid in 51 pregnancies of 49 patients identified in literature between 1981 and 2004. All patients had developed heparin intolerance (32 due to heparin-induced thrombocytopenia, 19 mainly due to heparin-induced skin rashes) and had a current and/or past history of thromboembolic complications. The initial danaparoid dose regimens ranged from 1000 to 7500 U/day administered s.c. or i.v.. The median duration of danaparoid use was 10 weeks. Danaparoid was used until delivery of a healthy infant in 37 pregnancies. In the remaining 14 pregnancies it was stopped earlier, because anticoagulant treatment was no longer required (3/14) or an adverse event led to a treatment discontinuation (11/14). Four maternal bleeding events were recorded during pregnancy, delivery or postpartum, two of them were fatal due to placental problems. Three fetal deaths were recorded, all associated with maternal complications antedating danaparoid use. Danaparoid cross-reactivity was suspected in 4 HIT patients and 5 non-HIT patients with skin reactions and was confirmed serologically in one of the two HIT patients tested. In none of five fetal cord blood- and three maternal breast milksamples anti-Xa activity transfer was observed. In conclusion danaparoid can be used as an alternative antithrombotic agent in pregnant women with high thrombotic risk and intolerance to heparins.

Topics: Adult; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Evaluation; Drug Hypersensitivity; Exanthema; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; MEDLINE; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Retrospective Studies; Thrombocytopenia; Thrombosis

Recommendations for transitioning from therapy with heparin or a low-molecular-weight heparin preparation to therapy with an oral anticoagulant in patients with acute venous or arterial thromboembolism have undergone several changes during the last two decades. Physicians are now comfortable with beginning treatment with an oral anticoagulant once the diagnosis is confirmed, and loading doses are no longer considered to be necessary. Exceptions to early transition may be necessary in patients with an extensive iliofemoral or axillary-subclavian vein thrombosis or pulmonary embolism where thrombolytic agents may be indicated, or in individuals who require surgery or other invasive procedures, or if there are concerns about bleeding. The avoidance of early transition to oral anticoagulants in patients with acute heparin-induced thrombocytopenia also has been advised because of the potential for further thrombotic complications, including venous limb gangrene and warfarin-induced skin necrosis.

Topics: Administration, Oral; Anticoagulants; Arginine; Blood Coagulation; Blood Coagulation Factors; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Gangrene; Heparin; Heparitin Sulfate; Hirudins; Humans; Ischemia; Leg; Necrosis; Pipecolic Acids; Recombinant Proteins; Skin; Sulfonamides; Thrombocytopenia; Thrombosis; Warfarin

Heparin-induced thrombocytopenia (HIT) is caused by heparin-dependent, platelet-activating IgG antibodies that increase thrombin generation in vivo, producing a prothrombotic phenotype. In addition to platelet activation, there is in vitro evidence that activation of endothelium and monocytes occurs, perhaps directly by HIT antibodies, but more likely through activated platelet (or microparticle)-endothelial-leukocyte interactions. Patients with cardiac disease receiving heparin present important diagnostic and therapeutic issues when unexpected thrombocytopenia arises. Concomitant vascular disease burden and intravascular catheter use further increase risk of HIT-associated arterial thrombosis in this patient population. Whether arterial thrombosis simply reflects the "hypercoagulability state" of HIT interacting with diseased or injured arteries, or whether arterial "white clots" reflect additional prothrombotic effects of HIT via endothelial and monocyte activation, remains uncertain. Patients with HIT can also develop deep-vein thrombosis, which can progress to limb loss if coumarin (warfarin) leads to severe protein C depletion (coumarin-induced venous limb gangrene). Therapy for patients strongly suspected to have HIT should focus on inhibiting thrombin (or its generation) pharmacologically. Two direct thrombin inhibitors (lepirudin, argatroban) are approved for treating HIT. When using these agents, coumarin anticoagulation should be delayed pending substantial resolution of thrombocytopenia, before cautiously introducing overlapping coumarin therapy.

Topics: Antibodies; Anticoagulants; Cardiovascular Diseases; Coumarins; Heparin; Heparitin Sulfate; Humans; Immunoglobulin G; Models, Biological; Monocytes; Phenotype; Platelet Activation; Platelet Factor 4; Thrombin; Thrombocytopenia; Thrombosis

Platelet factor 4 (PF4) is a platelet-specific protein that is stored in platelet alpha granules and released following platelet activation. PF4 was the first chemokine that was isolated, but unlike other chemokines, it may not have a clear role in inflammation. Gathering evidence suggests that unlike other chemokines that bind to specific receptors, PF4's biology depends on its unusually high affinity for heparan sulfates and other negatively charged molecules at concentrations attained in the immediate vicinity of activated platelets. There has been one report that PF4 binds to CXCR3B, a chemokine receptor isoform that may be present in some vascular beds, but the biological relevance of this single observation is not clear. We propose that the main biological role of PF4 and the basis for its presence in the alpha granules of all known mammalian platelets is to neutralize surface heparan sulfate side-chains of glycosaminoglycans and to optimize thrombus development at sites of vascular injury. In addition, the binding of PF4 to surface glycosaminoglycans may also underlie its angiostatic and proatherogenic properties. Additionally, PF4 binds to several other proteins that are central to thrombosis, angiogenesis, and atherogenesis. These interactions may also contribute to its biological and pathobiological effects. Certainly, future studies using in vivo models to test biological relevance of each of these proposed mechanisms by which PF4 interacts with the vasculature are needed, as are studies to define the importance of PF4 binding to CXCR3B.

Topics: Animals; Blood Platelets; Blood Vessels; Chemokines; Dose-Response Relationship, Drug; Endothelium, Vascular; Glycosaminoglycans; Heparitin Sulfate; Humans; Inflammation; Mice; Models, Biological; Neovascularization, Pathologic; Platelet Activation; Platelet Factor 4; Protein Binding; Protein Isoforms; Receptors, Chemokine; Receptors, CXCR3; Thrombosis

Heparin-induced thrombocytopenia (HIT), a serious side effect of heparin treatment, requires alternative anticoagulation in most affected patients. The recombinant hirudin (r-hirudin) lepirudin has been approved for this purpose after two prospective trials in laboratory-confirmed HIT patients. Other drugs available for this purpose are danaparoid sodium (a heparinoid) and argatroban, a synthetic direct thrombin inhibitor. In this article, recommendations for optimal use of r-hirudin in HIT are given, covering therapy in uncomplicated patients as well as in special situations such as heparin reexposure of HIT patients. Because lepirudin's half-life depends on renal function, it may vary between 1 and 200 hours, which requires individual dose adjustments. Lepirudin compares favorably with danaparoid, based on retrospective data. No direct comparisons of lepirudin with argatroban are available, but argatroban might offer advantages in patients with renal failure, because it is mainly eliminated hepatically. Major hemorrhage, the main risk of lepirudin treatment, occurring in about 15% of patients, makes close monitoring important. New monitoring tools, such as the ecarin clotting time (ECT), might further reduce bleeding risks. Antihirudin antibodies, which can alter the pharmacokinetics as well as the pharmacodynamics of hirudin, can also be countered by close monitoring and appropriate dose adjustments. Whereas hirudins have not yet managed to gain importance in non-HIT indications such as unstable coronary syndromes, they have a major role to play in the treatment of HIT. The choice between the available drugs for HIT, namely lepirudin, danaparoid, and argatroban, has to be made according to the clinical presentation of the patient.

Topics: Anticoagulants; Antithrombins; Arginine; Blood Coagulation; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Time Factors

Patients receiving heparin are at risk of developing heparin-induced thrombocytopenia (HIT). Whereas in HIT I only reversible mild thrombocytopenia occurs within the first days of heparin treatment, HIT II may lead to potentially life-threatening thromboembolic events. Pediatric patients suffering from HIT II have been reported in a study on newborns and in a few reports on children and adolescents. However, thrombotic complications can be as severe in children as they are in adults. In the case of HIT II, the withdrawal of heparin is required and alternative anticoagulation should be started. In contrast to numerous investigations in adult patients, including prospective studies, experience with alternative anticoagulants in pediatric patients is limited. The available data were analyzed according to HIT II complications, alternative anticoagulation, and clinical outcome. In conclusion, HIT II represents a potentially dangerous complication of heparin therapy in pediatric patients also. Alternative anticoagulation applied in pediatric patients mainly included danaparoid sodium and recombinant hirudin. In most patients treated with these anticoagulants, effective anticoagulation and clinical improvement were observed. Because of limited experience, more data are required for optimal management of HIT II in young patients.

Topics: Adolescent; Anticoagulants; Child; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Male; Thrombosis; Time Factors

Review of the frequency, clinical and biological features and treatment of type II heparin-induced thrombocyopenia.. Case report and literature review.. A 65 years old woman received as antithrombotic prophylaxis low molecular weight heparin (LMWH) after prosthetic knee replacement. Day 8, asymptomatic deep vein thrombosis was discovered after systematic echodoppler examination. Curative anticoagulation was started with LMWH. A fall in the platelet count (17 G/L) was noted day 12. Danaparoid was immediately introduced and heparin discontinued. However, day 16 a massive pulmonary embolism occurred which required transfer to an intensive care unit. Danaparoid was changed for lepirudin the same day. It took longer than three weeks for platelet count to return to normal value after heparin discontinuation. The suspicion of heparin-induced thrombocyopenia was confirmed by specific tests.. HIT type II are rare but life-threatening and thrombosis events are the most frequent complications. The diagnosis is a high probability proved by both clinical and biological patterns. The treatment consists in alternative thrombin inhibitors such as danaparoid and lepirudin. The platelet count usually requires less than ten days to recover normal values after heparin withdrawal. Cases in which the delay to a normal platelet count exceeds 3 weeks have been reported specially after LMWH therapy.. Type II HIT are rare but life-threatening events can occur. The platelet count check-up during heparin therapy must be systematic.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Thrombocytopenia; Thrombosis

Most patients with heparin-induced thrombocytopenia (HIT), a serious adverse effect of heparin mediated by platelet-activating heparin-dependent antibodies, require alternative anticoagulation. This is because HIT is highly prothrombotic and is characterized by markedly increased thrombin generation. Unfractionated heparins seem to induce HIT more often than low molecular weight heparins. There are three anticoagulants for which there is an emerging consensus for their efficacy in management of HIT, and which are currently approved for treatment of HIT in several countries: the recombinant hirudin, lepirudin, a direct thrombin inhibitor; the synthetic direct thrombin inhibitor, argatroban; and the heparinoid, danaparoid sodium, mainly exhibiting antifactor-Xa activity. Recommendations for optimal use of these drugs in HIT are given in this review stressing the need for immediate treatment of patients with HIT without awaiting laboratory diagnosis. Hirudin, the drug for which most data from prospective trials exists, can be safely and effectively used in patients with HIT, its dramatically increased elimination half-life in patients with renal failure being the most important drawback. Argatroban, which is mainly eliminated by the liver, could be used preferentially in such patients with renal impairment. Interference with the international normalized ratio makes oral anticoagulation, which is necessary in many patients with HIT, problematic. Activated partial thromboplastin time is sufficient to monitor lepirudin and argatroban treatment in most cases. Danaparoid sodium, with an antifactor-X activity half-life of about 24 hours seems to be best suited for thrombosis prophylaxis in patients with HIT. In some patients monitoring by determining antifactor-Xa activity is necessary. No antidote is available for any of the drugs discussed, and bleeding complications are the most important adverse effects. In situations such as hemodialysis or cardiopulmonary bypass, not only the characteristics of the drug in use itself, but also availability of monitoring methods play an important role. Adjunctive treatments have not been systematically evaluated and should be used cautiously. Recent data suggest that re-exposure of patients with a history of HIT with heparin, for example during cardiopulmonary bypass, can be well tolerated provided no circulating HIT antibodies are detectable at the time of re-exposure, and heparin is strictly avoided pre- and postoperatively

Topics: Animals; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; Thrombin; Thrombocytopenia; Thrombosis

Despite the progress made in the development of cardiopulmonary bypass (CPB) equipment, systemic anticoagulation with unfractionated heparin and post-bypass neutralization with protamine are still used in most perfusion procedures. However, there are a number of situations where unfractionated heparin, protamine or both cannot be used for various reasons. Intolerance of protamine can be addressed with extracorporeal heparin removal devices, perfusion with (no) low systemic heparinization and, to some degree, by perfusion with alternative anticoagulants. Various alternative anticoagulation regimens have been used in cases of intolerance to unfractionated heparin, including extreme hemodilution, low molecular weight heparins, danaparoid, ancrod, r-hirudin, abciximab, tirofiban, argatroban and others. In the presence of heparin-induced thrombocytopenia (HIT) and thrombosis, the use of r-hirudin appears to be an acceptable solution which has been well studied. The main issue with r-hirudin is the difficulty in monitoring its activity during CPB, despite the fact that ecarin coagulation time assessment is now available. A more recent approach is based on selective blockage of platelet aggregation by means of monoclonal antibodies directed to GPIIb/IIIa receptors (abciximab) or the use of a GPIIb/IIIa inhibitor (tirofiban). An 80% blockage of the GPIIb/IIIa receptors and suppression of platelet aggregation to less than 20% allows the giving of unfractionated heparin and running CPB in a standard fashion despite HIT and thrombosis. Likewise, at the end of the procedure, unfractionated heparin is neutralized with protamine as usual and donor platelets are transfused if necessary. GPIIb/IIIa inhibitors are frequently used in interventional cardiology and, therefore, are available in most hospitals.

Topics: Abciximab; Ancrod; Antibodies, Monoclonal; Anticoagulants; Arginine; Cardiopulmonary Bypass; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Drug Hypersensitivity; Factor Xa Inhibitors; Hemodilution; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Humans; Immunoglobulin Fab Fragments; Perfusion; Pipecolic Acids; Platelet Aggregation Inhibitors; Protamines; Sulfonamides; Thrombocytopenia; Thrombophilia; Thrombosis; Tirofiban; Tyrosine

Heparin therapy has two potential adverse effects: bleeding and heparin-induced thrombocytopenia (HIT). There are two types of HIT: type I is more common but less severe; type II occurs less frequently but involves severe thrombocytopenia and a high risk for thrombotic events. Treatment involves discontinuing heparin, allowing the platelet count to return to normal, and treating any thrombosis. Lepirudin (Refludan) is the only agent currently approved for the treatment of HIT-related thrombosis, but other agents may have a role in combination therapy. Prevention includes using low molecular weight heparin instead of unfractionated heparin and limiting unfractionated heparin therapy to less than 5 days.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Epoprostenol; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Platelet Aggregation Inhibitors; Recombinant Proteins; Thrombocytopenia; Thrombosis

Topics: Adult; Ancrod; Antibodies; Anticoagulants; Antigen-Antibody Complex; Antithrombins; Child; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Extracorporeal Circulation; Female; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Platelet Factor 4; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia; Thrombolytic Therapy; Thrombosis

After 10 days of intravenous heparin treatment of a 25-year-old woman with recurrent pulmonary emboli, thrombocytopenia occurred with a platelet drop from 1.52 x 10(5)/microliter to 3.6 x 10(4)/microliter. Heparin-induced platelet activation assays confirmed the diagnosis of heparin-induced thrombocytopenia (HIT). The detected heparin-dependent antibodies exhibited in vitro cross-reactivity with low-molecular-weight heparins, but not with danaparoid.. After heparin was stopped and platelet counts were normal, a massive thrombosis of the iliofemoral veins and the inferior vena cava occurred. Under protection of a temporary vena cava filter, systemic anticoagulation with danaparoid (anti-factor Xa-activity 0.4-0.8 U/ml) and transcatheter thrombolysis with urokinase (70,000 U/h) was initiated. Within 8 days of treatment a complete recanalisation of the occluded iliofemoral and caval veins was achieved. Oral anticoagulation with phenprocoumon was started and the patient has since then been free of symptoms.. The case demonstrates successful treatment of massive iliofemoral and caval thrombosis in the HIT syndrome achieved by combined transcatheter administration of urokinase and systemic infusion of danaparoid.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Femoral Vein; Heparin; Heparinoids; Heparitin Sulfate; Humans; Iliac Vein; Plasminogen Activators; Pulmonary Embolism; Recurrence; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Urokinase-Type Plasminogen Activator; Vena Cava Filters; Vena Cava, Inferior

Growing evidence suggests that moderately elevated levels of homocysteine are associated not only with arterial thrombosis and atherosclerosis but also with venous thrombosis as well. We have reviewed recent studies that indicate that homocysteine inhibits several different anticoagulant mechanisms that are mediated by the vascular endothelium. The protein C enzyme system appears to be one of the most important anticoagulant pathways in the blood. Homocysteine inhibits the expression and activity of endothelial cell surface thrombomodulin, the thrombin cofactor responsible for protein C activation. Homocysteine inhibits the antithrombin III binding activity of endothelial heparan sulfate proteoglycan, thereby suppressing the anticoagulant effect of antithrombin III. Homocysteine also inhibits the ecto-ADPase activity of human umbilical vein endothelial cells (HUVECS). Because ADP is a potent platelet aggregatory agent, this action of homocysteine is prothrombotic. Homocysteine also interferes with the fibrinolytic properties of the endothelial surface because it inhibits the binding of tissue plasminogen activator. Homocysteine stimulates HUVEC tissue factor activity. We have found that lipoprotein(a) [Lp(a)] also stimulates HUVEC tissue factor activity. The combination of Lp(a) plus homocysteine induced more tissue factor activity than either agent alone. These disruptions in several different vessel wall-related anticoagulant functions provide plausable mechanisms for the occurrence of thrombosis in hyperhomocysteinemia.

Topics: Animals; Apyrase; Endothelium, Vascular; Hemostasis; Heparitin Sulfate; Homocysteine; Humans; Muscle, Smooth, Vascular; Protein C; Thromboplastin; Thrombosis; Tissue Plasminogen Activator

On the basis of the results of the 11 studies reviewed, thromboprophylaxis with unfractionated heparin, low molecular weight (LMW) heparin or a heparinoid (danaparoid sodium; Org 10172) in patients undergoing total hip replacement did not show any important clinical differences with respect to the tolerability profiles of the different compounds. However, as a result of the great variability in the presentation and evaluation of blood losses and bleeding complications in these studies, it is mandatory to perform a direct comparison of the different compounds in question in a double-blind, prospective clinical study.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Hemorrhage; Heparin; Heparinoids; Heparitin Sulfate; Hip Prosthesis; Humans; Molecular Weight; Postoperative Complications; Thrombocytopenia; Thrombosis; Wound Infection

Topics: Capillary Permeability; Cell Division; Coronary Artery Disease; Endothelium, Vascular; Epoprostenol; Foam Cells; Heparitin Sulfate; Humans; Lipoproteins, LDL; Muscle, Smooth, Vascular; Nitric Oxide; Thrombomodulin; Thrombosis

The author presents an account of the main contemporary findings on the functional importance of heparan sulphate (HS), which is an important part of the endothelial glycocalyx. Based on the ability to form complexes with proteins, HS interferes in particular with antithrombotic properties of the endothelium and modulates in a significant way the proliferative activity of the endothelium and other cells of the vascular wall. The author mentions its pathogenetic role, possibilities of its diagnostic use and therapeutic perspectives in the area of vascular diseases.

Topics: Animals; Endothelium, Vascular; Heparitin Sulfate; Humans; Thrombosis

The strategies used to prevent and treat thrombosis are based on our understanding of how to ameliorate the pathophysiological responses to injury, such as using inhibitors of platelet activation and inhibitors of coagulation. Both platelets and the coagulation pathway are activated in response to injury. An alternative strategy which has not been investigated to the same extent, is to use substances which contribute to the biocompatibility of blood and vessel wall which predominate under normal conditions. This latter strategy exploits the concept of restoring blood/vessel wall compatibility without risk of bleeding such as can occur when platelets as rendered haemostatically defective (antiplatelet therapies) or maintaining the patient hypocoagulated (anticoagulant therapies). Recent studies suggest that by better understanding the biocompatibility of the healthy endothelium with blood, we may be able to identify those substances which contribute to blood/vessel wall biocompatibility in the healthy environment, and subsequently which may achieve effective antithrombotic therapy with minimal risk of bleeding side-effects. In this review, we identify three such substances all of which are produced by the blood vessel wall. These agents are 13-hydroxyoctadecadienoic acid (13-HODE), a lipoxygenase metabolite of linoleic acid, and two glycosaminoglycans, heparan sulfate and dermatan sulfate.

Topics: Animals; Antithrombins; Dermatan Sulfate; Endothelium, Vascular; Epoprostenol; Hemostasis; Heparitin Sulfate; Humans; Linoleic Acids; Nitric Oxide; Platelet Aggregation; Thrombosis

Orgaran is a mixture of glycosaminoglycans extracted from animal mucosa. It consists of heparan, dermatan and chondroitin sulfate; a small proportion of heparan sulfate (4%) has high affinity for antithrombin III (AT III). Orgaran is devoid of heparin or heparin fragments. Orgaran catalyses the inactivation of factor Xa and thrombin. Compared to heparin and most low-molecular-weight heparins, Orgaran has a much higher anti-Xa/anti-IIa ratio. The inactivation of factor Xa is mediated by AT III and that of thrombin by both AT III and heparin cofactor II. Compared to heparin, which is a strong inhibitor of thrombin generation, Orgaran has only moderate inhibitory effects on thrombin generation. Orgaran shows minimal or no effects on platelet function in vitro or in vivo. It inhibits the formation of various types of thrombi (clot-like and mixed thrombi) with approximately the same potency as heparin. Both the high- and low-affinity fraction for AT III contribute to the antithrombotic activity. In contrast to heparin, Orgaran does not inhibit platelet deposition in experimental mixed thrombi unless very high doses of the heparinoid are used. Orgaran is more efficacious than heparin in preventing the extension of established venous thrombosis. Orgaran promotes less bleeding-enhancing activity than heparin in various experimental models. In addition, compared to heparin, it has only minimal effects on platelet degranulation during hemostatic plug formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Carbohydrate Sequence; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Molecular Sequence Data; Platelet Aggregation; Rabbits; Rats; Thrombin; Thrombolytic Therapy; Thrombosis

Pharmacokinetic investigations on Orgaran (Org 10172) have been conducted by monitoring the following biological effects: plasma anti-Xa, anti-IIa and IIa-generation-inhibiting (IIaGI) activities. In addition, a limited number of studies were conducted on the basis of concentrations of the No-affinity glycosaminoglyc(uron)an (NoA-GAG) fraction as determined by a competitive binding assay. In humans, widely different pharmacokinetic profiles for various biological effects were observed, with relatively short elimination half-lives for the anti-IIa and IIaGI activities of 4.3 +/- 3.5 and 6.7 +/- 3.2 h, respectively, but a relatively long elimination half-life of anti-Xa activity of 24.5 +/- 9.6 h. These differences in half-life mainly reflect differences in the rate of elimination of individual components of Orgaran. Rapid elimination of some of these components may explain why twice daily dosing is required for optimal thrombosis prophylaxis with Orgaran. In a comparative study in healthy male volunteers, the pharmacokinetics of the following low molecular weight heparin(oid)s were determined after intravenous administration: Orgaran (3,750 anti-Xa units), Fragmin (5,000 anti-Xa units), Fraxiparine (7,500 IC units) and Clexane (40 mg). Between these products, wide differences in pharmacokinetics were observed. Particularly, the half-lives of anti-Xa activity and IIaGI activity were much longer for Orgaran than for the other products. At the same time, a relatively low area under the curve of anti-IIa activity was observed. The absolute bioavailability of Orgaran following subcutaneous administration was determined on the basis of plasma anti-Xa and IIaGI activities and the NoA-GAG fraction concentrations. Absorption from subcutaneous tissues was found to be close to 100%, which is significantly higher than of heparin; a finding which indicates that the subcutaneous route is reliable for the administration of Orgaran. The elimination of Orgaran components occurs by renal and possibly non-renal routes. With respect to anti-Xa activity, about 50% of the total clearance can be accounted for by urinary excretion. Therefore, in severe renal failure, a reduction of the maintenance dose of Orgaran would seem to be indicated. Studies on the influence of enzyme induction as a result of treatment with pentobarbital suggest that the pharmacokinetics of Lomoparan are relatively insensitive to changes in hepatic function. In a number of studies, the influence of conditi

Topics: Adult; Aged; Animals; Binding, Competitive; Biological Availability; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation, Preclinical; Drug Interactions; Factor Xa Inhibitors; Female; Glycosaminoglycans; Half-Life; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Humans; Male; Metabolic Clearance Rate; Middle Aged; Prothrombin; Rats; Thrombosis

Topics: Animals; Autoantibodies; Blood Platelets; Cattle; Cohort Studies; Glycosaminoglycans; Hemorrhagic Disorders; Heparin; Heparinoids; Heparitin Sulfate; Humans; Immunoglobulin G; Prospective Studies; Structure-Activity Relationship; Swine; Thrombocytopenia; Thrombosis

Topics: Animals; Anticoagulants; Blood Coagulation; Cerebrovascular Disorders; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation, Preclinical; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Incidence; Mammals; Molecular Weight; Platelet Aggregation; Postoperative Complications; Rabbits; Renal Dialysis; Thrombocytopenia; Thrombophlebitis; Thrombosis

There are three distinct syndromes of heparin-induced thrombocytopenia: an acute reversible from seen immediately after intravenous bolus injection, a delayed-onset antibody-mediated form seen several days after the initiation of therapy, and an intermediate type characterized by mild thrombocytopenia developing just a few days after starting therapy. Delayed-onset heparin-induced thrombocytopenia, clinically the most important form, results from the formation of heparin-dependent antibodies that are directed against the platelet membrane. In the presence of heparin, these antibodies may induce in vitro or in vivo platelet aggregation. Consequently, the course may be complicated by arterial thromboses. Treatment of this syndrome includes the prompt cessation of heparin. Since continued or future anticoagulation is usually necessary, alternative means of anticoagulation have been explored. Oral anticoagulation is often started but requires several days to take effect. Other options include low-molecular-weight heparins, antiplatelet agents, prostacyclin analogues, and low-molecular-weight dextran. In vitro laboratory tests may be helpful in guiding alternative therapy in some, but not all cases. Unfortunately, none of these agents have proved to be uniformly effective and additional agents and clinical investigation are needed before a definitive option becomes available.

Topics: Aspirin; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Epoprostenol; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Iloprost; Necrosis; Platelet Aggregation Inhibitors; Skin; Skin Diseases; Thrombocytopenia; Thrombosis

Topics: Animals; Cardiopulmonary Bypass; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Factor X; Factor Xa; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Kinetics; Molecular Weight; Postoperative Complications; Rats; Renal Dialysis; Thrombocytopenia; Thrombosis; Uremia

During the use of fractionated or unfractionated heparin adverse events frequently occur that can endanger the continuation of therapy. Especially in pregnant patients with thromboembolic complications it may be difficult to find a suitable alternative anticoagulant when heparin-induced thrombocytopenia type II (HIT II) or allergic skin reactions occur. There are still limited data on the use of danaparoid in pregnancy. The main reason for heparin intolerance in the 59 reviewed pregnancies were either HIT II, described in 37/59 (62.7%) pregnancies, or cutaneous adverse effects in 19/22 (86.4%) of non-HIT-associated pregnancies (22/59, 37.3%).. 40/59 pregnancies were carried to term under use of danaparoid and resulted in the delivery of a healthy infant. In 16/19 pregnancies, danaparoid was stopped due to a major adverse event. Five patients showed bleeding complications, seven fetal losses were documented, but there was no association with the use of danaparoid. In 31/59 (52.5%) pregnancies adverse events were documented, 14/31 (45.2%) could be attributed to danaparoid. Anti-Xa-activity was not detected in five fetal cord blood samples and in four maternal breast-milk samples.. Danaparoid can be used as an alternative anticoagulant in pregnant women with high risk for thrombosis and heparin intolerance.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Female; Heparin; Heparitin Sulfate; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Thrombocytopenia; Thrombosis

To compare clinical outcomes in a randomised comparison of treatment with danaparoid sodium (a heparinoid), or dextran 70, for heparin-induced thrombocytopaenia (HIT) plus thrombosis.. Forty-two patients with recent thrombosis and a clinical diagnosis of probable HIT who presented at ten Australian hospitals during a study period of six and one half years were randomly assigned to open-label treatment with intravenous danaparoid or dextran 70, each combined with oral warfarin. Thirty-four patients (83%) had a positive platelet aggregation or 14C-serotonin release test for HIT antibody. Twenty-five received danaparoid as a bolus injection of 2400 anti-Xa units followed by 400 units per hour for 2 h, 300 units per hour for 2 h, and then 200 units per hour for five days. Seventeen received 1000 mL dextran 70 on day one and then 500 mL on days 2-5. Patients were reviewed daily for clinical evidence of thrombus progression or resolution, fresh thrombosis or embolism, bleeding or other complications. The primary trial endpoint was the proportion of thromboembolic events with complete clinical resolution by the time of discharge from hospital.. With danaparoid, there was complete clinical recovery from 56% of thromboembolic events compared to 14% after dextran 70 (Odds Ratio 10.53, 95% Confidence Interval 1.6-71.4; p = 0.02). Clinical recovery with danaparoid was complete or partial in 86% of thromboembolic events compared with 53% after dextran 70 (Odds Ratio 4.55, 95% Confidence Interval 1.2-16.7; p = 0.03). Overall clinical effectiveness of danaparoid was rated as high or moderate in 88% of patients compared with 47% for dextran 70 (p = 0.01). One patient given danaparoid died of thrombosis compared with three patients given dextran 70. The platelet count returned to normal after a mean of 6.7 days with danaparoid and 7.3 days with dextran 70. There was no major bleeding with either treatment.. danaparoid plus warfarin treatment for HIT with thrombosis is effective, safe, and superior to dextran 70 plus warfarin.

Topics: Aged; Chondroitin Sulfates; Dermatan Sulfate; Dextrans; Drug Combinations; Drug Therapy, Combination; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Prospective Studies; Survival Rate; Therapeutic Equivalency; Thrombocytopenia; Thrombosis; Treatment Outcome; Warfarin

In a double-blind, randomised trial Org 10172 low-molecular-weight (LMW) heparinoid was compared with placebo in the prevention of deep-vein thrombosis in patients with acute thrombotic stroke. Prophylaxis was started within 7 days of the onset of stroke with a loading dose of 1000 anti-factor-Xa units intravenously followed by a fixed dose of 750 anti-factor-Xa units twice a day subcutaneously; it was continued for 14 days or until hospital discharge, if earlier. 50 patients were randomised to receive Org 10172 and 25 to receive placebo. All patients underwent surveillance with I125-fibrinogen leg scanning and impedance plethysmography. Venography was carried out if either test became positive. Venous thrombosis occurred in 2 of 50 patients (4.0%) given Org 10172 and 7 of 25 patients (28.0%) given placebo (p = 0.005); the corresponding rates of proximal-vein thrombosis were 0% and 16%, respectively (p = 0.01). There was one major haemorrhage in the Org 10172 group and one minor bleed in the placebo group.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Cerebrovascular Disorders; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Female; Fibrinolytic Agents; Follow-Up Studies; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Radiography; Random Allocation; Thrombosis; Time Factors

In preparation for an efficacy study, the effect of the low molecular weight heparinoid Org 10172 on postoperative blood loss was assessed in a randomized double-blind, placebo controlled study in patients undergoing transurethral resection of the prostate (TURP). Org 10172 and placebo were given twice daily as i.v. injection for three postoperative days starting one hour preoperatively. Three doses of Org 10172 (800, 1600, and 2400 anti-Xa units b.d.) were evaluated against placebo in three consecutive patient blocks respectively. Each block consisted of 20 patients, 15 receiving Org 10172 and 5 patients placebo. The study was discontinued after 9 patients of the third block had completed the protocol because of excessive urinary blood loss. Data analysis showed a dose-dependent increase in postoperative haemoglobin loss, this was not significant for the 800 anti-Xa units b.d. dosage but was significant in those patients treated with 1600 (p less than 0.05) and 2400 anti-Xa units b.d. (p less than 0.01). It was concluded that the heparinoid Org 10172 caused a dose dependent increase in urinary blood loss following TURP.

Topics: Aged; Aged, 80 and over; Bleeding Time; Chondroitin Sulfates; Dermatan Sulfate; Double-Blind Method; Erythrocyte Transfusion; Glycosaminoglycans; Hematocrit; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Molecular Weight; Placebos; Prostate; Random Allocation; Thrombosis; Urethra

Topics: Animals; Cardiopulmonary Bypass; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Factor X; Factor Xa; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Kinetics; Molecular Weight; Postoperative Complications; Rats; Renal Dialysis; Thrombocytopenia; Thrombosis; Uremia

Dysregulated inflammation and coagulation are underlying mechanisms driving organ injury after trauma and hemorrhagic shock. Heparan sulfates, cell surface glycosaminoglycans abundantly expressed on the endothelial surface, regulate a variety of cellular processes. Endothelial heparan sulfate containing a rare 3-. Male Sprague-Dawley rats were pre-treated subcutaneously with vehicle (saline) or dekaparin (2 mg/kg) and subjected to a trauma/hemorrhagic shock model through laparotomy, gut distention, and fixed-pressure hemorrhage. Vehicle and dekaparin-treated rats were resuscitated with Lactated Ringer's solution (LR) and compared to vehicle-treated fresh-frozen-plasma-(FFP)-resuscitated rats. Serial blood samples were collected at baseline, after induction of shock, and 3 hours after fluid resuscitation to measure hemodynamic and metabolic shock indicators, inflammatory mediators, and thrombin-antithrombin complex formation. Lungs and kidneys were processed for organ injury scoring and immunohistochemical analysis to quantify presence of neutrophils.. Induction of trauma and hemorrhagic shock resulted in significant increases in thrombin-antithrombin complex, inflammatory markers, and lung and kidney injury scores. Compared to vehicle, dekaparin treatment did not affect induction, severity, or recovery of shock as indicated by hemodynamics, metabolic indicators of shock (lactate and base excess), or metrics of bleeding, including overall blood loss, resuscitation volume, or hematocrit. While LR-vehicle-resuscitated rodents exhibited increased lung and kidney injury, administration of dekaparin significantly reduced organ injury scores and was similar to organ protection conferred by FFP resuscitation. This was associated with a significant reduction in neutrophil infiltration in lungs and kidneys and reduced lung fibrin deposition among dekaparin-treated rats compared to vehicle. No differences in organ injury, neutrophil infiltrates, or fibrin staining between dekaparin and FFP groups were observed. Finally, dekaparin treatment attenuated induction of thrombin-antithrombin complex and inflammatory mediators in plasma following trauma and hemorrhagic shock.. Anti-thromboinflammatory properties of a synthetic 3-

Topics: Animals; Fibrin; Heparitin Sulfate; Inflammation; Male; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic; Sulfates; Thromboinflammation; Thrombosis

Evaluating prospective anticoagulant therapies in animal thrombosis and bleeding models are standard pre-clinical approaches. Mice are frequently used for initial evaluations because a variety of models have been developed in this well-characterized species, and mice are relatively inexpensive to maintain. Because mice seem to be resistant to forming "spontaneous" thrombosis, vessel injury is used to induce intravascular clot formation. For the purpose of testing heparin-based drugs, we adapted a well-established model in which thrombus formation in the carotid artery is induced by exposing the vessel to ferric chloride. For studying anticoagulant effects on venous thrombosis, we use a model in which the inferior vena cava is ligated and the size of the resulting clots are measured. The most common adverse effect of anticoagulation therapy is bleeding. We describe a simple tail bleeding time that has been used for many years to study the effects of anticoagulants on hemostasis. We also describe a more reproducible, but more technically challenging, saphenous vein bleeding model that is also used for this purpose.

Topics: Animals; Anticoagulants; Disease Models, Animal; Hemorrhage; Heparitin Sulfate; Mice; Prospective Studies; Thrombosis

Thrombotic complication has been an important symptom in critically ill patients with COVID-19. It has not been clear whether the virus spike (S) protein can directly induce blood coagulation in addition to inflammation. Heparan sulfate (HS)/heparin, a key factor in coagulation process, was found to bind SARS-CoV-2 S protein with high affinity. Herein, we found that the S protein can competitively inhibit the bindings of antithrombin and heparin cofactor II to heparin/HS, causing abnormal increase in thrombin activity. SARS-CoV-2 S protein at a similar concentration (~10 μg/mL) as the viral load in critically ill patients can cause directly blood coagulation and thrombosis in zebrafish model. Furthermore, exogenous heparin/HS can significantly reduce coagulation caused by S protein, pointing to a potential new direction to elucidate the etiology of the virus and provide fundamental support for anticoagulant therapy especially for the COVID-19 critically ill patients.

Topics: Animals; Blood Coagulation; Heparitin Sulfate; Humans; Mice; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Thrombosis

Chagas and COVID-19 are diseases caused by Trypanosoma cruzi and SARS-CoV-2, respectively. These diseases present very different etiological agents despite showing similarities such as susceptibility/risk factors, pathogen-associated molecular patterns (PAMPs), recognition of glycosaminoglycans, inflammation, vascular leakage hypercoagulability, microthrombosis, and endotheliopathy; all of which suggest, in part, treatments with similar principles. Here, both diseases are compared, focusing mainly on the characteristics related to dysregulated immunothrombosis. Given the in-depth investigation of molecules and mechanisms related to microthrombosis in COVID-19, it is necessary to reconsider a prompt treatment of Chagas disease with oral anticoagulants.

Topics: Anticoagulants; Blood Platelets; Chagas Disease; Complement Activation; COVID-19; Endothelium; Heparitin Sulfate; Humans; Pathogen-Associated Molecular Pattern Molecules; Platelet Activation; SARS-CoV-2; Thrombosis; Trypanosoma cruzi

While malignant pleural effusion (MPE) is a common and significant cause of morbidity in patients with cancer, current treatment options are limited. Human heparanase, involved in angiogenesis and metastasis, cleaves heparan sulfate (HS) side chains on the cell surface.. To explore the coagulation milieu in MPE and infectious pleural effusion (IPE) focusing on the involvement of heparanase.. Samples of 30 patients with MPE and 44 patients with IPE were evaluated in comparison to those of 33 patients with transudate pleural effusions, using heparanase ELISA, heparanase procoagulant activity assay, thrombin and factor Xa chromogenic assays and thromboelastography. A cell proliferation assay was performed. EMT-6 breast cancer cells were injected to the pleural cavity of mice. A peptide inhibiting heparanase activity was administered subcutaneously.. Levels of heparanase, factor Xa and thrombin were significantly higher in exudate than transudate. Thromboelastography detected almost no thrombus formation in the whole blood, mainly on MPE addition. This effect was completely reversed by bacterial heparinase. Direct measurement revealed high levels of HS chains in pleural effusions. Higher proliferation was observed in tumour cell lines incubated with exudate than with transudate and it was reduced when bacterial heparinase was added. The tumour size in the pleural cavity of mice treated with the heparanase inhibitor were significantly smaller compared with control (p=0.005).. HS chains released by heparanase form an anticoagulant milieu in MPE, preventing local thrombosis and enabling tumour cell proliferation. Inhibition of heparanase might provide a therapeutic option for patients with recurrent MPE.

Topics: Animals; Anticoagulants; Biomarkers, Tumor; Blood Coagulation; Case-Control Studies; Cell Proliferation; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glucuronidase; Heparitin Sulfate; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Pleural Effusion, Malignant; Reference Values; Statistics, Nonparametric; Thrombelastography; Thrombosis; Tumor Cells, Cultured

Hospitalized cancer patients are at increased risk of thrombosis and prophylaxis with heparin is recommended. Heparanase is a protein capable of degrading heparan sulfate (HS) chains. The first objective of the study was to examine the effects of weight on anti-Xa levels in cancer patients treated with a fixed dose of enoxaparin as thromboprophylaxis. The second aim was to assess a potential correlation between plasma pre-treatment coagulation parameters and anti-Xa levels in an assumption that heparanase degradation activity towards heparins and HS chains could affect anti-Xa levels. Two blood samples (prior to and 3 h after drug injection) of 76 cancer patients with an indication for prophylaxis with enoxaparin (40 mg) were evaluated for coagulation markers. Sub-prophylactic levels of anti-Xa (< 0.2 U/ml) were found in 16/76 (21%) patients; in 13/76 (13%) patients the values were supra-prophylactic (> 0.5 U/ml). In the subgroup of patients weighing > 80 kg, 7/14 (50%) individuals had a sub-prophylactic level. Overall, anti-Xa levels appeared to correlate with patient's weight (r = - 0.48, p < 0.0001), pre-treatment partial thromboplastin time (PTT), D-dimer, HS, heparanase levels and procoagulant activity. We concluded that plasma anti-Xa levels correlated with patient's weight. A substantial portion of cancer patients receiving enoxaparin prophylaxis was undertreated. For patients > 80 kg, a weight-adjusted prophylactic dose of enoxaparin could be considered. Elevated enoxaparin anti-Xa levels correlated with pre-treatment parameters of coagulation system activation. High pre-treatment HS and elevated plasma anti-Xa levels may potentially serve as biomarkers for the identification of patients at increased thrombosis risk.

Topics: Anticoagulants; Biomarkers, Pharmacological; Blood Coagulation; Body Weight; Drug Dosage Calculations; Enoxaparin; Factor Xa; Female; Fibrin Fibrinogen Degradation Products; Heparitin Sulfate; Humans; Male; Middle Aged; Neoplasms; Thrombosis

A 33-year-old man presented with hepatic encephalopathy and was diagnosed to have a noncirrhotic extrahepatic portosystemic shunt (NCPSS). He presented with abdominal pain 16 months after the NCPSS diagnosis. Computed tomography revealed thrombosis between the intrahepatic portal vein and the left internal iliac vein, including the NCPSS, and varices of the sigmoid colon. Thrombosis was treated with danaparoid sodium and antithrombin III followed by edoxaban. After treatment, the thrombosis disappeared from the intrahepatic portal vein, but it remained in the NCPSS. The sigmoid colon varices were followed up without any treatment. Follow-up is needed in NCPSS patients in order to make an early detection of complications.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Colon, Sigmoid; Dermatan Sulfate; Factor Xa Inhibitors; Heparitin Sulfate; Hepatic Encephalopathy; Humans; Male; Portal Vein; Portasystemic Shunt, Transjugular Intrahepatic; Pyridines; Thiazoles; Thrombosis; Treatment Outcome; Varicose Veins

Heparin is widely used to prevent clotting of the extracorporeal circuit during haemodialysis (HD). Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin, leading to a pro-thrombotic state. Danaparoid is an alternative anticoagulant used in patients on HD with HIT but its dosing recommendations in obese patients on HD are relatively scarce.. We report a case of a 48-year-old morbidly obese patient who received weight-based dosing of danaparoid for HD with monitoring of anti-Xa activity. However, despite the patient's anti-Xa level being within the therapeutic range at various time points, the circuit lines kept clotting during HD.. The report provides evidence that the manufacturer's recommendations on dosing danaparoid based on body weight may lead to sub-optimal therapeutic benefit and highlight the need for higher than recommended weight-based dosing in obese individuals on dialysis.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Female; Heparin; Heparitin Sulfate; Humans; Obesity, Morbid; Renal Dialysis; Thrombocytopenia; Thrombosis

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Computed Tomography Angiography; Dermatan Sulfate; Diagnosis, Differential; Female; Heparin; Heparitin Sulfate; Humans; Platelet Count; Syndrome; Thrombectomy; Thrombocytopenia; Thrombosis

Heparanase is an endo-glucuronidase that specifically cleaves heparan sulfate (HS) and heparin polysaccharides. The enzyme is expressed at low levels in normal tissues, but is often upregulated under pathological conditions such as cancer and inflammation. Normal human platelets express exceptionally high levels of heparanase, but the functional consequences of this feature remain unknown. We investigated functional roles of heparanase by comparing the properties of platelets expressing high (Hpa-tg) or low (Ctr) levels of heparanase. Upon activation, Hpa-tg platelets exhibited a much stronger adhesion activity as compared to Ctr platelets, likely contributing to a higher thrombotic activity in a carotid thrombosis model. Furthermore, we found concomitant upregulated expression of both heparanase and CD62P (P-selectin) upon activation of mouse and human platelets. As platelets play important roles in tumor metastasis, these findings indicate contribution of the platelet heparanase to hyper-thrombotic conditions often seen in patients with metastatic cancer.

Topics: Animals; Blood Platelets; Carotid Arteries; Cell Separation; Chlorides; Crosses, Genetic; Erythrocytes; Female; Ferric Compounds; Flow Cytometry; Gene Expression Regulation; Glucuronidase; Glycosaminoglycans; Heparitin Sulfate; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; P-Selectin; Platelet Activation; Platelet Adhesiveness; Selenoprotein P; Thrombosis; Up-Regulation

Evaluating anticoagulants in animal thrombosis models is a standard component of preclinical drug testing. Mice are frequently used for these initial evaluations because a variety of thrombosis models have been developed and are well characterized in this species, and the animals are relatively inexpensive to maintain. Because mice have a natural resistance to forming intravascular thrombi, vessel injury is required to induce intravascular clot formation. Several methods have been established for inducing arterial or venous thrombosis in mice. For the purpose of testing heparin-based drugs, we adapted a well-established model in which thrombus formation in the carotid artery is induced by exposing the vessel to ferric chloride. For studying anticoagulant effects on venous thrombosis, we use a model in which the inferior vena cava is ligated and the size of the resulting clots is measured. The most common adverse effect of anticoagulation therapy is bleeding. The effect of heparin-based anticoagulants can be tested in mice in a simple tail bleeding assay.

Topics: Animals; Anticoagulants; Chlorides; Disease Models, Animal; Ferric Compounds; Hemorrhage; Heparitin Sulfate; Mice, Inbred C57BL; Tail; Thrombosis; Vena Cava, Inferior

Early clinical signs of heparin induced thrombocytopenia (HIT) are nonspecific and include a sudden drop in the number of platelets as well as formation of arterial and venous thromboses. Regional citrate anticoagulation (RCA) is increasingly used as a very effective modality to prevent filter clotting during renal replacement therapy (RRT). We report the first case where repeated premature filter clotting despite RCA indicated a manifestation of HIT.. A 71-year old woman admitted to the ICU for a compartment syndrome of the leg developed septic shock with acute kidney injury requiring continuous veno-venous hemodialysis (CVVHD). Because of unexpected and repeated premature filter clotting during CVVHD using RCA, HIT was suspected.. The diagnosis of HIT was confirmed by the presence of IgG antibodies against heparin and platelet factor (PF) 4 complexes and six points in the 4T score. Discontinuation of heparin administration and initiation of systemic anticoagulation with danaparoid sodium resulted in the normalization of platelet count and hemofilter lifetime.. RCA does not seem to be sufficient to prevent hemofilter clotting during HIT. Thus, in case of repeated premature filter clotting despite RCA, one should suspect HIT and prompt diagnostic workup as well as a switch to alternative anticoagulation.

Topics: Acute Kidney Injury; Aged; Anticoagulants; Chondroitin Sulfates; Citrates; Dermatan Sulfate; Equipment Failure; Female; Heparin; Heparitin Sulfate; Humans; Immunoglobulin G; Platelet Factor 4; Renal Dialysis; Shock, Septic; Thrombocytopenia; Thrombosis

An 84-year-old woman with hepatitis C virus-related cirrhosis, hepatocellular carcinoma and atrial fibrillation, who presented with hematemesis, was initially treated with endoscopic variceal ligation (EVL) for an esophageal varix hemorrhage. However, computed tomography (CT) upon admission had revealed portal vein thrombosis, despite having received warfarin for existing atrial fibrillation. We subsequently initiated a 2-week treatment with danaparoid;warfarin being discontinued in order to reduce the risk of re-hemorrhage. A follow-up CT after treatment revealed complete reduction of the portal vein thrombosis. This is the first successful report of danaparoid use in the treatment of portal vein thrombosis that developed in a patient who had received warfarin.

Topics: Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparitin Sulfate; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Portal Vein; Thrombosis; Warfarin

This case describes the medical history of a 61-year-old woman treated for cerebral venous thrombosis (CVT) leading to diagnosis of essential thrombocythemia (ET). During treatment with unfractionated heparin, after initial improvement of clinical state, signs of cerebral hypertension reappeared. Although the platelet count decreased, heparin-induced thrombocytopenia (HIT) was only suspected 2 days later when it dropped below the standard 150 × 10(9) L(-1) threshold. HIT diagnosis was confirmed by the presence of anti-PF4/heparin IgG. This late finding was the cause of the extension of CVT with worsening of cerebral hypertension necessitating decompressive craniectomy. Elevated basal platelet count due to ET can delay diagnosis and treatment of HIT. In this case, physicians should be more attentive to platelet count variations rather than thrombocytopenia threshold.

Topics: Anticoagulants; Cerebral Veins; Chondroitin Sulfates; Decompressive Craniectomy; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Humans; Intracranial Hypertension; Middle Aged; Platelet Count; Radiography; Thrombocythemia, Essential; Thrombocytopenia; Thrombosis; Treatment Outcome; Venous Thrombosis

Topics: Aged, 80 and over; Anticoagulants; Aortic Valve Stenosis; Chondroitin Sulfates; Dermatan Sulfate; Echocardiography, Transesophageal; Female; Fibrinolytic Agents; Heart Valve Prosthesis; Heparin; Heparitin Sulfate; Humans; Middle Aged; Thrombocytopenia; Thrombosis; Tomography, X-Ray Computed

We undertook a survey of French university hospital hematological laboratories to ascertain the clinical characteristics of patients with suspected HIT, the laboratory tests performed, and the therapeutic strategy adopted in current practice.. A standardized medical records database for patients with suspected HIT was sent to 19 laboratories. During two months, all consecutive patients for whom a biological test was performed were included.. 169 patients were included, 27 (16%) patients having a final diagnosis of HIT. At the time HIT was suspected, the heparin duration and the level of thrombocytopenia were similar in HIT- positive and HIT-negative groups. The use of unfractionated heparin, a therapeutic heparin dose regimen and the presence of thrombotic complications were significantly more frequent in HIT-positive patients. When the heparin dose regimen was taken into account, only thrombotic complications under a therapeutic dose regimen were significantly increased in HIT-positive patients. Eighty-six percent of patients presented at least one alternative diagnosis of thrombocytopenia without significant difference between the two groups. Laboratory tests were performed after a mean of 0.3days and mainly consisted of antigen assays. At the time HIT was suspected, heparin was stopped in 56 (33%) patients, being replaced mainly by danaparoid. Only three laboratories declared they usually received all the necessary clinical information to establish the likelihood of HIT.. In current practice in France, the clinical probability of HIT is rarely established, leading to systematic requests for laboratory HIT tests.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chondroitin Sulfates; Clinical Laboratory Techniques; Data Collection; Dermatan Sulfate; Female; France; Heparin; Heparitin Sulfate; Hospitals, University; Humans; Male; Medical Records; Middle Aged; Practice Patterns, Physicians'; Thrombocytopenia; Thrombosis; Young Adult

The present study aimed to assess whether the fibrin network structure is modified by the direct thrombin-inhibitors lepirudin, argatroban or bivalirudin and by the indirect Xa-inhibitor danaparoid. Using an in vitro assay that imitates the physiological process of coagulation from thrombin generation to fibrin formation, we examined a normal plasma pool spiked with one of the inhibitors. At concentrations considered to be the plasma levels observed during therapy, almost no influence was detected for lepirudin despite clear-cut effects on "clotting time". However, argatroban, bivalirudin and danaparoid increased the fibrin gel permeability (Ks) to a similar extent. At concentrations higher than the "therapeutic" levels, the dose-response curve in the Ks assay became very steep for lepirudin while those were shallow for the others. In parallel with the drug-induced increases of Ks, larger network pores in 3D-microscopic images and significant shortenings in "clot lysis time" induced by addition of rtPA were observed. Recombinant factor VIII (rFVIII) added to danaparoid-treated samples profoundly counteracted the increase of Ks but had only a slight or no effect on the other drugs. Thus, in vitro, argatroban, bivalirudin and danaparoid have comparable anticoagulating effects, rendering the fibrin network more permeable and less resistant to fibrinolysis. For lepirudin, the steep dose-response curve supports previous clinical findings, i.e. this thrombin inhibitor has a narrow therapeutic window. Furthermore, our data suggest that the haemostatic agent, rFVIII, might be effective in treatment of bleeding complications induced by danaparoid.

Topics: Antithrombins; Arginine; Chondroitin Sulfates; Chromatography, Gel; Dermatan Sulfate; Factor VIII; Factor Xa Inhibitors; Fibrin; Fibrinolysis; Heparinoids; Heparitin Sulfate; Hirudins; Humans; In Vitro Techniques; Microscopy, Confocal; Peptide Fragments; Pipecolic Acids; Plasma; Porosity; Protein Multimerization; Recombinant Proteins; Sulfonamides; Thrombosis; Tissue Plasminogen Activator

An 81-year-old woman was referred to our hospital with a diagnosis of acute cholangitis. Endoscopic retrograde cholangiography revealed a common bile duct (CBD) stone. In addition, CT showed thrombus of the right portal vein. Endoscopic sphincterotomy was performed to remove the CBD stone. Thrombosis was treated successfully with danaparoid sodium. It was speculated that the treatment of the acute cholangitis induced thrombolysis by the auto-fibrinolysis system and danaparoid sodium prevented the development of thrombus formation in this case.

Topics: Acute Disease; Aged, 80 and over; Anticoagulants; Cholangitis; Chondroitin Sulfates; Dermatan Sulfate; Female; Gallstones; Heparitin Sulfate; Humans; Portal Vein; Thrombosis

Heparin cofactor II (HCII)-deficient mice form occlusive thrombi more rapidly than do wild-type mice following injury to the carotid arterial endothelium. Dermatan sulfate (DS) and heparan sulfate (HS) increase the rate of inhibition of thrombin by HCII in vitro, but it is unknown whether vascular glycosaminoglycans play a role in the antithrombotic effect of HCII in vivo. In this study, we found that intravenous injection of either wild-type recombinant HCII or a variant with low affinity for HS (K173H) corrected the abnormally short thrombosis time of HCII-deficient mice, while a variant with low affinity for DS (R189H) had no effect. When HCII was incubated with frozen sections of the mouse carotid artery, it bound specifically to DS in the adventitia. HCII was undetectable in the wall of the uninjured carotid artery, but it became concentrated in the adventitia following endothelial injury. These results support the hypothesis that HCII interacts with DS in the vessel wall after disruption of the endothelium and that this interaction regulates thrombus formation in vivo.

Topics: Animals; Carotid Arteries; Chondroitin Lyases; Dermatan Sulfate; Female; Fibrinolytic Agents; Heparin Cofactor II; Heparitin Sulfate; Humans; Light; Male; Mice; Mice, Inbred C57BL; Mutant Proteins; Recombinant Proteins; Substrate Specificity; Swine; Thrombin; Thrombosis; Time Factors

During extracorporeal membrane oxygenation, anticoagulation therapy is usually achieved with unfractionated heparin. We report on an extracorporeal membrane oxygenation with danaparoid sodium for a patient with severe respiratory failure due to massive pulmonary embolism and suspected type 2 heparin-induced thrombocytopenia. Danaparoid, a low molecular weight heparinoid, is an alternative to heparin for patients who develop type 2 heparin-induced thrombocytopenia. Danaparoid was given at 400 IU/h with an objective of antifactor Xa activity of 0.6-0.8 U/mL, which was monitored twice a day. No excessive bleeding or clotting of the circuit was noted. The patient was weaned from extracorporeal membrane oxygenation after 9 days of treatment.

Topics: Adult; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Echocardiography, Transesophageal; Extracorporeal Membrane Oxygenation; Factor Xa; Heparitin Sulfate; Humans; Iliac Vein; Male; Portal Vein; Pulmonary Embolism; Thrombocytopenia; Thrombosis; Tomography, X-Ray Computed

The decision for an anticoagulant for renal replacement therapy (RRT) in patients with acute renal failure and heparin-induced thrombocytopenia (HIT) has to be made carefully. Based on results from the literature argatroban is favoured in patients without hepatic dysfunction, referring to its short halftime and easy feasable monitoring. In the case of coexsisting hepatic disorder, danaparoid provides a safe alternative therapy. However, long halftime and the difficult elimination of the substance are unfavourable. Lepirudin represents another possible anticoagulant therapy. Bleeding complications and monitoring of the ecarin clotting time imposes limitations. Experiences with bivalirudin, fondaparinux and prostaglandines are limited and future trials will have to determine the significance of their application in RRT in HIT patients. Furthermore it has to be proven whether the combination of alternative anticoagulants with citrate prolongates circuit halftime of CVVH.

Topics: Acute Kidney Injury; Anticoagulants; Arginine; Blood Coagulation Tests; Chondroitin Sulfates; Citrates; Critical Care; Dermatan Sulfate; Diagnostic Errors; Dose-Response Relationship, Drug; Epoprostenol; Fondaparinux; Hemofiltration; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Iloprost; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sodium Citrate; Sulfonamides; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) represents a serious side effect caused by an atypical immune response to platelet factor 4 leading to platelet activation and thrombin formation. These patients are at high risk of thromboembolism, with a rapid drop in platelet count between days 5 and 14 after the initiation of heparin treatment. In single cases, especially after major surgery, platelet count reduction might be absent or hidden by preceding thrombocytosis. Different clinical manifestations of HIT include unspecific skin reactions with potential necrosis at the site of heparin injection, mostly after the application of unfractionated heparin but also with low molecular weight heparin. In heparin-induced skin necrosis, administration of unfractionated or low molecular weight heparin is contraindicated and heparin therapy should be stopped immediately. Instead, an alternative anticoagulant in the form of a direct thrombin inhibitor such as argatroban, and respectively lepirudin, or danaparoid sodium must be administered. Due to frequent misinterpretations of heparin-induced unspecific skin reactions, especially in the absence of thrombocytopenia, we present two case reports which should increase the awareness of HIT's various clinical pictures.

Topics: Adult; Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Eruptions; Female; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Male; Pipecolic Acids; Platelet Count; Platelet Factor 4; Postoperative Complications; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Time Factors

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Eruptions; Heparitin Sulfate; Humans; Hypersensitivity, Delayed; Injections, Subcutaneous; Intradermal Tests; Male; Thrombosis

Immune-mediated heparin-induced thrombocytopenia (HIT) is an uncommon but serious complication of therapy with heparins. It affects all ages and requires replacement of the causative anticoagulant. However, information on alternative antithrombotic use in children with HIT is limited. This paper reviews 27 published and 7 unpublished case reports of children aged 2 weeks to 17 years treated with danaparoid. Thirty-three suffered from HIT or suspected HIT, and 1 child without HIT had a high bleeding risk. All children had severe underlying problems increasing their thrombotic and/or bleeding risk. HIT diagnosis was confirmed serologically or clinically in 26 cases (78.8%). Danaparoid regimens were similar to those used in adults, but in general, younger children needed higher daily doses of danaparoid to achieve the same target plasma anti-Xa levels than teenagers or adults. Of those with a known outcome 28/33 children (84.8%) survived, 7 having suffered from a serious adverse event. Five deaths occurred including 1 thrombotic and 2 major bleeds. Three of the in total 4 major bleeding events occurred in children undergoing surgery with cardiopulmonary bypass. We conclude that despite the reported adverse events danaparoid can be used as an alternative antithrombotic for children who are intolerant of the heparins, except in cases requiring cardiopulmonary bypass surgery.

Topics: Adolescent; Adult; Child; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Infant; Infant, Newborn; Male; Purpura, Thrombocytopenic, Idiopathic; Risk Factors; Thrombosis

Type 2 heparin-induced thrombocytopenia is an uncommon but often fatal complication of heparin, frequently difficult to diagnose after cardiac surgery. In this series, we record the clinical presentation, temporal relationship, and treatment outcome of patients diagnosed with heparin-induced thrombocytopenia postoperatively.. Thirty-three consecutive patients (1.1%) with a diagnosis of heparin-induced thrombocytopenia established by a greater than 50% drop in platelet count with or without a thrombotic event and a positive platelet factor-4 assay were reviewed. We recorded the clinical presentation, the time to presentation, treatment, and outcome (thrombosis, mortality). Univariate analysis was performed on 13 preoperative, operative, and postoperative variables.. The cohort was at increased mortality risk as a result of age (69.4 years), reduced cardiac function (46.8%), nonbypass operations (57.6%), emergency surgery (21.2%), and implantation of three assist devices. The mean time to suspect heparin-induced thrombocytopenia postoperatively was 5.4 days, with 22 cases (66.6%) occurring within 5 days. All patients had previous (within 3 months) exposure to heparin, and 66.6% had ongoing treatment with heparin before surgery. Overall mortality was 33%; thrombotic complications occurred in 15 patients (45.5%), with a mortality of 7 (46.6%) despite immediate cessation of heparin and treatment with a nonheparin analog. Thrombocytopenia without thrombosis occurred in 18 patients (54.5%), but a subgroup of 5 patients with nonthrombotic complications accounted for the 4 (22.2%) deaths.. Heparin-induced thrombocytopenia after cardiac surgery is uncommon but may occur within 5 days of surgery, further complicating diagnosis and treatment. Thrombotic complications result in a high mortality despite treatment with a nonheparin analog, and a subgroup of patients with thrombocytopenia fared poorly.

Topics: Aged; Aged, 80 and over; Anticoagulants; Autoantibodies; Cardiac Surgical Procedures; Chondroitin Sulfates; Cohort Studies; Dermatan Sulfate; Diabetes Complications; Female; Gangrene; Heparin; Heparitin Sulfate; Hospital Mortality; Humans; Ischemia; Male; Middle Aged; Platelet Factor 4; Postoperative Complications; Postoperative Period; Retrospective Studies; Risk Factors; Thrombocytopenia; Thrombosis; Time Factors; Treatment Outcome

Patients with heparin-induced thrombocytopenia urgently requiring surgery with cardiopulmonary bypass (CPB) present a unique management challenge that must be addressed by the use of alternative anticoagulants. Although clinical success with the direct thrombin inhibitor hirudin has been reported, there is sparse information in the literature supporting the efficacy of this drug as an anti-thrombotic to prevent fibrin formation during CPB. In this report, we describe the efficacy of this drug to prevent thrombin-mediated fibrin formation during CPB.

Topics: Adult; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Contraindications; Dermatan Sulfate; Endarterectomy; Fibrinolytic Agents; Fibrinopeptide A; Heparin; Heparitin Sulfate; Hirudins; Humans; Hypertension, Pulmonary; Hypothermia, Induced; Male; Peptide Fragments; Postoperative Complications; Prothrombin; Pulmonary Embolism; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Thrombectomy; Thrombin; Thrombosis

The role of different glycosaminoglycan species from the vessel walls as physiological antithrombotic agents remains controversial. To further investigate this aspect we extracted glycosaminoglycans from human thoracic aorta and saphenous vein. The different species were highly purified and their anticoagulant and antithrombotic activities tested by in vitro and in vivo assays. We observed that dermatan sulfate is the major anticoagulant and antithrombotic among the vessel wall glycosaminoglycans while the bulk of heparan sulfate is a poorly sulfated glycosaminoglycan, devoid of anticoagulant and antithrombotic activities. Minor amounts of particular a heparan sulfate (< 5% of the total arterial glycosaminoglycans) with high anticoagulant activity were also observed, as assessed by its retention on an antithrombin-affinity column. Possibly, this anticoagulant heparan sulfate originates from the endothelial cells and may exert a significant physiological role due to its location in the interface between the vessel wall and the blood. In view of these results we discuss a possible balance between the two glycosaminoglycan-dependent anticoagulant pathways present in the vascular wall. One is based on antithrombin activation by the heparan sulfate expressed by the endothelial cells. The other, which may assume special relevance after vascular endothelial injury, is based on heparin cofactor II activation by the dermatan sulfate proteoglycans synthesized by cells from the subendothelial layer.

Topics: Anticoagulants; Aorta, Thoracic; Dermatan Sulfate; Endothelium, Vascular; Fibrinolytic Agents; Heparin Cofactor II; Heparitin Sulfate; Humans; Saphenous Vein; Thrombosis

46-year-old woman developed painful ulcers over her lower abdomen in the form of reticulate erythema after injecting interferon beta-1b subcutaneously for multiple sclerosis. Skin biopsy revealed multiple superficial thrombosed vessels with focal epidermal necrosis as well as prominent interstitial mucinosis. Treatment with low-molecular-weight heparin followed by a heparinoid resulted in slow healing of the ulcers but also allowed the subcutaneous interferon injections to be continued.

Topics: Abdominal Wall; Adjuvants, Immunologic; Chondroitin Sulfates; Dermatan Sulfate; Enoxaparin; Female; Fibrinolytic Agents; Heparitin Sulfate; Humans; Injections, Subcutaneous; Interferon beta-1b; Interferon-beta; Middle Aged; Mucinoses; Multiple Sclerosis; Thrombosis; Treatment Outcome; Ulcer

Heparin-induced thrombocytopenia (HIT) is a common immunological drug reaction. After exposure to heparin, some patients develop heparin dependent antibodies with no evidence of thrombosis, while others are at risk of thrombocytopenia, thrombosis, limb loss, and death. We conducted a retrospective chart review on all patients serologically positive for HIT by HPIA ELISA in a single tertiary-care hospital, to determine whether patients with malignancy had an increased risk of thrombotic complications. Medical records of 55 patients who tested positive for HIT and met clinical criteria for HIT were analyzed. All patients had been treated with unfractionated heparin. Malignancy was diagnosed in 11 patients, either at surgery or post-mortem examination. A higher rate of venous thrombosis and pulmonary embolism was observed in patients with HIT and malignant disease when compared to patients with no underlying malignancy (odds ratio 13.6, 95% CI 2.9-63.8).

Topics: Aged; Aged, 80 and over; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Retrospective Studies; Risk Factors; Thrombocytopenia; Thrombosis; Venous Thrombosis

A novel variant of antithrombin, the major serpin inhibitor of coagulation proteases, has been identified in a patient with early onset thrombosis and abnormal plasma antithrombin activity. Sequencing of the antithrombin genes of the patient revealed that one of the two alleles was abnormal due to an in-frame deletion of the codon for the P1 arginine residue. The abnormal antithrombin was separated from the normal inhibitor by complexing the latter with thrombin followed by heparin-agarose affinity chromatography. The purified variant, antithrombin London, was completely inactive as a thrombin or factor Xa inhibitor even after heparin activation. Surprisingly, the variant bound heparin with a K(D) reflecting an approximately 10-fold greater affinity than the normal inhibitor. Stopped-flow kinetic analysis showed that this was almost entirely due to a more favorable conformational activation of the variant than the normal inhibitor, as reflected by a decreased rate constant for reversal of the activation. Consistent with its higher than normal heparin affinity, the inactive antithrombin variant was a potent competitive antagonist of the heparin-catalyzed reaction of normal antithrombin with thrombin but did not affect the uncatalyzed reaction. These results suggest that deletion of the antithrombin P1 residue partially activates the serpin by inducing strain in the reactive center loop, which destabilizes the native loop-buried state and favors the activated loop-exposed state with high heparin affinity. The unusually severe thrombosis associated with the heterozygous mutation may be explained by the ability of antithrombin London to bind endogenous heparan sulfate or heparin molecules with high affinity and to thereby block activation of the normal inhibitor.

Topics: Age of Onset; Antithrombin Proteins; Antithrombins; Arginine; Binding, Competitive; Blood Coagulation; Chromatography, Affinity; Chromatography, Liquid; Electrophoresis, Polyacrylamide Gel; Factor Xa Inhibitors; Family Health; Female; Gene Deletion; Heparin; Heparitin Sulfate; Heterozygote; Humans; Kinetics; Male; Models, Biological; Pedigree; Protein Binding; Proteins; Thrombin; Thrombosis; Time Factors

We describe a case where danaparoid was used prophylactically in a high-risk twin pregnancy following the development of heparin-allergy while on prophylactic dalteparin. Danaparoid was substituted for dalteparin at 20 weeks of pregnancy following the development of a severe skin reaction while on the low molecular weight heparin. Although there was no significant fall in platelet count, an aggregation assay for heparin-induced thrombocytopaenia was positive. The skin lesions rapidly resolved following the change to subcutaneous danaparoid. Delivery was by emergency caesarian section at 35 weeks under a general anaesthetic, as a dose of danaparoid had been given 6 h prior to delivery. A sample of breast milk showed no anti-activated factor X activity. Danaparoid was continued post-delivery until the patient was fully warfarinized. To our knowledge, there are no previous reports of the use of danaparoid in this setting.

Topics: Adult; Anticoagulants; Cesarean Section; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Eruptions; Emergencies; Female; Heparin; Heparitin Sulfate; Humans; Infant, Newborn; Injections, Subcutaneous; Platelet Count; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy, High-Risk; Pregnancy, Multiple; Puerperal Disorders; Pulmonary Embolism; Thrombocytopenia; Thrombosis; Warfarin

Patients with heparin-induced thrombocytopenia (HIT) (with or without thrombosis) require alternative anticoagulation because of their extreme risk of new thromboembolic complications. The first effective agent for this purpose may be danaparoid, a less-sulfated low molecular weight heparinoid. Recently, direct thrombin inhibitors have been used.. Five HIT patients, who developed new thromboembolic complications while receiving danaparoid, were analyzed to consider possible reasons for treatment failure and to promulgate strategies that improve efficacy.. Three patients had acute HIT, one had recent HIT, and one with remote HIT was re-exposed to heparin during heart surgery. Danaparoid was started as intravenous bolus and infusion in one patient, and as 1250 units subcutaneously twice daily in four patients. The new complications that emerged on danaparoid were new venous thrombi in three patients (one with pulmonary emboli), lower extremity arterial thrombosis in one, myocardial ischemia in one, thromboembolic cardiovascular accidents in one, and fatal bowel necrosis in one (two patients suffered more than one complication). Platelet counts did not improve or worsened in four, improved partially in the other, and parameters of disseminated intravascular coagulation failed to improve in one patient. Four patients responded relatively dramatically when direct thrombin inhibitors were substituted. Possible reasons for danaparoid failure include that: 1) no treatment is expected to completely prevent complications, 2) antithrombin III consumption can blunt efficacy in some patients, 3) low or intermediate doses may be insufficient, and 4) there was clinically significant cross-reactivity of the pathogenic HIT antibodies.. It is emphasized that the possibility of clinically significant antibody cross-reactivity and that low or intermediate dosage may be inadequate when using danaparoid in therapy of HIT. The latter problem probably extrapolates to other anticoagulants used for HIT.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Disseminated Intravascular Coagulation; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Platelet Count; Thrombocytopenia; Thrombosis; Treatment Failure

Heparin-induced thrombocytopenia (HIT), with or without thrombosis, is a common and often serious complication of heparin therapy. Platelet-activating, heparin-induced antibodies characteristic of HIT are thought to be specific for complexes formed between platelet factor 4 (PF4) and heparin, and such complexes are routinely used for antibody detection. We studied the binding of HIT antibodies to PF4 complexed with heparin fractions of uniform molecular size or linear polyanions other than heparin and found that many compounds other than heparin form complexes with PF4 that are suitable for antibody detection, provided they carry strong negative charges spaced about 0.5 nm apart along the molecular backbone and are of sufficient length to span about 40% of the circumference of the PF4 tetramer. Polyvinyl phosphonate was among the compounds that were equivalent to heparin. Thus neither a polysaccharide chain nor sulfate side groups--the hallmarks of heparin structure--are required for HIT antibody detection. The findings support the view that antibodies associated with HIT are specific for conformational changes that take place in the positively charged PF4 molecule when it reacts with a suitable, linear polyanion.

Topics: Antibody Specificity; Anticoagulants; Antigen-Antibody Reactions; Blood Platelets; Epitopes; Heparin; Heparitin Sulfate; Humans; In Vitro Techniques; Platelet Activation; Platelet Factor 4; Polyelectrolytes; Polymers; Polysaccharides; Polyvinyls; Thrombocytopenia; Thrombosis

We report on four children with heparin-induced thrombocytopenia type II. In three patients, therapy with unfractionated heparin was associated with development of cardiac thrombi or with thrombosis progression up to the inferior vena cava or with aggravation of peripheral arterial occlusion. In the fourth child, the disease was recognized early on, and no complication occurred. Heparin-induced thrombocytopenia type II was confirmed by heparin-induced platelet activation assay and/or heparin/platelet factor 4-ELISA. Concomitant elevated antiphospholipid antibodies were seen in all patients. Danaparoid sodium applied at a dosage of between 1.2 and 7.1 U/kg/h stopped the disease progression in each patient. Three children had a clinical recovery with partial recanalization, but for the child with peripheral arterial occlusion disease, amputation of some of the toes became necessary.. Our data indicate that heparin-induced thrombocytopenia type II is a potential life-threatening disease in children and danaparoid sodium is beneficial in this age group.

Topics: Adolescent; Antibodies, Antiphospholipid; Anticoagulants; Child; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Humans; Male; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is an immune-mediated drug reaction that occurs 5-14 d after initiation of heparin therapy and is a potentially life-threatening thrombotic complication. The antibody-heparin-PF4 complexes cause platelet activation and generation of platelet microparticles. The need for anticoagulant treatment in asymptomatic thrombocytopenia is uncertain. However, treatment is warranted in HITTS, as illustrated in the case reported here. Danaparoid, r-Hirudin and argatroban are effective drugs. Danaparoid has a 10-50% in vitro cross-reactivity rate with the HIT antibodies, but has been proven to be clinically efficacious even in these cases. Here, we report a case of in vivo cross-reactivity with danaparoid, the patient showed an excellent recovery with r-Hirudin.

Topics: Aged; Antibodies; Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Factor Xa; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; International Normalized Ratio; Male; Platelet Count; Syndrome; Thrombocytopenia; Thrombosis

The purpose of this study was to evaluate the efficacy and safety of danaparoid in the treatment of critically ill patients with acute renal failure and suspected heparin-induced thrombocytopenia (HIT) needing renal replacement therapy (RRT). We conducted a retrospective analysis of 13 consecutive intensive care patients with acute renal failure and suspected HIT who were treated with danaparoid for at least 3 days during RRT. In eight patients, continuous venovenous hemofiltration was performed. The mean infusion rate of danaparoid was 140 +/- 86 U/hour. Filter exchange was necessary every 37.5 hours. In five patients, continuous venovenous hemodialysis was used. A bolus injection of 750 U danaparoid was followed by a mean infusion rate of 138 +/- 122 U/hour. Filters were exchanged every 24 hours. In 7 of 13 patients, even a low mean infusion rate of 88 +/- 35 U/hour was efficient. Mean anti-Xa (aXa) levels were approximately 0.4 +/- 0.2 aXa U/mL. Persistent thrombocytopenia despite discontinuation of heparin treatment was observed in 9 of 13 patients, owing to disseminated intravascular coagulation (DIC). HIT was confirmed by an increase in platelet count and positive heparin-induced antibodies in 2 of 13 patients. No thromboembolic complications occurred, but major bleeding was observed in 6 of 13 patients, which could be explained by consumption of coagulation factors and platelets due to DIC in 5 of 6 patients. Nine of 13 patients died of multiorgan failure or sepsis, or both. In none of these patients was the fatal outcome related to danaparoid treatment. In critically ill patients with renal impairment and suspected HIT, a bolus injection of 750 U danaparoid followed by a mean infusion rate of 50 to 150 U/hour appears to be a safe and efficient treatment option when alternative anticoagulation is necessary.

Topics: Adult; Aged; Anticoagulants; Chondroitin Sulfates; Contraindications; Critical Care; Dermatan Sulfate; Drug Combinations; Drug Evaluation; Female; Hemorrhage; Heparin; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Multiple Organ Failure; Renal Replacement Therapy; Retrospective Studies; Thrombosis; Treatment Outcome

Topics: Aged; Angina, Unstable; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Disease; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Humans; Male; Reoperation; Thrombocytopenia; Thrombosis; Treatment Failure

Perlecan, a heparan sulfate proteoglycan, has been suggested to be critical for regulation of vascular repair. We generated clones of endothelial cells expressing an antisense vector targeting domain III of perlecan. Transfected cells produced significantly less perlecan than parent cells and showed a reduced ability to inhibit the binding and mitogenic activity of fibroblast growth factor-2 in vascular smooth muscle cells. Endothelial cells were seeded onto three-dimensional polymeric matrices and implanted adjacent to porcine carotid arteries subjected to deep injury. Although the parent endothelial cells prevented occlusive thrombosis, perlecan-deficient cells were completely ineffective. The ability of endothelial cells to inhibit intimal hyperplasia, however, was abrogated only in part by perlecan suppression. The differential regulation by perlecan of these different aspects of vascular repair may explain why control of clinical clot formation does not lead to full control of intimal hyperplasia. Thus the use of genetically modified tissue-engineered cells provides a new approach for dissecting the role of specific factors within the complex environment of the blood vessel wall.

Topics: Animals; Antisense Elements (Genetics); Cattle; Cell Division; Cells, Cultured; Endothelium, Vascular; Fibroblast Growth Factor 2; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Hyperplasia; Male; Muscle, Smooth, Vascular; Proteoglycans; Swine; Thrombosis

Topics: Ancrod; Anticoagulants; Antithrombins; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia; Thrombosis; Warfarin

Topics: Ancrod; Anticoagulants; Aprotinin; Cardiopulmonary Bypass; Chondroitin Sulfates; Coronary Disease; Dermatan Sulfate; Drug Combinations; Heparin; Heparitin Sulfate; Humans; Serine Proteinase Inhibitors; Thrombocytopenia; Thrombosis; Treatment Failure

Reduced heparin and heparan sulfate (HS) proteoglycans (PG) have been observed in both inflammation and atherosclerosis. Methods to increase endogenous heparin and heparan sulfate are not known. We found that incubation of endothelial cells with 500-1,000 micrograms/ml high density lipoprotein (HDL) increased 35SO4 incorporation into PG by 1.5-2.5-fold. A major portion of this increase was in HS and was the result of increased synthesis. Total PG core proteins were not altered by HDL; however, the ratio of 35SO4 to [3H]glucosamine was increased by HDL, suggesting increased sulfation of glycosaminoglycans. In addition, HDL increased the amount of highly sulfated heparin-like HS in the subendothelial matrix. HS from HDL-treated cells bound 40 +/- 5% more 125I-antithrombin III (requires 3-O sulfated HS) and 49 +/- 3% fewer monocytes. Moreover, the HS isolated from HDL-treated cells inhibited smooth muscle cell proliferation (by 83 +/- 5%) better than control HS (56 +/- 6%) and heparin (42 +/- 6%). HDL isolated from apolipoprotein E (apoE)-null mice did not stimulate HS production unless apoE was added. ApoE also stimulated HS production in the absence of HDL. ApoE did not increase 35SO4 incorporation in macrophages and fibroblasts, suggesting that this is an endothelial cell-specific process. Receptor-associated protein inhibited apoE-mediated stimulation of HS only at higher (20 micrograms/ml) doses, suggesting the involvement of a receptor-associated protein-sensitive pathway in mediating apoE actions. In summary, our data identify a novel mechanism by which apoE and apoE-containing HDL can be anti-atherogenic. Identification of specific apoE peptides that stimulate endothelial heparin/HS production may have important therapeutic applications.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Cattle; Cells, Cultured; Endothelium, Vascular; Glycosaminoglycans; Heparitin Sulfate; Lipoproteins, HDL; Mice; Mice, Knockout; Rats; Thrombosis

Only few reports exist addressing the problem of temporary pacemaker leads associated with thromboembolic disease. We report the case of a 67-year-old patient who required a temporary transfemoral pacemaker due to AV block grade III. The patient developed extensive right atrial and ventricle thrombus formation attached to the pacing wire, as well as venous thrombosis at the insertion site due to heparin-induced thrombocytopenia type II (HIT type II). After short-term thrombolysis with 1 mg rt-PA/kg b.w. complete resolution of all clots could be shown by B-mode sonography and transthoracic, as well as transesophageal echocardiography.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heart Atria; Heart Diseases; Heart Ventricles; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pacemaker, Artificial; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator

Heparin-induced thrombocytopenia is a rare and serious complication of anticoagulation therapy. There remains a paucity of information pertaining to alternative anticoagulation strategies for use during cardiopulmonary bypass concomitant with heparin-induced thrombocytopenia, especially in children. We report the successful treatment of heparin-induced thrombocytopenia and subsequent hemorrhagic complications postoperatively in a 2-year-old child with Danaparoid (orgaran). Emergent conduit revision with cardiopulmonary bypass was required for a thrombosed systemic-venous to pulmonary-arterial connection (completion modified Fontan procedure). Required doses of Danaparoid were consistently twofold that previously reported for adults.

Topics: Anticoagulants; Cardiopulmonary Bypass; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heart Defects, Congenital; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Thrombocytopenia; Thrombosis

An 80-year-old woman had been hospitalized in a psychiatric clinic where, on the 22nd day, she sustained a fracture of the neck of the left femur, which was treated by internal screw fixation. The postoperative course was at first without complication. But 9 days postoperatively her platelet count had fallen to 59,000/microliter. As heparin induced type II thrombocytopenia (HIT II) was suspected, the thrombosis prophylaxis with low-molecular heparin was replaced by sodium danaparoid (twice 750 units subcutaneously). Despite this, ischaemia of the right lower leg developed and required amputation. On the following day the left lower leg and foot also became ischemic, where upon she was admitted to the author's hospital (37 days after her admission to the psychiatric clinic).. The patient was in a reduced general condition (body-mass index 19.5 kg/m2). She was disoriented as to place and time. Her blood pressure was 140/80 mmHg, her pulse irregular with a ventricular rate of 100/min. The skin below the middle of the left lower leg was cold and livid and the pedal pulses were not palpable.. Haemoglobin content was 9.7 g/dl, the white cell count 9,200/microliter, and platelet count 54,000/microliter. Electrolytes and creatinine were within normal limits.. Thrombendarterectomy was performed once via the left groin under danaparoid anticoagulation. There was no re-occlusion and the patient was able to walk again.--It was ascertained subsequently, she had already been given ordinary heparin in the psychiatric clinic for 20 days. Her platelet count of around 70,000/microliter returned to normal even though heparin administration was continued.. A reduction in platelet count by more than half during heparin treatment suggests heparin-induced thrombocytopenia, in which case heparin should be discontinued at once. In high-risk patients adequate treatment should be initiated with other anticoagulants even before the occurrence of thromboembolism.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Endarterectomy; Female; Heparin; Heparinoids; Heparitin Sulfate; Humans; Ischemia; Leg; Recurrence; Thrombocytopenia; Thromboembolism; Thrombosis

Topics: Aged; Anticoagulants; Arteries; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fatal Outcome; Heparinoids; Heparitin Sulfate; Humans; Male; Pulmonary Embolism; Thrombocytopenia; Thrombosis

Heparan sulfate, a glycosaminoglycan component of vascular endothelial proteoglycans, provides the anticoagulant functions associated with heparin on the endothelial cell surface. We have demonstrated the presence of spontaneous occurring antibodies to heparin polysaccharides (HPS) in humans. Elevation of serum anti-HPS antibodies were closely associated with the prevalence of thrombosis or fetal loss in patients with autoimmune disease. Affinity purified anti-HPS antibodies inhibited heparin dependent formation of thrombin-antithrombin III complexes. In order to further analyze these autoantibodies, a murine IgG monoclonal anti-HPS antibody, designated H16, was generated. H16 mAb specifically bound to heparin, heparan sulfate and human umbilical vascular endothelial cells (HUVEC). The binding of H16 mAb to HUVEC was specifically inhibited by heparin. Further, H16 mAb inhibited the binding of antithrombin III to heparin in a dose dependent manner. These results indicate that this mAb could recognize antithrombin III-binding sites on vascular endothelial heparan sulfate, leading to procoagulant states through the inhibition of heparin/heparan sulfate dependent anticoagulant process.

Topics: Abortion, Spontaneous; Animals; Antibodies, Monoclonal; Antithrombin III; Autoantibodies; Autoimmune Diseases; Binding Sites; Endothelium, Vascular; Female; Heparitin Sulfate; Humans; Mice; Peptide Hydrolases; Pregnancy; Thrombosis

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Humans; Male; Thrombocytopenia; Thrombosis

Acute graft thrombosis is a severe complication in vascular surgery that may require limb amputation or even cause death. Because nearly all patients undergoing vascular surgery have had previous exposure to heparin, the presence of heparin-related anti-platelet antibodies typical for heparin-associated thrombocytopenia (HAT) is one underlying possible mechanism of acute graft thrombosis. Although thrombocytopenia is a typical finding of HAT, it is not clear whether the occurrence of clinically important HAT is necessarily associated with thrombocytopenia.. Ten out of 246 patients undergoing vascular surgery were diagnosed with HAT because of otherwise unexplained acute graft thrombosis that required recurrent surgical interventions.. In all of the 10 patients, heparin-related anti-platelet antibodies were detected although the platelet counts were within the normal range. When HAT was diagnosed, heparin administration was stopped and, after autoantibody cross-reactivity with the heparinoid Danaparoid had been excluded, anticoagulation was continued using this anticoagulant. After heparin therapy was discontinued none of the 10 patients developed further thrombotic complications.. The data presented demonstrate clearly that a normal platelet count does not exclude the possibility of HAT. As a consequence of this, HAT should be suspected in patients who develop thrombotic complications during heparin treatment, regardless of the actual platelet counts.

Topics: Adult; Aged; Anastomosis, Surgical; Arterial Occlusive Diseases; Autoantibodies; Blood Platelets; Blood Vessel Prosthesis; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Graft Occlusion, Vascular; Heparin; Heparinoids; Heparitin Sulfate; Humans; Intraoperative Complications; Male; Middle Aged; Platelet Count; Reoperation; Thrombosis; Vascular Patency

Binding of recipient natural antibodies to the endothelium of the graft, complement activation, endothelial cell activation, and microvascular thrombosis are major events in the hyperacute rejection of organ xenografts. The aim of this study was to investigate the effects of two new synthetic sulfated oligosaccharides (A and B) on the survival of discordant cardiac xenografts in the guinea pig-to-rat model. In untreated recipients, hyperacute rejection occurred in 5 min (median; range, 4-6 min) and immunohistological analysis of all the grafts revealed deposition of IgM and C3 along the endothelium. Administration of oligosaccharides A and B prior to revascularization prolonged the survival of xenografts in a dose-dependent manner, up to 113 min (median; range, 42-145 min) and 86 min (median; range, 35-108 min), respectively, when doses of 20 mg/kg were used. There were no bleeding complications. Histological examination of the rejected grafts showed a picture of hyperacute rejection, with no difference in IgM and C3 deposition as compared with the untreated animals. In cell culture experiments, the release of heparan sulfate from guinea pig cardiac endothelial cells induced by rat serum was inhibited by both saccharides in a dose-dependent manner. The results indicate that these new synthetic sulfated oligosaccharides are effective for prolongation of discordant xenograft survival, possibly by interfering with endothelial cell activation. Such substances may be of value in other xenotransplant combinations.

Topics: Acute Disease; Animals; Carbohydrate Sequence; Endothelium, Vascular; Graft Survival; Guinea Pigs; Heart Transplantation; Heparitin Sulfate; Male; Molecular Sequence Data; Oligosaccharides; Rats; Rats, Sprague-Dawley; Sulfates; Thrombosis

Heparin-induced thrombocytopenia (HIT) with thrombosis is a rare, but important complication of heparin therapy. We describe the case of a 53-year-old patient hospitalized with complicated pelvic fracture. Intravenous infusion of unfractionated heparin (15'000 IU/24 h) was given for thrombosis prevention. After 11 days' treatment the patient developed deep venous thrombosis of the left calf, complicated 2 days later by massive bilateral pulmonary embolism. Simultaneous with these thromboembolic events, thrombocytopenia, signs of activated coagulation, and antibodies to heparin occurred. In the context of this case the diagnostic and therapeutic possibilities of HIT, and in particular treatment with the heparinoid danaproid (Orgaran), are discussed.

Topics: Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fractures, Bone; Heparin; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Pelvic Bones; Pulmonary Embolism; Thrombocytopenia; Thrombosis

We report the cases of two patients who last lims as a result of heparin-induced thrombocytopenia (HIT). On the basis of these cases, the incidence, pathophysiology and the diagnosis of HIT are reviewed. For the diagnosis of HIT, the platelet aggregation test and ELISA are used. For HIT prophylaxis and treatment of thromboembolic complications is recommended Orgaran. Exact dosage schedules are provided.

Topics: Aged; Amputation, Surgical; Arm; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Humans; Middle Aged; Platelet Aggregation; Risk Factors; Thrombocytopenia; Thrombosis

Topics: Animals; Arginine; Aspirin; Blood Pressure; Cats; Epoprostenol; Extracorporeal Circulation; Fibrinolysis; Heparitin Sulfate; Iloprost; Infusions, Intravenous; Injections, Intravenous; Molsidomine; Nitric Oxide; Nitroarginine; Platelet Aggregation; Streptokinase; Thrombosis; Vasodilator Agents

The 29-year-old, heroin-addicted patient received an aortic valve prosthesis (SJM) 10 years ago because of aortic valve stenosis III. One year after surgical treatment he refused to take Phenprocoumon and thus received no anticoagulation for 9 years. The patient was hospitalized due to cardial decompensation and thrombosis of the aortic valve prosthesis was diagnosed. Under heparinization, he developed heparin-induced thrombocytopenia type II, which disappeared after changing the medication to Danaparoid-Sodium. In order to avoid any further heparin exposure, we also carried out the surgical replacement of the aortic valve prosthesis under anticoagulation with Danaparoid-Sodium.

Topics: Adult; Aortic Valve Stenosis; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heart Valve Prosthesis; Heparin; Heparitin Sulfate; Heroin Dependence; Humans; Male; Platelet Count; Postoperative Complications; Prosthesis Failure; Reoperation; Thrombocytopenia; Thrombosis

Venous thrombosis and pulmonary embolism are the two faces of thromboembolic disease. In over 90% of cases, the initial treatment of the pulmonary embolism is anticoagulant therapy, the necessity and efficacy of which were demonstrated over 30 years ago with a reduction of mortality of 25 to 6%. Intravenous heparin relayed rapidly (1st to 3rd day) is still the conventional treatment protocol. Heparin therapy adapted to the result of the activated cephalin time (two to three times the control value) and oral vitamin K antagonists with a dosage adapted to keep the International Normalized Ratio between 2 and 3 is the safest and most effective treatment to date. The efficacy is shown by the low rate of recurrency, about 5% under anticoagulant therapy, lethal recurrence being very rare (less than 1%), and safety is attested by the low rate of severe bleeding complications (3 to 5%). The introduction of low molecular weight heparin and the excellent results observed in the treatment of deep vein thrombosis will probably lead to rapid extension of its indications to mild or moderate but haemodynamically well-tolerated pulmonary embolism. Hirudine and heparinoids will probably be the next step in the treatment of pulmonary embolism.

Topics: Anticoagulants; Chondroitin Sulfates; Coumarins; Dermatan Sulfate; Drug Administration Schedule; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Humans; Injections, Intravenous; Partial Thromboplastin Time; Pulmonary Embolism; Thrombolytic Therapy; Thrombosis; Treatment Outcome

Previous studies showed that homocysteine, a thrombo-atherogenic and atherogenic agent, inhibits an endothelial thrombomodulin-protein C anticoagulant pathway. We examined whether homocysteine might affect another endothelial anticoagulant mechanism; i.e., heparin-like glycosaminoglycan-antithrombin III interactions. Incubations of porcine aortic endothelial cell cultures with homocysteine reduced the amount of antithrombin III bound to the cell surface in a dose- and time-dependent fashion. The inhibitory effect was observed at a homocysteine concentration as low as 0.1 mM, and the maximal suppression occurred at 1 mM of homocysteine after 24 h. In contrast with a marked reduction in the maximal antithrombin III binding capacity (approximately 30% of control), the radioactivity of [35S]sulfate incorporated into heparan sulfate on the cell surface was minimally (< 15%) reduced. The cells remained viable after homocysteine treatment. Although neither net negative charge nor proportion in total glycosaminoglycans of cell surface heparan sulfate was altered by homocysteine treatment, a substantial reduction in antithrombin III binding capacity of heparan sulfate isolated from homocysteine-treated endothelial cells was found using both affinity chromatography and dot blot assay techniques. The antithrombin III binding activity of endothelial cells decreased after preincubation with 1 mM homocysteine, cysteine, or 2-mercaptoethanol; no reduction in binding activity was observed after preincubation with the same concentration of methionine, alanine, or valine. This sulfhydryl effect may be caused by generation of hydrogen peroxide, as incubation of catalase, but not superoxide dismutase, with homocysteine-treated endothelial cells prevented this reduction, whereas copper augmented the inhibitory effects of the metabolite. Thus, our data suggest that the inhibited expression of anticoagulant heparan sulfate may contribute to the thrombogenic property resulting from the homocysteine-induced endothelial cell perturbation, mediated by generation of hydrogen peroxide through alteration of the redox potential.

Topics: Animals; Anticoagulants; Antithrombin III; Catalase; Cell Survival; Cells, Cultured; Copper; Copper Sulfate; Endothelium, Vascular; Heparitin Sulfate; Homocysteine; In Vitro Techniques; Protein Binding; Superoxide Dismutase; Swine; Thrombosis

The mode of action of glycosaminoglycans (GAGs) towards thrombus formation in a rat arteriovenous shunt was studied by simultaneous examination of thrombus weight, platelet consumption and thrombin generation during 45 min of blood circulation. A comparison was made between the effects of heparin, the heparinoid Org 10172 (Orgaran), and the chemically synthesized methoxy derivative of the antithrombin III binding pentasaccharide fragment of heparin (Org 31540). All three compounds inhibited thrombus growth by 30% at a dose of 80 anti-Xa U/kg i. v. when assessed after 15 min of circulation through the shunt. In addition, a systemic decrease of 27% of platelet numbers in the placebo group was inhibited by heparin and Orgaran with 63% and by pentasaccharide with 48%. At a later stage, after 45 min of circulation, at comparable plasma anti-Xa levels, thrombi which had formed in the presence of Orgaran or pentasaccharide, but not in the presence of heparin, became less or non thrombogenic. This non-thrombogenicity was reflected by i) an inhibition of the local deposition of [51Cr]platelets of 75% with Orgaran and of 57% with pentasaccharide, and ii) an inhibition of ex-vivo thrombus-induced thrombin generation in pooled rat plasma of 67% with Orgaran and of 52% with pentasaccharide (inhibition compared to placebo). Although the mechanism of inducing non-thrombogenicity of a (developing) thrombus by Orgaran and pentasaccharide requires further investigation, the suppression of the local thrombin generation potency, measured by thrombus-induced thrombin generation in pooled plasma, is much more correlated with thrombus growth than systemic anticoagulant activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arteriovenous Shunt, Surgical; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Glycosaminoglycans; Heparin; Heparitin Sulfate; Male; Oligosaccharides; Platelet Adhesiveness; Platelet Count; Prothrombin; Rats; Rats, Wistar; Thrombin; Thrombosis; Time Factors

Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Female; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Infusions, Intravenous; Male; Middle Aged; Platelet Aggregation; Thrombocytopenia; Thrombosis

Native heparin was very effective in models of arterial and venous thrombosis as well as in a model demonstrating the effect on endothelial stability in rats. The effect on venous thrombosis was particularly prominent. The activities of LMW-heparin were about the same in all three models, the absolute effective dose against arterial thrombosis being much lower than with native heparin. A heparan sulfate-related preparation (suleparoide) was much less effective in both thrombosis models, especially in the venous one, while the activity was most specifically directed to the maintenance of endothelial stability.

Topics: Animals; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Rats; Rats, Inbred Strains; Thrombophlebitis; Thrombosis

We report two cases of heparin induced thrombocytopenia (HIT), in patients who required anticoagulation for extracorporeal procedures (haemodialysis and cardiopulmonary bypass) one associated with recurrent thrombosis of the artificial circuits. Resolution of thrombocytopenia and successful anticoagulation were achieved using a low molecular weight heparinoid (LMWH) Org 10172. Anticoagulation was monitored using estimations of plasma anti-factor Xa activity. These cases demonstrate that LMWH provides safe and effective anticoagulation in patients in whom unfractionated heparin has caused HIT.

Topics: Aged; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Female; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Renal Dialysis; Thrombocytopenia; Thrombosis

Org 10172 shows dose-dependent antithrombotic activity in various experimental thrombosis models. It produces less hemorrhage at an equivalent antithrombotic effect than commercial heparin in various experimental bleeding models. It shows a better benefit (antithrombotic) to risk (bleeding) ratio than SP54 and commercial heparin. The benefit to risk ratio of Org 10172 is better than some LMW heparins and equivalent to other LMW heparins, depending on the method of preparation. The antithrombotic effect of Org 10172 in animal models has a much longer duration than that of commercial heparin and also LMW heparins. Org 10172 predominantly inactivates generated thrombin via the formation of HC II-thrombin complexes, whereas commercial heparin and LMW heparins inactivate generated thrombin via AT III-thrombin complexes.

Topics: Animals; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation, Preclinical; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Injections, Intravenous; Injections, Subcutaneous; Rabbits; Rats; Thrombosis

Topics: Animals; Blood Coagulation Tests; Chondroitin; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparin; Heparitin Sulfate; Male; Rabbits; Thrombosis

Two experimental thrombosis models in rats have been compared with regard to the composition of the formed thrombi and the effects of various treatments on thrombus formation. In the first model thrombosis is induced in the vena cava by a combination of venous stasis and hypercoagulability; these thrombi consist merely of red cells and fibrin with only a few platelets. In the second model thrombosis is induced in an arterio-venous shunt in which the formed thrombi consist of red cells, fibrin and a large amount of platelet aggregates adhering to the foreign material. Antiplatelet serum and acetylsalicylic acid, which reduce blood platelet activity, inhibited thrombus formation only in the arteriovenous shunt model. Dicumoxane, an oral anticoagulant, was active in both models. The glycosaminoglycans heparin, Org 10172, Fragmin and the pentasaccharide, representing the AT-III binding sequence of heparin, were active in both models. However, there were qualitative and quantitative differences between the effects of the glycosaminoglycans suggesting differences in their modes of action.

Topics: Animals; Arteriovenous Shunt, Surgical; Aspirin; Blood Coagulation Factors; Blood Platelets; Chondroitin Sulfates; Coumarins; Dermatan Sulfate; Disease Models, Animal; Fibrin; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Immune Sera; Ligation; Male; Oligosaccharides; Rats; Thrombosis; Venae Cavae; Vitamin K

Studies were performed to determine the cross-reaction rate of the heparin-dependent antibody with Org 10172, a new low molecular weight heparinoid, and to investigate the effect of Org 10172 on platelet activation induced by the antibody. The plasmas of 17 patients with thrombocytopenia induced by standard heparin were shown, by platelet aggregation studies, to contain the heparin-dependent antibody. Of these 17 patient plasmas, only three cross-reacted with the heparinoid, producing a cross-reaction rate of 18%. When Org 10172 was added to a reaction mixture containing normal platelet-rich plasma, patient plasma, and standard heparin with non-cross-reacting plasmas, it inhibited platelet aggregation and thromboxane B2 production induced by the antibody, provided that the ratio of Org 10172 concentration (anti-Xa U/mL) to standard heparin concentration (IU/mL) exceeded 2.5 to 5.0. This inhibitory effect was observed only with platelet activation mediated by the antibody, but not by collagen (2 micrograms/mL) or ADP (5.0 mumol/L). Additionally, three of 17 patients with serious thrombosis, whose plasma showed no cross-reaction with the heparinoid, received Org 10172 treatment with a good response in each case. These findings suggest that Org 10172 may be a useful drug for the treatment of heparin-induced thrombocytopenia.

Topics: Antigen-Antibody Reactions; Blood Platelets; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; In Vitro Techniques; Molecular Weight; Platelet Aggregation Inhibitors; Thrombocytopenia; Thrombosis; Thromboxane B2

Time response curves of the anti-thrombotic effects, bleeding enhancing effects, effects on APTT, anti-Xa activities, anti-thrombin activities and thrombin generation inhibitory activities of the low molecular weight heparinoid Org 10172 and heparin have been compared in rats. The time courses of these effects were similar for heparin but quite different for Org 10172. Org 10172 induced anti-thrombotic and anti-Xa effects which lasted approximately 3 times longer than those at the same anti-Xa doses of heparin, whereas the bleeding enhancing effects and effects on APTT of Org 10172 were of shorter duration than those of heparin. The half-life of the anti-thrombin effect after Org 10172 seemed somewhat longer than after heparin administration. Thrombin generation inhibition by Org 10172 showed a slightly longer duration than by heparin. The similarities between the time courses of the anti-thrombotic effect and the anti-Xa activity after Org 10172 administration suggest that the most appropriate parameter to monitor Org 10172 treatment is the plasma anti-Xa level.

Topics: Animals; Bleeding Time; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparitin Sulfate; Male; Molecular Weight; Rats; Rats, Inbred Strains; Serine Endopeptidases; Thrombin; Thrombosis

We studied the possibility that immune injury to endothelial cells may have a role in the development of thrombosis in some patients with heparin-associated thrombocytopenia. Serum samples from each of 27 patients who had this clinical diagnosis contained heparin-dependent platelet antibodies and deposited more than normal amounts of IgG, IgA, or IgM on endothelial cells, stimulating the production of tissue factor. Binding of immunoglobulins to endothelial cells was no longer detected when the patients were studied after heparin was withdrawn, but reappeared within several days upon reexposure to heparin in a patient who experienced a clinical recurrence. Binding of immunoglobulin to endothelial cells was partially reduced by the preadsorption of serum samples with heparin or heparan sulfate bound to Sepharose or by enzymatic cleavage of cell-bound heparan sulfate, and was augmented by the addition of heparan sulfate. Thus, serum from some patients with heparin-associated thrombocytopenia may contain antibodies that react with heparin bound to endothelial cells or with heparan sulfate synthesized by endothelial cells. Immune injury to both platelets and endothelial cells may play a part in the development of thrombosis in some patients after heparin therapy.

Topics: Blood Platelets; Blood Vessels; Endothelium; Heparin; Heparitin Sulfate; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; In Vitro Techniques; Thrombocytopenia; Thrombosis

Recent studies with heparin fractions indicate that it is possible to dissociate the antithrombotic and hemorrhagic effects of heparin and so improve its therapeutic potential. Heparin inhibits blood coagulation by 3 independent mechanisms by augmenting the effect of antithrombin III (the major effect), by augmenting the inhibitory effect of thrombin or heparin cofactor II, and by disrupting the activation of blood coagulation on the platelet surface; it has an additional effect on hemostasis through its interaction with blood platelets. Some insight into the mechanism of heparin-induced bleeding has been provided by studies with low molecular weight heparins. These heparins have reduced antithrombin activity but retain anti-Xa activity and have antithrombotic properties in animals with a reduced risk of bleeding. There is evidence that the reduction in the bleeding risk is unrelated to the anticoagulant effect of these low molecular weight heparins, but that it may be related to the observation that they inhibit platelet function less than standard heparin. The very low molecular weight heparins (molecular weight 3,000 daltons), have virtually no anti-IIa activity and are relatively weaker antithrombotic agents than low molecular weight heparins of 5,000 daltons. A minimal amount of anti-IIa activity is required for full expression of the antithrombotic activities of these low molecular weight heparins.

Topics: Animals; Anticoagulants; Antithrombin III; Blood Coagulation; Factor X; Factor Xa; Hemorrhage; Heparin; Heparitin Sulfate; Molecular Weight; Structure-Activity Relationship; Thrombosis

Topics: Adult; Antithrombin III Deficiency; Chondroitin Sulfates; Dermatan Sulfate; Female; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thrombosis

Org 10172 is a heparinoid prepared during the manufacture of porcine mucosal heparin. This compound has been compared with a standard commercial grade heparin in vitro and in vivo using experimental thrombosis and bleeding models in rabbits. Increasing doses of both the heparin and the heparinoid resulted in a similar prolongation of a Xa clotting time and the APTT, but the heparinoid had no effect on the thrombin clotting time over the concentration range 0-3.0 units/ml. Both preparations were antithrombotic using a stasis prophylaxis model but inhibition of thrombosis was independent of the ex vivo anti-Xa heparin levels achieved. Relative to heparin, the heparinoid failed to induce hemorrhage. A potential therapeutic advantage for Org 10172 as an antithrombotic agent for clinical use can be predicted.

Topics: Animals; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparitin Sulfate; Rabbits; Thrombosis

Topics: Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Pulmonary Embolism; Thrombocytopenia; Thrombosis