chondroitin-sulfates 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

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

Platelets participate in a variety of responses of the blood to injury. An emerging body of evidence suggests that these cells express an intrinsic capacity to interact with and trigger both classical and alternative pathways of complement. This activity requires cell activation with biochemical agonists and/or shear stress, and is associated with the expression of P-selectin, gC1qR, and chondroitin sulfate. Platelet mediated complement activation measurably increases soluble inflammatory mediators (C3a and C5a). Platelets may also serve as targets of classical complement activation in autoimmune conditions such as antiphospholipid syndromes (APS) and immune thrombocytopenia purpura (ITP). Retrospective correlation with clinical data suggests that enhanced platelet associated complement activation correlates with increased arterial thrombotic events in patients with lupus erythematosus and APS, and evidence of enhanced platelet clearance from the circulation in patients with ITP. Taken together, these data support a role for platelet mediated complement activation in vascular inflammation and thrombosis.

Topics: Animals; Antiphospholipid Syndrome; Blood Platelets; Carrier Proteins; Chondroitin Sulfates; Complement Activation; Complement C3a; Complement C5a; Humans; Inflammation Mediators; Lupus Erythematosus, Systemic; Mitochondrial Proteins; P-Selectin; Purpura, Thrombocytopenic, Idiopathic; Thrombosis; Vasculitis

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

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), 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

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

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; 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

Effects of isomers of chondroitin sulfate on atherosclerosis were clinically compared, based on sulfate linkage and the amount of sulfate, by using chondroitin 4-sulfate, chondroitin 6-sulfate and chondroitin polysulfate. Fourty eight age-matched atherosclerotic subjects were selected from a home for the elderly in order to the treatment with the agents. The isomers of chondroitin sulfate were given a daily dose of 4.5 g perorally. During the experimental period for 64 months, mortality, serum cholesterol, thrombus-formation time and thrombus weight were examined. The result obtained was as follows: mortality in the groups treated with the isomers of chondroitin sulfate was less than the age-matched untreated control group. Serum cholesterol value in the group treated by the isomers of chondroitin sulfate, chondroitin polysulfate group in particular, fell lower than the pre-treatment value. Thrombus formation time prolonged 150% in the group treated with chondroitin polysulfate over the untreated control group and the resultant thrombus weight was reduced in the treated group. Thus, these data indicated that the isomers of chondroitin sulfate are clinically effective on the treatment of atherosclerosis in the order of chondroitin polysulfate, chondroitin 4-sulfate and/or chondroitin 6-sulfate.

Topics: Aged; Arteriosclerosis; Blood Coagulation; Cholesterol; Chondroitin; Chondroitin Sulfates; Clinical Trials as Topic; Humans; Isomerism; 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

Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders.. We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (<5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality.. We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden).. As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.

Topics: Adolescent; Adult; Child; Chondroitin Sulfates; Female; Humans; Male; Middle Aged; Thrombosis; Whole Genome Sequencing; Young Adult

Extracellular histones induce lethal thrombosis by promoting platelet aggregation, neutrophil migration, and cell injuries. Heparin, which has negative charges, can bind to extracellular histones; however, heparin strongly inhibits the activation of coagulation. Since chondroitin sulfate (CS) shows less effect on the coagulation system than heparin does, CS has the potential to become an effective drug for lethal thrombosis with high risk of bleeding. To elucidate the therapeutic mechanisms of CS in lethal thrombosis, we investigated the interaction between CS and extracellular histones. Mouse vascular endothelial cells were incubated with histones in the presence of heparin or CS, and the expression of caspase-3/7 was measured. The interactions between histones and heparin or CS were measured by surface plasmon resonance analysis. Vascular permeability, platelet counts, liver and renal functions, and coagulation times were evaluated in an in vivo assay. The apoptosis induced by histones was inhibited by treatment with heparin or CS. Heparin and CS showed strong binding to histones and inhibited vascular hyperpermeability. The platelet counts as well as liver and renal functions were not decreased by the treatment with heparin or CS. Moreover, CS showed less effect on the coagulation system than heparin did. These results suggested that CS can be a novel agent for lethal thrombosis with the risk for hemorrhage. Since vascular endothelial cell injuries occur at an early stage of lethal thrombosis, administration of CS might be a useful approach.

Topics: Animals; Anticoagulants; Blood Coagulation; Capillary Permeability; Chondroitin Sulfates; Disease Models, Animal; Endothelial Cells; Hemorrhage; Heparin; Histones; Humans; Male; Mice; Mice, Inbred DBA; Platelet Aggregation; Platelet Function Tests; Surface Plasmon Resonance; Thrombosis; Treatment Outcome

Fucosylated chondroitin sulfate (FucCS) is a potent anticoagulant polysaccharide extracted from sea cucumber. Its anticoagulant activity is attributed to the presence of unique branches of sulfated fucose. Although this glycosaminoglycan exerts an antithrombotic effect following oral administration, high doses are necessary to achieve the maximum effect. The diminished activity of FucCS following oral administration is likely due to its degradation in the gastrointestinal tract and its limited ability to cross the intestinal cell membranes. The latter aspect is particularly difficult to overcome. However, gastro-resistant tablet formulation may help limit the degradation of FucCS in the gastrointestinal tract. In the present work, we found that the oral administration of FucCS as gastro-resistant tablets produces a more potent and prolonged anticoagulant effect compared with its administration as an aqueous solution, with no significant changes in the bleeding tendency or arterial blood pressure. Experiments using animal models of arterial thrombosis initiated by endothelial injury demonstrated that FucCS delivered as gastro-protective tablets produced a potent antithrombotic effect, whereas its aqueous solution was ineffective. However, there was no significant difference between the effects of FucCS delivered as gastro-resistant tablets or as aqueous solution in a venous thrombosis model, likely due to the high dose of thromboplastin used. New oral anticoagulants tested in these experimental models for comparison showed significantly increased bleeding tendencies. Our study provides a framework for developing effective oral anticoagulants based on sulfated polysaccharides from marine organisms. The present results suggest that FucCS is a promising oral anticoagulant.

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Carotid Artery Diseases; Chondroitin Sulfates; Disease Models, Animal; Drug Compounding; Female; Hemorrhage; Male; Rats, Wistar; Tablets, Enteric-Coated; Thrombosis; Time Factors; Venous Thrombosis

Fucosylated chondroitin sulfate (FCS), a glycosaminoglycan extracted from the body wall of sea cucumber, is a promising antithrombotic agent. The chemical structures of FCSc isolated from sea cucumber Cucumaria frondosa and its depolymerized fragment (dFCSc) were characterized for the first time. Additionally, anticoagulant and antithrombotic activities were evaluated in vitro and in vivo. The results demonstrated that dFCSc exhibited better antithrombotic-hemorrhagic ratio than native FCSc on the electrical induced arterial thrombosis model in rats. Compared to FCSt obtained from Thelenota ananas, FCSc possessed different sulfation patterns but similar antithrombotic effects. Therefore, sulfation pattern of FCS might not affect anticoagulation and antithrombosis as much as molecular weight may. Our results proposed a new point of view to understand the structure-activity relationship of FCS as alternative agents.

Topics: Animals; Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Fibrinolytic Agents; Male; Mice; Peptide Fragments; Polymerization; Rats; Rats, Wistar; Sea Cucumbers; Thrombosis

Antibodies specific for platelet factor 4 (PF4)/heparin complexes are the hallmark of heparin-induced thrombocytopenia and thrombosis (HIT), but many antibody-positive patients have normal platelet counts. The basis for this is not fully understood, but it is believed that antibodies testing positive in the serotonin release assay (SRA) are the most likely to cause disease. We addressed this issue by characterizing PF4-dependent binding of HIT antibodies to intact platelets and found that most antibodies testing positive in the SRA, but none of those testing negative, bind to and activate platelets when PF4 is present without any requirement for heparin (P < .0001). Binding of SRA-positive antibodies to platelets was inhibited by chondroitinase ABC digestion (P < .05) and by the addition of chondroitin-4-sulfate (CS) or heparin in excess quantities. The findings suggest that although all HIT antibodies recognize PF4 in a complex with heparin, only a subset of these antibodies recognize more subtle epitopes induced in PF4 when it binds to CS, the major platelet glycosaminoglycan. Antibodies having this property could explain "delayed HIT" seen in some individuals after discontinuation of heparin and the high risk for thrombosis that persists for weeks in patients recovered from HIT.

Topics: Antibodies; Blood Platelets; Chondroitin Sulfates; Enzyme-Linked Immunosorbent Assay; Epitopes; Glycosaminoglycans; Heparin; Humans; Immunoglobulin G; P-Selectin; Platelet Activation; Platelet Factor 4; Polysaccharide-Lyases; Protein Binding; Serotonin; Thrombocytopenia; Thrombosis

Fucosylated chondroitin sulfate (FCS), a structurally unusual glycosaminoglycan, has distinct anticoagulant properties, and is an especially strong inhibitor of the intrinsic factor Xase (anti-Xase). To obtain a highly selective inhibitor of human Xase, we purified six native FCSs with various sulfation patterns, prepared a series of FCS derivatives, and then elucidated the relationship between the structures and the anticoagulant activities of FCSs. FCSs 1-3 containing higher Fuc2S4S exhibit stronger AT-dependent anti-IIa activities, whereas 4-6 containing more Fuc3S4S produce potent HCII-dependent anti-IIa activities. Saccharides containing a minimum of 6-8 trisaccharide units, free carboxyl groups, and full fucosylation of GlcA may be required for potent anti-Xase activity, and approximately six trisaccharide units and partial fucosylation of GlcA may contribute to potent HCII-dependent activity. Decreasing of the molecular weights markedly reduces their AT-dependent anti-IIa activities, and even eliminates human platelet and factor XII activation. Furthermore, in vitro and in vivo studies suggested that fractions of 6-12 kDa may be very promising compounds as putative selective intrinsic Xase inhibitors with antithrombotic action, but without the consequences of major bleeding and factor XII activation.

Topics: Animals; Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Cysteine Endopeptidases; Dose-Response Relationship, Drug; Enzyme Inhibitors; Factor XII; Fibrinolytic Agents; Humans; Mice; Mice, Inbred Strains; Molecular Conformation; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thrombosis

Chondroitin sulfate (CS) is a glycosaminoglycan (GAG) composed of alternating N-acetyl galactosamine and glucuronic acid units within disaccharide building blocks. CS is a key functional component in proteoglycans of cartilaginous tissues. Owing to its numerous biological roles, CS is widely explored in the pharmaceutical market as nutraceutical ingredient commonly utilized against arthritis, osteoarthrosis, and sometimes osteoporosis. Tissues like shark cartilage and bovine trachea are common sources of CS. Nonetheless, a new CS type has been introduced and investigated in the last few decades in what regards its medical potentials. It is named fucosylated chondroitin sulfate (FucCS). This less common CS type is isolated exclusively from the body wall of sea cucumbers. The presence of fucosyl branching units in the holothurian FucCS gives to this unique GAG, therapeutic properties in various pathophysiological systems which are inexistent in the common CS explored in the market. Examples of these systems are coagulation, thrombosis, hemodialysis, atherosclerosis, cellular growth, angiogenesis, fibrosis, tumor growth, inflammation, viral and protozoan infections, hyperglycemia, diabetes-related pathological events and tissue damage. This report aims at describing the medical benefits gained upon fucosylation of CS. Clinical prospects of these medical benefits are also discussed herein.

Topics: Animals; Anticoagulants; Atherosclerosis; Blood Coagulation; Cell Proliferation; Chondroitin Sulfates; Glycosylation; Humans; Hyperglycemia; Neovascularization, Physiologic; Protozoan Infections; Sea Cucumbers; Thrombosis; Virus Diseases

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

Marine organisms are a rich source of sulfated polysaccharides with unique structures. Fucosylated chondroitin sulfate (FucCS) from the sea cucumber Ludwigothurea grisea and sulfated galactan from the red alga Botryocladia occidentalis are one of these unusual molecules. Besides their uncommon structures, they also exhibit high anticoagulant and antithrombotic effects. Earlier, it was considered that the anticoagulant activities of these two marine glycans were driven mainly by a catalytic serpin-dependent mechanism likewise the mammalian heparins. Its serpin-dependent anticoagulant action relies on promoting thrombin and/or factor Xa inhibition by their specific natural inhibitors (the serpins antithrombin and heparin cofactor II). However, as opposed to heparins, these two previously mentioned marine glycans were proved still capable in promoting coagulation inhibition using serpin-free plasmas. This puzzle observation was further investigated and clearly demonstrated that the cucumber FucCS and the red algal sulfated galactan have an unusual serpin-independent anticoagulant effect by inhibiting the formation of factor Xa and/or thrombin through the procoagulants tenase and prothrombinase complexes, respectively. These marine polysaccharides with unusual anticoagulant effects open clearly new perspectives for the development of new antithrombotic drugs as well as push the glycomics project.

Topics: Animals; Anticoagulants; Carbohydrate Sequence; Chondroitin Sulfates; Cysteine Endopeptidases; Factor Xa; Factor Xa Inhibitors; Fibrinolytic Agents; Galactans; Humans; Molecular Sequence Data; Neoplasm Proteins; Polysaccharides; Protein Binding; Rhodophyta; Sea Cucumbers; Thrombin; Thromboplastin; Thrombosis

Neonatal limb ischaemia (NLI) is a rare but potentially catastrophic condition. Although medical therapy remains as first-line treatment, surgery has an important role when limb-threatening events are present. In this paper we outline the milking technique for open thrombectomy used by the senior author in the treatment of 5 NLI cases. We also present the use of Integra and it's specific benefits in the management of wounds in these challenging situations. Skin grafts over the Integra can be avoided by staged excision of the silicone layer from the margins. We believe this is a novel approach to the use of Integra.

Topics: Biocompatible Materials; Chondroitin Sulfates; Collagen; Humans; Infant, Newborn; Ischemia; Thrombectomy; Thrombosis; Upper Extremity; Wound Closure Techniques

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

Sulfated polysaccharides from marine invertebrates have well-defined structures and constitute a reliable class of molecules for structure-activity relationship studies. We tested the effects of two of these polysaccharides, namely a sulfated fucan and a fucosylated chondroitin sulfate, on coagulation, thrombosis and bleeding. The compounds share similar 2,4-disulfated fucose units, which are required for high anticoagulant activity in this class of polymer. These residues occur either as branches in fucosylated chondroitin sulfate or as components of the linear chain in the sulfated fucan. These polysaccharides possess anticoagulant activity but differ significantly in their mechanisms of action. The fucosylated chondroitin sulfate inhibits thrombin by heparin cofactor II, whereas sulfated fucan inhibits thrombin by both antithrombin and heparin cofactor II. In addition, these polysaccharides also have serpin-independent anticoagulant activities. Fucosylated chondroitin sulfate, but not sulfated fucan, activates factor XII. As a result of the complex anticoagulant mechanism, the invertebrate polysaccharides differ in their effects on experimental thrombosis. For instance, the sulfated fucan inhibits venous thrombosis at lower doses than fucosylated chondroitin sulfate. In contrast, fucosylated chondroitin sulfate is significantly more potent than sulfated fucan in arterial thrombosis. Finally, fucosylated chondroitin sulfate increases bleeding, while sulfated fucan has only a discrete effect. In conclusion, the location of 2,4-disulfated fucose units in the polysaccharide chains dictates the effects on coagulation, thrombosis and bleeding.

Topics: Animals; Anticoagulants; Blood Coagulation; Carbohydrate Conformation; Carbohydrate Sequence; Carotid Artery Thrombosis; Chondroitin Sulfates; Drug Evaluation, Preclinical; Enzyme Activation; Factor XII; Female; Fibrinolytic Agents; Fucose; Hemorrhage; Male; Molecular Sequence Data; Molecular Structure; Polysaccharides; Rats; Rats, Wistar; Sea Cucumbers; Structure-Activity Relationship; Thrombosis; Venous Thrombosis

Fucosylated chondroitin sulfate is a glycosaminoglycan from sea cucumber composed of a chondroitin sulfate-like core with branches of sulfated fucose. This glycosaminoglycan has high anticoagulant and antithrombotic activities. Its serpin-dependent anticoagulant activity is mostly due to activating thrombin inhibition by heparin cofactor II. Here, we evaluated the anticoagulant activity of fucosylated chondroitin sulfate using antithrombin- and heparin cofactor II-free plasmas. In contrast to mammalian heparin, the invertebrate glycosaminoglycan is still able to prolong coagulation time and delay thrombin and factor Xa generation in serpin-free plasmas. These observations suggest that fucosylated chondroitin sulfate has a serpin-independent anticoagulant effect. We further investigated this effect using purified blood coagulation proteins. Clearly, fucosylated chondroitin sulfate inhibits the intrinsic tenase and prothrombinase complexes, which are critical for thrombin generation. It is possible that the invertebrate chondroitin sulfate inhibits interactions between cofactor Va and factor Xa. We also employed chemically modified polysaccharides in order to trace a structure versus activity relationship. Removal of the sulfated fucose branches, but not reduction of the glucuronic acid residues to glucose, abolished its activity. In conclusion, fucosylated chondroitin sulfate has broader effects on the coagulation system than mammalian glycosaminoglycans. In addition to its serpin-dependent inhibition of coagulation protease, it also inhibits the generation of factor Xa and thrombin by the tenase and prothrombinase complexes, respectively. In plasma systems, the serpin-independent anticoagulant effect of fucosylated chondroitin sulfate predominates over its serpin-dependent action. This glycosaminoglycan opens new avenues for the development of antithrombotic agents.

Topics: Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Cysteine Endopeptidases; Factor Xa; Fucose; Glucuronic Acid; Glycosaminoglycans; Humans; Models, Chemical; Neoplasm Proteins; Partial Thromboplastin Time; Serpins; Thrombin; Thromboplastin; Thrombosis

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

Fucosylated chondroitin sulfate is a potent anticoagulant polysaccharide extracted from sea cucumber. Its anticoagulant activity is attributed to the presence of sulfated fucose branches. We have shown that intravascular injection of fucosylated chondroitin sulfate inhibits thrombus formation in a venous and an arterial shunt model in rats. Since this compound resists digestion by enzymes that cleave mammalian glycosaminoglycans, we investigated the possibility that fucosylated chondroitin sulfate might be absorbed after oral administration. In fact, after oral administration of fucosylated chondroitin sulfate to rats, we observed a dose-dependent increase in the plasma anticoagulant activity, as assessed by assays for activated partial thromboplastin time (aPTT) and thrombin time (TT) (about 3- and 5-fold, respectively) and by anti-IIa activity. Furthermore, animals receiving daily oral doses of this glycosaminoglycan showed a decrease in thrombus weight on experimental models of venous and arterial shunt thrombosis. This antithrombotic action clearly has a strong relationship with anticoagulant activity. Similar doses of heparin administered orally had no effect on the plasma anticoagulant activity or on the thrombus weight. Finally, we observed that fucosylated chondroitin sulfate given orally to rats did not modify the bleeding time. Overall, our results indicate that fucosylated chondroitin sulfate is absorbed after oral administration and could become a promising oral anticoagulant.

Topics: Administration, Oral; Animals; Anticoagulants; Bleeding Time; Blood Coagulation; Chondroitin Sulfates; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinolytic Agents; Heparin; Partial Thromboplastin Time; Prothrombin; Rats; Rats, Wistar; Sea Cucumbers; Thrombin Time; Thrombosis; Time Factors

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

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

Vascular wall protection can be achieved by preventive attachment to the vascular wall of antioxidants and elimination/neutralization of toxic products after their disproportioning. For this purpose we have prepared covalent conjugates between the vascular wall glycosaminglycan chondroitin sulfate (CHS) and the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). The following conjugates were obtained: SOD-CHS, CAT-CHS and SOD-CHS-CAT. Their anti-thrombotic activity was compared in a rat model of arterial thrombosis by measuring the time of occlusion emergence and thrombus mass. It is noteworthy that the effectiveness of single bolus injections of SOD-CHS/CAT-CHS mixture was much lower than that of the bienzymic SOD-CHS-CAT conjugate. The conjugate SOD-CHS-CAT proved to be anti-thrombotically effective in doses two orders of magnitude lower than the native biocatalysts and an order of magnitude lower than SOD-CHS and CAT-CHS derivatives. For effective anti-thrombotic protection in oxidative conditions it is important to maintain the stable connection of SOD and CAT activity on the vascular wall and the large size of these conjugates. Covalent conjugate SOD-CHS-CAT is the best prospect for pharmaceutical development.

Topics: Animals; Antioxidants; Catalase; Chlorides; Chondroitin Sulfates; Disease Models, Animal; Ferric Compounds; Injections, Intravenous; Male; Rats; Structure-Activity Relationship; Superoxide Dismutase; Thrombosis

Heparinization of artificial surfaces has been proven to reduce the intrinsic thrombogenicity of such surfaces. The mechanism by which immobilized heparin reduces thrombogenicity is not completely understood. In the present study heparin-, alginic acid- and chondroitin-6-sulphate-coated surfaces were examined for protein adsorption, platelet adhesion and thrombin generation. The protein-binding capacity from solutions of purified proteins was significantly higher for heparin-coated surfaces when compared with alginic acid- and chondroitin sulphate-coated surfaces. Yet, when the surfaces were exposed to flowing plasma, only the heparinized surface adsorbed significant amounts of antithrombin. None of the surfaces adsorbed fibrinogen under these conditions, and as a result no platelets adhered from flowing whole blood. Our results indicate that protein adsorption and platelet adhesion from anticoagulated blood cannot be used to assess the thrombogenicity of (coated) artificial surfaces. Indeed, the thrombin generation potentials of the different surfaces varied remarkable: while non-coated surface readily produced thrombin, alginic acid- and chondroitin sulphate-coated surfaces showed a marked reduction and virtually no thrombin was generated in flowing whole blood passing by heparinized surfaces.

Topics: Adsorption; Alginates; Animals; Anticoagulants; Blood Proteins; Chondroitin Sulfates; Coated Materials, Biocompatible; Fibrinolytic Agents; Glucuronic Acid; Heparin; Hexuronic Acids; Humans; Materials Testing; Platelet Adhesiveness; Polysaccharides; Surface Properties; Thrombin; Thrombosis

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

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

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

The antithrombotic activity of a fucosylated chondroitin sulfate extracted from the body wall of a sea cucumber was assessed using a stasis thrombosis model in rats. Intravenous administration of the polysaccharide reduced thrombosis in a dose-dependent manner. We also compared the antithrombotic action of the sea cucumber chondroitin sulfate with that of standard mammalian glycosaminoglycans, mainly heparin and dermatan sulfate. Intravascular injection of fucosylated chondroitin sulfate at the dose totally preventing thrombus formation produced a much more intense modification of the plasma anticoagulant activity than antithrombotic doses of unfractionated heparin, low-molecular-weight heparin and mammalian dermatan sulfate. Thus, it is possible that the mechanism of antithrombotic action of these polysaccharides are different. For fucosylated chondroitin sulfate, it depends mostly on modifications of the plasma anticoagulant activity, but it may involve additional effects in the case of mammalian glycosaminoglycans, perhaps modifications induced in the cells of the vessel wall. The anticoagulant and possibly the antithrombotic actions of fucosylated chondroitin sulfate are mostly dependent on heparin cofactor II activity, and both are markedly reduced with the decrease of the chain size of the polymer. Overall, the sulfated polysaccharide from the invertebrate revealed an unequivocal effect in preventing experimental venous thrombosis, is a useful tool to investigate the antithrombotic action in mammals and may offer an alternative for future development of a new therapeutic agent.

Topics: Animals; Anticoagulants; Carbohydrate Sequence; Chondroitin Sulfates; Dermatan Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Echinodermata; Female; Fibrinolytic Agents; Fucose; Glycosaminoglycans; Heparin; Male; Molecular Sequence Data; Molecular Weight; Partial Thromboplastin Time; Rats; Sulfur Radioisotopes; 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

Individual antithrombotic activities of superoxide dismutase (SOD) and sodium chondroitin sulfate (CHS) as well as the activities of covalent and noncovalent complexes of SOD with CHS were compared in a rat model of arterial thrombosis induced by ferrous chloride. Covalent conjugate of SOD with CHS exerted the most potent antithrombotic effect, which was associated with adsorption of the conjugate on the glycocalyx of the vascular wall cells and stability of the covalent bond between CHS and SOD subunits. Theoretical and practical directions in the investigation of SOD and CHS preparations are outlined.

Topics: Animals; Carotid Arteries; Chondroitin Sulfates; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Stability; Ferrous Compounds; Fibrinolytic Agents; Glycocalyx; In Vitro Techniques; Male; Rats; Superoxide Dismutase; Thrombosis

The antithrombotic activity of a fucosylated, chondroitin-sulphate-like polysaccharide extracted from the body wall of sea cucumber, and of chemically modified derivatives of the same polysaccharide, have been assessed using a stasis thrombosis model in rabbits. Intravenous administration of the native polysaccharide reduced thrombosis in a dose-dependent manner and, at a dose of 1.5 mg/kg (60 IU/kg) body weight, completely prevented thrombosis after 10 min stasis. Removal of the sulphated fucose branches of the polysaccharide abolished antithrombotic effectiveness. After intravenous injection of an antithrombotic dose of radioactively labelled polysaccharide, a correlation was observed between removal of radioactivity from the plasma and decrease in ex vivo APTT values, demonstrating that antithrombotic effectiveness depends on the level of circulating polysaccharide rather than on an indirect effect of the polysaccharide on the vascular endothelium. Reduction of the glucuronic acid carboxyl groups in the polysaccharide did not affect its in vitro and in vivo activities. Both partial defucosylation and desulphation of the polysaccharide abolished all its anticoagulant or antithrombotic action.

Topics: Animals; Anticoagulants; Bleeding Time; Blood Coagulation; Chondroitin Sulfates; Dose-Response Relationship, Drug; Fibrinolytic Agents; Fucose; Injections, Intravenous; Polysaccharides; Rabbits; Sea Cucumbers; Thrombosis

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

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

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

Pharmacologic control of intimal hyperplasia has been attempted through oral and intravenous administration of smooth muscle cell inhibitors. We report a more direct method of altering arterial healing using a novel bioresorbable membrane that can be applied to the lumen of an artery or anastomosis following endarterectomy or vascular reconstruction. Following a standard balloon injury, the infrarenal aortas of 3 kg female New Zealand white rabbits were opened and a thin membrane composed of collagen/chondroitin 6-sulfate copolymer was sutured to the posterior wall of each artery. Animals were killed at intervals of up to 3 months. All arteries remained patent. By 24 hours the membrane had become infiltrated with fibrin and red blood cells. An inflammatory response ensued and by 8 days the membrane was filled with mononuclear cells. At 3 months only a small remnant of the membrane remained. Intimal hyperplasia developed throughout the injured aorta. However, the hyperplastic response beneath the membrane was no greater than that observed in the adjacent injured aorta. A bioresorbable membrane can be sutured into the lumen of a small-diameter vessel without inducing thrombosis and without locally increasing intimal hyperplasia. A prosthesis of this type might be used to deliver inhibitors of smooth muscle cell proliferation and migration to the injured arterial wall.

Topics: Absorption; Animals; Bioprosthesis; Chondroitin Sulfates; Collagen; Female; Hyperplasia; Membranes, Artificial; Prostheses and Implants; Rabbits; Thrombosis; Tunica Intima; Vascular Surgical Procedures; Wound Healing

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

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

Elevated levels of plasma homocysteine are associated with both venous and arterial thrombosis. Homocysteine inhibits the function of thrombomodulin, an anticoagulant glycoprotein on the endothelial surface that serves as a cofactor for the activation of protein C by thrombin. The effects of homocysteine on thrombomodulin expression and protein C activation were investigated in cultured human umbilical vein endothelial cells and CV-1(18A) cells that express recombinant human thrombomodulin. Addition of 5 mM homocysteine to endothelial cells produced slight increases in thrombomodulin mRNA and thrombomodulin synthesis without affecting cell viability. In both cell types, thrombomodulin synthesized in the presence of homocysteine remained sensitive to digestion with endoglycosidase H and failed to appear on the cell surface, suggesting impaired transit along the secretory pathway. In a cell-free protein C activation assay, homocysteine irreversibly inactivated both thrombomodulin and protein C in a process that required free thiol groups and was inhibited by the oxidizing agents diamide or N-ethylmaleimide. By inhibiting both thrombomodulin surface expression and protein C activation, homocysteine may contribute to the development of thrombosis in patients with cystathionine beta-synthase deficiency.

Topics: Cells, Cultured; Chondroitin Sulfates; Ethylmaleimide; Glycosylation; Homocysteine; Humans; Oxidation-Reduction; Platelet Membrane Glycoproteins; Protein C; Receptors, Cell Surface; Receptors, Thrombin; 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

Topics: Animals; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Fat Emulsions, Intravenous; Fibrinolytic Agents; Humans; Lipase; Male; Phosphatidylcholines; Rats; Rats, Inbred Strains; Sheep; Structure-Activity Relationship; 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

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

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: Anticoagulants; Chondroitin Sulfates; Factor X; Factor Xa; Heparin; Humans; Molecular Weight; Pentosan Sulfuric Polyester; Thrombosis

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

Topics: Aorta; Arteriosclerosis; Chondroitin Sulfates; Factor VIII; Fibrin; Glycosaminoglycans; Heparin; Humans; Polymers; Solubility; Thrombelastography; Thrombosis; Tissue Extracts; Trypsin

Topics: Animals; Blood Sedimentation; Blood Vessel Prosthesis; Blood Vessels; Cattle; Chondroitin Sulfates; Dextrans; Dogs; Electrochemistry; Electrophoresis; Erythrocytes; Heart Valve Prosthesis; Heparin; Humans; Hydrogen-Ion Concentration; Models, Biological; Thrombosis

Topics: Anticoagulants; Chondroitin Sulfates; Drug Combinations; Embolism; Heparin; Thrombosis