heparitin-sulfate and Hemorrhage

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

Type II heparin-induced thrombocytopenia is currently managed by withdrawing heparin and replacing it with danaparoid sodium. Argatroban, a direct thrombin inhibitor anticoagulant (like lepirudin), is now authorised for this indication in France, following authorisation in several other countries since the early 2000s. Argatroban has not been compared with danaparoid in clinical trials. About 700 patients treated with argatroban in 2 trials were compared to historical controls managed by simple withdrawal of heparin and, in some cases, switching to an oral anticoagulant. Argatroban had no apparent advantages in terms of death or the need for amputation. Argatroban did not appear to increase the risk of bleeding in these trials, but evidence provided by historical comparisons is weak. The adverse effect profile includes hepatic disorders (notably fulminant hepatitis). The risk of pharmacokinetic interactions appears to below. In practice, given the absence of a proven therapeutic advantage, it is better to continue to use danaparoid for first-line treatment, reserving argatroban for the rare situations in which danaparoid is inappropriate.

Topics: Anticoagulants; Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Interactions; Drug Substitution; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Patient Selection; Pipecolic Acids; Risk Assessment; Risk Factors; Sulfonamides; Thrombocytopenia; Treatment Outcome; Venous Thrombosis

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

Numerous acquired hemostatic abnormalities have been identified in renal insufficiency. Hemodialysis procedures add to these disturbances as they repetitively imply turbulent blood flow, high shear stress, and contact of blood to artificial surfaces. This nonphysiological environment leads to activation of platelets, leukocytes, and the coagulation cascade, resulting in fouling of the membrane and ultimately in clotting of fibers and the whole hemodialyzer. Anticoagulation in hemodialysis is targeted to prevent this activation of coagulation during the procedure. Most agents inhibit the plasmatic coagulation cascade. Still commonly used is unfractionated heparin, followed by low-molecular-weight heparin preparations with distinct advantages. Immune-mediated heparin-induced thrombocytopenia constitutes a potentially life-threatening complication of heparin therapy requiring immediate switch to nonheparin alternative anticoagulants. Danaparoid, lepirudin, and argatroban are currently being used for alternative anticoagulation, all of which possess both advantages and limitations. In the past, empirical strategies reducing or avoiding heparin were applied for patients at bleeding risk, whereas nowadays regional citrate anticoagulation is increasingly used to prevent bleeding by allowing procedures without any systemic anticoagulation. Avoidance of clotting within the whole hemodialyzer circuit is not granted. Specific knowledge of the mechanisms of coagulation, the targets of the anticoagulants in use, and their respective characteristics constitutes the basis for individualized anticoagulation aimed at achieving full patency of the circuit throughout the procedure. Patency of the circuit is an important prerequisite for optimal hemodialysis quality.

Topics: Anticoagulants; Arginine; Blood Coagulation; Chondroitin Sulfates; Dermatan Sulfate; Equipment Failure; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Sulfonamides

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. Despite thrombocytopenia, bleeding is rare; rather, HIT is strongly associated with thromboembolic complications involving both the arterial and venous systems. A number of laboratory tests are available to confirm the diagnosis; however, when HIT is clinically suspected, treatment should not be withheld pending the result. Fortunately, therapeutic strategies have been refined, and new and effective therapeutic agents are available. Treatment options are focused on inhibiting thrombin formation or direct thrombin inhibition. Warfarin should not be used until the platelet count has recovered.

Topics: Anticoagulants; Arginine; Cardiovascular Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Renal Dialysis; Sulfonamides; Thrombocytopenia; Warfarin

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

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

New platelet antagonists act on the activation by ADP (clopidogrel, ATP analogue) or on the mechanism of aggregation itself, by binding to the IIb/IIIa glycoprotein complex. The new anticoagulants are as follows: saccharide structures such as danaparoïd and the pentasaccharide of antithrombin binding, and direct thrombin inhibitors, such as recombinating hirudines (desirudine, lepirudine), bivalirudine, melagatran.... Other molecular targets are possible, both at platelet and blood clotting levels but, for the moment, the dilemma remains and reinforcement of antithrombotic activity goes hand in hand with a greater decrease in the defensive mechanisms against bleeding. In general, there is no antidote and the products are often associated, which increases the risk of haemorrhage. The research and development in this field are handicapped by the lack of biological tools for pertinent, homogenous, reproducible evaluation of the effects on haemostasis. The present tendency is to do without biological monitoring for adapting dosage in favour of optimisation of the impact in a given situation, perhaps, above all, with respect to the preceding problem.

Topics: Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Hemorrhage; Heparitin Sulfate; Hirudin Therapy; Humans; Platelet Aggregation; Risk Factors; Thromboembolism

Heparin-induced thrombocytopenia (HIT) may be complicated by severe thrombotic complications and death. Currently no specific laboratory test is available to make the diagnosis. When HIT is clinically suspected, heparin should be discontinued immediately. While no specific therapy for HIT exists, there is increasing evidence that acute antithrombin therapy may significantly reduce morbidity and mortality. Among several agents, the direct antithrombins, such as r-hirudin and argatroban, look the most promising for acute treatment.

Topics: Ancrod; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Forecasting; Gangrene; Hemorrhage; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Platelet Aggregation; Protein C; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Warfarin

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

This report presents data from pilot studies of Org 10172 in the management of patients with acute ischemic stroke. The studies have established a potentially optimal dosage and treatment regimen and have provided information for the development of a large randomized trial. The trial of Org 10172 in acute stroke treatment is now underway in the United States.

Topics: Brain Ischemia; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation; Factor Xa Inhibitors; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Incidence; Pilot Projects; Prothrombin; Thrombolytic Therapy; Treatment Outcome; United States

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

Heparin-induced thrombocytopenia (HIT) is a hypercoagulable syndrome strongly associated with thrombosis that is usually treated with drugs that inhibit factor Xa (danaparoid) or thrombin (lepirudin). In the present study the outcome of HIT-patients treated with danaparoid or lepirudin was compared using the single or combined endpoints of new thromboembolic complications (new TECs), amputations and/or death, and major bleeding. HIT-patients treated with lepirudin were enrolled in two prospective trials and patients, who were identified in the same two laboratories during the same time period, who were not enrolled into these studies but treated with danaparoid, were assessed retrospectively according to a standardized questionnaire. 126 danaparoid (60.3% female) and 175 lepirudin treated patients (58.3% female) fulfilled the same inclusion and exclusion criteria. In a time-to-event-analysis the cumulative risk of combined endpoint was higher in HIT-patients without thromboembolic complication at baseline treated with danaparoid (usually in prophylactic dose 750 anti-factor Xa units b.i.d. or t.i.d.s.c.) as compared to lepirudin (aPTT adjusted) (P = 0.020). Whereas HIT-patients with TEC at baseline who were usually treated with therapeutic dose had a similar outcome in both treatment groups (P = 0.913). Major bleeding occurred in 2.5% (95% CI 0.5-7.0%) of danaparoid treated patients as compared to 10.4% (95% CI 6.3-15.9%) of lepirudin treated patients until day 42 (P = 0.009). This indicates that the efficacies of therapeutic doses of danaparoid or lepirudin in preventing death, amputation or new TEC in HIT-patients do not differ largely, but the risk of bleeding seems to be higher in lepirudin treated patients. The prophylactic dose of danaparoid approved in the European Union for HIT without TEC at baseline seems suboptimal. A prospective comparative trial is required to verify these preliminary conclusions.

Topics: Age Factors; Aged; Amputation, Surgical; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Drug Evaluation; Female; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Humans; Incidence; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Surveys and Questionnaires; Thrombocytopenia; Thromboembolism; Treatment Outcome

Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism.. Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial.. One university and 2 regional teaching hospitals.. 188 patients treated with heparin or danaparoid for acute venous thromboembolism.. The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively.. Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders.. A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Topics: Acenocoumarol; Acute Disease; Adult; Aged; Body Surface Area; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Combinations; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Neoplasms; Odds Ratio; Prospective Studies; Risk Factors; Single-Blind Method; Thromboembolism; Thrombolytic Therapy

To compare the efficacy and safety of two subcutaneous doses of danaparoid with that of continuous intravenous administration of unfractionated heparin in the treatment of venous thromboembolism.. An open-label, randomized, multicenter clinical trial.. One university hospital and two university-affiliated hospitals.. 209 patients suspected to have venous thromboembolism. Of these, 188 had a confirmed diagnosis (by ventilation-perfusion lung scan and ultrasonography or contrast venography of the leg) and received study medication.. Patients were randomly assigned to either low-dose danaparoid (intravenous loading dose of 1250 U followed by 1250 U administered subcutaneously twice daily [n = 65]); high-dose danaparoid (intravenous loading dose of 2000 U followed by 2000 U administered subcutaneously twice daily [n = 63]); or unfractionated heparin (intravenous loading dose of 2500 U followed by dose-adjusted continuous infusion [n = 60]). Treatment lasted at least 5 days and was continued until anticoagulation (achieved with acenocoumarol) was adequate.. Efficacy determined clinically and by repeated imaging tests on treatment days 5 to 8; safety determined by daily assessment for bleeding.. Two lung scans were done in each of 179 patients; ultrasonography or venography of the leg was done twice in each of 173 patients; and both repeated leg and lung tests were done in 166 patients. A significant reduction in recurrence or extension of venous thromboembolism was seen in patients receiving high-dose danaparoid (8 of 63 [13%]) compared with patients receiving intravenous unfractionated heparin (17 of 60 [28%]; relative risk, 0.45 [95% CI, 0.21 to 0.96]). Four of 61 patients receiving high-dose danaparoid (7%) and 14 of 58 patients receiving unfractionated heparin (24%) had recurrence of pulmonary embolism (relative risk, 0.27 [CI, 0.09 to 0.78]); 3 of 58 patients receiving high-dose danaparoid (5%) and 6 of 54 patients receiving unfractionated heparin (11%) had recurrence of deep venous thrombosis (relative risk, 0.47 [CI, 0.12 to 1.77]). Occurrence of major and minor bleeding was similar in the three groups; major bleeding occurred in 1 patient receiving low-dose danaparoid, 1 patient receiving high-dose danaparoid, and 2 patients receiving heparin.. Our results suggest that high-dose danaparoid is safer and more effective than unfractionated heparin for the treatment of venous thromboembolism.

Topics: Adult; Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Drug Administration Schedule; Drug Combinations; Female; Hemorrhage; Heparin; Heparinoids; Heparitin Sulfate; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Pulmonary Embolism; Thromboembolism; Treatment Outcome

This double-blind, randomised, multicentre trial in 513 patients having elective surgery for intra-abdominal or intrathoracic malignancy compared the efficacy and safety of venous thrombosis (VT) prophylaxis using 750 anti-factor Xa units of Orgaran (a mixture of low molecular weight heparinoids) given subcutaneously (sc) twice-daily with that of twice-daily injections of 5,000 units standard heparin. The main study endpoints were the development of postoperative VT detected by 125I-fibrinogen leg scanning, and the onset of clinically significant venous thromboembolism or bleeding. "Intent to treat" analysis showed a statistically non-significant trend towards less VT during Orgaran prophylaxis (10.4%) than after heparin (14.9%) and there was no difference in bleeding complications between the two study groups. Results remained similar if only patients who completed the intended course of therapy ("compliant patients") were analysed. Other trials have shown that Orgaran prevents VT after hip surgery and stroke. We now show it is also safe and effective in patients having major surgery for cancer.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Double-Blind Method; Elective Surgical Procedures; Female; Gastrointestinal Neoplasms; Glycosaminoglycans; Hematologic Tests; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Lung Neoplasms; Male; Middle Aged; Postoperative Complications; Pulmonary Embolism; Thrombophlebitis

Two studies evaluating the effect of Orgaran prophylaxis on the incidence of postoperative thrombosis in hip fracture surgery are reported. In one Scandinavian study, dextran was used in the comparative group, and in the US study, warfarin was used. In both, Orgaran was significantly more effective in reducing the frequency of deep vein thrombosis without producing an increase in bleeding complications or other side effects.

Topics: Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Dextrans; Female; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Hip Fractures; Humans; Incidence; Male; Postoperative Complications; Pulmonary Embolism; Scandinavian and Nordic Countries; Single-Blind Method; Thrombophlebitis; United States; Warfarin

This report presents data from pilot studies of Org 10172 in the management of patients with acute ischemic stroke. The studies have established a potentially optimal dosage and treatment regimen and have provided information for the development of a large randomized trial. The trial of Org 10172 in acute stroke treatment is now underway in the United States.

Topics: Brain Ischemia; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation; Factor Xa Inhibitors; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Incidence; Pilot Projects; Prothrombin; Thrombolytic Therapy; Treatment Outcome; United States

To compare the relative safety and efficacy of a low-molecular-weight heparinoid (ORG 10172) with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke.. Double-blind randomized trial.. Seven Canadian university-affiliated hospitals.. Eighty-seven patients with acute ischemic stroke resulting in lower-limb paresis.. Patients received either low-molecular-weight heparinoid, 750 anti-factor Xa units twice daily, or unfractionated heparin, 5000 units subcutaneously twice daily. Treatment was continued for 14 days or until hospital discharge if sooner.. Deep vein thrombosis was diagnosed using 125I-labeled fibrinogen leg scanning and impedance plethysmography. Venography was indicated if either test was positive. Overt hemorrhage, major or minor, was assessed clinically.. Venous thrombosis occurred in four patients (9%) given low-molecular-weight heparinoid and in 13 patients (31%) given heparin (relative risk reduction, 71%; 95% CI, 16% to 93%. The corresponding rates for proximal vein thrombosis were 4% and 12%, respectively (relative risk reduction, 63%; P greater than 0.2). The incidence of hemorrhage was 2% in both groups.. Low-molecular-weight heparinoid, given in a fixed dose of 750 anti-factor Xa units subcutaneously twice daily, is more effective than subcutaneous low-dose heparin for the prevention of deep vein thrombosis in patients with acute ischemic stroke.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antithrombin III; Brain Ischemia; Chondroitin Sulfates; Dermatan Sulfate; Double-Blind Method; Female; Fibrinolytic Agents; Follow-Up Studies; Glycosaminoglycans; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Thrombophlebitis

A prospective, randomized, assessor-blind trial has been undertaken to compare the thromboprophylactic effect and safety of the heparinoid Org 10172 (a mixture of low molecular-weight sulfated glycosaminoglycuronides) and dextran 70 in patients operated on for hip fracture. Prestudy biostatistical calculations led to the need for 260 patients. Three hundred eight patients were randomized and 19 were excluded after randomization, the majority because of postponed surgery. Analyses were made on the 289 patients on an intention-to-treat basis, as well as on the 247 patients given correct prophylaxis. Diagnosis of deep vein thrombosis was based on bilateral ascending phlebography on postoperative days 10 through 12. The frequency of deep vein thrombosis on an intention-to-treat basis was 10% in the Org 10172 group and 30% in the dextran 70 group and, on the basis of correct prophylaxis, 12% and 31%, respectively, both differences being significant (p less than 0.001). Two-month mortality rates were equal in the groups. Three fatal pulmonary emboli were seen in the dextran group. Significantly more patients in the dextran group received postoperative transfusions; no other differences in various hemorrhagic parameters were seen. Thus it can be concluded that Org 10172 has a significantly better thromboprophylactic effect than does dextran in patients with hip fractures without significant side effects.

Topics: Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Dextrans; Female; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Hip Fractures; Humans; Male; Single-Blind Method; Thrombophlebitis

We have measured the effects of Org 10172 (a mixture of naturally occurring glycosaminoglycans derived from hog intestinal mucosa) on blood loss after transurethral prostatectomy (TURP), using doses which are likely to prevent postoperative venous thrombosis (VT). 48 patients entered a double-blind randomised pilot study: 18 were given subcutaneous (sc) injections of a placebo and 30 received sc Org 10172 (750 anti-Xa units/day, 500 units twice daily (bid), or 750 units bid, starting just before TURP and continued until discharge; 10 patients per group). No Org 10172 regimen increased peroperative blood loss but all caused a similar trend towards increased urinary bleeding after surgery. Since there was no apparent dose effect gradient, it was decided to pool the data from all three dosing blocks: this analysis showed that Org 10172 increased geometric mean blood loss during the first 2 days after surgery from 10.4 gm hemoglobin (Hgb; range = 3.2-71) to 20.5 gm Hgb (range = 1.9-147) (p = .005), an effect which retained its significance after allowing for two other major determinants of postoperative bleeding, the weight of prostate resected and the length of surgery, and also when pooling was restricted to the twice daily Org 10172 injection groups and their corresponding controls. Bleeding was not severe, but our results indicate a need for caution when considering the use of Org 10172 in this setting.

Topics: Aged; Chondroitin Sulfates; Dermatan Sulfate; Double-Blind Method; Glycosaminoglycans; Hematuria; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Prostatectomy; Randomized Controlled Trials as Topic; Thrombophlebitis; Urologic Diseases

The potential antithrombotic effect of a new low molecular weight heparinoid, Org 10172, was examined in a randomized, double-blind, placebo-controlled, dose-ranging pilot study of the prevention of deep venous thrombosis (DVT) in 45 high-risk patients having major thoracic or abdominal surgery for cancer. Org 10172 was given in doses of 500, 750 or 1000 U bd subcutaneously. DVT occurred in 9 of 14 patients given placebo and in 4 of 11 patients given 500 U bd but in none of the 20 patients given 750 or 1000 U bd. Operative blood loss and post-operative bleeding were not significantly different between the groups but one patient given 1000 U bd had major post-operative bleeding. Average mid-interval and trough plasma anti-Xa levels reached 0.26 and 0.20 U/ml respectively following the highest dose. It is concluded that Org 10172 is a potentially useful antithrombotic agent and that the effective and safe dose appears to be between 500 and 1000 U bd for prevention of DVT in high-risk patients.

Topics: Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Factor X; Factor Xa; Female; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Humans; Injections, Subcutaneous; Male; Middle Aged; Neoplasms; Pilot Projects; Research Design; Thoracic Surgery; Thrombophlebitis

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

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

Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan.. To compare the clinical results of the treatment of DIC with danaparoid or SPIs.. We retrospectively examined 188 patients with hematological malignancy-related DIC.. DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21-4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15-13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278).. Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Component Transfusion; Chondroitin Sulfates; Dermatan Sulfate; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hematologic Neoplasms; Hemorrhage; Heparitin Sulfate; Humans; Male; Middle Aged; Plasma; Protease Inhibitors; Prothrombin Time; Retrospective Studies; Treatment Outcome

Heparin-like substances (HLS) have been described in various clinical situations, including in settings of liver disease associated with infection, transplant, and metastasis. HLS are generally attributed to circulating glycosaminoglycans. Initial results for this patient showed coagulopathy due to liver disease without HLS. Two weeks after liver transplantation, a 10 year-old female with liver failure patient began to bleed from catheter insertion sites, mouth, and nares and HLS was suspected. The patient subsequently died and these clinical samples resulted in the isolation of a single heparan sulfate (HS) present at high concentrations in the plasma. Analysis of this HS showed it had an intermediate between heparin and HS with low antithrombin-mediated anticoagulant activity. We speculate that this 10-year old patient might have a platelet function defect influenced by this unusual HS. Endothelial defects not measurable by our methods might have also contributed to the observed bleeding complications.

Topics: Anticoagulants; Child; Female; Hemorrhage; Heparitin Sulfate; Humans; Liver Failure

Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label.. The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT.. In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings.. Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed "true" HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux.. Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238).

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Hospital Mortality; Hospitalization; Humans; Male; Necrosis; Off-Label Use; Partial Thromboplastin Time; Patient Safety; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Registries; Retrospective Studies; Sulfonamides; Thrombocytopenia; Thromboembolism; Treatment Outcome

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

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

The structural characterization and the anticoagulant potential of a novel heparin/heparan sulfate-like compound from the heads of Litopenaeus vannamei shrimp are described. While it is distinct from either heparin or heparan sulfate, enzymatic depolymerization and nuclear magnetic resonance spectroscopy analyses revealed that this molecule does share some structural features with heparin, such as the high degree of N- and 6-O-sulfation and minor N-acetylation, and with heparan sulfate, in the glucuronic acid content. Its ability to stabilize human antithrombin explains its significant anticoagulant activity in aPTT and Factor-Xa inhibition assays. Interestingly, in contrast to mammalian heparin, the shrimp compound displayed negligible hemorrhagic effect. Together, these findings have particular interest since they reveal a novel molecule with significant anti-Xa activity coupled with low bleeding effects which make the shrimp heparin/HS-like compound a potential alternative for mammalian heparin.

Topics: Acetylation; Animals; Anticoagulants; Antithrombins; Cattle; Chromatography, Ion Exchange; Factor Xa; Factor Xa Inhibitors; Glucuronic Acid; Head; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Intestines; Pancreas; Partial Thromboplastin Time; Penaeidae; Rats; Swine; Tail

The anti-inflammatory properties of a heparin-like compound from the shrimp Litopenaeus vannamei are related. Besides reducing significantly (p<0.001) the influx of inflammatory cells to injury site in a model of acute inflammation, shrimp heparin-like compound was able to reduce the matrix metalloproteinase (MMPs) activity in the peritoneal lavage of inflamed animals. Moreover, this compound also reduced almost 90% the activity of MMP-9 secreted by human activated leukocytes. Negligible anti-coagulant activities in aPPT assay and a poor bleeding potential make this compound a better alternative than mammalian heparin as a possible anti-inflammatory drug.

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Endothelium, Vascular; Glycosaminoglycans; Hemorrhage; Heparin; Heparitin Sulfate; Inflammation; Leukocytes; Matrix Metalloproteinase 9; Neutrophils; Penaeidae; Peritoneal Cavity; Rabbits; Rats; Swine

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

Heparin-induced thrombocytopenia (HIT) is the most common form of drug-induced immune-mediated thrombocytopenia. HIT may be aggravated by life-threatening arterial and venous thrombosis and, to a lesser extent, hemorrhagic complications. We investigated the incidence of thromboembolic and hemorrhagic complications in critically ill patients with the multiple organ dysfunction syndrome and HIT.. Case-control study.. A 33-bed general intensive care unit in a university-affiliated teaching hospital.. Twenty consecutive patients with laboratory-proven HIT compared with 20 contemporary, consecutive patients without HIT.. Unfractionated heparin or low-molecular-weight heparin were replaced by danaparoid sodium in patients with HIT.. Heparin-induced thrombocytopenia was proven by a positive platelet aggregation test. The HIT group consisted of 14 males and 6 females aged 65.2+/-10.8 years (mean +/- standard deviation) with APACHE II scores of 26.7+/-5.4. Thrombocytopenia less than 100 x 10(9)/l developed within 6.4+/-7.0 days. In 12 patients thrombocytopenia resolved after discontinuation of unfractionated heparin in 8.8+/-6.4 days. Arterial and venous thromboembolic complications occurred more frequently in HIT patients than in non-HIT patients (10/20 (50%) versus 0/20 (0%); chi-square p<0.001). Hemorrhagic complications also occurred more frequently in HIT patients than in non-HIT patients (17/20 (85%) versus 7/20 (35%); chi-square p=0.001).. In critically ill patients with HIT, the incidence of thromboembolic complications and hemorrhagic complications was remarkably high.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Chondroitin Sulfates; Critical Illness; Dermatan Sulfate; Drug Combinations; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Incidence; Intensive Care Units; Male; Middle Aged; Multiple Organ Failure; Risk Factors; Thrombocytopenia; Venous 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

Heparin-induced thrombocytopenia (HIT) has become more prevalent in today's cardiac setting and has resulted in the need for alternative anticoagulant therapies. Danaparoid sodium, one alternative to heparin, has been used in six cardiopulmonary bypass procedures in this hospital. This clinical experience has resulted in the progressive refinement of a protocol for the 'safe' clinical use of danaparoid sodium. Although there were six positive outcomes with the use of danaparoid sodium, alternatives must be explored in order to find the optimal anticoagulant for the treatment of HIT.

Topics: Adult; Aged; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Postoperative Complications; Thrombocytopenia

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

Topics: Acute Kidney Injury; Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Lung Diseases; Male; Phlebography; Renal Dialysis; Thrombocytopenia; Venous Thrombosis

Dermatan sulfate and heparan sulfate are currently under development as potential antithrombotic drugs. In our studies we have evaluated the relative antithrombotic and bleeding effects of these two agents in comparison to heparin, the commonly used anticoagulant. In a rabbit model of stasis thrombosis, a 500 micrograms/kg IV dose of dermatan or heparan produced 50-60% inhibition of induced in vivo thrombosis. At 750 micrograms/kg, both agents produced greater than 75% inhibition of thrombosis. Ex vivo measurement of plasma samples obtained from these animals demonstrated variable clotting effects at the lower dose and a proportional increase in the clotting activity at the higher dose. No anti-Xa or anti-IIa activity was observed in any sample. In contrast, animals treated with only 100 micrograms/kg heparin showed complete inhibition of induced thrombosis with significant anti-Xa and anti-IIa activities as well as prolongation of the clotting assays (APTT, TT and HeptestR). In the hemorrhagic studies utilizing a rabbit ear blood loss model, a 5.0 mg/kg IV dose of dermatan or heparan produced much less blood loss than heparin. On a gravimetric basis, dermatan and heparan were 10 fold less hemorrhagic than heparin. These results indicate that the relative contribution of plasmatic and cellular sites to the mediation of the antithrombotic action of heparin, dermatan and heparan differ. Although the antithrombotic dosages of dermatan and heparan are higher than heparin, due to the different mechanisms of action of each agent, a better safety index may be provided by dermatan and heparan than heparin.

Topics: Animals; Blood Coagulation Tests; Dermatan Sulfate; Dose-Response Relationship, Drug; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Rabbits

We evaluated the safety and possible efficacy of large doses of the heparinoid ORG 10172 in 57 patients with acute or progressing ischemic stroke. Patients received a loading bolus of the drug followed by a maintenance intravenous infusion for 7 days. The plasma level of ORG 10172 was monitored by the degree of inhibition of coagulation factor Xa. In general, the drug was well tolerated and few hemorrhagic complications occurred. Two patients with large cardioembolic hemispheric strokes had intracranial hemorrhagic complications. Most patients improved during treatment. By 3 months after the stroke, 37 patients (65%) had a favorable outcome (minimal or no residual disability). This study suggests that high-dose intravenous infusions of ORG 10172 can be safely given to patients with acute ischemic stroke.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain Ischemia; Cerebrovascular Disorders; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Humans; Injections, Intravenous; Middle Aged; Pilot Projects

An intravenous infusion of a low molecular weight heparinoid, with a reduced risk of hemorrhage, may be an alternative to heparin in the management of acute ischemic stroke. To evaluate this hypothesis, we studied the safety of the heparinoid, ORG 10172, in a dose-escalation study in 26 patients. The drug was administered as a loading bolus followed by a 7-day infusion in five rates with target anti-factor Xa levels from 0.2 to 1.0 U/ml. The drug was well tolerated; no major bleeding complications or thrombocytopenia occurred. There were no deaths or hemorrhagic transformation of cerebral infarctions. The results indicate that ORG 10172 at doses to achieve a level of 1.0 U/ml or less may be used safely in management of acute cerebral infarction.

Topics: Adult; Aged; Aged, 80 and over; Cerebrovascular Disorders; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Female; Glycosaminoglycans; Hemorrhage; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Molecular Weight

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

Topically applied heparin and heparan sulfate disaccharides, with the basic structure delta-4,5 uronyl-(1----4)-glucosamine and bearing a sulfate at the C-6 position of the glucosamine residue, are antihemostatics as potent as heparin, producing uncontrollable hemorrhage from small blood vessels. The finding that other sulfated disaccharides with the same sulfate:hexosamine:uronic acid ratios but with the sulfate at a different position (C-2), or with different glycosidic linkage (1----3), were inactive as inhibitors of hemostasis indicates that a specific structure is needed to produce the effect. The inhibitory activity of the normal hemostatic process could be reversed by ATP. Molecular models show that part of the disaccharide inhibitors and ATP hold a similar structural conformation.

Topics: Adenosine Triphosphate; Animals; Cattle; Chemical Phenomena; Chemistry; Disaccharides; Glycosaminoglycans; Hemorrhage; Hemostasis; Heparin; Heparitin Sulfate; Structure-Activity Relationship

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

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

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

Postoperative hemorrhage remains a serious complication in cardiopulmonary bypass (CPB) surgery. In our study, alternative anticoagulation with a new low molecular weight (LMW) heparinoid (Org 10172) was compared with a standardized heparin regimen. A preliminary dose-finding study indicated the minimal effective heparinoid dose to be 260 anti-Xa U/kg body weight, which was comparable to the standardized heparin regime, as revealed by similar plasma anti-Xa values. The following randomized open pilot study in 12 mongrel dogs undergoing CPB showed the heparinoid to be as effective as heparin, with an additional advantageous decrease in postoperative blood loss in the Org 10172 group. Our randomized blind study in 16 mongrel dogs undergoing CPB was performed to confirm previous results. Both antithrombotic agents were effective in the prevention of clot formation within the extracorporeal circuit. Hematocrit values and erythrocyte and platelet counts showed no significant intergroup differences. Post-CPB leukocyte counts revealed a significantly more rapid increase in the group given heparinoid (P less than 0.05). In the group given heparin, the expected prolongations of both the thrombin time (TT) and activated partial thromboplastin time (APTT) were noted, whereas in the group given heparinoid, only a transient peak prolongation of the TT after dose administration was revealed, and no significant prolongation of the APTT. Mean anti-Xa plasma levels were similar during CPB, showing a rapid decrease in the group given heparin on protamine administration, as did the APTT. Assessment of the operating field indicated an elevated intraoperative blood loss in the group given heparin. Postoperative blood loss measured over a period of 2.5 hours after closure of the thorax was significantly lower in the group given heparinoid than in the heparinized animals (625 +/- 100.0 ml, mean +/- SD, and 806 +/- 178.2 ml, respectively; P less than 0.05). Our observations suggest that the LMW heparinoid Org 10172 has an increased benefit/risk ratio over standard heparin and is effective in CPB in dogs. Additional investigations in humans should verify the possibility of use of this substance as an alternative means of anticoagulation during CPB in patients in whom heparin is relatively contraindicated.

Topics: Animals; Antithrombins; Blood Coagulation Tests; Blood Volume; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Dogs; Drug Evaluation, Preclinical; Fibrinolytic Agents; Glycosaminoglycans; Hematocrit; Hemorrhage; Heparin; Heparitin Sulfate; Leukocyte Count; Molecular Weight; Platelet Count; Postoperative Complications; Random Allocation

We have identified a circulating, heparin-like anticoagulant in a patient with multiple myeloma (IgG4 lambda) who had serious clinically evident bleeding that contributed to his death. Purification of the patient's circulating coagulation inhibitor was accomplished by ammonium sulfate concentration, anion exchange chromatography, and affinity chromatography on protamine sulfate. Analysis of the purified inhibitor showed that it was a proteoglycan that comigrated with heparan sulfate on lithium acetate-agarose-gel electrophoresis and that it contained 39 per cent L-iduronic acid. Control samples of heparan sulfate and heparin contained 29 and 68 per cent L-iduronic acid, respectively. Functional coagulation studies revealed that the purified inhibitor had cofactor activity with antithrombin III that could be abolished by prior incubation with protamine sulfate or platelet factor 4. Recognition of the existence of this or of other similar inhibitors in bleeding patients is important because of the potential for treatment with agents such as protamine sulfate and platelet factor 4, which neutralize the anticoagulant effects of proteoglycans.

Topics: Blood Coagulation; Blood Coagulation Tests; Chromatography, Affinity; Chromatography, Ion Exchange; Electrophoresis, Agar Gel; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Humans; Iduronic Acid; Male; Middle Aged; Multiple Myeloma

Org 10172, a new, natural heparinoid, was used as the sole anticoagulant in twelve patients with acute or acute-on-chronic renal failure, who underwent haemodialysis 55 times. All patients had either intercurrent bleeding or a high risk of severe haemorrhagic complications if given standard heparin therapy. After a single loading dose of 300-600 mg of Org 10172, plasma anti-Xa levels in the range 0.42 - 0.93 U/ml were achieved. All haemodialysis runs were completed without adverse side-effects. There were no haemorrhagic complications and deposition of 125I-fibrinogen on the renal dialysis membrane was successfully inhibited in the 4 patients in whom this was studied. Org 10172 seems to prevent thrombosis during renal haemodialysis. It may have a lower risk/benefit ratio than other anticoagulants, such as heparin, in patients at high risk of haemorrhagic complications undergoing haemodialysis.

Topics: Acute Kidney Injury; Adult; Aged; Blood Platelet Disorders; Chondroitin Sulfates; Dermatan Sulfate; Drug Evaluation; Female; Fibrinolytic Agents; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Risk