refludan and Hemorrhage

This review describes some natural proteins, which can be employed, either as factor concentrates derived from human plasma or as recombinant drug, to modulate the coagulation system. I will address some biochemical characteristics and the physiological role of von Willebrand factor, the coagulation factors of the extrinsic and intrinsic pathways, and the physiological anticoagulant protein C. In addition, I will detail the pharmacological compounds, which are available for influencing or substituting the coagulation proteins: desmopressin (DDAVP), single coagulation factor concentrates, prothrombin complex concentrates, and protein C concentrate. In particular, I will address some treatment topics of general medical interest, such as the treatment of massive bleeding, the correction of the coagulopathy induced by vitamin K-antagonists in patients with cerebral haemorrhage, and of the coagulopathy of meningococcemia. Finally, I will describe some properties and practical clinical applications of the recombinant anticoagulans lepirudin and bivalirudin, which are derived from hirudin, the natural anticoagulant of the medical leech.

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Proteins; Cerebral Hemorrhage; Hemorrhage; Hirudins; Humans; Peptide Fragments; Protein C; Recombinant Proteins; Vitamin K; von Willebrand Factor

The options for drug-controlled anticoagulation are becoming noticeably more manifold. In the area of anaesthesiology and intensive care, there are furthermore special disease patterns, such as heparin-induced thrombocytopenia (HIT) to be known, diagnosed and treated. This article gives a review of the substance groups of the direct thrombin inhibitors (DTI) as alternative anticoagulants for HIT in combination with cardiovascular diseases. For the administration of DTIs, experience and the correct dose are the keys to success and are the deciding factors for the two sides of haemostasis: thrombosis and haemorrhage.

Topics: Anesthesia; Anticoagulants; Cardiovascular Surgical Procedures; Critical Care; Hemorrhage; Hemostasis; Heparin; Heparin Antagonists; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombin; Thrombosis

Patients with or at risk of heparin-induced thrombocytopenia (HIT) who are undergoing percutaneous coronary intervention (PCI) are at particular risk of thrombosis due to the prothrombotic nature of HIT and the endovascular disruption from PCI. Patients require aggressive anticoagulation during PCI, and alternative, nonheparin anticoagulation is recommended over heparin in patients with acute or previous HIT. Argatroban, bivalirudin, and lepirudin are nonheparin, fast-acting, parenteral direct thrombin inhibitors (DTIs). Multicenter, prospective studies have demonstrated that argatroban and lepirudin each reduce thrombosis in HIT and that argatroban and bivalirudin each provide adequate anticoagulation during PCI in patients with or at risk of HIT. We review current therapeutic practices with direct thrombin inhibitors in patients with or at risk of HIT during PCI, including individuals requiring periprocedural anticoagulation, and the factors influencing the choice of DTI in this setting.

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Arginine; Drug Interactions; Economics, Pharmaceutical; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

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

The anticoagulant properties of heparin were discovered in 1916, and by the 1930s researchers were evaluating its therapeutic use in clinical trials. Treatment of unstable angina with unfractionated heparin (UFH), in addition to aspirin, was introduced into clinical practice in the early 1980s. UFH was combined with aspirin to suppress thrombin propagation and fibrin formation in patients presenting with acute coronary syndromes (ACS) or patients undergoing percutaneous coronary intervention (PCI). However, UFH stimulates platelets, leading to both activation and aggregation, which may further promote clot formation. Clinical trials have demonstrated that newer agents, such as the low-molecular-weight heparins (LMWHs), are superior to UFH for medical management of unstable angina or non-ST-segment elevation myocardial infarction. Increasingly, the LMWHs have been used as the anticoagulant of choice for patients presenting with ACS. For patients undergoing PCI, LMWH provides no sub-stantial benefit over UFH for anticoagulation; however, direct thrombin inhibitors (DTIs) have demonstrated safety and efficacy in this setting. UFH is likely to be replaced by more effective and safer antithrombin agents, such as DTIs. DTIs have antiplatelet effects, anticoagulant action, and most do not bind to plasma proteins, thereby providing a more consistent dose-response effect than UFH. The FDA has approved 4 parenteral DTIs for various indications: lepirudin, argatroban, bivalirudin, and desirudin. The antiplatelet, anticoagulant, and pharmacokinetic properties of bivalirudin support its use as the anticoagulant of choice for both lower- and higher-risk patients, including those undergoing PCI.

Topics: Acute Disease; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Models, Molecular; Molecular Structure; Myocardial Ischemia; Peptide Fragments; Pipecolic Acids; Platelet Activation; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombosis

To assess efficacy and safety of lepirudin in patients with heparin-induced thrombocytopenia (HIT) in a prospective study (HAT-3) as well as in a combined analysis of all HAT study data.. Patients with laboratory-confirmed HIT were treated with lepirudin in three different aPTT-adjusted dose regimen and during cardiopulmonary bypass (CPB). Endpoints were new thromboembolic complications (TEC), limb amputations, and death and major bleeding. A historical control group (n = 120) was used for comparison.. After start of lepirudin in 205 patients treated in HAT-3, the combined endpoint occurred in 43 (21.0%). Thirty (14.6%) patients died, 10 (4.9%) underwent limb amputation, and 11 (5.4%) new TECs occurred. Major bleeding occurred in 40 patients (19.5%) (seven during CPB surgery). Combining all prospective HAT trials (n = 403), after start of lepirudin treatment, the combined endpoint occurred in 82 patients (20.3%), with 47 deaths (11.7%), 22 limb amputations (5.5%), 30 new TECs (7.4%), and 71 (17.6%) major bleedings. Compared with the historical control group (log-rank test), the combined endpoint after start of treatment was reduced (29.7% vs. 52.1%, P = 0.0473), primarily because of reduction in new thromboses (11.9% vs. 32.1%, P = 0.0008). Mean lepirudin maintenance doses ranged from 0.07 to 0.11 mg kg(-1) h(-1). Major bleeding was more frequent in the lepirudin-treated patients (29.4% vs. 9.1%, P = 0.0148).. The rate of new TECs in HIT patients is low after start of lepirudin treatment. The rate of major bleeding of 17.6% might be reduced by reducing the starting dose to 0.1 mg kg(-1) h(-1).

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Anticoagulants; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Secondary Prevention; Survival Analysis; Thrombocytopenia; Thromboembolism

Heparin-induced thrombocytopenia (HIT) is a serious and common complication of heparin therapy that can lead to significant losses of life and limb. It is often under-recognized and, therefore, goes untreated until thrombosis develops. This article is meant to provide specific recommendations for treating patients with immune-mediated HIT, whether or not it is associated with thrombosis. These recommendations are based on our clinical experience treating patients with HIT and our evaluation of the published data on the efficacy and safety of lepirudin and argatroban, the 2 drugs approved by the Food and Drug Administration for treating HIT. Based on these criteria, we consider lepirudin the treatment of choice in all patients with HIT except those with severe or deteriorating renal function.

Topics: Algorithms; Anticoagulants; Antigen-Antibody Complex; Arginine; Clinical Trials as Topic; Diagnosis, Differential; Disease Management; Follow-Up Studies; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Immunoglobulin G; Pipecolic Acids; Platelet Activation; Platelet Count; Platelet Factor 4; Prognosis; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombophilia; Time Factors

Routine haemodialysis is performed with systemic anticoagulation, usually with heparin, to prevent thrombosis in the extracorporeal blood circuit. However, systemic anticoagulation can produce haemorrhagic complications in patients at high risk of bleeding. To minimize the risk of bleeding, a number of alternative regimens have been proposed: regional heparinization with protamine reversal; minimal heparinization; no heparin with saline flushes; regional anticoagulation with citrate; or prostacyclin anticoagulation. Although the incidence of bleeding complications has been reduced, each of these methods has its own limitations and complications. Among the types of membrane used in dialysers, cellulose membranes have been made more biocompatible by attaching N,N-diethyl-aminoehtyl (DEAE) groups to cellulose backbone. Positively charged DEAE groups on Hemophan enable negative charged heparin to be bound with the membrane. Haemodialysis using heparin-bound Hemophan has been reported to be a possible modality for patients at risk of bleeding. We designed more simplified heparin binding technique and have performed haemodialysis using heparin-bound Hemophan in patients at risk of bleeding during the past 7 years. In this review, current strategies to minimize bleeding complications and our experience of haemodialysis using heparin-bound Hemophan will be discussed.

Topics: Anticoagulants; Cellulose; Citrates; Epoprostenol; Hemodialysis Solutions; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Membranes, Artificial; Recombinant Proteins; Renal Dialysis; Risk Factors; Sodium Citrate

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

Critically ill patients often require renal replacement therapy accompanied by thrombocytopenia. Thrombocytopenia during heparin anticoagulation may be due to heparin-induced thrombocytopenia with need for alternative anticoagulation. Therefore, we compared argatroban and lepirudin in critically ill surgical patients.. Following institutional review board approval and written informed consent, critically ill surgical patients more than or equal to 18 years with suspected heparin-induced thrombocytopenia, were randomly assigned to receive double-blind argatroban or lepirudin anticoagulation targeting an activated Partial Thromboplastin Time (aPTT) of 1.5 to 2 times baseline. In patients requiring continuous renal replacement therapy we compared the life-time of hemodialysis filters. We evaluated in all patients the incidence of bleeding and thrombembolic events.. We identified 66 patients with suspected heparin-induced thrombocytopenia, including 28 requiring renal replacement therapy. Mean filter lifetimes did not differ between groups (argatroban 32 ± 25 hours (n = 12) versus lepirudin 27 ± 21 hours (n = 16), mean difference 5 hours, 95% CI -13 to 23, P = 0.227). Among all 66 patients, relevant bleeding occurred in four argatroban- versus eleven lepirudin-patients (OR 3.9, 95% CI 1.1 to 14.0, P = 0.040). In the argatroban-group, three thromboembolic events occurred compared to two in the lepirudin group (OR 0.7, 95% CI 0.1 to 4.4, P = 0.639). The incidence of confirmed heparin-induced thrombocytopenia was 23% (n = 15) in our study population.. This first randomized controlled double-blind trial comparing two direct thrombin inhibitors showed comparable effectiveness for renal replacement therapy, but suggests fewer bleeds in surgical patients with argatroban anticoagulation.. Clinical Trials.gov NCT00798525. Registered 25 November 2008.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Arginine; Critical Illness; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pipecolic Acids; Recombinant Proteins; Renal Insufficiency; Renal Replacement Therapy; Sulfonamides; Surgical Procedures, Operative; Thrombocytopenia

To assess efficacy and safety of lepirudin in patients with heparin-induced thrombocytopenia (HIT) in a prospective study (HAT-3) as well as in a combined analysis of all HAT study data.. Patients with laboratory-confirmed HIT were treated with lepirudin in three different aPTT-adjusted dose regimen and during cardiopulmonary bypass (CPB). Endpoints were new thromboembolic complications (TEC), limb amputations, and death and major bleeding. A historical control group (n = 120) was used for comparison.. After start of lepirudin in 205 patients treated in HAT-3, the combined endpoint occurred in 43 (21.0%). Thirty (14.6%) patients died, 10 (4.9%) underwent limb amputation, and 11 (5.4%) new TECs occurred. Major bleeding occurred in 40 patients (19.5%) (seven during CPB surgery). Combining all prospective HAT trials (n = 403), after start of lepirudin treatment, the combined endpoint occurred in 82 patients (20.3%), with 47 deaths (11.7%), 22 limb amputations (5.5%), 30 new TECs (7.4%), and 71 (17.6%) major bleedings. Compared with the historical control group (log-rank test), the combined endpoint after start of treatment was reduced (29.7% vs. 52.1%, P = 0.0473), primarily because of reduction in new thromboses (11.9% vs. 32.1%, P = 0.0008). Mean lepirudin maintenance doses ranged from 0.07 to 0.11 mg kg(-1) h(-1). Major bleeding was more frequent in the lepirudin-treated patients (29.4% vs. 9.1%, P = 0.0148).. The rate of new TECs in HIT patients is low after start of lepirudin treatment. The rate of major bleeding of 17.6% might be reduced by reducing the starting dose to 0.1 mg kg(-1) h(-1).

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Anticoagulants; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Secondary Prevention; Survival Analysis; Thrombocytopenia; Thromboembolism

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

Despite the use of heparin and aspirin, 5-10% of patients with unstable angina develop myocardial infarction or refractory angina in hospital. We tested the hypothesis that recombinant hirudin (lepirudin), a direct thrombin inhibitor, would be superior to heparin, an indirect thrombin inhibitor, in patients with acute ischaemic syndromes who were receiving aspirin.. 10,141 patients with unstable angina or suspected acute myocardial infarction without ST elevation were randomly assigned heparin (5000 units bolus then 15 units kg(-1) h(-1); n=5058) or hirudin (0.4 mg/kg bolus then 0.15 mg kg(-1) h(-1) infusion; n=5083) for 72 h in a double-blind trial. The primary outcome measure was cardiovascular death or new myocardial infarction at 7 days. Analysis was by intention to treat.. At 7 days, 213 (4.2%) patients in the heparin group and 182 (3.6%) in the hirudin group had experienced cardiovascular death or new myocardial infarction (relative risk 0.84 [95% CI 0.69-1.02]; p=0.077). The numbers with cardiovascular death, new myocardial infarction, or refractory angina at 7 days were 340 (6.7%) with heparin and 284 (5.6%) with hirudin (0.82 [0.70-0.96]; p=0.0125). These differences were primarily observed during the 72 h treatment period (cardiovascular death or myocardial infarction relative risk 0.76 [0.59-0.99], p=0.039: cardiovascular death, myocardial infarction, or refractory angina 0.78 [0.63-0.96], p=0.019). Although there was an excess of major bleeding requiring transfusion with hirudin (59 [1.2%] vs 34 [0.7%] with heparin; p=0.01), there was no excess in life-threatening episodes (20 in each group) or strokes (14 in each group).. The data from OASIS-2 suggest that recombinant hirudin is superior to heparin in preventing cardiovascular death, myocardial infarction, and refractory angina with an acceptable safety profile in patients with unstable angina or acute myocardial infarction without ST elevation. Thus, a direct thrombin inhibitor is more effective than an indirect thrombin inhibitor.

Topics: Angina, Unstable; Cardiovascular Diseases; Double-Blind Method; Electrocardiography; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Recombinant Proteins; Risk Factors; Treatment Outcome

We prospectively investigated lepirudin for further parenteral anticoagulation in patients with heparin-induced thrombocytopenia (HIT).. Patients with confirmed HIT (n=112) received lepirudin according to need for 2 to 10 days (longer if necessary): A1, treatment: 0.4 mg/kg IV bolus, followed by 0.15 mg. kg(-1). h(-1) intravenous infusion, n=65; A2, treatment in conjunction with thrombolysis: 0.2 mg/kg, followed by 0.10 mg. kg(-1). h(-1), n=4; and B, prophylaxis: 0.10 mg. kg(-1). h(-1), n=43. Outcomes from 95 eligible lepirudin-treated patients were compared with those of historical control patients (n=120). Complete laboratory response (activated partial thromboplastin time ratio >1.5 with /=1 outcome (cumulative incidence 30.9% versus 52.1%; relative risk [RR] 0.71; P=0.12, log-rank test). Bleeding events were more frequent in the lepirudin group than the historical control group (cumulative incidence at 35 days, 44.6% versus 27.2%; RR 2.57; P=0.0001, log-rank test). No difference was observed in bleeding events requiring transfusion (cumulative incidence at 35 days, 12.9% versus 9.1%; RR 1.66; P=0.23, log-rank test); no intracranial bleeding was observed in the lepirudin group.. Lepirudin effectively prevents death, limb amputations, and new thromboembolic complications and has an acceptable safety profile in HIT patients. Treatment should be initiated as soon as possible if HIT is suspected.

Topics: Aged; Amputation, Surgical; Anticoagulants; Autoimmune Diseases; Female; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Life Tables; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Recurrence; Safety; Survival Analysis; Thrombocytopenia; Thrombosis; Treatment Outcome

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

To evaluate the safety, effectiveness, and dosing of off-label bivalirudin to argatroban and lepirudin in patients with heparin-induced thrombocytopenia (HIT) using a new pharmacist driven protocol.. Retrospective cohort study of forty eight patients treated with lepirudin, argatroban, or bivalirudin from November 2010 to February 2012 for suspected HIT. Patients were excluded if the bivalirudin therapy was being used for acute coronary syndrome or if the treatment duration was less than 24 hours. The primary endpoint was time to therapeutic activated partial thromboplastin time (aPTT 50-90 seconds for argatroban and bivalirudin and 50-85 seconds for lepirudin). The secondary endpoints were elevation in international normalized ratio (INR), bleeding episodes, and percent time in aPTT target range.. Patients receiving bivalirudin reached a therapeutic aPTT more quickly than those receiving argatroban and lepirudin (3.7 hours vs. 14.2 hours vs. 14.7 hours, p <0.001). The INR was increased more in patients treated with argatroban than lepirudin and bivalirudin (1.3 vs. 0.3 vs. 0.4, p = 0.4). Clinically significant bleeding in patients treated with bivalirudin was significantly lower than that observed with argatroban or lepirudin (7% vs. 22% vs. 56%, p = 0.02). The average percentage of therapeutic aPTTs drawn was higher for patients treated with bivalirudin than those patients treated with argatroban and lepirudin (90% vs. 66% vs. 67%, p = 0.2).. A pharmacist-driven protocol for bivalirudin provided a significantly shorter time to therapeutic aPTT and lower bleeding rate for patients being treated for HIT when compared to lepirudin and argatroban. A larger study should be considered to confirm the results of this single center study.

Topics: Aged; Anticoagulants; Antithrombins; Arginine; Dose-Response Relationship, Drug; Female; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia

Parenteral direct thrombin inhibitors (DTIs) may be used in pediatric patients with contraindications to heparin therapy, such as heparin-induced thrombocytopenia. Few data exist regarding the use of DTIs in pediatric patients.. To characterize the use of DTIs in pediatric patients, including monitoring strategies and bleeding complications.. A retrospective descriptive study was designed and the Pediatric Health Information System database was queried from 2004 to 2011 for pediatric patients receiving a parenteral DTI. Patient demographic and hospital data, mortality, disease state, and procedure information (from International Classification of Diseases, Ninth Revision codes) were collected from the query. DTI monitoring information was also collected. Patients were divided into 2 time periods (2004-2007, 2008-2011) to evaluate trends.. Two hundred eight patients met study criteria (50.9% male, 64.4% white), and children (2-12 years of age) represented 34.6% of the population. Congenital heart disease was present in 43.8% and cardiovascular surgical procedure occurred in 28.4%. Argatroban was most commonly used (73.1%) and bivalirudin use increased (P < .001). Bleeding complications were present in 37.9% of patients and mortality was 19.7%. Bleeding complications were associated with lepirudin (62.5%) and argatroban (41.7%) more often as compared with bivalirudin (18.8%) (P < .001). Activated partial thromboplastin time and prothrombin time were used more often in patients receiving argatroban and lepirudin in comparison with bivalirudin, and thrombin time was used more often in patients receiving lepirudin (P < .001). Activated clotting time use increased over time (5.1% versus 17.5%, P = .02).. Pediatric use of DTIs is infrequent and occurs in patients with high morbidity and mortality.

Topics: Adolescent; Age Factors; Antithrombins; Arginine; Child; Child, Preschool; Databases, Factual; Female; Health Information Systems; Hemorrhage; Hirudins; Humans; Incidence; Infant; Infant, Newborn; Infusions, Parenteral; Male; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia; Young Adult

Patients with central nervous system (CNS) malignancies have a substantial risk for developing both thrombotic and bleeding disorders. The risk of venous thromboembolism (VTE) is substantially higher in these patients, both in the perioperative period and throughout their disease course. Patients with CNS malignancy harbor a latent hypercoagulability, which predisposes to VTE, as do postoperative immobility, hemiparesis, and other factors. The management of VTE in these patients is complex, given the significant morbidity and mortality associated with intratumoral hemorrhage. In the past, the perceived risk of intracranial hemorrhage limited the use of anticoagulation for the management of VTE with many favoring nonpharmacologic methods for prophylaxis and treatment. Inferior vena cava (IVC) filters have since lost favor at many centers given significant complications, which appear to be more frequent in patients with CNS malignancy. Recent studies have demonstrated safe and efficacious use of anticoagulation in these patients with a low incidence of intracranial hemorrhage. Treatment of established VTE is now recommended in this population with many centers favoring low-molecular-weight heparin (LMWH) versus oral warfarin for short- or long-term treatment. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, we recommend LMWH in patients with newly diagnosed VTE and a CNS malignancy.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Bevacizumab; Central Nervous System Neoplasms; Fondaparinux; Glioblastoma; Glioma; Hemorrhage; Heparin, Low-Molecular-Weight; Hirudins; Humans; Pipecolic Acids; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Vena Cava Filters; Venous Thromboembolism; Venous Thrombosis; Warfarin

Topics: Acute Disease; Anticoagulants; Arginine; Blood Coagulation; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Pipecolic Acids; Platelet Count; Polysaccharides; Recombinant Proteins; Research Design; Sulfonamides; Thrombin; Thrombocytopenia; Treatment Outcome; Venous Thrombosis; Warfarin

The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia (HIT) is compromised by an increased risk for bleeding. A retrospective observational analysis in 181 patients (median age, 67 years) with confirmed HIT treated in routine practice with lepirudin was performed to identify predictive factors for thrombotic and bleeding complications. Lepirudin was administered at a mean (+/- SD) dose of 0.06 +/- 0.04 mg/kg/h (compared with a recommended initial dose of 0.15 mg/kg/h). Mean activated partial thromboplastin time was greater than 1.5 times baseline value in 99.4% of patients. Median treatment duration was 7.7 days. Until discharge from the hospital, 13.8% and 20.4% of patients experienced a thrombotic or a major bleeding event, respectively. On multivariate analysis, mean lepirudin dose was not a significant predictive factor for thrombosis. In contrast, mean lepirudin dose greater than 0.07 mg/kg/h, long duration of lepirudin treatment, and moderate to severe renal impairment were significant positive factors for major bleeding. Overall, these results suggest that the recommended dose of lepirudin in patients with HIT is too high; the use of reduced doses may be safer with regard to bleeding risk and does not compromise antithrombotic efficacy.

Topics: Adolescent; Adult; Aged; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Treatment Outcome

Although both argatroban and lepirudin are used for the management of heparin-induced thrombocytopenia (HIT), data comparing these agents are lacking. The objective of this project was to compare the clinical outcomes of lepirudin vs argatroban therapy. Patients who received a direct thrombin inhibitor (DTI) from January 2000 to December 2001 were identified. Medical charts were retrospectively reviewed and relevant data extracted. The primary efficacy outcome was effective anticoagulation and the primary safety outcome was major bleeding. Data were analyzed using the t test and Fisher's exact test. Sixty-one lepirudin patients and 29 argatroban patients received a DTI during the study period. A new diagnosis of HIT was the indication for DTI therapy in 44.8% of argatroban patients and 57.4% of lepirudin patients. Effective anticoagulation was achieved in 77.8% of argatroban patients and 69.5% of lepirudin patients (p = .61). Major bleeding occurred in 10.3% and 11.5% of argatroban and lepirudin patients, respectively (p = 1.0). Argatroban and lepirudin demonstrated comparable safety and efficacy outcomes.

Topics: Aged; Anticoagulants; Arginine; Female; Hemorrhage; Hirudins; Humans; Male; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin; Treatment Outcome

Hirudin, a potent and specific thrombin inhibitor, is a protein of nonhuman origin and therefore potentially immunogenic. The primary objectives of this investigation were to determine the incidence of antihirudin antibodies (ahir-ab) in patients with heparin-induced thrombocytopenia (HIT) who received lepirudin as parenteral anticoagulation and to determine the incidence of death, limb amputation, new thromboembolic complications (TECs), and major hemorrhage in patients who had ahir-ab, compared with patients who were ahir-ab negative. The investigation used data from 2 prospective multicenter studies with the same study protocol, in which HIT patients received 1 of 4 intravenous lepirudin dosage regimens. The treatment duration was 2 to 10 days. Ahir-ab were determined by a newly developed enzyme-linked immunosorbent assay (ELISA). Eighty-seven of 196 evaluable patients (44.4%) had ahir-ab of the IgG class. Development of ahir-ab was dependent on the duration of treatment (ahir-ab-positive patients 18.6 days vs ahir-ab-negative patients 11.8 days; P =.0001). Fewer ahir-ab-positive than ahir-ab-negative patients died (P =.001). Ahir-ab did not cause an increase in limb amputation (P =.765), new TECs (P >.99), or major bleedings (P =.549). In 23 of 51 (45.1%) evaluable patients in whom ahir-ab developed during treatment with lepirudin ( = 12% of all lepirudin treated patients), the ahir-ab enhanced the anticoagulatory effect of lepirudin. Ahir-ab are frequent in patients treated with lepirudin for more than 5 days. Ahir-ab are the first example for a drug-induced immune response causing enhanced activity of a drug. Therefore, during prolonged treatment with lepirudin, anticoagulatory activity should be monitored daily to avoid bleeding complications.

Topics: Amputation, Surgical; Antibodies; Anticoagulants; Extremities; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Immunoglobulin G; Partial Thromboplastin Time; Recombinant Proteins; Thrombocytopenia; Thromboembolism; Time Factors

Topics: Anticoagulants; Drug Overdose; Heart Failure; Hemodiafiltration; Hemorrhage; Hirudins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Partial Thromboplastin Time; Recombinant Proteins; Renal Dialysis

A serious retroperitoneal bleeding occurred in a 56-year-old male patient receiving unfractionated heparin due to multiple pulmonary embolism. After reducing the heparin dose, the patient developed a new pulmonary embolism and a large thrombus in the right atrium. Concomitantly, the platelet count dropped to a value of 29 g/l. Heparin-induced thrombocytopenia (HIT) was confirmed by a functional assay, the heparin-induced platelet activation (HIPA) assay, whereas the results of a platelet factor 4/heparin complex ELISA were repeatedly negative. This indicated that the patient's HIT antibodies were directed towards an antigen other than platelet factor 4/heparin complexes. For treatment of the atrial thrombus, an ultra-low-dose lysis with rt-PA (2 mg/h, intravenously) was administered for a period of 52 h, overlapping with systemic treatment with recombinant hirudin (Lepirudin, Refludan, 0.06-0.14 mg/kg/h intravenously). The aim was to enhance lysis of the thrombus without increasing the haematoma, and at the same time keep the risk of fulminant pulmonary embolism due to thrombus fragmentation as low as possible. The cardiac thrombus disappeared within 48 h, without new signs of pulmonary embolism. Platelet counts normalized within nine days.

Topics: Anticoagulants; Arrhythmias, Cardiac; Autoimmune Diseases; Heart Atria; Heart Diseases; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Phenprocoumon; Plasminogen Activators; Pulmonary Embolism; Recombinant Proteins; Retroperitoneal Space; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator; Vena Cava Filters