hirudin and Thrombophilia

Inhibition of coagulation greatly limits cancer metastasis in many experimental models. Cancer cells trigger coagulation, through expression of tissue factor or P-selectin ligands that have correlated with worse prognosis in human clinical studies. Cancer cells also affect coagulation through expression of thrombin and release of microparticles that augment coagulation. In the cancer-bearing host, coagulation facilitates tumour progression through release of platelet granule contents, inhibition of Natural Killer cells and recruitment of macrophages. We are revisiting this literature in the light of recent studies in which treatment of clinical cohorts with anticoagulant drugs led to diminished metastasis.

Topics: Animals; Anticoagulants; Blood Coagulation; Blood Platelets; Cysteine Endopeptidases; Cytoplasmic Granules; Hirudins; Humans; Killer Cells, Natural; Lung Neoplasms; Macrophages; Mice; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms, Experimental; Neoplastic Cells, Circulating; Neuraminidase; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Rats; Thrombin; Thrombophilia; Thromboplastin

The standard multipotent anticoagulants (unfractionated and low molecular weight heparins, antagonists of vitamin K) are commonly used for treatment and/or prophylaxis of different thrombotic complications, such as deep vein thrombosis, thrombophilia, pulmonary embolism, myocardial infarction, stroke and so on. Advantages and shortcomings of these anticoagulants are considered. The modern tendencies to use small selective direct inhibitors of thrombin or factor Xa are surveyed. The search of the new targets in the coagulation cascade for development of new promising anticoagulants and improvement in antithrombotic therapy is discussed.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Factor Xa; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Hirudins; Humans; Platelet Aggregation Inhibitors; Thrombin; Thromboembolism; Thrombophilia; Venous Thrombosis; Vitamin K; Warfarin

Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of approximately 50 to 60 x 10(9) platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

Topics: Anticoagulants; Arginine; Autoantibodies; Contraindications; Disseminated Intravascular Coagulation; Fondaparinux; Heparin; Hirudins; Humans; Pipecolic Acids; Platelet Count; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombophilia; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Angina, Unstable; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Morpholines; Myocardial Infarction; Peptide Fragments; Polysaccharides; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Thrombosis; Warfarin

Unfractionated heparin (UFH) is the most widely used antithrombin during percutaneous coronary intervention (PCI). Despite significant pharmacological and mechanical advancements in PCI, uncertainty remains about the optimal activated clotting time (ACT) for prevention of ischemic or hemorrhagic complications.. We analyzed the outcome of all UFH-treated patients enrolled in 4 large, contemporary PCI trials with independent adjudication of ischemic and bleeding events. Of 9974 eligible patients, maximum ACT was available in 8369 (84%). The median ACT was 297 seconds (interquartile range 256 to 348 seconds). The incidence of death, myocardial infarction, or revascularization at 48 hours, by ACT quartile, was 6.2%, 6.8%, 6.0%, and 5.7%, respectively (P=0.40 for trend). Covariate-adjusted rate of ischemic complications was not correlated with maximal procedural ACT (continuous value, P=0.29). Higher doses of UFH (>5000 U, or up to 90 U/kg) were independently associated with higher rates of events. The incidence of major or minor bleeding at 48 hours, by ACT quartile, was 2.9%, 3.5%, 3.8%, and 4.0%, respectively (P=0.04 for trend). In a multivariable logistic model with a spline transformation for ACT, there was a linear increase in risk of bleeding as the ACT approached 365 seconds (P=0.01), which leveled off beyond that value. Increasing UFH weight-indexed dose was independently associated with higher bleeding rates (OR 1.04 [1.02 to 1.07] for each 10 U/kg, P=0.001).. In patients undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest association with bleeding complications, driven mainly by minor bleeding. Lower values do not appear to compromise efficacy while increasing safety.

Topics: Abciximab; Aged; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Aspirin; Blood Coagulation Tests; Clopidogrel; Comorbidity; Coronary Restenosis; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Hirudins; Humans; Immunoglobulin Fab Fragments; Incidence; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Myocardial Ischemia; Peptide Fragments; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Recombinant Proteins; Retrospective Studies; Stents; Thrombophilia; Ticlopidine; Tirofiban; Tyrosine

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

Platelets are known to facilitate tumor metastasis and thrombocytosis has been associated with an adverse prognosis in ovarian cancer. However, the role of platelets in primary tumour growth remains to be elucidated. The present study demonstrated that the expression levels of various markers in platelets, endothelial adherence and angiogenesis, including, platelet glycoprotein IIb (CD41), platelet endothelial cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), lysyl oxidase, focal adhesion kinase and breast cancer anti‑estrogen resistance 1, were expressed at higher levels in patients with malignant carcinoma, compared with those with borderline cystadenoma and cystadenoma. In addition, the endothelial markers CD31 and VEGF were found to colocalize with the platelet marker CD41 in the malignant samples. Since mice transplanted with human ovarian cancer cells (SKOV3) demonstrated elevated tumor size and decreased survival rate when treated with thrombin or thrombopoietin (TPO), the platelets appeared to promote primary tumor growth. Depleting platelets using antibodies or by pretreating the cancer cells with hirudin significantly attenuated the transplanted tumor growth. The platelets contributed to late, but not early stages of tumor proliferation, as mice treated with platelet‑depleting antibody 1 day prior to and 11 days after tumor transplantation had the same tumor volumes. By contrast, tumor size in the early TPO‑injected group was increased significantly compared with the late TPO‑injected group. These findings suggested that the interplay between platelets and angiogenesis may contribute to ovarian cancer growth. Therefore, platelets and their associated signaling and adhesive molecules may represent potential therapeutic targets for ovarian cancer.

Topics: Animals; Antithrombins; Blood Coagulation; Blood Platelets; Cell Line, Tumor; Disease Models, Animal; Female; Heterografts; Hirudins; Humans; Mice; Neoplasm Staging; Neovascularization, Pathologic; Ovarian Neoplasms; Prognosis; Thrombophilia; Thrombosis; Tumor Burden

Patients with a previous history of heparin-induced thrombocytopenia are at a higher risk for thromboembolic events, and heparin administration is formally contraindicated. Bivalirudin has been reported as an alternative therapy whenever an intervention that requires systemic anticoagulation and cardiopulmonary by-pass pump is needed. We present the case of a patient diagnosed with heparin-induced thrombocytopenia and heparin-PF4 (+) antibodies requiring a triple cardiac valve replacement who developed fulminant coagulopathy after bivalirudin administration. A discussion on the serious difficulties that the management of these types of patients involves, as well as a review of prevention strategies are presented.

Topics: Acute Kidney Injury; Aged; Anticoagulants; Antithrombins; Blood Loss, Surgical; Coronary Artery Bypass; Disseminated Intravascular Coagulation; Drug Substitution; Fatal Outcome; Heart Failure; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Immunoglobulin G; Intraoperative Complications; Male; Multiple Organ Failure; Peptide Fragments; Platelet Factor 4; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Thrombophilia

Bivalirudin is an ultrashort acting direct thrombin inhibitor, which has been used in place of heparin in selected settings. We describe our preliminary experience with the use of bivalirudin in patients who required anticoagulation for a deep vein thrombosis, prosthetic heart valve, or hypercoagulable state but were felt to be at high risk for the use of heparin.. Eight patients in our neurocritical care unit required anticoagulation but were felt to be poor candidates for heparin either due to heparin-induced thrombocytopenia or due to high risk for intracranial hemorrhage. A standard protocol was utilized for bivalirudin with a loading dose of 0.75 mg/kg followed by a continuous infusion of 0.15 mg/kg hr. Serial aPTT levels were checked on a routine basis to monitor therapeutic effect. The bivalirudin infusion was continued for a period of 2 days to 2 weeks prior to starting coumadin therapy.. These patients were in the early postoperative period (within 48 h) following craniotomy, had suffered a recent large hemispheric infarct with hemorrhagic conversion, or had presented with an acute intracerebral hemorrhage. In this small series of patients, no intracranial hemorrhagic complications were encountered. No patients demonstrated progressive systemic thrombotic issues while on bivalirudin.. Based on these findings, bivalirudin may represent a reasonable alternative in patients for whom heparin anticoagulation is contraindicated. A larger multicenter trial of bivalirudin in this setting may be appropriate.

Topics: Adult; Aged; Aged, 80 and over; Antithrombins; Female; Heart Valve Prosthesis; Hirudins; Humans; Intracranial Hemorrhages; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thromboembolism; Thrombophilia; Treatment Outcome; Venous Thrombosis

Polycythemia vera is a Philadelphia chromosome-negative myeloproliferative disorder with incidence of 1% under the age of 25. The Budd-Chiari syndrome (BCS) is a well known complication of polycythemia vera even in children, and characterized by occlusion of hepatic outflow. A computerized archive search of medical records at Sheba Medical Center of the past three decades of patients with polycythemia vera and BCS under the age of 25 years was performed. A work-up for JAK2 V617F mutation and thrombophilia was done. Medical charts and imaging tests were carefully reviewed. Three patients under the age of 22 were finally recruited. Two of those were found in life-threatening condition and improved clinically following treatment with bivalirudin, a direct thrombin inhibitor. It is conceivable that bivalirudin contributed to a favorable outcome of those patients in comparison to historical outcome previously reported. In conclusion, polycythemia vera in the young is not a mild disease since BCS, which is one of its complication, can be fatal even in those age group unrelated to the presence of hereditary thrombophilia. Once BCS occurs, we would suggest giving a trial with bivalirudin before an invasive procedure is planned.

Topics: Adolescent; Antithrombins; Budd-Chiari Syndrome; Child; Female; Hirudins; Humans; Janus Kinase 2; Liver; Male; Mutation; Peptide Fragments; Polycythemia Vera; Recombinant Proteins; Thrombin; Thrombophilia; Treatment Outcome; Young Adult

Topics: Adult; Amputation, Surgical; Anticoagulants; Extremities; Female; Hirudins; Humans; Ischemia; Male; Middle Aged; Peripheral Vascular Diseases; Recombinant Proteins; Thrombin; Thrombophilia

Topics: Adult; Anticoagulants; Antithrombins; Budd-Chiari Syndrome; Cholecystitis; Disease Progression; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Factor V; Female; Follow-Up Studies; Hirudins; Humans; Infusions, Intravenous; Injections, Subcutaneous; Mutation; Odds Ratio; Recombinant Proteins; Thrombophilia; Treatment Outcome

Vascular complications remain the most common cause of early renal allograft loss in patients with end-stage renal failure. Underlying thrombophilic disorders increase the risk of early graft thrombosis. A male adolescent with high-risk thrombophilia because of combined heterozygous factor V Leiden (G1691A) and prothrombin gene (G20210A) mutation developed HIT II. Hemodialysis and subsequent renal transplantation were undertaken using recombinant hirudin, a direct and selective thrombin inhibitor, as an anticoagulant. Primary function in the transplanted kidney was excellent. No thrombotic or hemorrhagic events have occurred and follow-up showed excellent long-term graft survival. Patients on HD have an increased risk for the development of HIT, and therefore, they need repetitive screening for the development of acquired thrombotic risk factors (e.g. HIT II or lupus anticoagulant). R-hirudin is efficacious and safe on both HD and following renal transplantation.

Topics: Adolescent; Anticoagulants; Factor V; Fibrinolytic Agents; Follow-Up Studies; Heparin; Heterozygote; Hirudins; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Mutation; Prothrombin; Renal Dialysis; Risk Factors; Thrombocytopenia; Thrombophilia

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Drug Administration Schedule; Drug Therapy, Combination; Endothelium, Vascular; Enoxaparin; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Thrombophilia

Unfractionated heparin has been a near universal anticoagulant for cardiac surgery; however it is contraindicated in heparin-induced thrombocytopenia type II. Alternative anticoagulants such as bivalirudin (a direct thrombin inhibitor) are being utilized. Bivalirudin was successfully used in an immunologically complex patient (diagnoses of heparin-induced thrombocytopenia type II, systemic lupus erythematosus, antiphospholipid syndrome, and dialysis-dependent renal failure) requiring cardiopulmonary bypass. Thrombotic events are common in antiphospholipid syndrome patients undergoing cardiac surgery utilizing high-dose heparin. This may represent unrecognized heparin-induced thrombocytopenia type II. Our patient did not experience perioperative thrombotic or bleeding complications. The possible cross-reactivity between heparin induced thrombocytopenia type II and antiphospholipid syndrome has not been investigated.

Topics: Adult; Antibody Specificity; Anticoagulants; Antiphospholipid Syndrome; Autoantibodies; Cross Reactions; Drug Evaluation; Drug Therapy, Combination; Female; Heart Failure; Heparin; Hirudins; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Lupus Erythematosus, Systemic; Mitral Valve Insufficiency; Peptide Fragments; Platelet Count; Platelet Factor 4; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Thrombophilia; Warfarin

We report the case of 64-year-old female patient with pulmonary embolism and bilateral femoropopliteal deep vein thrombosis caused by heparin-induced thrombocytopenia type II (HIT II) resistant to danaparoid sodium and subsequently administered lepirudin in whom a single late plasmapheresis performed on day 6 of the initiation of treatment of HIT reversed the course of the disease, preventing its highly potential fatal outcome. Primarily administered lepirudin was not only ineffective but even led to further aggravation of the patient's clinical state and platelet count drop in the first stage of the HIT treatment. The improvement of the patient's clinical state was not achieved before therapeutic plasma exchange (TPE) had removed the greatest part of pathogenetic circulating substrate. Only after TPE, lepirudin, introduced again, led to the platelet count recovery. In the subsequent course of the treatment, lepirudin was combined with an overlapping oral anticoagulant. Previously positive heparin aggregation test and fast particle gel heparin-platelet factor 4 immunoassay were normalized as well as the patient's clinical status. Early plasmapheresis, administered within 4 days of the onset of thrombocytopenia in HIT, as a beneficial therapeutic measure in certain individual cases, is indisputable. However, our results do not concur with previously reported findings of the so far most comprehensive study on plasmapheresis performed in the management of HIT with thrombosis, discrediting late plasmapheresis administered 4 days after the onset of the disease not only as ineffective, but even as an aggravating factor. Our results suggest the possible beneficial impact of late plasmapheresis as a method that may reverse a prothrombotic process and lead to a fast improvement in the patient's platelet count, especially in cases initially resistant to thrombin inhibitors.

Topics: Arthroplasty, Replacement, Hip; Autoantibodies; Chondroitin Sulfates; Dermatan Sulfate; Drug Resistance; Female; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hip Fractures; Hirudins; Humans; Middle Aged; Partial Thromboplastin Time; Plasma; Plasmapheresis; Postoperative Complications; Pulmonary Embolism; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Salvage Therapy; Thrombophilia; Time Factors

The adsorption of thrombin to fibrin during clotting defines "Antithrombin I" activity. We confirmed that thrombin generation in afibrinogenemic or in Reptilase defibrinated normal plasma was higher than in normal plasma. Repletion of these fibrinogen-deficient plasmas with fibrinogen 1 (gamma A/gamma A), whose fibrin has two "low affinity" non-substrate thrombin binding sites, resulted in moderately reduced thrombin generation by 29-37%. Repletion with fibrinogen 2 (gamma'/gamma A), which in addition to low affinity thrombin-binding sites in fibrin, has a "high affinity" non-substrate thrombin binding site in the carboxy-terminal region of its gamma' chain, was even more effective and reduced thrombin generation by 57-67%. Adding peptides that compete for thrombin binding to fibrin [S-Hir53-64 (hirugen) or gamma'414-427] caused a transient delay in the onset of otherwise robust thrombin generation, indicating that fibrin formation is necessary for full expression of Antithrombin I activity. Considered together, 1) the increased thrombin generation in afibrinogenemic or fibrinogen-depleted normal plasma that is mitigated by fibrinogen replacement; 2) evidence that prothrombin activation is increased in afibrinogenemia and normalized by fibrinogen replacement; 3) the severe thrombophilia that is associated with defective thrombin-binding in dysfibrinogenemias Naples I and New York I, and 4) the association of afibrinogenemia or hypofibrinogenemia with venous or arterial thromboembolism, indicate that Antithrombin I (fibrin) modulates thromboembolic potential by inhibiting thrombin generation in blood.

Topics: Afibrinogenemia; Antithrombins; Fibrin; Fibrinogen; Hirudins; Humans; Peptide Fragments; Protein Binding; Prothrombin; Thrombin; Thrombophilia