warfarin and Hemolysis

Topics: Abnormalities, Drug-Induced; Anti-Infective Agents; Anticoagulants; Biomedical Research; Cytochrome P-450 Enzyme System; Drug Eruptions; Drug Interactions; Female; Folic Acid Deficiency; Hematologic Diseases; Hemolysis; Humans; Hyperkalemia; Hypoglycemia; Hypoglycemic Agents; Immunocompromised Host; Infant, Newborn; Infant, Small for Gestational Age; Kidney; Nervous System Diseases; Pregnancy; Trimethoprim, Sulfamethoxazole Drug Combination; Warfarin

Topics: Anticoagulants; Arteriosclerosis; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Coronary Disease; Drug Interactions; Fibrinolysis; Heart Diseases; Heart Valve Prosthesis; Hemolysis; Hemostasis; Heparin; Humans; Myocardial Infarction; Platelet Aggregation; Pulmonary Embolism; Stress, Physiological; Thrombophlebitis; Warfarin

Topics: Androgens; Anemia, Hemolytic, Autoimmune; Antigen-Antibody Reactions; Antigens; Autoantibodies; Blood Transfusion; Cold Temperature; Complement System Proteins; Dextrans; Hemagglutination; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppression Therapy; Prednisone; Splenectomy; Warfarin

We present herein a review of 95 patients who underwent valve replacement with the CarboMedics (CM) valve prosthesis between April 1990 and December 1992. The operative mortality for the entire group was 4.2%: 0% following aortic valve replacement (AVR), 2.7% following double valve replacement (DVR). All patients were prescribed warfarin and bucolome for anticoagulation, and were followed up for a mean period of 29.9 months. Late mortality was 8.4%; 3.1% following AVR, 10.8% following MVR, and 12.5% following DVR. There were no cases of mechanical prosthetic valve failure, significant hemolysis, infective prosthetic valve endocarditis, or bleeding complications. After 44 months of follow-up, the actuarial freedom from complications was calculated as: thromboembolism, 97.8 +/- 1.6%; valve thrombosis, 97.8 +/- 1.1%; paravalvular leak, 96.7 +/- 1.9%; and reoperation, 98.9 +/- 1.1%. The overall survival rate was 84.3 +/- 6.3% and all survivors showed a significant improvement in NYHA functional class, from 81% in classes III and IV preoperatively to 99% in classes I and II postoperatively. The CM valve exhibited no significant differences in hemolytic parameters or hemodynamic performance after isolated AVR or MVR compared with the similar type of St. Jude Medical bileaflet valve. The evidence provided by the present study therefore suggests that the CM valve prosthesis can achieve excellent mid-term clinical results and hemodynamic performance with a low incidence of thromboembolism and valve thrombosis.

Topics: Adolescent; Adult; Aged; Aortic Valve; Barbiturates; Female; Follow-Up Studies; Heart Valve Prosthesis; Hemodynamics; Hemolysis; Humans; Male; Middle Aged; Mitral Valve; Postoperative Complications; Survival Rate; Thromboembolism; Thrombosis; Warfarin

Topics: Abdominal Pain; Adult; Anemia, Hemolytic; Antibodies, Monoclonal, Humanized; Anticoagulants; Budd-Chiari Syndrome; Complement Inactivating Agents; Drug Therapy, Combination; Ferritins; Hemoglobin A; Hemoglobinuria, Paroxysmal; Hemolysis; Hepatomegaly; Humans; Male; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

In light of decreased intracranial hemorrhage with direct oral anticoagulants and concerns about their safety in continuous flow left ventricular assist devices, we conducted an ex vivo study of thrombus formation using multiple anticoagulation agents.. A continuous flow left ventricular assist device (HeartWare ventricular assist device) hemocompatibility loop was run using human blood under 7 conditions: control (no anticoagulation or antiplatelet); in vitro addition of aspirin; in vitro addition of apixaban at low dose (equivalent 2.5 mg twice daily); addition of apixaban at high dose (equivalent 5 mg twice daily); patients on warfarin; patients on apixaban (5 mg twice daily); and patients on dabigatran (150 mg twice daily). The primary outcome was time to formation of intrapump thrombosis. Secondary outcomes were reduction in clotting times over 1 hour, hemolysis, reduced platelet aggregation, and von Willebrand activity.. Twenty-one runs were completed. Times to thrombosis in median (interquartile range) were control, 131 (127-134.5); in vitro aspirin, 124 (114.5-137); and patients on dabigatran, 131 (130.5-135.5) minutes, respectively. Times in patients on warfarin were, 137 (136.5-143.5); in vitro low-dose apixaban, 141 (138.5-142); and patients on apixaban, 140 (138-142.5) minutes, respectively. No thrombus formed in the in vitro high-dose apixaban group. There were no significant differences between the individual groups. When all apixaban groups were compared with nonapixaban groups, the time to thrombosis formation was significantly longer, 143 (137-150) versus 133.5 (128.5-140) minutes,. In an in vitro study of anticoagulation using human blood in a mock loop with a HeartWare HVAD, we demonstrated similar thrombosis times for apixaban and warfarin. Time to clotting was longer in the combined apixaban groups compared with combined other groups, but thrombosis times between individual groups were not significantly different.

Topics: Anticoagulants; Blood Coagulation; Dabigatran; Heart Failure; Heart-Assist Devices; Hemolysis; Humans; Platelet Aggregation Inhibitors; Thrombosis; Warfarin

Pump thrombosis and hemolysis in patients with left ventricular assist devices (LVADs) are associated with significant morbidity and mortality. Intensification of anticoagulation has been suggested as potential therapy, with mixed results. The aim of this study is to assess the safety and efficacy of adding eptifibatide with or without an anticoagulation agent in managing patients with LVAD presenting with hemolysis and suspected pump thrombosis. This retrospective single center study included all patients who presented with their first episode of suspected pump thrombosis and were treated with eptifibatide with or without an anticoagulant between March 1, 2011 and July 30, 2015. A total of 27 patients (23 HeartMate II, 4 HeartWare) were identified. The average age was 55 years (range 19-75) and time from implant to event averaged 513 days (range 35-1760). The average lactate dehydrogenase on presentation was 1111 and 63% of patients had power elevations. The average international normalized ratio (INR) on admission was 2.4, with INR of ≥2 in 21/27 patients. All patients received eptifibatide: 10 received eptifibatide only, 9 received eptifibatide and argatroban, and 8 received eptifibatide and heparin. Warfarin was continued in 25/27 patients. Overall, 21 patients (77.8%) were successfully treated medically, 5 (18.5%) underwent pump exchange, and 1 (3.7%) died. There were no differences in outcomes or complications between the three treatment groups. Despite initial success, 12/21 patients developed repeat episodes of hemolysis at 1 year. The 1-year survival in the patients treated medically was 90% and surgically was 60%. Our experience indicates that medical therapy for hemolysis and suspected LVAD thrombosis with warfarin and eptifibatide alone or in combination with argatroban or heparin appears safe and may be effective, although the episodes of recurrent hemolysis after medical management remain high.

Topics: Adult; Aged; Anticoagulants; Arginine; Eptifibatide; Female; Heart Failure; Heart-Assist Devices; Hemolysis; Heparin; Humans; Male; Middle Aged; Peptides; Pipecolic Acids; Platelet Aggregation Inhibitors; Retrospective Studies; Sulfonamides; Thrombosis; Warfarin; Young Adult

Topics: Anemia, Hemolytic; Antibodies, Monoclonal, Humanized; Diagnosis, Differential; Fatigue; Female; Headache; Hematologic Agents; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Middle Aged; Patient Care Management; Thrombosis; Warfarin

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antilymphocyte Serum; Cerebrovascular Disorders; Child; Child, Preschool; Cyclosporine; Erythrocyte Transfusion; Female; Hemoglobinuria, Paroxysmal; Hemolysis; Heparin; Humans; Infant; Infant, Newborn; L-Lactate Dehydrogenase; Male; Middle Aged; Myocardial Infarction; Neutropenia; Neutrophils; Registries; Retrospective Studies; Thromboembolism; Warfarin

This study investigated the relationship between anti-factor Xa (anti-FXa) and activated partial thromboplastin time (aPTT) for monitoring intravenous unfractionated heparin (IV-UFH) in patients with continuous-flow left ventricular assist devices (CF-LVADs).. CF-LVADs have become mainstream therapy for patients with advanced heart failure. Thromboembolic events, device thrombosis, and bleeding continue to be a challenge with this technology. Adequate anticoagulation is required to prevent these adverse events.. A prospective study of consecutive patients implanted with a CF-LVAD was conducted. Paired samples were considered concordant if aPTT values fell into expected ranges for subtherapeutic, therapeutic, and supratherapeutic anti-FXa levels. Heparin dosing was on the basis of anti-Xa levels.. A total of 340 paired values from 38 patients were evaluated. Anti-FXa and aPTT were discordant in 253 samples (74.4%), with a high degree of variability in aPTT for any given anti-FXa level (r(2) = 0.57). Results were discordant in 104 samples (63.8%) from patients undergoing bridging therapy with warfarin and in 149 samples (84.2%) from patients with device obstruction and/or hemolysis (p < 0.001). The most common pattern of discordance was a supratherapeutic aPTT value despite a therapeutic anti-FXa level (49.1% for bridging vs. 75.8% for device obstruction and/or hemolysis; p < 0.001).. Levels of aPTT were disproportionately prolonged relative to the corresponding anti-FXa levels in CF-LVAD patients, particularly those with device obstruction. Hemolysis and warfarin administration may falsely elevate aPTT, resulting in overestimation of heparin concentration and under-anticoagulation. Use of aPTT and anti-FXa to guide heparin therapy may lead to different estimates of heparin concentration in the same patient.

Topics: Anticoagulants; Drug Administration Schedule; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Heart Failure; Heart-Assist Devices; Hemolysis; Heparin; Humans; Infusions, Intravenous; Male; Middle Aged; Partial Thromboplastin Time; Prospective Studies; Prosthesis Failure; Thromboembolism; Treatment Outcome; Warfarin

To attain fully functional biological activity, vitamin-K dependent coagulation factors (VKDCF) are γ-carboxylated prior to secretion from liver. Warfarin impairs the γ-carboxylation, and consequently their physiological function. Bothrops jararaca snake venom (BjV) contains several activators of blood coagulation, especially procoagulant enzymes (prothrombin and factor X activators) and thrombin-like enzymes. In order to clarify the relative contribution of prothrombin and factor X activators to the hemostatic disturbances occurring during experimental B. jararaca envenomation, warfarin was used to deplete VKDCF, prior to BjV administration. Male Wistar rats were pretreated with saline (Sal) or warfarin (War) and inoculated subsequently with BjV or saline, thus forming four groups: Sal + Sal (negative control), Sal + BjV (positive control), War + Sal (warfarinization control), and War + BjV. Three hours after inoculation, prothrombin and factor X levels fell 40% and 50%, respectively; levels of both factors decreased more than 97% in the War + Sal and War + BjV groups. Platelet counts dropped 93% and 76% in Sal + BjV and War + BjV, respectively, and plasma fibrinogen levels decreased 86% exclusively in Sal + BjV. After 6 and 24 h, platelet counts and fibrinogen levels increased progressively. A dramatic augmentation in plasma hemoglobin levels and the presence of schizocytes and microcytes in the Sal + BjV group indicated the development of intravascular hemolysis, which was prevented by warfarin pretreatment. Our findings show that intravascular thrombin generation has the foremost role in the pathogenesis of coagulopathy and intravascular hemolysis, but not in the development of thrombocytopenia, in B. jararaca envenomation in rats; in addition, fibrinogenases (metalloproteinases) may contribute to coagulopathy more than thrombin-like enzymes.

Topics: Animals; Blood Coagulation; Blood Platelets; Bothrops; Erythrocytes; Factor X; Fibrinogen; Hemolysis; Hemostasis; Hemostatics; Male; Platelet Count; Prothrombin; Rats; Rats, Wistar; Snake Bites; Snake Venoms; Thrombin; Thrombocytopenia; Warfarin

Thromboembolic events have been observed in heart failure (HF) patients supported by long-term mechanical circulatory support (MCS) devices. It has been hypothesized that these adverse events may be the result of platelet activation associated with high rotational speeds common to axial flow pumps. In this study, markers of platelet activation were investigated in HF patients supported by a HeartMate II left ventricular assist device (LVAD).. The study group consisted of 34 HF patients supported by a HeartMate II axial flow LVAD implanted for destination therapy (DT). This patient population was 94% male (31 M, 3 F), supported by LVAD for 30 to 723 days (average 268 days), and with an anticoagulation regimen of Coumadin (0-8 mg daily dose) and aspirin (0-325 mg daily dose). Platelet adhesion markers (soluble P-selectin and solube CD40 ligand), platelet count (PC), hematocrit (Hct), and creatinine (Cr) were measured.. The soluble P-selectin marker was within normal platelet activity limits for all end points. The soluble CD40 ligand marker indicated platelet inactivity for all end points. Despite high shear stresses associated with a high-speed axial flow pump, the HeartMate II had no discernable effect on platelet activation. Current clinical doses of aspirin also appear to have little effect on platelet activation. Platelet count, hematocrit, and creatinine were normal in these patients over duration of support.. There were no discernable changes in platelet activation markers soluble P-selectin and soluble CD40 ligand in HF patients support by HeartMate II LVAD independently of length of support, anti-platelet, and anti-coagulation regimens.

Topics: Aged; Anticoagulants; Aspirin; Biomarkers; CD40 Ligand; Creatinine; Cross-Sectional Studies; Female; Heart Failure; Heart-Assist Devices; Hematocrit; Hemolysis; Humans; Illinois; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Prosthesis Design; Time Factors; Treatment Outcome; Warfarin

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Arginine; Aspirin; Hemolysis; Humans; Hypertension, Pulmonary; Male; Middle Aged; Spherocytosis, Hereditary; Vasodilator Agents; Warfarin

The purpose of this study was to determine the criteria of valve selection from the long-term results of Hancock, Carpentier-Edwards, St Jude Medical and Bjork-Shiley prostheses, taking into special account the frequency of reoperation. Reoperations on the Hancock bioprosthesis were performed on six patients for tissue leaflet disruption with an incidence of 2.2 per cent/patient-year. Reoperations on the Carpentier-Edwards bioprosthesis were performed on 24 patients for tissue leaflet disruption in 23 patients and prosthetic valve endocarditis (PVE) in one, with an incidence of 3.8 per cent/patient-year. Reoperations on the Bjork-Shiley prosthesis were performed in two patients for severe hemolysis, with an incidence of 0.32 per cent/patient-year. Reoperations on the St Jude Medical prosthesis were performed on 3 patients, for valve thrombosis in one patient, PVE in one, and hemolysis in one, with an incidence of 0.23 per cent/patient-year. The overall mortality rate was 20 per cent, or 7 patients, and the indications for reoperation affected this. Patients with primary tissue failure had a mortality rate of 10.3 per cent; those with a thrombosed valve, 0 per cent; those with hemolysis, 66.7 per cent; and those with valve infection, 100 per cent. A good chance of survival may be achieved in patients facing prosthetic valve complications by performing reoperation as soon as possible after early detection, since mortality is high following emergency reoperation and in patients with severe symptoms. Currently, we recommend mechanical prostheses for valve replacement except in patients over 70 years old and in younger patients with absolute contraindications to anticoagulative therapy.

Topics: Aged; Aortic Valve; Bioprosthesis; Coronary Thrombosis; Evaluation Studies as Topic; Heart Valve Diseases; Heart Valve Prosthesis; Hemolysis; Humans; Mitral Valve; Prosthesis Failure; Reoperation; Time Factors; Tricuspid Valve; Warfarin

We examined hematological complications in 415 patients having valve replacement with the St. Jude mechanical prosthesis (212, aortic valve replacement [AVR]; 159, mitral valve replacement [MVR]; and 44, AVR + MVR). There were 164 men and 251 women with a mean age of 59 years (range, 20 to 88 years). Preoperatively 386 patients were in New York Heart Association functional classes III and IV. There were 154 associated procedures (37%), the most common being myocardial revascularization. Overall hospital mortality was 7.5% (31/415), 7% after AVR, 8% after MVR, and 7% after AVR + MVR. All operative survivors were anticoagulated with Coumadin (crystalline warfarin sodium) to maintain the prothrombin time at 1.5 times control. During a mean follow-up of 21 months (range, 6 to 60 months), there were 29 late deaths (7.6%) and 5 patients (1.3%) lost to follow-up. No patient experienced structural valve degeneration. At 48 months, actuarial freedom from thromboembolism was 87% +/- 3% after AVR and 91% +/- 9% after MVR; from anticoagulation-related hemorrhage, 97% +/- 3% after AVR and 91% +/- 3% after MVR; and from hemolysis, 100% after AVR and 98% +/- 2% after MVR. Freedom from all valve-related morbidity at 4 years was 82% +/- 5% after AVR and 75% +/- 10% after MVR. Actuarial survival at 48 months was 80% +/- 4% after AVR and 65% +/- 7% after MVR.

Topics: Adult; Aged; Aged, 80 and over; Aortic Valve; Drug Administration Schedule; Female; Follow-Up Studies; Heart Diseases; Heart Valve Prosthesis; Hematologic Diseases; Hemolysis; Hemorrhage; Humans; Male; Middle Aged; Mitral Valve; Thromboembolism; Warfarin

To evaluate the clinical performance of the St Jude Medical bileaflet heart valve prosthesis, we followed 150 consecutive patients (95 male and 55 female patients, mean age 54 years, range 1 to 74 years) for an average of 24 months. These included 74 patients with aortic, 56 patients with mitral, and 20 patients with multiple valve replacement. During the 2 year follow-up, there were a total of four perioperative and seven late deaths, two of which were prosthesis related. Reoperation was necessary in four patients, because of paravalvular leaks in two patients with mitral and one patient with aortic prostheses and because of leaflet dislodgment in one patient with a mitral prosthesis, a postoperative complication that has not been reported previously. The thromboembolic rate per 100 patient-years was 2.6 in aortic and 2.9 in mitral valve replacement, the symptoms being reversible in all patients. All patients were receiving anticoagulant therapy. A total of four complications of anticoagulant therapy (three minor and one fatal) were observed. Significant hemolysis was observed in none of the patients. In patients with dyspnea, the New York Heart Association functional classification was 2.7 +/- 0.8 preoperatively versus 1.3 +/- 0.6 postoperatively. In patients with angina, it was 2.6 +/- 0.6 preoperatively versus 1.03 +/- 0.2 postoperatively. Noninvasive Doppler measurements revealed excellent flow characteristics, values being close to those obtained in natural valves (mean +/- standard deviation of maximal flow velocity: 1.5 +/- 0.5 versus 0.9 +/- 0.1 m/sec in the aortic position; 1.1 +/- 0.3 versus 0.8 +/- 0.3 m/sec in the mitral position).

Topics: Adolescent; Adult; Aged; Aortic Valve; Blood Flow Velocity; Child; Child, Preschool; Evaluation Studies as Topic; Female; Follow-Up Studies; Heart Valve Diseases; Heart Valve Prosthesis; Hemolysis; Humans; Infant; Male; Middle Aged; Mitral Valve; Reoperation; Thromboembolism; Warfarin

A patient with a Bjork-Shiley aortic prosthesis inserted two years and four months prior to receiving adequate anticoagulant therapy suddenly had severe intravascular hemolysis develop as a result of thrombosis of her aortic prosthesis. There was no notable hemodynamic compromise. The mechanism of the intravascular hemolysis is discussed.

Topics: Aortic Valve; Female; Heart Valve Prosthesis; Hemolysis; Humans; Middle Aged; Thrombosis; Warfarin

Topics: Animals; Antigen-Antibody Complex; Complement Fixation Tests; gamma-Globulins; Guinea Pigs; Hemolysis; Humans; Immune Sera; Protein Conformation; Prothrombin; Rabbits; Warfarin

Advanced actuarial techniques are used to analyze late results in 912 patients who had isolated mitral or aortic valve replacement with ball valve prostheses from 1965 to 1974. Experience with noncloth-covered and cloth-covered valves is compared in terms of late survival, rate of thromboembolic complications and reoperation and the influence of anticoagulation. The cloth-covered prostheses have substantially reduced the incidence of emboli after mitral valve replacement (1.9 vs. 6 emboli per 100 patient years) and have thus far eliminated emboli after aortic valve replacement in patients receiving warfarin. Patients with a cloth-covered aortic valve who did not receive warfarin had nine emboli per 100 patient years. The safety of cloth-covered valves is clearly enhanced by warfarin therapy; the efficacy of anti-platelet drugs is still uncertain. Strut cloth wear was found at reoperation in 10 patients. This should be prevented in the new model 2400 composite strut ("track") valve by a narrow metal track on the inner surface of each strut. The substantial recent reductions in operative mortality and in prosthesis-related complications pose important questions regarding timing of operations and selection of prostheses. These decisions must be individualized for each patient on the basis of a thorough analysis of late results using modern statistical methods.

Topics: Aortic Valve; Aortic Valve Insufficiency; Aortic Valve Stenosis; Evaluation Studies as Topic; Female; Follow-Up Studies; Heart Valve Diseases; Heart Valve Prosthesis; Hemolysis; Humans; Male; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Stenosis; Polyethylene Terephthalates; Polypropylenes; Polytetrafluoroethylene; Prosthesis Design; Risk; Stress, Mechanical; Thromboembolism; Time Factors; Warfarin

1 The effects of various anti-inflammatory and non-anti-inflammatory drugs on complement mediated haemolysis have been studied. Drugs which were significantly protein bound were found to inhibit this form of immune lysis, but only at greater concentrations than achieved therapeutically. 2 Removal of the drugs by prolonged dialysis resulted in restoration of complement activity with the exceptions of phenylbutazone and warfarin sodium. 3 Reconstitution experiments indicated that C2 and some of the later components especially C7 were affected by the drugs. 4 Intra-articular injections of prednisolone (100 mg) in patients with rheumatoid arthritis, failed to produce significant changes in the synovial fluid complement system. 5 None of the drugs affected the binding of antibody to antigen, or the ability of sensitized sheep cells to fix complement.

Topics: Animals; Anti-Inflammatory Agents; Antigen-Antibody Reactions; Cloxacillin; Complement System Proteins; Dialysis; Hemolysis; Humans; Isoniazid; Phenylbutazone; Prednisolone; Sodium Salicylate; Warfarin

Topics: Adult; Animals; Antibodies; Budd-Chiari Syndrome; Complement Fixation Tests; Complement System Proteins; Female; Guinea Pigs; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Inulin; Male; Middle Aged; Prednisolone; Rabbits; Sheep; Snakes; Sucrose; Venoms; Warfarin

Topics: Agglutination Tests; Analysis of Variance; Animals; Antibody Formation; Antigens; Blood Coagulation; Complement System Proteins; Endotoxins; Fever; Hemagglutination Tests; Hemolysis; Immunoglobulin M; Mercaptoethanol; Precipitin Tests; Rabbits; Salmonella typhi; Ultracentrifugation; Warfarin

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California Medical Center, San Francisco. Taken from transcriptions, they are prepared by Drs. Martin J. Cline and Hibbard E. Williams, Associate Professors of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine.

Topics: Adult; Aged; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Congenital Abnormalities; Drug Hypersensitivity; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Isoniazid; Male; Pharmaceutical Preparations; Pharmacogenetics; Primaquine; Warfarin

Topics: Aminocaproates; Anemia, Hemolytic; Animals; Blood Cell Count; Erythrocytes; Fibrin; Fibrinogen; Fibrinolysis; Hemoglobinometry; Hemolysis; Heparin; Iodine Isotopes; Iron Isotopes; Male; Plasma; Rabbits; Thrombosis; Trypsin Inhibitors; Venoms; Warfarin