hirudin and Arterial-Occlusive-Diseases

Replacing heparin with bivalirudin has been beneficial in patients undergoing coronary intervention and coronary artery bypass. The use of this alternative anticoagulant during peripheral bypass operations has not been studied. Concerns over distal thrombosis using this direct thrombin inhibitor (DTI) prompted a single-arm, open-label, pilot prospective trial of bivalirudin in patients undergoing lower extremity bypass to assess perioperative safety and efficacy.. Between 2006 and 2007, 18 patients met criteria for enrollment and underwent primary lower extremity bypass using bivalirudin. All patients had severe symptomatic atherosclerotic disease requiring lower extremity bypass. Bivalirudin at a bolus dose of 0.75 mg/kg and continuous infusion of 1.75 mg/kg/hr was used as the sole anticoagulant.. Patients (mean age, 67 years) underwent femoral-popliteal (n = 14) or femoral-tibial (n = 4) bypass preferentially using saphenous vein (83%). Mean operative time was 261 minutes, with bivalirudin infusion time of 95 +/- 26 minutes (mean +/- standard deviation). Reliable anticoagulation was achieved with weight-based dosing with activated clotting time values at baseline (systemic) of 131 +/- 92 seconds, during infusion (systemic) of 347 +/- 36 seconds, and from the distal vasculature (limb) of 345 +/- 66 seconds. Distal limb bivalirudin levels were stable at 9755 +/- 3860 ng/mL during clamp occlusion. Mean estimated blood loss was 332 +/- 191 mL with four patients (22%) requiring blood products. One patient required revision of the proximal anastomosis during the initial hospitalization. At 30 days, all bypass operations were patent with improvement of mean ankle-brachial index from 0.57 to 0.81. There were no deaths, myocardial infarctions, or amputations in the 30-day postoperative period. Based on the Thrombolysis in Myocardial Infarction classification for bleeding, one patient had major bleeding (>2 units of packed red blood cells), and three patients had minor bleeding within the first 30 days.. Bivalirudin is a safe and effective anticoagulant for lower extremity bypass operations. Thrombosis beyond the distal clamp was not seen. A comparative trial to standard anticoagulation is warranted.

Topics: Aged; Ankle Brachial Index; Anticoagulants; Arterial Occlusive Diseases; Blood Loss, Surgical; Hemorrhage; Hirudins; Humans; Infusions, Intravenous; Lower Extremity; Ohio; Peptide Fragments; Pilot Projects; Prospective Studies; Recombinant Proteins; Reoperation; Saphenous Vein; Thrombin; Thrombosis; Time Factors; Treatment Outcome; Vascular Patency; Vascular Surgical Procedures

The present study evaluated the combined use of unfractionated heparin (UFH) and bivalirudin during ad hoc transradial interventional procedures.. As a result of its proven efficacy in recent clinical trials, the direct thrombin inhibitor bivalirudin is now increasingly utilized as the anticoagulant of choice for coronary interventions. However, it is currently not packaged for diagnostic procedures. Patients undergoing ad hoc transradial procedures thus need unfractionated heparin during the diagnostic catheterization to protect against radial occlusion. It is unclear how the transition to bivalirudin should be undertaken if a subsequent intervention were performed.. A total of 117 patients underwent ad hoc transradial procedures. Fifty-one patients underwent diagnostic catheterizations receiving only 5,000 Units of UFH in divided doses: (1) Group 1H (n = 26), 2,500 U after sheath insertion and 2,500 U at conclusion; (2) Group 2H (n = 25), 1,000 U followed by 4,000 U. Sixty-six patients subsequently underwent interventions as part of the same procedure and received standard bivalirudin (B) dosing in addition to the initial UHF dose: Group 1B (n = 40), 2,500 Units of UFH plus B; Group 2B (n = 26), 1,000 Units of UFH plus B. The primary endpoint was postprocedure radial occlusion; secondary endpoints were any major adverse cardiac event (MACE) and any bleeding complication.. One patient (1%) had postprocedure radial occlusion, but this recanalized at 1 month. There were no deaths, and urgent target lesion revascularization was not required. Non-Q wave myocardial infarction occurred in 7.5%, all in Group 1B. No bleeding complications occurred.. The administration of bivalirudin after a reduced heparin dose in patients undergoing ad hoc transradial interventional procedures was not associated with adverse events in this small pilot study.

Topics: Aged; Anticoagulants; Arterial Occlusive Diseases; Cardiac Catheterization; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Heparin; Hirudins; Humans; Incidence; Inpatients; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Pilot Projects; Prospective Studies; Radial Artery; Recombinant Proteins; Whole Blood Coagulation Time

High-risk patient characteristics and complexity of percutaneous peripheral intervention (PPI) procedures suggest a need for predictable and reliable anticoagulation. We undertook this study to assess the safety and efficacy of bivalirudin as the procedural anticoagulant in patients undergoing PPI of the renal, iliac, or femoral artery.. This was a prospective, open-label, single arm study inpatients undergoing PPI of the renal, iliac, or femoral vessels to assessbivalirudin as the sole procedural anticoagulant (0.75 mg/kg bolus/1.75 mg/kg/hr infusion). The primary endpoint was procedural success defined as residual stenosis < 20%. Secondary endpoints included ischemic events (death, myocardial infarction, unplanned revascularization, and amputation), and bleeding complications, as well as ACT values and times to sheath removal, ambulation, and discharge.. 505 patients were enrolled at 26 sites. Procedural success was achieved in 95.0% of patients. Ischemic events were low (1.4%) and similar between vessel types. Protocol-defined major hemorrhage and TIMI major hemorrhage rates were 2.2% and 0.4%, respectively. Mean ACTs were similar among treatment groups (renal 353.8 seconds(s); iliac 335.9s, femoral, 343.5s).. Bivalirudin provided consistent anticoagulation and similar outcomes in all vessel types treated at the dose tested. Ischemic and bleeding event rates were low, demonstrating the safe use of bivalirudin as a procedural anticoagulant in PPI.

Topics: Aged; Angioplasty, Balloon; Arterial Occlusive Diseases; Catheterization, Peripheral; Combined Modality Therapy; Female; Femoral Artery; Follow-Up Studies; Hirudins; Humans; Iliac Artery; Length of Stay; Male; Middle Aged; Peptide Fragments; Peripheral Vascular Diseases; Prospective Studies; Recombinant Proteins; Renal Artery Obstruction; Risk Assessment; Single-Blind Method; Survival Rate; Time Factors; Treatment Outcome; Vascular Patency

Thrombin plays a major role in thrombus formation through activation of platelets and conversion of fibrinogen to fibrin.. To investigate the antithrombotic effects of the oral direct thrombin inhibitor (DTI) ximelagatran and the parenteral DTI r-hirudin in humans.. Healthy male volunteers randomized into four parallel groups each with 15 subjects received either ximelagatran (20, 40 or 80 mg orally) or r-hirudin (0.4 mg kg-1 intravenous bolus + infusion of 0.15 mg kg-1 h-1 for 2 h and 0.075 mg kg-1 h-1 for 3 h). Antithrombotic effects were assessed as changes in total thrombus area (TTA) and total fibrin area (TFA) from baseline, using the Badimon perfusion chamber model at baseline and 2 h and 5 h after drug administration.. Two hours postdosing, ximelagatran showed antithrombotic effects at both high and low shear rates (TTA% of mean baseline value +/- SEM was 76 +/- 13% and 71 +/- 17% [both P < 0.05] for the 20-mg dose, 85 +/- 11% [P > 0.05] and 62 +/- 15% [P < 0.05] for the 40-mg dose and 60 +/- 11% and 26 +/- 7% [both P < 0.05] for the 80-mg dose, respectively). r-Hirudin also showed a significant antithrombotic effect at high and low shear rates (76 +/- 11% [P = 0.05] and 57 +/- 17% [P < 0.05] of baseline values, 2 h postdosing, respectively). The inhibitory effects on TFA were similar to those on TTA.. The oral DTI ximelagatran shows antithrombotic effects under both high and low shear conditions. The antithrombotic effect of 40-80 mg ximelagatran appeared comparable to that of parenterally administered r-hirudin, which has been previously demonstrated to be clinically effective in acute coronary syndromes.

Topics: Adult; Arterial Occlusive Diseases; Azetidines; Benzylamines; Blood Coagulation Tests; Fibrin; Fibrinolytic Agents; Hirudins; Humans; Male; Perfusion; Pharmacokinetics; Stress, Mechanical; Thrombin; Thrombosis; Veins

Anticoagulant therapy is required to prevent radial artery occlusion (RAO) after transradial catheterization. There is no data comparing bivalirudin to standard heparin.. We studied 400 consecutive patients. In case of diagnostic angiography-only (n = 200), they received an intravenous bolus of heparin (70 U kg(-1)) immediately before sheath removal whereas in case of angiography followed by ad hoc percutaneous coronary intervention (n = 200), they received bivalirudin (bolus 0.75 mg kg(-1), followed by infusion at 1.75 mg/kg/h). RAO was assessed 4-8 weeks later using two-dimensional echography-doppler and reverse Allen's test with pulse oximetry.. At follow-up, 21 of the 400 (5.3%) patients were found to have RAO with no significant difference between the two groups (3.5% bivalirudin vs. 7.0% heparin, P = 0.18). Patients with RAO had a significantly lower weight compared to patients without RAO (78 ± 13 kg vs. 86 ± 18 kg, P = 0.011). By multivariate analysis, a weight <84 kg (OR: 2.78, 95% CI 1.08-8.00, P = 0.032) and a procedure duration ≤20 min (OR: 7.52, 95% CI 1.57-36.0, P = 0.011) remained strong independent predictors of RAO. All cases of radial occlusion were asymptomatic and without clinical sequelae.. Delayed administration of bivalirudin or heparin for transradial catheterization provides similar efficacy in preventing RAO. Because of its low cost, a single bolus of heparin can be preferred in case of diagnostic angiography whereas bivalirudin can be contemplated in case of ad hoc percutaneous coronary intervention. © 2010 Wiley-Liss, Inc.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Arterial Occlusive Diseases; Cardiac Catheterization; Chi-Square Distribution; Constriction, Pathologic; Coronary Angiography; Echocardiography, Doppler; Female; Heparin; Hirudins; Humans; Infusions, Intravenous; Injections, Intravenous; Logistic Models; Male; Middle Aged; Odds Ratio; Oximetry; Patient Selection; Peptide Fragments; Radial Artery; Recombinant Proteins; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Arterial Occlusive Diseases; Cardiac Catheterization; Constriction, Pathologic; Coronary Angiography; Heparin; Hirudins; Humans; Infusions, Intravenous; Injections, Intravenous; Peptide Fragments; Radial Artery; Recombinant Proteins; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Topics: Anticoagulants; Arterial Occlusive Diseases; Aspirin; Clopidogrel; Drug Resistance; Drug Therapy, Combination; Factitious Disorders; Female; Graft Occlusion, Vascular; Heparin, Low-Molecular-Weight; Hirudins; Humans; Iliac Artery; Middle Aged; Munchausen Syndrome; Phenprocoumon; Platelet Aggregation Inhibitors; Recombinant Proteins; Recurrence; Reoperation; Ticlopidine; Treatment Refusal; Vascular Surgical Procedures

Fibrillar collagens are among the most potent activators of platelets and play an important role in the initiation of thrombosis. The glycoprotein VI (GPVI)/FcRgamma-chain complex is a central collagen receptor and inhibitors of GPVI produce a major defect in arterial thrombogenesis. In this study we have examined arterial thrombus formation in mice lacking the GPVI/FcRgamma-chain complex (FcRgamma(-/-)). Using 3 distinct arterial thrombosis models involving deep vascular injury, we demonstrate that deficiency of GPVI/FcRgamma is not associated with a major defect in arterial thrombus formation. In contrast, with milder vascular injury deficiency of GPVI/FcRgamma was associated with a 30% reduction in thrombus growth. Analysis of FcRgamma(-/-) platelets in vitro, using thrombin-dependent and -independent thrombosis models, demonstrated a major role for thrombin in overcoming the thrombosis defect associated with GPVI/FcRgamma deficiency. Inhibition of thrombin in vivo produced a much greater defect in thrombus formation in mice lacking GPVI/FcRgamma compared with normal controls. Similarly, thrombin inhibition produced a marked prolongation in bleeding time in FcRgamma(-/-) mice relative to wild-type mice. Our studies define an important role for thrombin in overcoming the hemostatic and thrombotic defect associated with GPVI/FcRgamma deficiency. Moreover, they raise the interesting possibility that the full antithrombotic potential of GPVI receptor antagonists may only be realized through the concurrent administration of anticoagulant agents.

Topics: Animals; Arterial Occlusive Diseases; Blood Platelets; Blood Vessels; Disease Models, Animal; Hirudins; Mice; Mice, Knockout; Platelet Activation; Platelet Membrane Glycoproteins; Receptors, IgG; Thrombin; Thrombosis

The objective of this retrospective chart review was to evaluate the safety and feasibility of using the direct thrombin inhibitor bivalirudin as the procedural anticoagulant in patients undergoing percutaneous peripheral intervention (PPI).. Patients with peripheral artery disease are in general a high-risk population that requires safe and reliable anticoagulation with complete thrombin inhibition. Bivalirudin, a direct thrombin inhibitor, has been shown to be as effective as heparin, but with fewer bleeding events in PCI trials, and recent data suggest that bivalirudin may provide the same benefits in PPI.. This was a retrospective chart review of patients who underwent PPI with bivalirudin as the foundation anticoagulant. Bivalirudin was administered as a 0.75 mg per kg bolus, followed by a 1.75 mg per kg per hour infusion for the duration of the procedure. The primary endpoint was procedural success defined as residual stenosis less than or equal to 20%. Ischemic and hemorrhagic events were collected, as well as time-to-sheath removal, ambulation and discharge.. Data were collected for 150 patients. Procedural success was achieved in 98.5%. Ischemic events were low: death (2.0%), myocardial infarction (0.0%), urgent revascularization (0.8%). Major and minor hemorrhage occurred in 4.7% and 2.0% of patients, respectively. Time-to-sheath removal, ambulation and discharge were short.. Bivalirudin provided effective anticoagulation in these generally high-risk patients undergoing PPI. Ischemic and bleeding events were low and comparable to those reported in the literature, suggesting that bivalirudin is safe to use in this population.

Topics: Aged; Angioplasty; Anticoagulants; Antithrombins; Arterial Occlusive Diseases; Feasibility Studies; Female; Hemorrhage; Hirudins; Humans; Incidence; Ischemia; Male; Medical Records; Middle Aged; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Retrospective Studies; Treatment Outcome; Urokinase-Type Plasminogen Activator

Topics: Adenocarcinoma; Adult; Anticoagulants; Arterial Occlusive Diseases; Autoimmune Diseases; Drug Resistance; Female; Heparin; Heparin, Low-Molecular-Weight; Hepatitis C, Chronic; Hirudins; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Neoplasms, Unknown Primary; Platelet Aggregation Inhibitors; Portal Vein; Pulmonary Embolism; Recombinant Proteins; Recurrence; Thrombocytopenia; Vena Cava, Inferior; Venous Thrombosis; Warfarin

Many heparin (UFH) limitations are overcome by bivalirudin (Angiomax ). The pharmacokinetic profile of bivalirudin appears well suited for percutaneous peripheral intervention (PPI), yet few data exist regarding its safety and feasibility in this setting.. One hundred and eighty renal and 75 iliac PPIs performed between May 2001 and June 2002 with bivalirudin as anticoagulation were compared to a historical UFH control. Variables evaluated included thrombotic events, intracranial bleeding, major surgical complications, sheath removal time, vascular access complication, time to ambulate and length of stay (LOS). Follow-up included 6-month renal and iliac duplex ultrasound and ankle-brachial index.. Procedural success was achieved in 100% of patients treated with bivalirudin, with no thrombotic events, intracranial bleeding or major surgical complications observed. Procedural success was achieved in 179/180 (99%) renal and 74/75 (98.6%) iliac patients treated with UFH. Significant differences were observed for sheath removal time < 60 minutes (84% versus 59%; p < 0.0001), time to ambulation < 6 hours (75.5% versus 58%; p < 0.0005) and LOS < 24 hours (85.5% versus 72%; p = 0.002) in bivalirudin-treated renal PPI patients versus UFH-treated patients, respectively. Significant differences were also observed in favor of bivalirudin for the iliac PPIs for sheath removal time < 60 minutes (p = 0.012) and time to ambulation < 6 hours (p = 0.039). Following 6-month renal and iliac duplex ultrasound, repeat PPI was required in 7/180 (3.9%) and 9/180 (5%) of renal, and 3/75 (4%) and 4/75 (5.3%) of iliac patients treated with bivalirudin or UFH, respectively.. Bivalirudin is a safe and feasible alternative anticoagulant in renal and iliac PPI and may offer decreased sheath removal time, time to ambulation and LOS. A larger prospective randomized multicenter trial is warranted.

Topics: Aged; Anticoagulants; Arterial Occlusive Diseases; Case-Control Studies; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Heparin, Low-Molecular-Weight; Hirudins; Humans; Iliac Artery; Infusions, Intravenous; Male; Middle Aged; Peptide Fragments; Peripheral Vascular Diseases; Recombinant Proteins; Renal Artery Obstruction; Retrospective Studies; Risk Assessment; Treatment Outcome; Vascular Patency

Topics: Aged; Arterial Occlusive Diseases; Diagnosis, Differential; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Recombinant Proteins; Thrombocytopenia

We report here a case of recurrent venous and arterial thromboembolism, Trousseau's syndrome, in a cancer patient who developed heparin-induced thrombocytopenia. She was treated with lepirudin and after establishing the patient-specific half-life for subcutaneous lepirudin, she was successfully maintained on this therapy for more than eight months. To our knowledge this case represents the longest reported use of subcutaneous lepirudin.

Topics: Anticoagulants; Arterial Occlusive Diseases; Female; Heparin; Hirudins; Humans; Injections, Subcutaneous; Kinetics; Middle Aged; Paraneoplastic Syndromes; Partial Thromboplastin Time; Recombinant Proteins; Recurrence; Thrombocytopenia; Thromboembolism; Venous Thrombosis

We present the first steps in the elaboration of an approach of extracellular matrix-targeted local drug delivery (ECM-LDD), designed to provide a high concentration, ubiquitous distribution, and long-term retention of a drug within the vessel wall after local intravascular delivery. The approach is based on the concept of a bifunctional drug comprising a "therapeutic effector" and an "affinity vehicle," which should bind to an abundant component of the vessel wall. The aim of the present study was to select molecules suitable for the role of affinity vehicles for ECM-LDD and to study their intravascular delivery and retention ex vivo and in an animal model. By use of fluorescence microscopy, the following molecules were selected on the basis of strong binding to cross sections of human vessels: protamine, polylysine, polyarginine, a glycosaminoglycan-binding peptide from vitronectin, and a synthetic dendrimer. With polylysine as a prototypic affinity vehicle, we showed that after intravascular delivery, polylysine was concentrated throughout a luminal layer of the vascular wall to an extremely high concentration of 20 g/L and was retained therein for at least 72 hours of perfusion without noticeable losses. Low molecular weight (fluorescein) and high molecular weight (hirudin) compounds could be chemically conjugated to polylysine and were retained in the vessel wall after intravascular delivery of the conjugates. In conclusion, by use of the ECM-LDD method, an extremely high concentration and long-term retention of locally delivered drug can be reached. Polycationic molecules can be considered as potential affinity vehicles for ECM-LDD.

Topics: Animals; Aorta; Arterial Occlusive Diseases; Arteries; Carotid Arteries; Culture Techniques; Drug Delivery Systems; Extracellular Matrix; Glycosaminoglycans; Hirudins; Humans; Male; Microscopy, Fluorescence; Peptides; Pharmaceutical Vehicles; Polylysine; Protamines; Rats; Rats, Wistar; Umbilical Arteries

We prospectively studied 15 patients suffering from acute heparin-induced thrombocytopenia (HIT) type II with and without thromboembolic events and 4 patients with anamnestically known HIT type II recurrently requiring thromboprophylaxis in order to develop new therapeutic strategies by subcutaneous recombinant hirudin administration. Patients with acute venous or arterial thromboembolism were treated with aPTT-controlled intravenous (mean: 19.3 days) followed by subcutaneous r-hirudin (mean: 22.5 days). Patients without thromboembolism were treated with subcutaneous r-hirudin (mean: 25.9 days). Four patients were readmitted to subcutaneous r-hirudin (mean: 32 days). When r-hirudin was administered subcutaneously following intravenous treatment, mean baseline (prior to the injection) and mean peak (1.5-2.5 hours after the injection) aPTT ratios were 1.1 (+/-0.2) to 1.7 (+/-0.48) and 2. 48 (+/-0.43) to 2.52 (+/-0.4) times normal value, respectively. Mean baseline and mean peak ECT ratios were 1.2 (+/-0.12) to 1.9 (+/-0. 22) and 2.2 (+/-0.25) to 2.6 (+/-0.11) times the upper normal value, respectively. When r-hirudin was initially administered subcutaneously, mean baseline and mean peak aPTT ratios were 1.41 (+/-0.25) to 1.61 (+/-00.28) and 1.88 (+/-0.26) to 2.06 (+/-0.09) times the normal value, respectively. Mean baseline and mean peak ECT ratios were 1.25 (+/-0.2) to 1.5 (+/-0.38) and 2.01 (+/-0.21) to 2.23 (+/-0.25) times the upper limit of normal, respectively. Patients who received recurrent subcutaneous r-hirudin had mean baseline and peak aPTT values of 1.5 (+/-0.35) to 1.75 (+/-0.156) and 2.0 (+/-0.33) to 2.1 (+/-0.18) times the normal value, respectively. Mean baseline and peak ECT ratios were 1.3 (+/-0.26) to 1.65 (+/-0.09) and 1.94 (+/-0.256) to 2.7 (+/-0.23) times the upper limit of normal, respectively. The overall cumulative incidence of r-hirudin antibodies was 12/19 (63%) with a significant accumulation of r-hirudin in antibody-positive patients compared to antibody-negative patients (p<0.05). No patient suffered a new thromboembolic or major bleeding event. Subcutaneous administration of recombinant hirudin provides a long-term thromboprophylaxis regimen in HIT type II patients after passivation of acute thromboembolism.

Topics: Adult; Aged; Aged, 80 and over; Antibodies; Arterial Occlusive Diseases; Creatine; Female; Hematoma; Heparin; Hirudin Therapy; Hirudins; Humans; Injections, Subcutaneous; Male; Middle Aged; Partial Thromboplastin Time; Pilot Projects; Prospective Studies; Recombinant Proteins; Thrombocytopenia; Thromboembolism; Time Factors

The novel recombinant hirudin analog CX-397 was investigated with respect to its pharmacological activity and antithrombin profiles in vivo and in vitro. In three different types of thrombosis models in rats, including stasis and thrombin-induced venous, glass surface-activated arterio-venous shunt, and ferric chloride-induced arterial thrombosis models, CX-397 and rHV-1 elicited potent antithrombotic effects, where the minimum effective doses of rHV-1 tended to be higher than those of CX-397 in the arterio-venous shunt and arterial thrombosis models. The hemorrhagic risk of CX-397 in template bleeding in rats was not higher than that of rHV-1, indicating that CX-397 is superior to rHV-1 for treating the platelet-dominant type of thrombosis. However, no differences were detected between CX-397 and rHV-1 in their effects on in vitro coagulation times and thrombin-induced platelet aggregation, suggesting the possibility that some unknown mechanisms other than simple thrombin inhibition are also involved in their antithrombotic actions.

Topics: Amino Acid Sequence; Animals; Arginine; Arterial Occlusive Diseases; Arteriovenous Shunt, Surgical; Chlorides; Drug Evaluation, Preclinical; Ferric Compounds; Fibrinolytic Agents; Glass; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Molecular Sequence Data; Pipecolic Acids; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Serine Proteinase Inhibitors; Sulfonamides; Thrombin; Thrombosis; Vena Cava, Inferior; Venous Thrombosis

Further to characterize the processes involved in the FeCl3-induced thrombosis model, we determined the effect of aspirin, heparin, hirudin, trans-4-(aminomethyl) cyclohexane carboxylic acid (AMCHA), thrombocytopenia, and flow modifications on time to occlusion (TTO) and thrombus weight (TW) in the rat carotid artery. Aspirin, from 3 to 100 mg/kg, showed no dose-response relation for either TTO or TW and did not significantly affect ex vivo platelet aggregation. Heparin, at doses that significantly increased the activated partial thromboplastin time (APTT), dose-dependently increased the TTO of animals that showed an occlusion during the monitoring period and also reduced the TW. Hirudin required constant infusion to prevent occlusion and reduce the TW, when the APTT was also significantly increased. AMCHA did not affect the TW but reduced the TTO. Animals made thrombocytopenic by the use of antiplatelet serum did not occlude during the monitoring period, and the TW was significantly reduced. Changes in flow showed that the TTO was not affected, but the TW showed an inverse correlation with average flow. The results obtained for platelet depletion and flow modifications expand on previous findings with this model and support the physiological relevance of the model.

Topics: Animals; Antifibrinolytic Agents; Antithrombins; Arterial Occlusive Diseases; Aspirin; Blood Platelets; Carotid Artery Diseases; Carotid Artery, Common; Chlorides; Ferric Compounds; Fibrinolytic Agents; Heparin; Hirudins; Immune Sera; Ligation; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Thrombosis; Tranexamic Acid

Polyethylene glycol (PEG)-hirudin is a derivative of hirudin with a long plasma half-life. We have compared the efficacy of PEG-hirudin with unfractionated heparin (UH) in preventing arterial thrombosis. Arterial thrombus formation was induced ex vivo in 12 healthy human volunteers by exposing a tissue factor-coated coverslip positioned in a parallel-plate perfusion chamber to flowing nonanticoagulated human blood drawn directly from an antecubital vein at an arterial wall shear rate of 2600 s-1 for 3.5 minutes. PEG-hirudin, UH, or saline (as control) were administered ex vivo through a heparin-coated mixing device positioned proximal to the perfusion chamber. Platelet and fibrin deposition was quantified by immunoenzymatic measure of the P-selectin and D-dimer content of dissolved plasmin-digested thrombi, respectively. UH was administered to a plasma concentration of 0.35 IU/mL. This concentration prolonged the activated partial thromboplastin time from 32+/-1 seconds to 79+/-4 seconds (P<0.01). UH did not significantly prevent platelet deposition. However, fibrin deposition was reduced by 39% (P<0.05). PEG-hirudin in plasma concentrations of 0.5, 2.5, and 5 microg/mL prolonged the activated partial thromboplastin time to 48+/-2, 87+/-4, and 118+/-4 seconds, respectively. In contrast to UH, PEG-hirudin prevented both platelet and fibrin deposition in a dose-dependent manner with a >80% reduction at 5 microg/mL (P<0.01). Furthermore, the plasma level of PEG-hirudin required to significantly prevent fibrin deposition (0.5 microg/mL) corresponded to a much shorter prolongation of activated partial thromboplastin time (48+/-2 seconds) than that needed for UH (79+/-4 seconds). Thus, our results are compatible with the view that thrombin is greatly involved in recruitment of platelets in evolving thrombi, and that PEG-hirudin is an effective agent for preventing arterial thrombosis in a human ex vivo experimental model.

Topics: Antithrombin III; Arterial Occlusive Diseases; beta-Thromboglobulin; Blood Coagulation; Blood Coagulation Tests; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Glass; Half-Life; Heparin; Hirudins; Humans; P-Selectin; Peptide Hydrolases; Platelet Activation; Sodium Chloride; Thromboplastin; Thrombosis

A 60-year-old woman was admitted because of acute ischemia of the right leg. The patient had been immobilized during diagnostic procedures for a thoracic paraspinal space-occupying lesion and over 5 days had received unfractionated sodium heparin by subcutaneous injection. The pedal pulses were no longer palpable.. The thrombocyte count had fallen from 207,000/microliter to 45,000/microliter. Angiography revealed occlusion of the common femoral artery. Heparin-induced platelet aggregation (HIPA) test demonstrated type II heparin-induced thrombocytopenia. Thrombectomy was performed and intraoperatively an i.v. bolus of the recombinant hirudin, lepirudin (Refludan), was given (0.2 mg/kg body weight), continual lepirudin infusion being continued postoperatively. Normal blood flow was re-established in the limb and the pedal pulse was palpable. There were no complications.. Recombinant hirudin is the only alternative licensed in Germany to heparin and seem to be suitable also for the intraoperative bolus administration in heparin-induced thromboembolic vascular occlusions.

Topics: Angiography, Digital Subtraction; Anticoagulants; Arterial Occlusive Diseases; Female; Femoral Artery; Heparin; Hirudin Therapy; Hirudins; Humans; Infusions, Intravenous; Injections, Intravenous; Intraoperative Care; Ischemia; Leg; Middle Aged; Platelet Aggregation; Platelet Count; Postoperative Care; Recombinant Proteins; Thrombectomy; Thrombocytopenia

Topics: Angioplasty, Balloon; Animals; Arterial Occlusive Diseases; Blood Vessels; Carotid Stenosis; Hirudin Therapy; Hirudins; Humans; Recurrence; Thrombin; Tunica Intima

To investigate the clinical implications and mechanisms of spontaneous platelet aggregation (SPA) in man, 150 normal subjects, 22 patient controls and 130 patients with vascular insufficiency were studied. SPA was negative in normal subjects and patient controls whereas it was positive in 36 of 66 (54%) patients with transient ischemic attacks, 6 of 32 (19%) patients with stable angina, 7 of 10 (70%) patients with acute myocardial infarction and 11 of 14 (80%) patients with acute peripheral arterial insufficiency. The SPA was inhibited with aspirin in vivo, and inhibited competitively in vitro by low concentrations of aspirin, 2-chloroadenosine, prostaglandin E1 or apyrase but only by high concentrations of heparin or hirudin. Addition of platelet-poor plasma from patients with positive SPA did not cause normal platelets to aggregate. Treatment of patients who had acute peripheral arterial insufficiency with aspirin and dipyridamole prevented SPA with notable clinical improvement of the ischemic changes.

Topics: Adenosine; Adult; Aged; Angina Pectoris; Apyrase; Arterial Occlusive Diseases; Aspirin; Coronary Disease; Dipyridamole; Heparin; Hirudins; Humans; Ischemic Attack, Transient; Middle Aged; Myocardial Infarction; Platelet Aggregation; Prostaglandins E