hirudin and Blood-Coagulation-Disorders

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 initiating event in unstable angina is plaque rupture. It triggers platelet activation and aggregation, leading to the formation of an intracoronary thrombus, which can be detected on autopsy, angiography, and by fiber-optic coronary angioscopy. Biochemical markers of platelet and thrombin activity are usually increased and support the pathophysiologic role of coronary thrombosis in unstable angina. Aspirin and heparin have been shown to be effective, whereas thrombolytic therapy has no beneficial clinical effect. Newer specific antithrombotic drugs (hirudin, hirulog) and GPIIb/IIIa platelet receptor inhibitors are being tested in clinical trials and seem to provide a new dimension for the treatment of acute coronary syndromes.

Topics: Angina, Unstable; Blood Coagulation Disorders; Coronary Thrombosis; Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Recombinant Proteins; Thrombin

To compare the efficacy and safety of hirudin and heparin for anticoagulation during continuous renal replacement therapy (CRRT) in critically ill patients.. Prospective, randomized controlled pilot study.. Single centre; interdisciplinary intensive care unit at a university hospital.. Seventeen patients receiving CRRT.. Patients were randomly allocated to two groups. Heparin group (nine patients): continuous administration of 250 IU/h heparin; dose was adjusted in 125 IU/h steps with a targeted activated clotting time (ACT) of 180-210 s. Hirudin group (eight patients): continuous infusion of 10 micrograms/kg/h hirudin, dose was adjusted in 2 micrograms/kg/h steps with a targeted ecarin clotting time (ECT) of 80-100 s. Observation time was 96 h.. Measured filter run patency and haemofiltration efficacy did not significantly differ between the two groups. Three bleeding complications were observed in the hirudin group, none in the heparin group (P < 0.01). At the onset of bleeding, which occurred 60 or more hours after the start of therapy, only one patient was still under continuous hirudin administration but levels were either in therapeutic range or below.. Hirudin can be used efficiently for anticoagulation in CRRT. Late bleeding complications may have been caused by possible hirudin accumulation, but this was not evident from hirudin plasma and ECT levels. Since bleeding complications were observed only in the presence of documented coagulation disorders, not only adequate drug monitoring but also the plasmatic and cellular coagulation status of the patient should be taken into consideration for adjusting hirudin dosage.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anticoagulants; APACHE; Blood Coagulation Disorders; Blood Coagulation Tests; Combined Modality Therapy; Female; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Intensive Care Units; Male; Middle Aged; Multiple Organ Failure; Renal Replacement Therapy

The initiation of coagulation in trauma is thought to originate from exposed tissue factor (TF); recent data have led to the alternative hypothesis that damage-associated molecular patterns may contribute to postinjury coagulation. In acute traumatic coagulopathy, aberrant coagulation is mediated via the activated protein C (aPC) pathway; the upstream regulators of this process and its relation to TF remain uncharacterized. To examine the role of the TF pathway in mediating acute traumatic coagulopathy, we used specific antibody blockades in an established murine model of traumatic hemorrhagic shock, hypothesizing that both coagulation activation after injury and aPC-mediated coagulopathy are driven by TF via thrombin.. Mice underwent an established model of trauma and hemorrhage and were subjected to either sham (vascular cannulation) or trauma-hemorrhage (cannulation, laparotomy, shock to mean arterial pressure of 35 mm Hg); they were monitored for 60 minutes before sacrifice. Mice in each group were pretreated with either targeted anti-TF antibody to block the TF pathway or hirudin for specific blockade of thrombin. Plasma was assayed for thrombin-antithrombin (TAT) and aPC by enzyme-linked immunosorbent assay.. Compared with controls, trauma-hemorrhage mice treated with anti-TF antibody had significantly reduced levels of TAT (2.3 ng/mL vs. 5.7 ng/mL, p = 0.016) and corresponding decreases in aPC (16.3 ng/mL vs. 31.6 ng/mL, p = 0.034), with reductions to levels seen in sham mice. Direct inhibition of thrombin yielded similar results, with reduction in aPC to levels below those seen in sham mice.. In this study, blockade of the TF pathway led to the attenuation of both thrombin production and aPC activation observed in traumatic shock. Specific thrombin inhibition achieved similar results, indicating that aPC-related coagulopathy is mediated via thrombin activated by the TF pathway. The near-complete blockade of TAT and aPC observed in this model argues for a dominant role of the TF-thrombin pathway in both coagulation activation after injury and traumatic coagulopathy.

Topics: Animals; Blood Coagulation Disorders; Enzyme-Linked Immunosorbent Assay; Hirudins; Male; Mice; Mice, Inbred C57BL; Protein C; Shock, Hemorrhagic; Shock, Traumatic; Thrombin; Thromboplastin; Wounds and Injuries

Acute coagulopathy is a serious complication of traumatic brain injury (TBI) and is of uncertain etiology because of the complex nature of TBI. However, recent work has shown a correlation between mortality and abnormal hemostasis resulting from early platelet dysfunction. The aim of the current study was to develop and characterize a rodent model of TBI that mimics the human coagulopathic condition so that mechanisms of the early acute coagulopathy in TBI can be more readily assessed. Studies utilizing a highly reproducible constrained blunt-force brain injury in rats demonstrate a strong correlation with important postinjury pathological changes that are observed in human TBI patients, namely, diminished platelet responses to agonists, especially adenosine diphosphate (ADP), and subarachnoid bleeding. Additionally, administration of a direct thrombin inhibitor, preinjury, recovers platelet functionality to ADP stimulation, indicating a direct role for excess thrombin production in TBI-induced early platelet dysfunction.

Topics: Acute Disease; Adenosine Diphosphate; Animals; Blood Cell Count; Blood Coagulation Disorders; Blood Platelets; Brain; Brain Injuries; Hirudins; Kinetics; Male; Partial Thromboplastin Time; Platelet Aggregation; Prothrombin; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Subarachnoid Hemorrhage; Thrombelastography; Thrombin; Wounds, Nonpenetrating

To describe management of anticoagulation with a decreased dose requirement of bivalirudin during cardiopulmonary bypass using deep hypothermic circulatory arrest (DHCA) and the reversal of the ensuing coagulopathy with recombinant factor VIIa (rFVIIa).. A 48-year-old male developed chest pain, hypertension, and an aortic aneurysm requiring urgent surgical repair. At the time of surgery, the patient reported an allergy to heparin, so bivalirudin was used for anticoagulation (1 mg/kg loading dose, followed by intermittent infusions of 1.25-2.5 mg/kg/h over the 5 hours of cardiopulmonary bypass). When the cooling process was initiated, bivalirudin was stopped in anticipation of loss of the clotting cascade function and potential slowing of drug elimination. Bivalirudin was restarted for 45 minutes during the rewarming period because of concern for potential clot formation in the bypass circuit with recovery of hemostasis; it was again stopped due to the patient's activated clotting time (ACT) of 504 seconds. Despite this measure, diffuse and severe coagulopathy was observed upon rewarming, with ACTs longer than 999 seconds. Although multiple blood products were administered, visualization of a clot in the surgical field was not notable. A total dose of rFVIIa 20 μg/kg was administered, resulting in visual clot formation within 4 minutes. On postsurgical day 6, bilateral asymptomatic distal deep vein thromboses were noted on imaging; on postsurgical day 8, fondaparinux 2.5 mg subcutaneously was administered daily to prevent clot extension. The patient was discharged on postoperative day 23 with no acute issues and no further anticoagulants.. Alternative anticoagulation agents such as bivalirudin are used in patients who have an allergy or contraindication to heparin. We propose that prolonged coagulopathy after the induction of hypothermia is due to decreased clotting cascade function as well as slowing of protease activity resulting in decreased bivalirudin elimination. We observed a positive response to low-dose rFVIIa, which could be due to activation of the extrinsic pathway and/or a thrombin burst, resulting in hemostasis. Currently, there is limited evidence supporting reversal of direct thrombin inhibitors with rFVIIa.. In the setting of DHCA, bivalirudin should be used cautiously, with frequent monitoring of the ACTs and potential cessation of the infusion in anticipation of prolonged drug effect with subsequent potential coagulopathy. If coagulopathy ensues, use of low-dose rFVIIa may be an option to initiate hemostasis. When using rFVIIa, it is important to consider the risk of thrombosis and monitor patients accordingly.

Topics: Antithrombins; Blood Coagulation Disorders; Cardiopulmonary Bypass; Circulatory Arrest, Deep Hypothermia Induced; Dose-Response Relationship, Drug; Drug Monitoring; Factor VIIa; Follow-Up Studies; Hirudins; Humans; Iatrogenic Disease; Male; Middle Aged; Peptide Fragments; Recombinant Proteins

Identifying factors that influence gene transfer efficacy is critical for a successful gene-based clinical study. Here we demonstrate that in vivo AAV-2-mediated gene transfer is efficiently inhibited by unfractionated heparin, but not by a heparin preparation containing mainly low-molecular-weight forms (LMWH). Surprisingly, inhibitors of thrombin or factor Xa (F.Xa) significantly reduced AAV-2 transduction in a dose-dependent manner. These effects were independent of the vector promoter, transgene, or strain of mice. Expression by alternate AAV serotypes 5 and 8 was not affected by anticoagulant drugs, which suggests an AAV-2-specific effect. Moreover, AAV-2-mediated gene expression was diminished in mice with deficiency in thrombin generation (factor IX deficiency) and enhanced in mice with procoagulant phenotype due to factor V Leiden. In addition, inhibitors of F.Xa diminished adenovirus-mediated gene expression. These results demonstrated that coagulation activity itself is critical to ensure optimal viral vector transduction. Since intravascular delivery of vectors often requires the use of anticoagulants, the use of LMWH appears to be safe. These observations are of relevance for approaches using AAV-2 or adenoviral vectors, especially in early phase studies designed to identify the minimum therapeutic doses.

Topics: Adenoviridae; Animals; Anticoagulants; Arthropod Proteins; Blood Coagulation Disorders; Cell Line; Dependovirus; Factor V; Factor Xa Inhibitors; Gene Dosage; Gene Transfer Techniques; Genetic Vectors; Heparin; Hepatocytes; Hirudins; Humans; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peptides; Species Specificity; Thrombin; Transduction, Genetic

Many pediatric patients requiring anticoagulation during interventional heart catheterizations have antithrombin (AT) deficiency. AT is a necessary cofactor for heparin inhibition of thrombin. Without sufficient AT, these patients are at increased risk for thrombotic complications. This case describes the successful use of bivalirudin, a direct thrombin inhibitor, as an anticoagulant in a 2-month old infant with AT deficiency undergoing stent placement.

Topics: Anticoagulants; Antithrombins; Blood Coagulation Disorders; Comorbidity; DiGeorge Syndrome; Hirudins; Humans; Infant; Male; Peptide Fragments; Pulmonary Artery; Radiography; Recombinant Proteins; Stents

Topics: Animals; Antibody Formation; Anticoagulants; Blood Coagulation Disorders; Dogs; Hirudins; Humans; Male; Rats; Recombinant Proteins; Swine; Thrombin; Thrombosis

Saos-2 cells, derived from a primary human osteosarcoma, caused dose-dependent platelet aggregation in heparinised human platelet-rich plasma. Saos-2 tumour cell-induced platelet aggregation (TCIPA) was completely inhibited by hirudin but unaffected by apyrase. The cell suspension shortened the plasma recalcification times of normal, factor VIII-deficient and factor IX-deficient human plasmas in a dose-dependent manner. However, the cell suspension did not affect the recalcification time of factor VII-deficient plasma. Moreover, a monoclonal antibody (MAb) against human tissue factor completely abolished TCIPA. Flow cytometric analysis using anti-integrin MAbs as the primary binding ligands demonstrated that the integrin receptors alpha v beta 3, alpha 5 beta 1 and alpha 6 beta 1 were present of Saos-2 cells, which might mediate tumour cell adhesion to extracellular matrix. Rhodostomin, an Arg-Gly-Asp (RGD)-containing snake venom peptide which antagonises the binding of fibrinogen to platelet membrane glycoprotein IIb/IIIa, prevented Saos-2 TCIPA as well as tumour cell adhesion to vitronectin, fibronectin and collagen type I. Likewise, the synthetic peptide Gly-Arg-Gly-Asp-Ser (GRGDS) showed a similar effect. On a molar basis, rhodostomin was about 18,000 and 1000 times, respectively, more potent than GRGDS in inhibiting TCIPA and tumour cell adhesion.

Topics: Amino Acid Sequence; Antibodies, Monoclonal; Apyrase; Blood Coagulation Disorders; Blood Coagulation Factors; Bone Neoplasms; Cell Adhesion; Enzyme Activation; Extracellular Matrix; Hirudins; Humans; Integrins; Molecular Sequence Data; Neoplasm Metastasis; Neoplasm Proteins; Oligopeptides; Osteosarcoma; Peptides; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Protein Binding; Thrombin; Tumor Cells, Cultured

Topics: alpha 1-Antitrypsin; Blood Coagulation Disorders; Factor IX; Factor VIII; Genetic Engineering; Hirudins; Humans; Thrombosis; Tissue Plasminogen Activator

The apparent amount of factor VII as determined in a one-stage test depends on the type of thromboplastin used: bovine thromboplastin only reacts with human factor VIIa whereas human thromboplastin interacts with unactivated human factor VII as well. Therefore the ratio factor VII activity as measured with bovine thromboplastin divided by the factor VII activity as assessed with human thromboplastin reflects the state of activation of factor VII in plasma. This approach was used to study the process of cold promoted factor VII activation and the involvement of different clotting factors therein. It could be shown that cold promoted activation does not occur in the absence of factors II and XII and is reduced for about 50% in factor IX deficient plasma. The other coagulation factors have a minor influence on the process. The results indicate that the cold promoted factor VII activation is the result of activation by both activated contact products and thrombin.

Topics: Adult; Animals; Blood Coagulation Disorders; Cattle; Cold Temperature; Factor VII; Factor VIIa; Female; Hirudins; Humans; Kallikreins; Male; Specimen Handling; Thrombin; Thromboplastin; Time Factors

Topics: Aminocaproates; Animals; Aprotinin; Blood Coagulation Disorders; Fibrin; Fibrinogen; Fibrinolysis; Hirudins; Iodine Radioisotopes; Protamines; Prothrombin Time; Shwartzman Phenomenon; Streptokinase; Thrombin; Time Factors

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Endopeptidases; Fibrinogen; Fibrinolysis; Heparin; Hirudins; Humans; Protease Inhibitors; Snakes; Thrombin; Venoms

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Cholecystectomy; Gastrectomy; Hirudins; Humans; Postoperative Complications; Thoracic Surgery; Thorax; Thyroidectomy; Time Factors

Topics: Blood Coagulation Disorders; Diagnosis, Differential; Hirudins; Humans

Topics: Anticoagulants; Blood Coagulation Disorders; Coumarins; Hemostatics; Hirudins; Humans; Prothrombin