hirudin and Antiphospholipid-Syndrome

Anticoagulation for cardiopulmonary bypass (CPB) is required to prevent acute disseminated intravascular coagulation and clot formation within the bypass circuit. Unfractionated heparin is the standard anticoagulant for CPB due to its many advantages and long history of successful use. However, heparin has the unique drawback of triggering Heparin-PF4 (PF4) antibodies potentially leading to heparin-induced thrombocytopenia (HIT). We have limited data regarding reformation of antibodies if a patient has had a prior (remote) antibody production or full HIT. Patients with antiphospholipid antibodies undergoing CPB with unfractionated heparin have a high complication rate, even in the absence of HIT. Antiphospholipid antibodies have a multifaceted, cumulatively inhibitory effect on the normal anticoagulation armamentarium in vivo. Even more concerning is the possibility that antiphospholipid syndrome and HIT may be synergistic. We report a patient with risk factors for both thromboembolic (remote history of HIT and antiphospholipid syndrome) and hemorrhagic complications who underwent an aortic valve replacement and coronary artery bypass grafting on CPB using bivalirudin. We discuss the complex decision making regarding anticoagulant for CPB, particularly with regard to American College of Chest Physicians guidelines.

Topics: Anticoagulants; Antiphospholipid Syndrome; Aortic Valve; Cardiopulmonary Bypass; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Practice Guidelines as Topic; Recombinant Proteins; Risk Factors; Thrombocytopenia; Thromboembolism

The occurrence of lupus anticoagulant is associated with the hazard of developing an antiphospholipid syndrome, a severe prothrombotic condition which may particularly occur after major surgical trauma. This disease requires certain considerations regarding surgical strategy and anticoagulation management. We describe the perioperative management of a patient scheduled for elective aortic valve replacement and diagnosed for having antiphospholipid antibodies. The procedure was successfully performed using a minimally invasive approach via transapical aortic valve replacement and anticoagulation with the nonreversible short-acting direct thrombin Inhibitor bivalirudin.

Topics: Aged; Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; Aortic Valve; Aortic Valve Stenosis; Cardiac Catheterization; Hirudins; Humans; Male; Minimally Invasive Surgical Procedures; Peptide Fragments; Perioperative Care; Recombinant Proteins; Transcatheter Aortic Valve Replacement

Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Antithrombins; Catastrophic Illness; Female; Heparin; Hirudins; Humans; Kidney Transplantation; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

This work was aimed at characterizing the interaction of β(2)-glycoprotein I (β(2)GPI), an abundant plasma protein of unknown function, with human thrombin, the final effector protease in the coagulation cascade.. The β(2)GPI-thrombin interaction was studied by surface plasmon resonance (SPR), fluorescence, and molecular modeling. The effect of β(2)GPI on the procoagulant (fibrin generation and platelet aggregation) and anticoagulant (protein C activation) functions of thrombin were investigated with turbidimetric, immunocytofluorimetric and enzymatic assays.. SPR and fluorescence data indicated that β(2)GPI tightly bound thrombin (K(d) = 34 nM) by interacting with both protease exosites, while leaving the active site accessible. This picture is fully consistent with the theoretical model of the β(2)GPI-thrombin complex. In particular, blockage of thrombin exosites with binders specific for exosite-1 (hirugen and HD1 aptamer) or exosite-2 (fibrinogen γ'-peptide and HD22 aptamer) impaired the β2 GPI-thrombin interaction. Identical results were obtained with thrombin mutants having one of the two exosites selectively compromised by mutation (Arg73Ala and Arg101Ala). Fluorescence measurements indicated that β(2)GPI did not affect the affinity of the enzyme for active site inhibitors, such as p-aminobenzamidine and the hirudin(1-47) domain, in agreement with the structural model. β(2)GPI dose-dependently prolonged the thrombin clotting time and ecarin clotting time in β(2)GPI-deficient plasma. β(2)GPI inhibited thrombin-induced platelet aggregation (IC50 = 0.36 μM) by impairing thrombin cleavage of protease-activated receptor 1 (PAR1) (IC50 = 0.32 μM), both on gel-filtered platelets and in whole blood. Strikingly, β(2) GPI did not affect thrombin-mediated generation of the anticoagulant protein C.. β(2) GPI functions as a physiologic anticoagulant by inhibiting the key procoagulant activities of thrombin without affecting its unique anticoagulant function.

Topics: Anticoagulants; Antiphospholipid Syndrome; Benzamidines; beta 2-Glycoprotein I; Blood Coagulation; Catalytic Domain; Chromatography, Gel; Coagulants; Enzyme Inhibitors; Fibrin; Flow Cytometry; Hemostasis; Hirudins; Humans; Hydrolysis; Inhibitory Concentration 50; Kinetics; Mutation; Nephelometry and Turbidimetry; Protein Binding; Receptor, PAR-1; Surface Plasmon Resonance; Thrombin

Topics: Adolescent; Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; Antithrombins; beta 2-Glycoprotein I; Diagnosis, Differential; Disease Progression; Dose-Response Relationship, Drug; Down Syndrome; Enoxaparin; Female; Hirudins; Humans; Immunoglobulin M; Recombinant Proteins; Renal Veins; Thrombophlebitis; Thrombosis; Vena Cava, Inferior

Topics: Anticoagulants; Antiphospholipid Syndrome; Cerebral Hemorrhage; Drug Administration Schedule; Half-Life; Heparin; Hirudins; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia; Treatment Outcome

Treatment of patients with heparin-induced thrombocytopenia type II (HIT II) and thrombosis in some cases that represents a clinical challenge, which, if unrecognized, may lead to treatment delay or disease progression with potentially lethal outcome. We present a case of a 19-year-old patient with antiphospholipid syndrome, factor V (FV) Leiden mutation in heterozygous state, and venous thromboembolism. The patient was subjected to intravenous infusions of unfractionated heparin (UFH), and 16 days after the beginning of the treatment, his condition worsened, with thrombocytopenia and extension of thrombosis. Whereas the patient had a high clinical score for HIT II, functional and antigenic assays for the presence of HIT antibodies were negative. After repeated negative functional and antigenic assays, pseudo-HIT was suspected and nadroparin was introduced, which resulted in further worsening of the clinical presentation. Disease remission, along with complete normalization of platelet count, was finally accomplished with the introduction of lepirudin. The presence of multiple comorbid states, such as antiphospholipid syndrome, can potentially make laboratory confirmation of disease more difficult in patients with HIT II. In our opinion, it is of great importance that HIT II diagnosis be primarily clinical and that laboratory test results are carefully interpreted, especially when HIT is indicated by high clinical score values.

Topics: Administration, Oral; Adult; Antibodies; Anticoagulants; Antiphospholipid Syndrome; Diagnosis, Differential; Factor V; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Mutation; Nadroparin; Platelet Count; Recombinant Proteins; Thrombocytopenia; Venous Thromboembolism

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

Immunoglobulin G (IgG) isolated from the blood plasma of a patient with secondary antiphospholipid syndrome (APS) expresses fibrinogen-clotting and amidolytic activity (the thrombin activity in 20 micromole IgG is equivalent to approximately 5 nmole pure thrombin), and activates factor XIII. Hirudin (1 microM) decreases the intrinsic thrombin activity of the APS IgG by only 25%, whereas it inhibits completely pure thrombin with equivalent activity. Under conditions, when antithrombin inactivates 60% of the thrombin activity in the presence of normal IgG, the APS IgG protects almost completely the added thrombin against inactivation by antithrombin. Heparin, however, partially relieves this protective effect and at the same time it facilitates the inhibition of the intrinsic thrombin activity by antithrombin. The APS IgG reduces the thrombin activity in protein C activation assay by 50% compared to the activity in the presence of normal IgG. All described properties are related to the Fab fragment of the antibody. The IgG preserving the fibrin-generating activity of thrombin with concomitant protection against inhibitors unravels a new aspect of the thrombotic mechanism in APS. This condition is probably rare: only one out of 23 examined patients with primary or secondary APS expresses IgG with the described properties.

Topics: Adult; Antigens; Antiphospholipid Syndrome; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Blotting, Western; Factor XIII; Female; Fibrinogen; Hirudins; Humans; Immunoglobulin G; Lupus Erythematosus, Systemic; Protein C; Thrombin; Time Factors

To report a case of a patient with antiphospholipid antibody syndrome and multiple thromboses who developed heparin-induced thrombocytopenia (HIT) and subsequent international normalized ratio (INR) prolongation possibly due to antiphospholipid antibodies.. A 56-year-old white woman with a history of antiphospholipid antibody syndrome and thrombosis taking chronic warfarin was admitted for gastrointestinal concerns and found to have an INR >14. Warfarin was discontinued, vitamin K was administered, and a heparin infusion was initiated. Over the next 2 days, thrombocytopenia, hypotension, tachycardia, hyponatremia, and progressive abdominal pain developed. Upon transfer to a tertiary care center, HIT was diagnosed, and a lepirudin infusion was initiated. Subsequently, a sudden elevation of the INR occurred (>14) with low prothrombin (factor II) activity. After INR values declined to 2-3, warfarin was reinitiated with dosing adjusted using factor X and II activity levels. Clotting factors II and X activities were measured to monitor long-term warfarin therapy, with no evidence of complications after 7 months.. Typically, the INR is used to assess the intensity of anticoagulation. The INR value represents the reduction of clotting factors II, VII, and X. In rare circumstances, an independent inhibitor or interfering substance can interfere with the process of measuring the INR. In such situations, an alternative approach can be direct measurement of clotting factor concentrations.. Factor II and/or factor X activity levels provided an alternative means for measuring the anticoagulant effects of warfarin in the presence of a significant inhibitor (antiphospholipid antibodies) that biased the INR measurements.

Topics: Anticoagulants; Antiphospholipid Syndrome; Factor VII; Factor X; Female; Hirudins; Humans; International Normalized Ratio; Middle Aged; Platelet Count; Prothrombin; Recombinant Proteins; Thrombocytopenia; Warfarin

A patient with antiphospholipid antibody syndrome (APS) and a history of heparin-induced thrombocytopenia required lepirudin therapy. The patient had an abnormal baseline activated partial thromboplastin time (aPTT), complicating management of his therapy. We investigated whether an alternative monitoring system, using a dry reagent technology [Thrombolytic Assessment System (TAS)], could be used to monitor the patient's whole blood ecarin clot time (ECT) and aPTT. Baseline values for the ECT and aPTT were normal with this system. During a continuous infusion of lepirudin, the patient's whole blood ECT was maintained between a desired range of 150-200 s for 73% of the time. Similarly, his whole blood aPTT was maintained between 60 and 80 s for 80% of the time. In contrast, the patient's plasma-based aPTT by standard methods was consistently > 150 s. The patient underwent surgical procedures without complications. To further investigate the finding that the patient's antibody did not affect the aPTT with this system, we performed the ECT and the aPTT assays on the TAS Analyzer with plasma samples from 10 patients with APS and abnormal aPTTs. All 10 samples had plasma ECT values within the normal range. Four patients had normalization of the aPTT, suggesting that a subset of patients with APS may benefit from the TAS aPTT assay when monitoring heparin or other anticoagulation therapy.

Topics: Anticoagulants; Antiphospholipid Syndrome; Drug Monitoring; Endopeptidases; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Recombinant Proteins; Thrombocytopenia; Whole Blood Coagulation Time