warfarin and Hemophilia-B

The present study summarizes the results of 12 cardiac surgical procedures performed in a carrier of Haemophilia B and in six patients with Haemophilia A at a single centre from 1979 to 1998. The median age of the patients at the time of intervention was 56 years ranging from 18 years to 73 years. The six patients with Haemophilia A ranged in severity from moderately to mildly affected. Three patients were hepatitis C antibody positive. No patients were HIV antibody or hepatitis B surface antigen positive. The cardiac procedures included cardiac catheterization (n=4), coronary artery bypass surgery (n=2), percutaneous transluminal coronary angioplasty (n=1), cardiac valve replacement (AVR n=1 and AVR/MVR n=2), and closure of an atrial septal defect and subsequent drainage of a pericardial effusion (n=1). No patients had demonstrable inhibitors at the time of surgery. Haemostasis was achieved with AHF in 10/11 procedures and high purity factor IX (Immunine) in one procedure. The initial procedures involved intermittent bolus factor therapy while more recently, AHF was administered by continuous intravenous infusion. All patients demonstrated excellent intra- and post-operative haemostasis. These results, although from a small and varied group of patients, demonstrate that cardiac surgical procedures can be performed safely in patients with Haemophilia.

Topics: Adolescent; Adult; Aged; Aortic Valve; Aspirin; Cardiac Catheterization; Coronary Angiography; Coronary Artery Bypass; Factor IX; Factor VIII; Heart Valve Prosthesis Implantation; Hemophilia A; Hemophilia B; Hemorrhage; Hemostasis; Hepatitis B Surface Antigens; Hepatitis C Antibodies; HIV Antibodies; Humans; Isoantibodies; Middle Aged; Myocardial Ischemia; Thoracic Surgical Procedures; Warfarin

The risk of bleeding due to anticoagulation therapy with warfarin rises exponentially, when the international normalized ratio (INR) exceeds 4.5. We present a 52-year-old male admitted to the hospital with severe bleeding in the lower limbs caused by warfarin. Laboratory tests showed therapeutic INR (2.1), however the activated partial tromboplastin time was unusually prolonged (135 sec.) and a severe, reversible reduction in factor IX was detected. These findings were suggestive of a mutation in the factor IX propeptide, but thrombocytopathy induced by selective serotonin re-uptake inhibitors could have worsened the bleeding.

Topics: Anticoagulants; Hemophilia B; Hemorrhage; Humans; International Normalized Ratio; Lower Extremity; Male; Middle Aged; Warfarin

The binding of the gamma-glutamyl carboxylase to its protein substrates is mediated by a conserved 18 amino acid propeptide sequence found in all vitamin K-dependent proteins. We recently found that the apparent affinities of the naturally occurring propeptides for the carboxylase vary over a 100-fold range and that the propeptide of bone Gla protein has severely impaired affinity for the carboxylase [Stanley, T. B., et al. (1999) J. Biol. Chem. 274, 16940-16944 (1)]. Here we report a consensus propeptide sequence that binds tighter (K(i) = 0.43 nM) to the carboxylase than any known propeptide sequence. Comparing the factor IX propeptide to the propeptides of protein C, bone Gla protein, and prothrombin, the weakest binding propeptides, allowed us to predict which residues might be responsible for these substrates' relatively weak binding to the carboxylase. We then made propeptides with the predicted amino acid changes and determined their binding affinities. The reduced binding affinity of these propeptides relative to that of FIX is due to residues -15 in protein C, -10 and -6 in bone Gla protein, and -9 in prothrombin. A role for the -9 position was not previously recognized but is further shown by our identification of a new, naturally occurring mutation at this position in factor IX which causes a warfarin-sensitive hemophilia B phenotype. In addition, we find that propeptides with mutations found in warfarin-sensitive patients have reduced affinity for the carboxylase, suggesting a physiological relevance of propeptide binding affinity.

Topics: Amino Acid Sequence; Amino Acids; Animals; Bone and Bones; Calcium-Binding Proteins; Carbon-Carbon Ligases; Chickens; Consensus Sequence; Extracellular Matrix Proteins; Factor IX; Hemophilia B; Humans; Male; Matrix Gla Protein; Middle Aged; Molecular Sequence Data; Point Mutation; Protein Binding; Protein C; Protein Sorting Signals; Prothrombin; Vitamin K; Warfarin

This report deals with clinical experience of urologic surgery of patients with hemostatic disorder or hemolytic disease. In the past 5 years from May 1986, 14 operations were conducted in our clinic on 13 patients, consisting of 4 with von Willebrand disease (vWd), 1 with hemophilia B, 4 who had warfarin administration, 3 with essential thrombocythemia and 2 with spherocytosis. Almost all patients were treated hematologically before the urological operations. Except in 1 case, the post-operative course was favorable and under hematologic control. Massive bleeding in 1 case was obviously attributable to over-dosage of warfarin. It is difficult to determine the optimal dose of warfarin under an unstable hemostatic condition during the operation and recovery periods. However, it is possible to carry out urologic surgery for these patients under appropriate hematologic control, and ESWL was safely performed without medical treatment on 3 patients; 1 with vWd, 1 treated with warfarin and 1 with spherocytosis.

Topics: Adult; Aged; Blood Coagulation Factors; Blood Transfusion, Autologous; Child; Child, Preschool; Factor VIII; Female; Fibrinogen; Hemophilia B; Humans; Hydroxyurea; Lithotripsy; Male; Middle Aged; Spherocytosis, Hereditary; Thrombocythemia, Essential; Urologic Diseases; von Willebrand Diseases; Warfarin

Two-site immunoradiometric assays (IRMAs) for factor IX antigen (IX:Ag) were developed using a monoclonal antibody (RFF-IX/1) on the solid-phase and either another monoclonal antibody (RFF-IX/4) or a human polyclonal inhibitor antiserum as tracer (M-M and M-I IRMA respectively). The lower sensitivity limits of these two assays for IX:Ag in normal reference plasma were 4 X 10(-4) (M-M IRMA) and 2 X 10(-4) (M-I IRMA) units/ml. In 20 samples of normal plasma, levels of factor IX coagulation activity (IX:C) and of factor IX antigen measured by both IRMAs were highly correlated. Mean values of approximately 1.0 units/ml were obtained in all three assays. In normal serum, IX:Ag levels were lower with means of 0.84 (M-M IRMA) and 0.83 (M-I IRMA) units/ml. 4/25 patients with haemophilia B were CRM neg., two were CRM + and the remaining 19 patients were CRMr variants. In two of these, IX:Ag was detectable by M-I IRMA whilst IX:C and IX:Ag measured by M-M IRMA were undetectable. In plasma from a fetus subsequently terminated on eugenic grounds, IX:C and IX:Ag by both M-M and M-I IRMA were undetectable. In warfarin-treated plasma (n = 12), the level of IX:C was low (mean 0.39 units/ml). The levels of IX:Ag measured by M-M IRMA (mean of 0.80 units/ml) and by M-I IRMA (0.70 units/ml) showed a discrepancy. M-M IRMA reflects the real amount of IX:Ag in warfarinized plasma because both monoclonal antibodies bind to epitopes distant from the light chain carboxylated region. Western blotting of denatured factor IX demonstrated that RFF-IX/1 binds an epitope that is lost after XIa activation. RFF-IX/4 binds the heavy chain. Antigen measured after activation but without denaturing showed loss of 60% reactivity after XIa activation but no change after RVV activation. These data indicate a binding site for RFF-IX/1 within the activation peptide (residues 146-180).

Topics: Antibodies, Monoclonal; Antigens; Factor IX; Factor VII; Factor VIIa; Factor XI; Factor XIa; Hemophilia B; Humans; Immune Sera; Radioimmunoassay; Vitamin K; Warfarin

Topics: Autoantibodies; Factor IX; Hemophilia A; Hemophilia B; Humans; Immunoassay; Isoantibodies; Reference Values; Warfarin

Two siblings with m ild hemorrhagic symptoms had combined functional deficiencies of vitamin K-dependent clotting factors. Prothrombin (0.18-0.20 U/ml) and Stuart factor (Factor X, 0.18-0.20 U/ml) and Stuart factor (Factor X, 0.18-0.20 U/ml) were most severely affected. Antigenic amounts of affected coagulation factors were normal and normal generation of thrombin activity occurred in the patients' plasmas after treatment with nonophysiologic activators that do not require calcium for prothrombin activation. Hepatobilary disease, malabsorptive disorders, and plasma warfarin were not present. Both parents had normal levels of all coagulation factors. The patients' plasmas contained prothrombin that reacted both with antibody directed against des-gamma-carboxyprothrombin and native prothrombin. Crossed immunoelectrophoresis of patients' plasmas and studies of partially purified patient prothrombin suggested the presence of a relatively homogeneous species of dysfunctional prothrombin, distinct from the heterologous species found in the plasma of warfarin-treated persons. These studies are most consistent with a posttranslational defect in hepatic carboxylation of vitamin K-dependent factors. This kindred uniquely possesses an autosomal recessive disorder of vitamin K-dependent factor formation that causes production of an apparently homogeneous species of dysfunctional prothrombin; the functional deficiencies in clotting factors are totally corrected by oral or parenteral administration of vitamin K1.

Topics: Adolescent; Adult; Binding Sites; Calcium; Factor X Deficiency; Female; Hemophilia B; Humans; Hypoprothrombinemias; Immunoelectrophoresis, Two-Dimensional; Male; Partial Thromboplastin Time; Prothrombin; Prothrombin Time; Vitamin K Deficiency; Warfarin

Topics: Antigens; Edetic Acid; Electrophoresis, Agar Gel; Factor IX; Hemophilia B; Humans; Warfarin

The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

Topics: Factor VII; Factor VII Deficiency; Factor X; Factor XI Deficiency; Factor XII Deficiency; Freezing; Hemophilia A; Hemophilia B; Humans; Hyaluronoglucosaminidase; Prothrombin; Thromboplastin; Warfarin

Thrombotest clotting times of mixtures of coumarin plasmas and normal plasma yielded a patterm similar to that observed in mixtures of plasma with congenital coagulation disorders and normal plasma. The presence of 10 or 20% of test plasma in the mixture failed to affect the clotting times which resulted in normal limits. The only exception to this rule was the hemophilia BM plasma. In this case even the presence of 10-20% of patient plasma in the mixture caused a prolongation of the clotting time. This indicates that no inhibitor is present in coumarin plasmas and in the plasma of congenital coagulation disorders of the prothrombin complex save for hemophilia BM plasma which does contain an inhibitor.

Topics: Acenocoumarol; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Hemophilia B; Humans; Male; Prothrombin; Thromboplastin; Warfarin

Factor IX, isolated from normal human plasma, was homogenous by polyacrylamide gel electrophoresis in urea and sodium dodecyl sulfate. On the latter, it migrated as a single polypeptide chain with or without reducing agents and had an apparent mol wt of 62,000. After iodination by chloramine-T, a single peak of 125I was found on gels. Immunoelectrophoresis in agarose with rabbit antifactor IX sera gave a single arc against both isolated and partially purified factor IX preparations. The rabbit antibody was specific as it failed to inhibit the activities of prothrombin or factors VII or X in normal plasma. At an additional 20-fold dilution, factor IX activity was inhibited 50%. In a double-antibody radioimmunoassay, excess rabbit anti-human factor IX precipitated 90-95% of the 125I-human factor IX. Control without specific antibody gave 6-8%. Dilutions of a pool of normal human plasma paralleled dilutions of the isolated preparation and were used for the standard curve. Of 39 plasma samples from normal donors, the mean factor IX antigen level was 93% of that of a separate normal pool. The radioimmunoassay detected the abnormal factor IX produced in patients on warfarin therapy. After Al(OH)3 adsorption of warfarin treated patient's plasma, factor IX antigen, but not activity, was present in the supernate. Samples from 28 patients on warfarin gave a mean factor IX clotting activity of 27% with a mean antigen of 69%. The antigen level from the warfarin group was significantly lower than the antigen level of the normal group (P less than 0.001). The factor IX antigen level was then assessed in 36 patients from 29 pedigrees with hemophilia B. The median antigen level was 17% of normal. The distribution of the antigen level was wide with two patients around 100% of normal; only two had levels below the limits of resolution of the radioimmunoassay as currently performed (less than 2%). Within each of the five pedigrees in which more than one affected member was tested, activity and antigen levels were the same. The degree of neutralization of the antibody's inhibition of normal plasma by patient's plasma was highly correlated. Additional evidence for the detection of abnormal protein was provided by immunodiffusion of plasmas concentrated by lyophilization. Reactions of complete identity occurred between normal, a warfarin treated and a hemophilia B subject's plasmas.

Topics: Adolescent; Adult; Antigens; Blood Coagulation Tests; Factor IX; Female; Hemophilia B; Humans; Male; Middle Aged; Radioimmunoassay; Warfarin

Activated partial thromboplastin times (APTT's) performed with a semi-automated electrical-conductivity type of clot timer on plasmas from patients with hepatic disease and intravascular coagulation, and on warfarin or heparin therapy, were significantly lower than when done on the same plasmas with either a manual optical method or an automated optical-endpoint instrument. Results of APTT's done on normal plasmas by the three methods were not significantly different. Substitution of different activator-phospholipid reagents resulted in some variability in results, but these differences were less than those between the different done with both the electrical clot timer and the automated optical instrument on prepared plasmas containing 5.0 or 1.0% of factor II, V, VIII, IX, OR X revealed shorter times with the electrical clot timer only in the case of factor II- and factor V-deficient plasmas. APTT's done on normal plasmas to which 0.1 or 0.3 units per ml. of heparin had been added vitro also were shorter with the electrical clot itmer than the automatic optical instrument. Prothrombin times done on normal and abnormal control plasmas and on a series of plasmas from patients on warfarin therapy showed no significant difference between the two methods.

Topics: Autoanalysis; Blood Chemical Analysis; Blood Coagulation Tests; Erythrocyte Aggregation; Factor V Deficiency; Factor X Deficiency; Hemophilia A; Hemophilia B; Heparin; Hydrogen-Ion Concentration; Hypoprothrombinemias; Liver Diseases; Optics and Photonics; Phospholipids; Prothrombin Time; Thromboplastin; Time Factors; Warfarin

Topics: Adult; Aged; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Blood Coagulation Factors; Child; Factor IX; Factor VII; Factor X; Female; Hemophilia B; Hepatitis A; Hepatitis B Antigens; Humans; Liver Diseases; Liver Function Tests; Male; Middle Aged; Poisoning; Prothrombin; Warfarin

Patients with disorders of hemostasis who undergo surgical procedures are in danger of hemorrhage. While the careful medical history remains the most sensitive test of a bleeding tendency, some such patients can give no suggestive history. In three patients with coagulopathy-one with mild classical hemophilia, one with Christmas disease, and one with warfarin toxicity-the abnormality was missed by routine preoperative history but promptly detected by the routine preoperative use of the activated coagulation time (act). Either this test or the activated partial thromboplastin time should be included in the routine preoperative work-up, along with appropriate additional tests of the hemostatic mechanism.

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Child; Female; Hemophilia A; Hemophilia B; Humans; Male; Middle Aged; Postoperative Complications; Preoperative Care; Warfarin

Topics: Child; Factor IX; Factor VII; Factor X; Hemophilia B; Hepatitis B; Humans; Male; Prothrombin; Warfarin