warfarin and Factor-VII-Deficiency

Oral anticoagulant therapy has been widely employed to prevent and treat a variety of thrombotic disorders, although a new generation of antithrombotic drugs, which offer inhibition of clot-bound as well as fluid-phase thrombin, has been developed and tested in several clinical trials. Although most anticoagulant responses to hydroxycoumarin compounds are well established, there are controversial evidences on their influence on activated factor VII (FVIIa). After analyzing the prothrombin time (PT) (International Normalized Ratio reference range, 0.92-1.08), factor VII clotting activity (FVII:C) (reference range, 75-130 U/dl) and activated factor VII clotting activity (FVIIa:C) (reference range, 30-110 U/l) in 46 consecutive patients on stable warfarin therapy for atrial fibrillation, a consistent trend towards decreased values of both FVII:C and FVIIa:C was observed as PT values increased. At moderate-intensity anticoagulation, with international normalized ratios between 2 and 3, the mean activities of FVII:C and FVIIa:C dropped to 28 U/dl (range, 9-61 U/dl) and 5.8 U/l (range, 1-18 U/l), respectively. Results of our investigations indicate that warfarin therapy decreases FVIIa:C, highlighting the potential benefits of oral anticoagulants in thrombotic disorders and other clinical conditions characterized by increased levels of FVIIa. Owing to the good correlation with FVIIa:C, we also hypothesize that the PT and/or FVII:C might be employed for monitoring recombinant FVIIa therapy.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Blood Coagulation Tests; Factor VII; Factor VII Deficiency; Factor VIIa; Female; Humans; Male; Middle Aged; Prothrombin Time; Reference Values; Warfarin

Topics: Anticoagulants; Blood Coagulation Factors; Cardiomyopathies; Cardiopulmonary Bypass; Factor VII Deficiency; Heart-Assist Devices; Humans; Male; Middle Aged; Ventricular Dysfunction, Left; Warfarin

Topics: Aged; Aneurysm, False; Anticoagulants; Bleeding Time; Defibrillators, Implantable; Diagnosis, Differential; Echocardiography, Doppler; Factor VII Deficiency; Female; Femoral Artery; Follow-Up Studies; Hematoma; Hemorrhage; Humans; Postoperative Care; Risk Assessment; Thigh; Tomography, X-Ray Computed; Warfarin

A 50-year-old male patient with hypertrophic cardiomyopathy and atrial fibrillation was anticoagulated, with warfarin following insertion of a cardioverter defibrillator. He became markedly over anticoagulated after standard moderate induction doses of warfarin. His baseline prothrombin time was prolonged and further investigation showed the patient to have a mild factor VII deficiency. He was restarted on low-dose warfarin and successfully stabilized with a target international normalized ratio (INR) of 3.0 (range 2.5-3.5). We used the data from factor VII levels and thrombin generation studies before and after anticoagulation to control dosage and to decide on a suitable therapeutic range for the INR. Molecular studies showed him to have two separate mutations in the factor VII gene. This report highlights the importance of noting the baseline prothrombin time before initiating oral anticoagulation and describes how well tolerated anticoagulation can be achieved in a patient with congenital factor VII deficiency.

Topics: Anticoagulants; Atrial Fibrillation; Cardiomyopathy, Hypertrophic; Drug Monitoring; Factor VII; Factor VII Deficiency; Humans; International Normalized Ratio; Male; Middle Aged; Mutation; Prothrombin Time; Warfarin

Topics: Adult; Anticoagulants; Blindness; Diagnosis, Differential; Factor VII Deficiency; Female; Humans; Retrobulbar Hemorrhage; Tomography, X-Ray Computed; Venous Thrombosis; Warfarin

We report the case of a 71-year-old man on warfarin for chronic atrial fibrillation presenting with a massive spontaneous soft tissue bleed. Despite reversing the effects of warfarin with large doses of intravenous vitamin K and fresh frozen plasma, bleeding continued, and his prothrombin time and activated partial thromboplastin time remained prolonged. The prothrombin time and activated partial thromboplastin time failed to correct with 50% normal plasma. Further investigations confirmed a lupus inhibitor with low levels of factors II, V, VII and XI. Factor II, V and XI levels normalized, however, when the patient's plasma was diluted 1:16 in buffer, suggesting the lupus inhibitor may have been interfering with these factor assays causing artefactual low results. Factor VII levels remained consistently low at all dilutions. The patient subsequently died following a massive left haemothorax despite surgical intervention and treatment with activated recombinant factor VII concentrate. We presumed the primary problem was bleeding from a local vascular lesion but the patient was never well enough to undergo confirmatory angiography. This case highlights the fact that patients with lupus inhibitors can develop severe haemorrhagic complications, and illustrates the complexities involved in both the investigation and treatment of abnormal bleeding in these patients.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Contusions; Factor VII Deficiency; Fatal Outcome; Hemorrhage; Hemothorax; Humans; Lupus Coagulation Inhibitor; Male; Partial Thromboplastin Time; Prothrombin Time; Warfarin

Topics: Aged; Anticoagulants; Atrial Fibrillation; Factor VII Deficiency; Female; Humans; Vitamin K 1; Warfarin

I describe a method to measure blood coagulation properties, based on the hypothesis that the distance the serum component of a clotted plasma sample moves through a suitable absorbent material should be proportional to the blood's ability to clot. A simple apparatus was constructed to test this principle, in which an absorbent strip contacts clotted plasma samples. At various times, the liquid migration distance into the strip was measured and correlated with clotting times determined by well-accepted procedures. Use of this device to test lyophilized normal and barium-absorbed plasmas, factor VII-deficient plasma, frozen normal plasmas, plasmas from patients undergoing oral anticoagulation, and saline-diluted plasmas (as for Quick Percent assays) showed that clotting times correlated with migration distances for all types of samples (r2 = 0.93-0.99). The device distinguishes between samples from normal and coumadin-treated subjects. The concept can be integrated into an inexpensive, point-of-care coagulation monitor.

Topics: Absorption; Anticoagulants; Barium; Blood Coagulation; Blood Coagulation Tests; Drug Monitoring; Factor VII; Factor VII Deficiency; Freeze Drying; Hemostasis; Humans; Monitoring, Physiologic; Reference Values; Thromboplastin; Warfarin

Topics: Anticoagulants; Factor VII Deficiency; Humans; Lipoproteins; Prothrombin Time; Serine Proteinase Inhibitors; Warfarin

Plasma from healthy individuals, pregnant women and patients on warfarin were distributed to 3 laboratories supporting major cardiovascular surveys (Northwick Park, Muenster and Houston) for assay of factor VII coagulant activity (VIIc) with their own bio-assays. The mean VIIc in 147 samples agreed to within 1% of standard in Northwick Park and Houston, but was 14% of standard lower in Muenster owing to its more potent standard. In samples with an increased VIIc the Northwick Park assay gave a higher result than the other assays owing to its increased responsiveness to activated factor VII (VIIa). Thus when VIIa concentrations were determined directly with a clotting assay which utilises a soluble recombinant tissue factor, the increase in VIIc with increase in VIIa was considerably greater with the Northwick Park assay than the Muenster assay. This feature of the Northwick Park assay was traced to the virtual absence of protein C in its substrate plasma. Factor Va appears rate-limiting for the coagulant expression of VIIa in test plasma. If the thrombotic response to release of tissue factor is determined by the circulating concentration of VIIa, then the Northwick Park factor VII bio-assay may be preferable to other bio-assays currently employed to estimate risk of acute coronary events.

Topics: Adult; Blood Coagulation Tests; Coronary Disease; Enzyme Activation; Factor VII; Factor VII Deficiency; Female; Humans; Laboratories; Male; Pregnancy; Protein C; Protein S; Reproducibility of Results; Risk Factors; Sensitivity and Specificity; Thromboplastin; Warfarin

Three mouse monoclonal antibodies (RFF-VII/1, RFF-VII/2, and RFF-VII/3) which bind specifically to different epitopes on human factor VII antigen were raised. Two of the antibodies, RFF-VII/1 and RFF-VII/2, bound strongly to factor VII antigen (VII:Ag), but only RFF-VII/1 and RFF-VII/3 were potent inhibitors of factor VII coagulation activity (VII:C). RFF-VII/1 and RFF-VII/2 were used in a one step, double monoclonal immunoradiometric assay for VII:Ag. This was highly reproducible and detected as little as 0.05U/dl VII:Ag. Values for VII:Ag obtained for plasma samples from normal subjects (n = 20), patients with liver disease (n = 20), patients treated with warfarin (n = 20), and those congenitally deficient in factor VII (n = 7) correlated very well (r = 0.96) with data obtained in a radioimmunoassay using polyclonal rabbit antiserum to factor VII. This simple and sensitive monoclonal antibody based assay offers a convenient method for the detection of VII:Ag in various disease states.

Topics: Animals; Antibodies, Monoclonal; Antigens; Factor VII; Factor VII Deficiency; Humans; Liver Diseases; Mice; Mice, Inbred BALB C; Radioimmunoassay; Warfarin

A high affinity monoclonal antibody to factor VII (RFF-VII/1), coupled to sepharose, was used to immunodeplete factor VII from normal plasma. The plasma could be used as a substrate in a one stage coagulation assay and performed as well as, or better than, commercially available factor VII deficient plasma or plasma from congenitally deficient factor VII patients. Plasma from normal donors (n = 20), patients with liver disease (n = 20), and patients receiving warfarin (n = 20), or congenitally factor VII deficient patients (n = 7) was assayed for VII:C concentration in a one stage coagulation assay. The concentration of VII:C detected with the immunodepleted plasma substrate was comparable in all cases with that seen with a commercially available substrate (r = 0.95).

Topics: Antibodies, Monoclonal; Blood Coagulation Factors; Chromatography; Electrophoresis, Polyacrylamide Gel; Factor VII; Factor VII Deficiency; Humans; Liver Diseases; Methods; Warfarin

A radioimmunoassay (RIA) for factor VII was developed using 125I-factor VII, anti-factor VII rabbit serum and anti-rabbit IgG goat serum. The lower limit of sensitivity in normal reference plasma was 3 X 10(-3) units/ml. Although the level of factor VII antigen (VII:Ag) in normal plasma samples (n = 20) 0.944 +/- 0.176 units/ml, correlated with that of factor VII coagulant activity (r = 0.89), VII:Ag level in paired normal sera showed a higher value (1.469 +/- 0.376 units/ml). The level of antigen according to RIA of factor VIIa activated by factor Xa increased 2.5-fold compared with that of unactivated factor VII. It is suggested that the polyclonal anti-factor VII produced in a rabbit had higher affinity for factor VIIa than for factor VII. In two out of seven patients with congenital factor VII deficiency, VII:Ag was detectable (0.04, 0.31 units/ml, respectively) whereas VII:C was less than 0.01 units/ml. In 12 warfarin-treated individuals, VII:C showed a lower level (0.121 +/- 0.063 units/ml) that that of VII:Ag (0.518 +/- 0.186 units/ml). During 4 weeks observation after stopping warfarin, VII:C and VII:Ag reached normal levels in 1 week. However, VII:C did not reach equivalence with VII:Ag until 4 weeks had elapsed.

Topics: Animals; Antigens; Factor VII; Factor VII Deficiency; Factor VIIa; Goats; Humans; Immune Sera; Rabbits; Radioimmunoassay; Warfarin

A rabbit model was developed to examine the effect of sodium warfarin on peripheral blood monocyte tissue factor (MTF) activity. After three days of treatment with sodium warfarin, MTF expression was significantly impaired (p less than 0.003). Vitamin K reversed this inhibition despite continued treatment with warfarin. Animals resistant to warfarin did not become anticoagulated and failed to demonstrate inhibition of MTF expression. Cells grown in plasma from warfarin-treated animals expressed reduced amounts of MTF activity, while cells grown in normal rabbit plasma demonstrated procoagulant activity in assays using both normal and factor VII-deficient substrate plasmas. These studies suggest that normal factor VII binds to monocytes during the culture period. Moreover, a plasma component in warfarin-treated animals, possibly abnormal factor VII, may bind to monocytes and block expression of MTF activity. This may represent another mechanism for warfarin-mediated inhibition of cell-mediated coagulation reactions in vivo.

Topics: Animals; Cell Adhesion; Cell Survival; Cells, Cultured; Culture Media; Factor VII Deficiency; Factor X Deficiency; Female; Granulocytes; Humans; Kinetics; Monocytes; Prothrombin Time; Rabbits; Warfarin

Several murine monoclonal anti-human Factor VII antibodies were produced using hybridoma technology. Two noncompetitive monoclonal antibodies were used to examine by Western blotting the Factor VII cross-reactive material (CRM) in normal human plasma and three commercially available congenitally Factor VII-deficient plasmas, and to construct a facile "sandwich" immunoassay for plasma Factor VII. A second, previously undescribed, form of Factor VII CRM was detected in human plasma, which on Western blotting stained with an apparent intensity 5-8% that of Factor VII. This glycoprotein, tentatively called VII*, has a molecular weight 4,500 D less than Factor VII, lacks detectable Factor VII functional activity, does not bind to barium citrate, and is not recognized by a monoclonal antibody that recognizes Factor VII but not alpha-chymotrypsin-treated Factor VII. VII* was not proteolytically produced from Factor VII during in vitro coagulation or after infusion of human Factor VII into rabbits. As determined by Western blotting, the human hepatoma cell line, HepG2, cultured in the presence of vitamin K, secreted relatively greater levels of VII* in proportion to VII (75%) than that found in human plasma. Warfarin treatment of HepG2 cells decreased the quantity of VII secreted by 77%, whereas it only inhibited the secretion of VII* by 14%. Immunologic studies of the plasmas from a patient on chronic warfarin therapy and an individual given a short course of high dose warfarin therapy corroborated the in vitro synthetic studies obtained with HepG2 cells. The data are consistent with the production of VII* by posttranslational, proteolytic, modification of VII, that, at least in the HepG2 cells studied, occurs intracellularly. However, other mechanisms for the production of VII*, in particular, alternative RNA splicing of the transcript from a single gene, cannot be excluded.

Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Atrial Fibrillation; Carcinoma, Hepatocellular; Collodion; Cross Reactions; Electrophoresis, Polyacrylamide Gel; Factor VII; Factor VII Deficiency; Humans; Isoantigens; Liver Neoplasms; Mice; Rabbits; Warfarin

The effect of both congenital and acquired factor VII deficiency on the cuticle bleeding time (CBT) was evaluated in dogs. The CBT has been previously documented to be a sensitive indicator of factor VIII:C deficiency in hemophilic dogs. Serial CBT determinations were made on normal dogs treated with high-dose warfarin. At 48 hours post-treatment, the CBT was normal, although the factor VII level was less than 1%, whereas the levels of factors II, IX, and X were 44%, 25%, and 17%, respectively. At 120 hours the CBT became abnormal when all vitamin K-dependent clotting factors had dropped to less than 18%. Administration of a plasma concentrate of factors II, IX, and X corrected the CBT, despite the factor VII level remaining at less than 1%. Similar studies in a congenitally factor VII-deficient dog (factor VII less than 2%) confirmed that this deficiency state was not associated with an abnormality of the CBT. Administration of heparin to both normal and factor VII-deficient animals was associated with prolongation of the CBT, but the heparin dose required in the normal animals was substantially higher than in the factor VII-deficient animals. These data do not suggest that factor VII/VIIa has an exclusive role in generating factor Xa, either directly or indirectly, by way of factor IXa generation, in vivo. However, the increase in heparin sensitivity of the factor VII-deficient animals does suggest that factor VII/VIIa may, in some circumstances, present a significant alternative pathway of factor X activation, although the activation pathway involved cannot be determined from the studies performed.

Topics: Animals; Bleeding Time; Dogs; Factor VII; Factor VII Deficiency; Female; Hemostasis; Heparin; Male; Warfarin

The effect of warfarin-induced factor VII deficiency on the skin bleeding time was investigated in 10 consecutive patients with mean prothrombin times of 33 sec and factor VII levels of 7%. Bleeding times in all but one subject were entirely within the normal range. We conclude that warfarin administration, even to the point of prolonging the prothrombin time beyond the therapeutic range, is not associated with an abnormal bleeding time. Furthermore, from the above evidence and a review of the literature, it is considered doubtful that factor VII plays a major role in primary hemostasis.

Topics: Bleeding Time; Factor VII; Factor VII Deficiency; Humans; Platelet Function Tests; Prothrombin Time; Warfarin

Highly purified single-chain factor VII was isolated from plasma and used to generate monospecific antibodies. A double-antibody equilibrium radioimmunoassay was constructed. The assay was tested for and met all the criteria required for a specific, sensitive, and accurate determination of factor VII in plasma. The range of sensitivity of the assay was between 1 and 500 ng factor VII/ml, and the coefficient of variation was 1%-3% within assay and 12%-16% between assays. Pure factor VII and plasmic factor VII from normal, warfarin-treated, and hereditary deficient individuals inhibited competition assays with parallel slopes, indicating the expression of similar epitopes by these molecules and validating the measurement of this protein in plasma. The concentration of factor VII in normal plasma (n = 41) was 470 +/- 112 ng/ml, and the measurement of factor VII antigen correlated with activity (r = 0.82). Factor VII concentration in the plasma of individuals on warfarin therapy (n = 24) was 238 +/- 73 ng/ml. Factor VII activity was about 38% of normal and correlated less well with factor VII antigen (r = 0.53). The specific activity of these molecules was 78% of normal (p less than 0.01), suggesting the presence of nonfunctional or partially functional molecules in the circulation of individuals undergoing drug therapy. Analysis of two hereditary deficient patients revealed that, while there were significant levels of factor VII protein, the procoagulant activity was less than 2%, indicating a discordant relationship of these parameters in individuals expressing the deficient factor VII phenotype.

Topics: Animals; Blood Proteins; Electrophoresis, Polyacrylamide Gel; Factor VII; Factor VII Deficiency; Humans; Immune Sera; Immunoglobulin G; Rabbits; Radioimmunoassay; Sodium Dodecyl Sulfate; 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

Topics: Animals; Blood Coagulation Disorders; Cattle; Factor VII Deficiency; Factor X; Humans; Hypoprothrombinemias; Prothrombin; Rabbits; Swine; Thromboplastin; Warfarin

Topics: Agranulocytosis; Anus Diseases; Anus Neoplasms; Blood Coagulation Disorders; Blood Platelet Disorders; Blood Platelets; Blood Transfusion; Colitis, Ulcerative; Colonic Diseases; Colonic Neoplasms; Factor V Deficiency; Factor VII Deficiency; Gastrointestinal Hemorrhage; Hemophilia A; Humans; Hypoprothrombinemias; Liver Diseases; Lymphoma; Rectal Diseases; Warfarin

Topics: Animals; Blood Coagulation Tests; Factor VII; Factor VII Deficiency; Humans; Immune Sera; Jaundice, Chronic Idiopathic; Neutralization Tests; Prothrombin Time; Rabbits; Warfarin

Topics: Antibodies; Antigen-Antibody Reactions; Antigens; Blood Coagulation Tests; Blood Proteins; Factor VII; Factor VII Deficiency; Humans; Immune Sera; Liver Diseases; Neutralization Tests; Vitamin K Deficiency; Warfarin

Topics: Analysis of Variance; Animals; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Brain; Cattle; Coumarins; Factor VII; Factor VII Deficiency; Factor X; Humans; Hypoprothrombinemias; Indicators and Reagents; Methods; Prothrombin Time; Rabbits; Thromboplastin; Warfarin

Topics: Animals; Cattle; Dogs; Factor V; Factor VII; Factor VII Deficiency; Factor X; Fibrinogen; Humans; Male; Methods; Phosphatidylethanolamines; Plasma; Prothrombin; Prothrombin Time; Thromboplastin; Warfarin