Factor VII Padua 2: another factor VII abnormality with defective ox brain thromboplastin activation and a complex hereditary pattern.

A new factor VII abnormality is presented. The propositus was a 9-yr-old child who presented a mild bleeding tendency characterized by epistaxis and easy bruising. The parents were not consanguineous, but they came from the same area. The laboratory features were mild prolongation of prothrombin time and P.P. test and normal partial thromboplastin and Stypven cephalin clotting times. The Thrombotest was moderately prolonged. Factor VII was 40%-50% of normal using rabbit or human brain thromboplastin, but only 13%-24% using ox brain thromboplastin. Factor VII cross-reacting material (CRM) was about 50% of normal. The father, a paternal aunt, and a paternal cousin showed similar clinical and laboratory findings. The brother of the propositus, the mother, and other members of her family showed about 50% factor VII activity and CRM and were considered to be heterozygotes for true factor VII deficiency. Similar findings were also present in the father and in the brother of the affected cousin. The defect in the propositus seems to consist of a double heterozygosity between abnormal factor VII and heterozygous factor VII true deficiency. The factor VII abnormality appears to consist of abnormal reactivity toward ox brain tissue thromboplastins and appears to be different from previously described factor VII abnormalities. The name factor VII Paudua2 is proposed for this condition.     

Clinico-hematologic profile of factor XIII-deficient patients.

A retrospective analysis of clinico-hematologic parameters of 18 factor XIII-deficient patients was carried out. The hematologic tests included activated partial thromboplastin time (APTT), prothrombin time (PT), and clot solubility. Laboratory diagnosis of FXIII deficiency was made where bleeding time, PT, APTT, and thrombin time were normal and the clot solubility test result with 5M urea was positive. Factor XIII level with family screening was performed using commercially available kits. History of prolonged bleeding from the umbilical stump was present in four (22.2%) patients. The most common site of bleeding was the skin (11 of 18 patients). Three patients were given prophylaxis (FFP in two, factor XIII in one). A high prevalence of recurrent abortion in female patients with FXIII deficiency (two of the three patients in this study) was observed.     

Comparison of bleeding tendency, factor XI coagulant activity, and factor XI antigen in 25 factor XI-deficient kindreds

The relationship of clinical bleeding tendency and factor XI antigen (XI:Ag) in factor XI deficiency was studied in 78 members of 25 factor XI-deficient kindreds. Factor XI:Ag was measured in a competitive radioimmunoassay, using monospecific, heterologous anti-factor XI antibody. 125I-labeled factor XI, and staphylococcal protein A as the precipitating agent. Deficiency of factor XI clotting activity (XI:C), less than 0.62 U/mL, occurred in 48 individuals, 22 of whom experienced postoperative or posttraumatic bleeding: Their mean factor XI:C was 0.21 +/- 0.04 U/mL (SEM), and factor XI:Ag was 0.23 +/- 0.04 U/mL. The remaining 26 had no clinical bleeding, many despite surgical challenge: Their mean factor XI:C was 0.30 +/- 0.04 U/mL, and factor XI:Ag was 0.34 +/- 0.05 U/mL. In all, 13 kindreds had between 1 and 11 members with bleeding; the other 12 had none with deficient hemostasis. Two heterozygous factor XI-deficient individuals appeared to be positive for cross-reacting material (CRM+). The slope of the regression line for factor XI:C and factor XI:Ag data points in the 78 individuals tested did not differ from control, and all points fell within 95% confidence limits derived from control. In conclusion, bleeding tendency appears to be consistent within a given kindred and is not determined exclusively by factor XI:C or factor XI:Ag levels.     

Congenital Haemorrhagic Condition Similar but Not Identical to Factor X Deficiency

A 23-year-old white male with a bleeding tendency since early childhood presented a congenital coagulation defect similar but not identical to factor X deficiency. A first and second stage defect were demonstrated, characterized by a prolonged prothrombin time, prolonged partial thromboplastin time, abnormal thromboplastin generation, abnormal prothrombin consumption. The Stypven clotting time was slightly prolonged on fresh plasma but was normal on frozen plasma. Factors I, II, V, VIII, IX, XI, and XII were all within normal limits; factor VII was at the lower limits of normally or slightly decreased. Mr. Stuart's plasma failed to correct the defect of the patients plasma; however, a known factor VII deficient plasma was able to correct the abnormality. Factor X levels showed low (3–13%) only when assayed using tissue whole thromboplastin or tissue partial thromboplastin; the factor X assay using a Stypven-cephalin mixture yielded normal or near normal values. The factor II + factor X level using a Stypven-cephalin mixture appeared normal also. The significance of the findings is discussed. The results are tentatively interpreted as being due to an abnormal factor X rather than to a real deficiency.     

Further studies on factor VII padua defect: the report of the fourth homozygous patient from the same valley

Summary A new patient with factor VII Padua abnormality is presented. The proposita is an 11-year-old girl who showed a mild bleeding tendency and a laboratory pattern characterized by a prolonged prothrombin time corrected by normal serum, normal partial thromboplastin time and normal Thrombotest. Factor VII assay was 10% using rabbit brain thromboplastin and 100% of normal using ox brain thromboplastin. Factor VII cross-reaction material was normal. The parents were not consanguineous but both came from the same area and were found to be heterozygous for the abnormality. The discovery of the present patient, the fourth in three years, indicates that the defect might be more frequent than originally thought.Supported by grants from the M.P.I. (grant 1592–1980), Rome and from the Veneto Regional Government, Venice     

Hereditary factor VII deficiency: heterogeneity defined by combined functional and immunochemical analysis

Twenty-six patients with hereditary factor VII deficiency (VII:C less than 10%) were evaluated using a panel of three thromboplastins of varying species and tissue origin in both coagulant and chromogenic assay systems. Normal values for the coagulation and chromogenic assays were 104% +/- 7% and 108% +/- 21%, respectively. Factor VII antigen was measured by a specific radioimmunoassay (normal, 470 +/- 112 ng/mL). The patients were divided into two groups based on the factor VII:Ag assay results. Group 1, 18 patients, had decreased levels of factor VII:Ag and group 2, eight patients, had normal levels of factor VII:Ag. The two groups were further subdivided on the basis of discrepant factor VII:C levels in the chromogenic and coagulant assays. The number of observed patterns of functional factor VII:C activity suggests a high degree of complexity of factor VII and thromboplastin interaction. Whereas no clinical bleeding was reported in any of the nine black patients evaluated, all Caucasians (16) and one Hispanic presented with mild to severe bleeding. Patients with factor VII:C greater than 10% using a human thromboplastin had a negative bleeding history, regardless of the activity measured with other thromboplastins. Factor VII activity measured with a human thromboplastin appears to correlate best with the clinical picture.     

Uneventful Cesarean Delivery with Administration of Factor XI Concentrate in a Patient with Severe Factor XI Deficiency

Factor XI (FXI) is a procoagulant factor and antifibrinolytic agent, and its absence causes a bleeding tendency. FXI deficiency is autosomal in inheritance, with severe FXI deficiency in homozygotes and partial deficiency in heterozygotes. A 24-year-old primigravida with an uneventful pregnancy and no history of bleeding manifestations was admitted to our department at 38 weeks of gestation. Her blood count and serum biochemistry findings were normal except for a coagulation screen, which revealed a prolonged activated partial thromboplastin time (APTT) of 63 seconds (normal range, 24-35 seconds). The measured FXI coagulant activity of 8 IU/dL (reference range, 70-150 IU/dL) established a diagnosis of severe FXI deficiency. The breech presentation of the fetus prompted the decision for cesarean delivery under general anesthesia. We administered a single dose of FXI concentrate (15 IU/kg), which corrected the APTT to 34 seconds. The cesarean delivery was uncomplicated, and postpartum recovery of the mother and her baby was uneventful with no bleeding complications. The finding of an isolated prolonged APTT should prompt obstetricians to consider FXI deficiency. The appropriate use of factor FXI concentrate in managing obstetric patients with FXI deficiency can minimize potential bleeding complications and ensure an optimal outcome for both mother and neonate.     

Life-threatening bleeding in a patient with a lupus inhibitor and probable acquired factor VII deficiency.

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.     

High-titer idiopathic acquired factor V inhibitor patient showing decreased activities of multiple coagulation factors

A 72-year-old male presented with oral bleeding resulting from acquired factor V (FV) inhibitor. We observed abnormalities in prothrombin time (PT) (8%) and activated partial thromboplastin time (APTT) (>200 seconds). FV activity was less than 3%, and a mixing test did not correlate with PT. FV inhibitor assay demonstrated 240 Bethesda units/ml. The patient also showed markedly decreased activity of Factors II (13%) and X (14%). Oral bleeding disappeared and coagulation abnormalities improved with prednisolone therapy. High titer FV inhibitor might affect coagulation assays even in a patient with normal factor activity.     

DDAVP administration in a case of congenital combined factor V and factor VIII deficiency

Combined deficiency of factor V and factor VIII, a rare bleeding disorder, was found in a 43 year-old male. He had often presented manifestations of easy bruising since childhood, but none of his family had shown evidence of a bleeding tendency. We examined him and his family as far as we could and his abnormality of blood coagulation was apparent, but the members of his family were normal. The prothrombin time and activated partial thromboplastin time of this patient were prolonged, but his thrombin time was normal. Factor V and factor VIII coagulant activity were low, but von Willebrand factor antigen and activity (ristocetin cofactor activity) levels were normal. Protein C and Protein C inhibitor antigen and activity levels were also found to be normal. Following 1-deamino-8-D-arginine vasopressin (DDAVP) injection, he had immediate increases in factor VIII coagulant activity, but both von Willebrand factor antigen, activity levels and factor V coagulant activity remained low. Moreover, there was no rapid decline in factor VIII complex activity. These findings suggest that the endogenous factor VIII in this patient is metabolized normally and that at least the deficiency of factor VIII does not result from accelerated degradation in plasma.     

A "new" congenital haemorrhagic condition due to the presence of an abnormal factor X (factor X Friuli): study of a large kindred

Summary Three related patients are presented who show a congenital coagulation disorder with laboratory features intermediate between classical factor-VII and factor-X deficiencies. A woman and two men had suffered from bleeding since early childhood, with epistaxis, bleeding from the gums, post-traumatic haemarthroses, bleeding after tooth extractions and other surgical procedures. Investigation demonstrated a prolonged prothrombin time, prolonged partial thromboplastin time, abnormal prothrombin consumption and abnormal thromboplastin generation corrected by normal serum. Platelet and vascular tests were normal and no hyperfibrinolysis was found. Factors I, II, V, VII, IX, XI and XII were within normal limits in all three patients. Mutual correction was demonstrated with a known factor-VII-deficient plasma but not with Stuart (X-deficient) plasma. Factor-X assay yielded low (4–9%) levels using tissue whole thromboplastin or tissue partial thromboplastin; but the results were normal with a Stypven-cephalin mixture. In agreement with these results, the Stypven-cephalin clotting time, the Stypven clotting time and the factor II + factor X level using a Stypven-cephalin mixture were normal, ‘correction’ being attributable to the Russell's Viper venom. These results were thought to indicate an abnormal factor X rather than a real deficiency. The presence of abnormal factor X was demonstrated by the antibody neutralization technique and by the immunodiffusion studies. The defect, like classical factor X deficiency, is transmitted as an autosomal incompletely recessive trait. The heterozygote population has factor-X levels varying from 32% to 55% of normal and are usually asymptomatic. The term ‘Factor X Friuli’ is proposed for the abnormality, due to a locally common mutant gene.     

Possible homozygous factor VIIR disorder associated with fibrinolytic hyperactivity

A family with inherited factor VII deficiency is described. The propositus is a 9-year-old girl with chronic haemorrhagic history of epistaxis and bleeding after tooth extractions. Her factor VII coagulant activity was less than 3% using rabbit thromboplastin. She had a factor VII antigen level of 50%. Both parents were heterozygous for factor VII deficiency. The father had procoagulant factor VII (VII-C) of 44% and factor VII antigen (VII-Ag) of 74%, and the mother had 54% of factor VII-C and 85% of VII-Ag. Her only brother had normal levels of factor VII-C (100%). Additionally, some abnormalities in the fibrinolytic system were detected both in the propositus and her brother with shortened euglobulin lysis times and increased functional levels of plasminogen activator. To our knowledge, the clinical association of inherited factor VII deficiency and familial fibrinolytic disturbances has not been described so far.     

Assessment of a new instrument (Coag-A-Mate X2) for performing global clotting tests and specific factor assays

Coag-A-Mate X2 (General Diagnostics) is an automated photo-optical system for detection of clots, which can be used for measuring prothrombin time (PT) and activated partial thromboplastin time (APTT) and assaying coagulation factors. We have compared results obtained with this instrument with those obtained by the manual method used routinely in our specialized laboratory. The instrumental results showed good precision (PT: between-assay CV from 1.3 to 3.0, APTT: from 2.2 to 3.1), and high degree of correlation with the manual results (for PT r = 0.99, for APTT r = 0.95). There was also good correlation between the two methods (0.98-0.99) for factor assays (V, VII, VIII, IX, X, XI, and XII). High output, reproducibility, comparability and flexibility make this instrument suitable for both clinical and research laboratories.     

Life-threatening bleeding in a case of autoantibody-induced factor VII deficiency

A male patient presented with life-threatening bleeding induced by autoantibody-induced factor VII (F.VII) deficiency. This patient had macroscopic hematuria, skin ecchymosis, gastrointestinal bleeding, and a neck hematoma that was causing disturbed respiration. He developed acute renal failure and acute hepatic failure, probably due to obstruction of the ureters and the biliary tract, respectively. Although activated partial thromboplastin time was normal, prothrombin time (PT) was remarkably prolonged at 71.8 seconds compared to 14.0 seconds in a normal control. Both the immunoreactive level of F.VII antigen and the F.VII activity of the patient's plasma samples were < 1.0% of normal. Although an equal part of normal plasma was added to the patient's plasma, PT was not corrected. The patient's plasma inhibited F.VII activity. These findings suggested the presence of a plasma inhibitor for F.VII. After administration of large doses of methylprednisolone, PT was gradually shortened and plasma levels of F.VII increased over time. Bleeding, acute renal failure, and acute hepatic failure improved markedly following the steroid treatment. These observations suggest that life-threatening bleeding can be induced by autoantibody-induced F.VII deficiency and that immunosuppressive therapy using large doses of steroid can be successful in inhibiting the production of the autoantibody.     

Hereditary Factor VII Deficiency in a Chinese Family

Hereditary deficiency of factor VII is demonstrated in a Chinese family. The proposita was a 32-year-old female with bleeding diathesis consisting of spontaneous ecchymosis, menorrhagia and recurrent haemarthrosis. The prothrombin time was prolonged and the prothrombin and proconvertin test was 10% of normal. The activated partial thromboplastin time and the Stypven-cephalin clotting time were normal. The prolonged prothrombin time could be corrected by the addition of normal serum, but not by adsorbed normal or coumadin plasma. The factor VII level was 3.6% of normal. One of her brothers had bleeding symptoms and died at age 25, suggesting that factor VII deficiency might have been present. 13 of her family members had partial deficiency of factor VII with plasma levels ranging from 24 to 50%. These results suggest an autosomal recessive inheritance with a homozygous state occurring in the proposita and possibly in her brother, and a heterozygous state occurring in 13 of her family members. Our study marks an extensive survey of factor VII deficiency in an Oriental family.     

Factor IX is activated in vivo by the tissue factor mechanism

Despite significant progress in elucidating the biochemistry of the hemostatic mechanism, the process of blood coagulation in vivo remains poorly understood. Factor IX is a vitamin K-dependent glycoprotein that can be activated by factor XIa or the factor VII-tissue factor complex in vitro. To investigate the role of these two pathways in factor IX activation in humans, we have developed a sensitive procedure for quantifying the peptide that is liberated with the generation of factor IXa. The antibody population used for the immunoassay was raised in rabbits and chromatographed on a factor IX-agarose immunoadsorbent to obtain antibody populations with minimal intrinsic reactivity toward factor IX. We determined that the mean level of the factor IX activation peptide (FIXP) in normal individuals under the age of 40 years was 203 pmol/L and that levels increased significantly with advancing age. The mean concentration of FIXP was markedly reduced to 22.7 pmol/L in nine patients with hereditary factor VII deficiency (factor VII coagulant activity less than 7%) but was not significantly different from normal controls in nine subjects with factor XI deficiency (factor XI coagulant activity less than 8%). These data indicate that factor IXa generation in vivo results mainly from the activity of the tissue factor mechanism rather than the contact system (factor XII, prekallikrein, high molecular-weight kininogen, factor XI). Our results may also help to explain the absence of a bleeding diathesis in many patients with deficiencies of the contact factors of coagulation.     

Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation.

A study was carried out on mechanisms, independent of activated Factor XI, capable of activating Factor IX. The reaction product of tissue factor and Factor VII functioned as a potent Factor IX activator in the assay system used. Activated Factor IX itself activated Factor X; thrombin failed to activate Factor IX. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis confirmed that the reaction product of tissue factor and Factor VII activated Factor IX, with replacement of the band corresponding to native factor IX [molecular weight (Mr) 55,000] by bands corresponding to the heavy chain (Mr 27,000) and light chain (Mr 17,000) of activated Factor IX. When either Factor VII or calcium ions were left out of incubation mixtures, the band of native Factor IX persisted unchanged. Contact of blood with tissue factor represents a second mechanism, bypassing activated Factor XI, for the activation of Factor IX during hemostasis. It may help to explain the discrepancy between the mild bleeding of hereditary Factor XI deficiency and the severe bleeding of hereditary Factor IX deficiency.     

Identification of a defective factor XI cross-reacting material in a factor XI-deficient patient

A homozygous factor XI-deficient girl, who appeared to be positive for cross-reacting material (CRM+) was studied for clarification. Factor XI antigen (F XI:Ag) was measured by radial immunodiffusion using monospecific, heterologous anti-factor XI antibodies. Factor XI coagulant activity (F XI:C) was determined in a modified activated partial thromboplastin time (APTT) test. The ratio of F XI:C to F XI:Ag was 0.04 for the proposita, as compared with 0.7 to 0.74 in the other family members. In contrast, 12 normal individuals had ratios of F XI:C to F XI:Ag of 1.04 +/- 0.15. F XI esterolytic activity was clearly higher than F XI:C in the proband, but not in her relatives. Immunoblotting studies demonstrated F XI CRM in the patient's plasma. Chromatography on diethylaminoethanol (DEAE)-Sephadex at pH 8.4 led to an almost complete removal of F XI from the plasma. The defective F XI was not bound to a negatively charged kaolin surface due to an abnormal interaction with high-mol-wt kininogen (HMWK).     

Type I coagulation factor V deficiency caused by compound heterozygous mutation of F5 gene

A 16-year-old Chinese female with prolonged bleeding after surgery has been studied. Routine clotting tests revealed a prolonged activated partial thromboplastin time (APTT; 126.6 s) and prothrombin time (PT; 42.8 s). The coagulation factors activities were normal except for factor V, which was only 0.3% of normal. DNA analysis of the FV gene revealed five nucleotide substitutions in exons, including two silent mutations (G327A and A5112G), one polymorphism (G1628A), a G1348T missense mutation and 4887 approximately 8delG. These abnormalities were associated with her FV deficiency, perhaps by causing a Gly392Cys substitution in FV amino acid sequence or by introducing a premature stop codon at amino acid position 1390. This is the third case in which FV deficiency is caused by compound heterozygous mutation of F5 gene, and is the first report from a Chinese family.     

Clinical manifestations in 28 Italian and Iranian patients with severe factor VII deficiency

There has been wide variation in the reported haemorrhagic manifestations of factor VII deficiency. We examined type and frequency of clinical manifestations in 28 Iranian and Italian patients with severe deficiency (factor VII coagulant activity 2% or less). The most frequent symptoms were epistaxis and menorrhagia, whereas soft tissue bleeding such as haemarthrosis and muscle haematoma was less frequent. Only 5 of 9 patient who underwent surgery without factor VII replacement therapy had postoperative bleeding severe enough to require blood transfusion. No thrombotic manifestation occurred. A factor VII functional assay based on the use of human thromboplastin was a better predictor of the bleeding tendency of these patients than a rabbit thromboplastin-based functional assay or immunoassay. On the whole, this study shows that in severe factor VII deficiency bleeding in mucosal tracts is not uncommon. Surgery can sometimes be performed without replacement therapy and without haemorrhagic complications.