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.     

Hemorrhagic diathesis associated with the presence of an anticoagulant in circulating blood; case report and laboratory studies

A new observation of a hemorrhagic diathesis associated with the presence ofan anticoagulant in the circulating blood is reported here. The patient was a 21year old male, appearing by clinical evaluation to have hemophilia, but withouta family history of hemophilia. The blood and plasma were strongly anticlottingand had a very long clotting time. The clotting time of recalcified citrated plasmawas greatly delayed by removing the platelets. Freezing and thawing of platelet-rich plasma resulted in a marked shortening of the clotting time. Dilution of theplasma shortened the clotting time, while the addition of calcium and storage ofthe plasma had no effect.

The prolonged clotting time was not corrected by the addition of normal plasmaor plasma fractions having antihemophilic activity. The prothrombin time wasnearly normal. Small quantities of thromboplastin were very effective in shortening the clotting time. The anticoagulant had no antithrombin activity. The "progressive" antithrombin and antifibrinolysin of the patient’s plasma were normal.

The anticoagulant acts during the first phase of coagulation by inhibiting an(plasma) activator of prothrombin. It appears to be identical with the anticoagulant described in three previous publications from the United States.

     

A Syndrome of Factor VII Deficiency and Abnormal Platelet Release Reaction

A 15-year-old girl with severe factor VII deficiency and chronic arthropathy showed an excessively prolonged bleeding time. Further studies demonstrated low platelet adhesiveness and abnormal platelet aggregation with ADP, collagen and epinephrine. Release of ¹⁴C-serotonin was deficient after aggregation with ADP and epinephrine, but was normal with thrombin. Transfusion of plasma or prothrombin complex concentrate resulted in a partial or complete correction of the bleeding time, respectively, but had no effect on in vitro platelet function tests. Both parents and the only sister had factor VII activities of 42 % - 72 % and factor VII antigen levels of 45 % - 66 % of normal and may thus be heterozygotes with respect to factor VII deficiency. All three had normal bleeding times in spite of abnormal in vitro platelet functions. The observations are interpreted to mean that in this family with factor VII deficiency and abnormal platelet release reaction the platelet abnormality as such was not sufficiently severe to prolong the bleeding time unless the factor VII activity was also very low.     

Plasma thromboplastin antecedent (PTA) deficiency; clinical,coagulation, therapeutic and hereditary aspects of a new hemophilia-like disease

1. An analysis of the original PTA deficient family, including coagulationstudies performed upon 13 members comprising 4 generations, has been presented.

2. PTA deficiency is transmitted as an autosomal dominant trait with a probable high degree of penetrance and variable expression of the gene.

3. PTA deficiency can occur its varying degrees ranging from a severe formwith prolonged clotting time and markedly abnormal heparin clotting time andprothrombin utilization to a mild form manifesting a normal clotting time andslightly impaired prothrombin utiliztition.

4. Studies on the treatment of PTA deficiency reveal that the defect is corrected by the administration of stored plasma with the effect gradually disappearing over the period of one week.

5. Various properties of PTA are discussed and compared with AHG andPTC.

Submitted on April 27, 1954 Accepted on July 6, 1954     

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.     

Hypoproaccelerinemia

This communication is concerned with the case of a 3-year old girl who hadshown a moderately severe bleeding tendency since the age of 6 months. Thecause of the bleeding could be clearly attributed to a marked deficiency in plasmaproaccelerin and platelet accelerator factor. Abnormalities were also found in theclotting time, prothrombin consumption and Quick test. That this was probablyfamilial in nature was suggested by moderately reduced plasma proaccelerinlevels in the patient’s parents and in one sibling.^*

Submitted on April 26, 1954 Accepted on July 21, 1954     

Recombinant factor VIIa for the treatment of congenital factor VII deficiency

Factor VII deficiency is a rare autosomal bleeding disorder with a highly variable hemorrhagic predisposition. Severe bleeding, including hemarthroses, may be encountered when plasma factor VII levels are below 1%. Patients have prolonged prothrombin times, and the final diagnosis is established by quantitative factor VII assays. Some patients have true deficiencies, that is, very low factor VII activity and low factor VII antigen (cross-reacting material) levels (CRM-); others have normal antigen levels but low activity (CRM+). Still others have reduced antigen levels (CRMR). There is a rather poor correlation between clinical symptoms and factor VII activity levels in plasma. Treatment of these patients consists of fresh frozen plasma, prothrombin complex concentrates, or factor VII concentrates. Recombinant activated factor VII (rFVIIa) is a very useful alternative, and several patients have been treated successfully. Because of the short half-life of factor VIIa, repeated doses have to be administered, and continuous infusion may be even better. Antibodies to factor VII have been reported but seem to be rather rare. From the available data it appears that rFVIIa is a safe and effective treatment modality for patients with congenital factor VII deficiency.     

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.     

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.     

Mild PTC (plasma thromboplastin component) deficiency occurring in two brothers

1. Thirteen cases of plasma thromboplastin component (PTC) deficiency orChristmas disease are reviewed and summarized. Of these cases, only in onewere the whole blood coagulation time and prothrombin consumption normal.

2. Two cases of a mild bleeding disorder, occurring in brothers with slightlyprolonged whole blood coagulation times and normal prothrombin consumptionare described.

3. In these two cases, the thromboplastin generation test revealed the deficiency of a serum factor essential for normal thromboplastin generation. Amild deficiency of PTC was demonstrated by the correction of the serum deficiency by the addition to the patients’ serum of a partially purified preparation of PTC.

4. The differentiation of PTC deficiency from hemophilia is discussed.

5. Mild bleeding disorders due to a moderate reduction of antihemophilicglobulin (AHG) or PTC can be differentiated by the use of the thromboplastingeneration test.

Submitted on December 28, 1953 Accepted on March 16, 1954     

A Plasma Coagulation Defect in Systemic Lupus Erythematosus Arising from Hypoprothrombinemia Combined with Antiprothrombinase Activity

A patient has been described with systemic lupus erythematosus and severebleeding. Her bleeding was associated with a complex plasma coagulationdisturbance consisting of profound hypoprothrombinemia plus an anticoagulant active against formed blood and tissue prothrombinase. The problem of the recognition of hypoprothrombinemia in the presence of this typeof anticoagulant has been discussed in detail.

An analysis of previously reported cases reveals that our patient’s findingsare not unique. It appears that the plasma coagulation disturbances ofsystemic lupus erythematosus characteristically result from a mixture ofanticoagulant activity and true hypoprothrombinemia. In an individual patientone or the other may predominate.

Submitted on April 7, 1959 Accepted on July 1, 1959     

Hypoprothrombinemia; studies of a case of the idiopathic type and the effect of serum administration

1. The reported cases of idiopathic hypoprothrombinemia are reviewed briefly,and a case observed for over three years is presented. Particular attention is calledto the similar clinical pattern presented by the chronic cases.

2. Studies are presented indicating that in this patient the delay in prothrombintime was due, at least in part, to a deficiency of a factor necessary for rapid conversion of prothrombin. This factor, or factors, which we have called Ac-globulin,is contained in a highly active state in fresh normal serum.

3. After the in vitro demonstration of a deficiency of Ac-globulin in the patient’sblood, it was possible to bring about a marked reduction in the patient’s prothrombin time by the intravenous administration of relatively small amounts (15 to45 cc.) of fresh normal (thrombin-free) serum. A further reduction of the prothrombin time to near normal values was brought about by combined wholeblood and serum administration. The evidence suggests that partial correction ofboth prothrombin and Ac-globulin deficiency respectively resulted from suchtherapy.

4. The possible effects of serum and whole blood upon the delayed prothrombinconversion rate of dicoumarolization and liver disease are discussed and preliminary observations in the former type suggest that such therapy may be useful.

Note: ACKNOWLEDGMENTSWe wish to express our appreciation to the following for their cooperation in this study:Dr. McLemore Birdsong, Associate Professor of Pediatrics, University of Virginia Medical School;The Department of Pediatrics, University of Virginia Hospital; The Department of Biochemistry, University of Virginia Medical School; Dr. Myers H. Hicks, Assistant Resident in Medicine, Universityof Virginia Hospital; Dr. Walter H. Seegers, Professor of Physiology, Wayne University College ofMedicine.

     

Use of factor VII-deficient beagles bred by artificial insemination to evaluate mechanisms of thrombosis associated with prothrombin complex concentrates.

Artificial insemination with frozen semen was used to breed beagles homozygous for a deficiency in clotting factor VII, with plasma concentrations of 2-3% of normal adult beagle pooled plasma. The factor VII-deficient beagles were used to determine if factor VII activity has a role in the thrombogenic activity of prothrombin complex concentrates (PCCs) containing factors II, IX and X by evaluating changes in selected indicators of thrombogenicity. No differences were seen between the responsiveness of the factor VII-deficient and normal beagles, indicating that the thrombogenic activities of PCCs are mediated via effects on the intrinsic clotting system.     

A novel congenital haemostatic defect: combined factor VII and factor XI deficiency.

Isolated deficiencies of factors VII and XI are both rare. Not surprisingly, therefore, combined factor VII and XI deficiency has not been reported previously. We report here a kindred with a combined heterozygous deficiency for both factors VII and XI. The proposita is a 28-year-old woman who had both a prolonged prothrombin time (PT) and a prolonged activated partial prothrombin time (APTT) associated with a mild bleeding tendency. Coagulation studies were performed on the six available members of this kindred. The PT and APTT were normal or mildly abnormal in five of these individuals. Factor VII coagulant activity (VII:C) varied from 0.33 to 0.77 units/ml in affected subjects. In contrast, the concentration of factor VII-related antigen for the six individuals ranged from 0.68 to 2.10 units/ml. Comparable factor VII:C levels were obtained when each subject's plasma was tested with either a rabbit or a human thromboplastin reagent. Factor XI coagulant activity was less than 0.5 units/ml in three of the six subjects and normal (approximately 1.0 units/ml) in the other three. The concentrations of thrombin-antithrombin-III and prothrombin fragment 1.2 were within normal limits for all individuals. In addition to being associated with heterozygous factor XI deficiency, the abnormal factor VII molecule in the plasma of affected individuals in this kindred appears to represent a newly described mutation. This is suggested by the pattern of reactivity with thromboplastin from different species, the normal tissue factor binding and the bleeding tendency in heterozygous individuals in this kindred.     

Postoperative bleeding in a patient with normal screening coagulation tests

A 54-year-old man was brought to the emergency room after a head-on collision. He had multiple fractures in his lower extremities and required immediate surgery. After surgery, the patient had a persistent drop in hemoglobin, hematocrit and platelets despite red blood cell transfusions. Laboratory studies included normal prothrombin time, activated partial thromboplastin time, normal plasminogen functional activity, negative antiplatelet antibodies, normal platelet functional analysis and negative disseminated intravascular coagulation screen. Factor XIII antigen levels were 25% of predicted, and the diagnosis of factor XIII deficiency was made. The patient was treated with cryoprecipitate, and the bleeding stopped. Patients with factor XIII deficiency have either a rare congenital or acquired coagulation disorder. Both presentations have normal standard laboratory clotting tests, and the diagnosis requires an assay measuring factor XIII activity or antigen levels. The usual treatment includes cryoprecipitate, fresh-frozen plasma or recombinant factor XIII. This deficiency should be considered in patients with unexplained spontaneous, traumatic or postoperative bleeding.     

Factor VII deficiency – an enigma; clinicohematological profile in 12 cases

Objective: Factor VII deficiency is the commonest of the rare bleeding disorders with limited knowledge on clinical profile. The objective of this study was to study the prevalence and clinico-hematological profile of factor VII-deficient patients.

Methods: It is a retrospective observational study of probable inherited factor VII deficiency covering 18 months. Their clinical profile, family history, investigation and treatment records were studied in detail.

Results: The study group comprised of total 12 factor VII deficiency cases with mean age of 17.5 years of onset of symptoms. The commonest symptom was menorrhagia (41.6%) followed by epistaxis (25%) and easy bruisability (16.6%). These 12 patients when categorized according to bleeding severity: severe bleeding – 2, moderate bleeding – 3, mild bleeding – 6 and asymptomatic – 1. All cases had prolonged prothrombin time (PT) with mean PT of 35.4?seconds (range 18–50?seconds) and mean prolongation of PT from upper limit of normal – 19.4?seconds (range 2–34?seconds). Factor VII levels ranged from < 1–40% in these patients. Clinical symptoms were not in concordance with factor levels. Of 12 patients, required treatment other than local measures.

Discussion and Conclusion: Inherited factor VII deficiency is the commonest autosomally inherited factor deficiency with marked variation in the age of presentation and clinical symptoms. The laboratory results in form of PT and factor VII levels do not correlate with the severity of clinical presentation. A comprehensive evaluation to exclude acquired causes of factor VII deficiency, e.g. obesity, liver diseases, vitamin K deficiency and acquired inhibitors is required before labeling it as inherited in the absence of family history and molecular studies.     

Hageman factor (HF) deficiency

A patient with Hageman factor (HF) deficiency is described. This syndromeis characterized by complete absence of any hemorrhagic tendency in the presence of laboratory findings which, as a rule, are associated with severe disturbances in the hemostatic mechanism. The clotting time was markedly prolonged,the plasma prothrombin time was normal, but prothrombin consumption wasdecreased. The thromboplastin generation test revealed that HF is essential forblood thromboplastin formation at least in vitro.

Procedures for the differentiation of HF deficiency from AHF, PTC and PTAdeficiency syndromes are outlined.

Transfusions of as little as 50 cc. of 20 day old blood normalized the abnormalclotting tests immediately for a period of about 36 hours.

The basis for the apparent lack of need for preoperative preparation withblood transfusions in HF deficiency is discussed.

Submitted on November 21, 1955 Accepted on February 6, 1956     

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.     

Molecular analysis of Polish patients with factor VII deficiency

We analyzed the mutations in patients from 10 Polish kindreds with a bleeding diathesis due to factor VII deficiency. Patients from eight families had plasma levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) that were less than 4% of normal. The coding sequence of the factor VII gene was amplified from genomic DNA by polymerase chain reaction (PCR). Sequencing demonstrated a C to T transition at position 10798 resulting in Ala294Val, a G to A transition at 10976 resulting in Arg353Gln, and a single bp deletion at 11125 to 11128 causing a frameshift mutation in the triplet encoding amino acid 404. Homozygosity for the three sequence alterations was confirmed with the restriction enzymes AvaII and MspI and allele specific PCR, respectively. A homozygous patient from a ninth family with levels of VII:C and VII:Ag of 4% and 17%, respectively, had Ala294Val and the frameshift mutation, but not Arg353Gln. Investigation of a homozygous patient from a tenth kindred with VII:C and VII:Ag of 11% and 47%, respectively, demonstrated Ala294Val and Arg353Gln, but not the frameshift mutation. Based on the above data, we conclude that the frameshift mutation in the codon for amino acid 404 is associated with marked reductions in VII:C, Arg353Gln can decrease plasma levels of factor VII in the presence of other mutations in the factor VII gene, and Ala294Val results in a dysfunctional factor VII molecule.     

The immunodepletion of factor VII from human plasma using a monoclonal antibody

A murine hybridoma cell line which secretes monoclonal antibody to factor VII has been prepared to facilitate the immunodepletion of this clotting factor from plasma. Specific monoclonal antibody was purified from mouse ascites tumours by protein A-Sepharose chromatography and shown to be of the IgG1 immunoglobulin subclass. On immunoblotting, this antibody reacted with a single protein band identical to purified factor VII. The purified monoclonal antibody was coupled to Sepharose 4B and was used to immuno-deplete factor VII from pooled normal human plasma. The prothrombin time of plasma immunodepleted in this way was 35 s compared to 12 s for the starting plasma. Specific factor assays of the immunodepleted plasma showed factor VII activity to be less than 1% while the levels of the other clotting factors were unchanged. The immunodepleted plasma was equivalent to severe congenital factor VII deficient plasma as a substrate for factor VII assays. Bound factor VII could be eluted from the immunoaffinity column with citrate buffer, pH 6.0, with good recovery.