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.     

Management of cesarean section under replacement therapy with factor VIII concentrates in a pregnant case with congenital combined deficiency of factor V and factor VIII

The congenital combined deficiency of Factor V and Factor VIII, a rare bleeding disorder, was identified in a 25-year-old woman. She was admitted to our hospital with a complaint of genital bleeding. Her prothrombin time and activated partial thromboplastin time were prolonged. She had low levels of Factor V coagulant activity (F. V:C) 14%, and Factor VIII coagulant activity (F. VIII:C), 12%, and normal levels of von Willebrand factor antigen (vWF:Ag), ristocetin cofactor (Rcof) and Protein C antigen. Her Protein C inhibitor level was slightly low. Her Rcof, vWF:Ag and F. VIII:C were elevated following administration of 1-deamino-8-D-arginine-vasopressin (DDAVP), but her F. V:C remained unchanged. Four years later, her F. VIII:C rose to 70% during the course of her pregnancy, but her F. V:C value remained low. It was expected that the vaginal delivery would be possible at the termination of pregnancy. Premature rupture of the membranes and an anomaly of rotation appeared in the course of delivery, however, and cesarean section was accomplished without excess bleeding under replacement therapy with Factor VIII concentrates. These findings suggested that DDAVP and Factor VIII concentrates were useful for management of her delivery. However the mechanisms of the rise of plasma F. VIII:C during pregnancy in a case with congenital combined deficiency of Factor V and Factor VIII are unclear.     

An immunological investigation of factor VIII associated antigen in combined factor v and factor VIII deficiency

Summary The behavior of factor VIII associated antigen of three patients with combined factor V and factor VIII deficiency has been evaluated in several immunological systems. Factor VIII associated antigen resulted to be normal or higher than normal in all three patients in the radial immunodiffusion and in the electroimmunoassay systems. In the bidimensional electrophoresis system only one factor VIII precipitate was evident and such factor VIII precipitate showed the same electrophoretic mobility as normal factor VIII antigen.These findings firmly establish the fact that the factor VIII defect in congenital combined factor V and factor VIII deficiency is of the hemophilia type.This study was supported in part by a grant from the C.N.R. (grant CT 74.00189.04).     

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.     

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.     

Combined factor V and factor VIII deficiency with normal protein C and protein C inhibitor. A family study

Combined deficiency of factor V and factor VIII, a rare bleeding disorder, is reported in a Syrian family. 2 siblings, 10 and 6 yr old are affected. They had mild bleeding manifestations. Their prothrombin time and partial thromboplastin time were prolonged, but thrombin time was normal. Both had low levels of factor V, (6% and 7%), factor VIII, (both 10%) factor VCAg (both 6%) and factor VIII CAg, (6% and 4%). All members of this family had normal levels of factor VIIIR:Ag, protein C, antigen and protein C inhibitor. The normal levels of protein C and protein C inhibitor in the 2 affected family members indicate that the combined deficiency of factors V and VIII has nothing to do with protein C. This contrasts with previous reports that deficiency of protein C inhibitor is the cause of combined factor V and factor VIII deficiency. The probable mode of inheritance of this defect is discussed.     

Characterization of the factor VIII inhibitor in a patient with chronic renal failure]

A 29-year-old women, who had been treated by hemodialysis for 5 years because of chronic renal failure, developed bleeding tendency in March 1989. Laboratory data showed prolonged activated partial thromboplastin time which was not corrected by addition of normal plasma; factor VIII activity was less than 1% and factor VIII inhibitor 70 Bethesda units/ml. The inhibitor was eluted in the second peak which corresponded to IgG when the plasma was subjected to Sephacryl S 200 column. The further purified IgG fraction by passing through protein A column showed a factor VIII inhibitor activity of 52 Bethesda units/ml. The factor VIII inhibitor epitopes were examined by western blotting technique using factor VIII purified by monoclonal antibody as the antigen. The factor VIII preparation used was composed of a doublet of light chain (Mr 80,000) and three heavy chains (Mr 160,000-200,000) when examined by immunoblotting using anti-factor VIII light and heavy chains monoclonal antibodies after SDS-PAGE. Factor VIII inhibitor that arose in a hemophilia A patient recognized the light chain, and the inhibitor in this case reacted to the heavy chain of factor VIII.     

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.     

Combined factor V/VIII deficiency: a case report including levels of factor V and factor VIII coagulant and antigen as well as protein C inhibitor

Comprehensive coagulation studies were performed on members of a family with combined factor V/VIII deficiency. The purpose of these studies was to investigate the hypothesis that combined factor V/VIII deficiency is due to a lack of the inhibitor to activated protein C. The analyses performed included routine APTT and PT, factor V and VIII coagulant activity and antigen levels, von Willebrand factor levels, protein C antigen assay, and both protein C inhibitor activity and antigen levels. Three of the 19 family members studied were found to have a deficiency of both factors V and VIII. These three individuals showed prolonged APTTs and PTs and decreased levels of factor V and factor VIII coagulant activity and antigen. Factor VIII related antigen and ristocetin cofactor (von Willebrand factor) levels were normal. Protein C and both protein C inhibitor activity and antigen levels were also found to be normal. These findings confirm the results of other recent investigators and indicate that the autosomal, inherited combined factor V/VIII deficiency is not due to a protein C inhibitor deficiency. The real defect in this combined deficiency remains to be determined.     

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.     

Severe fletcher factor (plasma prekallikrein) deficiency with partial deficiency of hageman factor (factor xii): Report of a case with observation on in vivo and in vitro leukocyte chemotaxis

A case of cross-reacting material-negative Fletcher trait with additional partial deficiency of Hageman factor (HF, Factor XII) is described. Although the patient presented with a recent history of frequent epistaxis, he had no other personal or family history of a tendency toward bleeding or infection. Similar to other cases of Fletcher trait, his plasma showed a markedly prolonged partial thromboplastin time which could be corrected by prolonged incubation with the surface-activator kaolin. Surface-induced fibrinolysis, amidolysis of α-N-benzoyl-proline-L -phenylalanine-L -arginine-p-nitro- anilide, and cold-promoted enhancement of factor VII activity, reactions requiring the presence in the plasma of Fletcher factor (pre-kallikrein), in addition to Hageman factor and Fitzgerald factor (high-molecular weight kininogen), were also defective. In vivo chemotaxis of polymorphonuclear leukocytes and monocytes (Rebuck's skin window technique) in response to skin abrasions was defective, but was normal when diphtheria-tetanus toxoid was also applied. In vitro leukocyte chemotaxis (Boyden chamber technique) in response to normal or patient's own serum activated with zymosan was normal. Together with previous observations that kallikrein generated chemotactic activity, possibly via activation of C5, the present observations suggest that prekallikrein activation may be important for in vivo leukocyte chemotactic response to skin abrasion. The inheritance of Fletcher trait in this patient is unclear. Although the father was an apparent heterozygote, the mother was completely normal for Fletcher factor procoagulant activity and antigen. The mild Hageman factor deficiency in the patient did not contribute significantly to the plasma defects described and was likely inherited from the father who had a low HF procoagulant activity.     

Combined factor V and factor VIII deficiency in a Thai patient: a case report of genotype and phenotype characteristics

A Thai woman, with no family history of bleeding disorders, presented with excessive bleeding after minor trauma and tooth extraction. The screening coagulogram revealed prolonged activated partial thromboplastin time and prothrombin time. The specific-factor assay confirmed the diagnosis of combined factor V and factor VIII deficiency (F5F8D). Her plasma levels of factor V and factor VIII were 10% and 12.5% respectively. The medications and blood product treatment to prevent bleeding from invasive procedure included 1-deamino-8-d-arginine vasopressin, cryoprecipitate, factor VIII concentrate, fresh frozen plasma and antifibrinolytic agent. Gene analysis of the proband identified two LMAN1 gene mutations; one of which is 823-1 G --> C, a novel splice acceptor site mutation that is inherited from her father, the other is 1366 C --> T, a nonsense mutation that is inherited from her mother. Thus, the compound heterozygote of these two mutations in LMAN1 cause combined F5F8D.     

A case of factor V inhibitor

A 57-year-old married Chinese male without a family history of bleeding disorder was presented with severe hemorrhagic tendency and was subsequently found to be suffering from an acquired inhibitor against coagulation factor V. The prolonged prothrombin time and activated partial thromboplastin time could not be corrected by the addition of normal plasma. Subnormal value of factor V level was noted accompanied with an abnormal platelet factor III availability test. With specific antisera and staphylococcal protein A, the inhibitor was characterized as an IgG(lambda) antibody. The hemorrhagic tendency and abnormal laboratory data were corrected after treating the patient with platelet concentrate transfusion and cyclophosphamide.     

The RIIIS/J inbred mouse strain as a model for von Willebrand disease

Mice of the RIIIS/J inbred strain have prolonged bleeding times (greater than 15 minutes) after experimental injury when compared with normal C57BL/6J mice (1.8 minutes) and other strains of mice. The prolonged bleeding time was accompanied by normal platelet counts. Platelet aggregation with collagen and agglutination with ristocetin were not significantly altered in RIIIS/J mice. Also, platelets from RIIIS/J mice had normal serotonin content and normal numbers of dense granules by electron microscopy. Thus, the bleeding abnormality is not due to platelet storage pool deficiency as has been found in several other mouse mutants. The activated partial thromboplastin time (APTT) which plasma from RIIIS/J mice was prolonged compared with normal mice, and factor VIII:C activity and von Willebrand antigen levels were one half to one third that of normal mouse plasma. Factor XI activity was also significantly deficient (levels at 42% to 64% of normal). Plasma of RIIIS/J mice contained the full complement of multimers of von Willebrand factor, although each multimer was lower in concentration compared with that in normal mice. Platelet alpha-granule von Willebrand antigen levels were similar to those of normal mice. The prolonged bleeding time of RIIIS/J mice was corrected by treatment with desmopressin. Heterozygous C57BL/6J x RIIIS/J F1 animals had low plasma von Willebrand antigen levels like the RIIIS/J parent and had variable bleeding times. Inheritance of the bleeding tendency was as an incomplete dominant, autosomal trait. These data indicate the RIIIS/J strain is a suitable animal model for type IA von Willebrand disease.     

A new family with classical factor X deficiency as demonstrated by electroimmunoassay

Summary A new family with classical factor X deficiency is described. The proposita is a 6 year old girl who presented with occasional epistaxis and a hematoma after an intramuscular injection. The main laboratory features consisted in a prolongation of partial thromboplastin, prothrombin and Stypven clotting times corrected by the addition of normal serum. Factor X activity varied between 3 and 6%. Factor X amydolytic activity was 15% of normal. Electroimmunoassay failed to show the presence of factor X antigen. No inhibitor was found in the proposita plasma. Parents and other family members showed intermediate levels of factor X activity and antigen and were considered to be heterozygotes. No consanguineity was found in the family.This study was supported by grants from the M.P.I., Rome (grant 1592–1981) and from the Veneto Region, Venice     

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     

A family of congenital combined deficiency of factor V and von Willebrand factor

A family with inherited combined deficiency of factor V and von Willebrand factor (vWF) is reported. Hematological examination of 41 year-old female proband and her younger brother revealed prolonged prothrombin time and Kaolin partial thromboplastin time. The level of both factor V activity and factor V antigen markedly decreased, below 15% of normal. The decreased levels of factor VIII activity and vWF activity are also seen. Furthermore, abnormal mobilities were observed in crossed immunoelectrophoresis. The protein C, S antigens and activities, and protein C inhibitor activity were within normal. Four sons have received the 50% levels of factor V from their parents. One of them also showed the 50% of factor VIII and vWF activities. From above results, this family is thought to be a case of inherited deficiency of factor V and vWF, which are transmitted as an autosomal trait apparently.     

Pseudo-factor-XI deficiency: effect of an inhibitor of factor XI adsorption to surface

Recently we have described a normal plasma activity that modulates contact activation by inhibiting adsorption of factor XI to activating surfaces. Here we report the first identified case in which a patient has abnormal clotting tests due to an excess of a similar activity. The patient's plasma had a prolonged partial thromboplastin time and low apparent factor XI assay. His plasma prolonged the partial thromboplastin time of normal plasma and partially neutralized normal factor XI activity in vivo and in vitro. Analysis in dilute plasma revealed normal amounts of factor XI activity and antigen. Factor XI adsorption from plasma to activating surfaces was tested by adding a small amount of 125I-labeled purified factor XI to plasma, exposing the mixture to a glass tube or kaolin, and determining the amount of factor XI adsorbed to the surface. Whereas normal plasma and plasmas deficient in factor XII, factor XI, or Fletcher factor yielded about 4% adsorption to glass, factor XI adsorption from patient's plasma was less than 1%, indicating the presence of an adsorption inhibitor. This inhibitor did not affect factor XI activation or the activity of preformed factor XIa. It was not adsorbed by AI(OH)3 and was present in serum and the macroglobulin peak on gel filtration of the plasma through Sephadex G-200. The patient's history does not allow a definitive conclusion as to whether this inhibitor was associated with abnormal bleeding.     

A female hemophilia A combined with hereditary coagulation factor XII deficiency: a case report.

A 2-year-old Japanese girl with easy bruising and arthropathy was demonstrated to have severe hemophilia A (Factor VIII activity: less than 0.01 U/ml). She had normal 46XX karyotype. Her brother also had hemophilia A, and her mother and grandmother seem to be hemophiliac carriers. Additionally, activated partial thromboplastin time (APTT) of the patient was disproportionately prolonged and there were reduced levels of coagulation factor XII in the patients and members of the maternal trait which are compatible with heterozygous factor XII deficiency. Her father had both normal factor VIII and factor XII levels. Southern blotting analysis of genomic DNA from the propositus and family members with factor VIII and factor XII DNA probes revealed no gross alterations. This patient represents a female hemophilia A combined with heterozygous factor XII deficiency. Nonrandom inactivation of a normal X-chromosome (extreme lyonization) may be the basis for the expression of hemophilia A in this female patient.     

Circulating anticoagulant in a family with prolonged bleeding time and factor VIII deficiency

A circulating anticoagulant against factor VIII activity was demonstrated in the plasma of a boy from a family with both factor VIII deficiency and prolonged bleeding time. However, the factor VIII- related antigen, ristocetin-induced platelet aggregation activity, platelet retention in glass bead columns, platelet aggregation with adenosine 5'-diphosphate, collagen and epinephrine, and clot retraction among affected members were normal. The electrophoretic mobility of factor VIII-related antigen on crossed immunoelectrophoresis was normal. The inactivation of factor VIII activity by the inhibitor was time dependent and was nonlinear as the concentration of the inhibitor was increased. Immunotyping showed that the inhibitor was IgG with k light chains.