Bleeding symptoms in 27 Iranian patients with the combined deficiency of factor V and factor VIII

Inherited deficiency of factors V and VIII is the most frequent combined coagulation defect. The cases reported so far are mostly single cases or small series from different centres, making it difficult to evaluate the overall pattern of clinical manifestations of the combined defect. We examined at a single institution 27 Iranian patients. Mucocutaneous and post-surgical bleeding were the most frequent clinical manifestations. The presence of two defects did not make the severity of bleeding greater than that expected in patients with single coagulation defects of similar degrees.     

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.     

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.     

Combined factor V and VIII deficiency in Indian population

The clinical and haematological heterogeneity in cases of the rare combined factor V and VIII deficiency has not been reported so far from India. Nine such cases belonging to five unrelated families have been analysed in the present study for the various haematological and clinical parameters. A very mild clinical presentation is seen in all these cases. The clinical manifestations, however, do not correlate with the plasma levels of these factors.     

Use of plasma exchange in hereditary deficiency of factor V and factor VIII

Combined hereditary deficiency of coagulation factors V and VIII is a very rare bleeding disorder. The severity of bleeding is determined by the level of these factors, although in general, this is less striking than the severe deficiency of either factor alone. We describe in this article a patient with this congenital defect, and the preoperative management for major surgery. © 1996 Wiley-Liss, Inc.     

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).     

Inherited combined deficiency of factor V and factor VIII: report of a case with normal factor VIII antigen and ristocetin-induced platelet aggregation

A patient with inherited combined deficiency of factor V and factor VIII is reported, who demonstrated normal levels of factor VIII antigen and plasma cofactor for ristocetin-induced platelet aggregation. The relationship of this condition to classical hemophilia and von Willebrand's disease is discussed. The data presented suggest that multiple loci on at least 2 chromosomes are necessary for the normal expression of factor VIII activity.     

Severe factor V deficiency and neonatal intracranial haemorrhage: a case report

We report a case of severe factor V (FV) deficiency (<1%) associated with multiple episodes of intracranial bleeding which presented at birth. The clinical course was further complicated by the development of an inhibitor, episodes of sepsis and cardiac failure. The management using virally inactivated FFP and platelets is discussed.     

Diagnosis of factor VIII deficiency

Summary.  The correct diagnosis of factor VIII deficiency and the assessment of severity of the disease are essential for a patient-tailored treatment strategy. An optimal diagnostic procedure comprises sensitive and specific screening methods and factor VIII activity assays. Different screening reagents show variable characteristics and receiver operator characteristic curves are presented showing the relation between sensitivity and specificity of eleven activated partial thromboplastin time reagents. The details of the three methods for factor VIII activity assay, one-stage and two-stage assay and chromogenic assays, are discussed. The chromogenic assay seems to be more sensitive than the one-stage assay with regard to the detection of severe haemophilia. Discrepant results obtained with one-stage and two-stage assays are reviewed and discussed.     

Haemorrhagic symptoms in patients with combined factors V and VIII deficiency in north-eastern Iran

Of the six types of dual coagulation factors deficiency, combined factors V and VIII are the most common type, a few cases of this disease have been reported in different populations. This accounts for the relatively low number of cases reported so far. Our report, which included 19 patients, is the second largest group that has been reported from one centre in north-eastern Iran. The most frequent spontaneous bleeding symptoms were epistaxis and haemarthrosis, and the most frequent traumatic bleeding symptoms were bleeding after dental extraction and bleeding after cutting any part of the body. It seemed that dual coagulation FV and FVIII deficiency is as severe as single coagulation factor (V or VIII) deficiency.     

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.     

Acquired von Willebrand factor deficiency during high-dose infusion of recombinant factor VIII

Constant infusion of factor VIII (FVIII) into patients with haemophilia A after major surgery has been recommended as optimal treatment to avoid peaks and valleys in the circulating levels of FVIII and to allow the use of much lower doses of FVIII than are historically required.
One of our young patients with severe (<0.01 U/ml FVIII) haemophilia suffered a subdural haematoma for which he received treatment with 815 190 recombinant FVIII (rFVIII) units over a period of 52 d. 2 weeks after admission, because of low FVIII levels and the presence of FVIII inhibitors, the infusion rate was increased to >100 U/kg/h for 14 d. During this time the FVIII level fluctuated between 0.6 and 4.2 U/ml. For some period it was not possible to detect ristocetin co-factor activity in this patient's plasma and the von Willebrand factor (VWF) level and VWF multimer pattern resembled those of a patient with von Willebrand's disease. Subsequently, when the rFVIII dose was increased 2-fold, this was not reflected by the plasma level of FVIII although antibodies were not detected.
The data suggest that the prolonged infusion of very high levels of rFVIII which is deficient in von Willebrand factor can result in depletion of VWF from existing stores, producing a laboratory picture which is consistent with the diagnosis of von Willebrand's disease. Further, in the absence of complexing with VWF, FVIII appears to be cleared from the circulation at an increased rate. This is expensive and potentially compromising. Therefore, when administering very high doses of FVIII concentrates devoid of VWF for prolonged periods of time, ristocetin cofactor and VWF levels should be monitored.     

Combined factors V and VIII deficiency — the solution

Summary. Combined deficiency of coagulation factor V and factor VIII is an autosomal recessive disorder which has been observed in a number of populations around the world. However, this disease appears to be most common in the Mediterranean basin, particularly in Jews of Sephardic and Middle Eastern origin living in Israel. We have taken a positional cloning approach toward identifying the gene responsible for this disorder. We initially studied 14 affected individuals from nine unrelated Jewish families using a panel of polymorphic genetic markers spaced throughout the human genome. The combined factors V and VIII deficiency gene was mapped to a locus on the long arm of chromosome 18 with a maximal LOD score of 13.22. A detailed genetic analysis identified two distinct haplotypes among these families, suggesting two independent founders or, alternatively, a single ancient founder with a more recent split of these subpopulations. Further work to identify and characterize the gene responsible for combined factors V and VIII deficiency should provide important insights into the biosynthesis of these homologous proteins.     

Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia

Factor VIII activity (factor VIII:C) and factor VIII antigen (factor VIII:Ag) levels above 150 IU/dl are associated with a five- to sixfold increased risk of venous thrombosis compared with levels < 100 IU/dl. These high levels are present in 25% of patients with a first episode of deep-vein thrombosis and in 11% of healthy controls. von Willebrand factor (VWF) and blood group are important determinants of the factor VIII level in plasma and therefore contribute to thrombotic risk, while factor VIII appears to be the final effector. Previously, we found familial clustering of factor VIII:C levels in women, which remained after adjustment for VWF and blood group. In the present study, we analysed the familial influence on factor VIII:Ag levels exceeding 150 IU/dl in 12 large families with thrombophilia in which high factor VIII:Ag levels contribute to thrombotic risk. As expected, blood group was a main determinant of the plasma factor VIII level: 58 relatives (32%) had factor VIII levels above 150 IU/dl and 50 (86%) of these had blood group non-O. After adjustment for blood group and age, we found an association between factor VIII:Ag levels in sister pairs (0.35, P = 0.003), brother pairs (0.35, P = 0.003), brother-sister pairs (0.35, P < 0.001) and in mother-son pairs (0.45, P = 0.02), but not in father-daughter or father-son pairs. The familial aggregation test was strongly positive for factor VIII:Ag levels (P < 0.001) and remained so after adjustment for the influence of blood group. We conclude that high factor VIII:Ag levels are a highly prevalent risk factor for venous thrombosis and contribute to risk in families with thrombophilia, and that these high levels are likely to be genetically determined by factors other than just blood group.     

A description of two cases of factor V deficiency

Summary We report two cases of factor V deficiency. A 12-year-old girl with thalassemia major was admitted for bone marrow transplant (mismatched). She was found to have a heterozygous deficiency of factor V (21%), but this was considered compatible with the transplant, which was performed without the support of suppernatant cryoprecipitate. A 14-year-old girl (factor V 2%) with a negative history (menarche at age 12, menstrual cycle regular and normal in quantity and length). One year previously she had complained of menorrhagia (length of period, 9 days); tests revealed server anaemia (Hb 4.9 g/dl). We show how even severe cases of factor V deficiency may often be silent, and not require transfusion in surgical procedures, thus avoiding the risks associated with such therapy.     

The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption

Osteopenia and osteoporosis have increasingly become a recognized morbidity of factor VIII (FVIII) deficiency. Recently, we demonstrated that FVIII knockout (KO) mice had significantly decreased bone mass and bone strength despite the fact that they did not have haemarthroses. The aim of this study was to explore the mechanism of bone disease associated with FVIII deficiency. We compared biochemical markers of bone formation and osteoclastogenesis, inflammatory cytokines, as well as static and dynamic histomorphometry of genetically engineered FVIII KO male mice to those of wild‐type (WT) controls. At 20 weeks of age, FVIII KO mice, as well as WT controls, were sacrificed. Serum and bones were obtained at the time of sacrifice to study biochemical markers of bone formation (osteocalcin) and osteoclastogenesis (receptor activator of nuclear factor kappa‐β and osteoprotegerin), levels of inflammatory cytokines (interleukin‐1α and interferon‐β) and to perform static and dynamic histomorphometry of tibia cancellous bone. There was no difference in the biochemical markers of bone formation or osteoclastogenesis. However, there were differences in the two bone‐associated cytokines studied. In addition, histomorphometric examination revealed cancellous osteopenia in FVIII KO mice as evidenced by decreased bone area and trabecular number and increased trabecular separation. Bone formation parameters were normal in FVIII KO mice. In contrast, osteoclast‐lined bone perimeter was increased. These data demonstrate that bone disease in FVIII KO mice is due to an increased rate of bone resorption.     

Severe coagulation factor V deficiency caused by a 4 bp deletion in the factor V gene

Factor V (FV) deficiency (parahaemophilia) is an autosomal recessive bleeding disorder with an incidence of 1:10⁶. We have studied a young girl with very mild bleeding symptoms and undetectable levels of plasma factor V antigen and activity (<0.3% and <1.6% of normal, respectively). Both parents showed plasma levels of factor V activity of about 50% of normal. Sequence analysis of the 5'- and 3'-untranslated, coding and adjacent regions of the factor V gene revealed the presence of a 4 bp deletion in exon 13. Subsequent screening of members of the family for the mutation showed that both parents were heterozygous for the mutation, that one healthy sister carried only normal alleles, and that the patient was homozygous for the mutated allele. The mutation introduced a frameshift and a novel premature stop codon in codon 1303, and would predict the synthesis of a truncated factor V molecule that lacks part of the B domain and the complete light chain. However, no factor V heavy chain could be detected in the plasma of the patient. Furthermore, factor V activity could not be detected in the patients' platelets. This is the first reported mutation in the factor V gene that predicts a type I quantitative factor V deficiency. Surprisingly, the patient, who is homozygous for the mutation, so far has only a very mild bleeding tendency.     

Response to desmopressin of factors XI, X and V in patients with factor VIII deficiency and von Willebrand disease

Desmopressin [1-deamino-8-d-arginine vasopressin (DDAVP)] has been successfully used in the treatment of type 1 von Willebrand disease (VWD) and mild haemophilia A (MHA). Data suggest that DDAVP can increase factor XI (FXI) plasma levels and may represent an effective treatment for mild FXI deficiency. We assessed the DDAVP response of FXI coagulant activity (FXI:C), FXI antigen (FXI:Ag), factor V coagulant activity (FV:C), and factor X coagulant activity (FX:C) in 33 individuals with VWD or MHA. DDAVP did not produce a clinically significant increase in FXI:C, FXI:Ag, FX:C or FV:C in any patient. The mean +/- SD FXI:C pre-DDAVP (time 0) and at 1 h post-DDAVP was 90.7 (+/-22.9) U/dl and 92.1 (+/-20.9) U/dl, respectively. The mean (+/-SD) FXI:Ag at time 0 and 1 h was 92.2 (+/-20.1) U/dl and 89.9 (+/-21.3) U/dl, respectively. There was a small reduction at 1 h post-DDAVP in both FV:C, from 101.8 (+/-20.9) U/dl to 97.2 (+/-21.4) U/dl (P < 0.001), and FX:C from 103 (+/-19.5) U/dl to 98.8 (+/-18.7) U/dl (P < 0.001). No significant increase in FXI:C, FXI:Ag, FV:C or FX:C levels was seen at 4 h post-DDAVP. This study failed to demonstrate a clinically significant increase in the levels of FXI, FX or FV following administration of DDAVP.