Symptoms of inherited factor V deficiency in 35 Iranian patients

The type of bleeding symptom has been evaluated in 35 Iranian patients with an inherited deficiency of factor V, with plasma levels between 1% and 10%. The most frequent symptoms included epistaxis and excessive bleeding after surgery. Haemarthroses and muscle haematomas were less common, even in severely deficient patients. More severe symptoms such as gastrointestinal and central nervous system bleeding were rare. The severity of bleeding symptoms was only partially related to the degree of factor V deficiency in plasma. On the whole, human factor V deficiency is characterized by a moderately severe bleeding phenotype.     

Late diagnosis of severe hemophilia A

Haemophilia A and B are congenital bleeding disorders caused by a deficiency of factor VIII:C or IX:C in plasma. An early diagnosis is crucial to reduce the risk of permanent handicaps. A case of a 14 year-old boy is described. He was admitted to hospital with haematuria at the age of 12, but remained undiagnosed for another two years, when he was readmitted with an iliopsoas muscle bleeding affecting the femoral nerve. Laboratory findings showed a severe haemophilia A. The symptoms leading to the diagnosis and the differences between the various degrees of haemophilia are discussed. Retrospectively, the patient could have been diagnosed earlier if one had accounted for the more rare manifestations. In haemophilia bleeding time, platelet count, fibrinogen and factor II, VII and X are all normal. Only APTT is prolonged and should lead to further tests including factor VIII:C and IX:C.     

Treatment of amyloidosis associated factor X deficiency

This is the tenth patient in thirteen years to be reported with the findings of an isolated factor X deficiency associated with primary amyloidosis. A favorable response to factor IX concentrate was manifested by temporary clinical and laboratory correction of her diathesis. This mode of treatment, therefore, provides an approach to therapy for bleeding complications in this group of patients who have previously failed to response to fresh frozen plasma.     

Side effects of chiropractic treatment: a prospective study

Bleeding in factor-XI-deficient patients is mainly injury-related. Parameters influencing bleeding particularly in patients with minor factor XI deficiency have not been defined. We utilized a logistic regression model to analyze parameters influencing bleeding tendency in subjects from 45 families with factor XI deficiency. Bleeding manifestations were documented in 58% of 26 homozygous or doubly heterozygous factor-XI-deficient patients, in 20% of 46 heterozygous factor-XI-deficient patients and in 9% of 47 family members with a normal factor XI genotype. Odds ratios for bleeding in homozygotes or double heterozygotes were 13 and in heterozygotes 2.6 with 95% confidence intervals of 3.8-45 and 0.8-9.0, respectively. Bleeding correlated negatively with factor XI level (r = -0.36, P = 0.0001) with major factor XI deficiency being a strong predictor of bleeding (P = 0.011). Minor factor XI deficiency and blood group O slightly contributed to bleeding. Although factor VIII and factor XI levels were correlated (r = 0.48, P = 0.0001), levels of factor VIII and von Willebrand factor were not predictors of bleeding. Bleeding was more common following operative procedure involving mucosal membranes (P < 0.01). The designed model enabled prediction of bleeding manifestations with an overall accuracy of 78% and 82% in heterozygotes.     

Recognition of hemophilia A in an elderly patient

Hemophilia A (classic hemophilia) is an hereditary coagulation disorder characterized by the absence, severe deficiency, or defective functioning of plasma coagulation factor VIII. It is inherited in an X-linked recessive manner and occurs almost exclusively in males. The first manifestations of bleeding are usually first noted as a young child since most of the patients with hemophilia A have a profound deficiency of factor VIII (less than 1% of normal value). However, in mild hemophilia (5-25% of normal level of factor VIII) the condition may escape detection with many of the patients developing bleeding only after trauma or surgery. Hemophilia A is the result of a recent genetic mutation in approximately one third of patients, for whom often there is no family history of a bleeding disorder. Here we present an elderly male patient with spontaneous bleeding in an extremity that has coagulation studies consistent with the diagnosis of hemophilia A. Physicians must be aware that mild hemophilia can present in this unusual manner and should consider this possibility in patients that have unexplained bleeding even if there is no clear personal or family history of an hereditary coagulation disorder.     

Transjugular liver biopsy is safe and diagnostic for patients with congenital bleeding disorders and hepatitis C infection

The prevalence of chronic hepatitis C virus (HCV) infection among patients with severe congenital bleeding disorders is as high as 98%. Advances in HCV treatment currently result in sustained virological response rates of > or =50%. Recent recommendations have reaffirmed that liver biopsy, which provides a direct histological assessment of liver inflammation and fibrosis, is still important for accurate diagnosis and therapeutic decision making. Percutaneous liver biopsy is a simple, standardized procedure that can be performed rapidly and relatively inexpensively, and has been safely performed in patients with congenital coagulopathies. However, the safety and efficacy of the transjugular approach (transjugular liver biopsy, TJLB), recommended for patients with acquired coagulopathies, has only been minimally studied in the congenital bleeding diathesis population. We now report our institutional experience with TJLB in 13 such adult patients (mean age 33 years) with severe/mild haemophilia A/B (10); von Willebrand disease (1); factor V deficiency (1) and factor XIII deficiency (1). Data were collected by retrospective chart review and the TJLB was performed according to institutional protocol as described. Haemostasis prophylaxis was given for 1-5 days. Patients were hospitalized for < or =48 h and all tolerated the procedure without bleeding. Three patients experienced self-limited abdominal discomfort; one episode was accompanied by transient transaminaemia. Diagnostic specimens were obtained from all patients and were instrumental in the therapeutic decision-making process. We suggest that with a co-ordinated multidisciplinary approach to care, TJLB is a safe, effective and potentially cost-effective alternative to the percutaneous approach in the congenital bleeding disorders population.     

Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene

Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue- and urokinase-type plasminogen activators, is considered a critical regulator of the fibrinolytic system. We previously reported a child with abnormal bleeding and complete PAI-1 deficiency caused by a frame-shift mutation in exon 4 of the PAI-1 gene. The purpose of this study was to provide genetic and clinical data on the extended pedigree of the original proband to better define the phenotype associated with PAI-1 deficiency. Allele-specific oligonucleotide hybridization was used to genotype individuals, and serum PAI-1 antigen was measured by enzyme-linked immunosorbent assay. By this approach we have identified 19 individuals who are heterozygous for the PAI-1 null allele and 7 homozygous individuals with complete PAI-1 deficiency. Clinical manifestations of PAI-1 deficiency were restricted to abnormal bleeding, which was observed only after trauma or surgery in homozygous affected individuals. A spectrum of bleeding patterns was observed, including intracranial and joint bleeding after mild trauma, delayed surgical bleeding, severe menstrual bleeding, and frequent bruising. Fibrinolysis inhibitors, including epsilon-aminocaproic acid and tranexamic acid, were effective in treating and preventing bleeding episodes. Other than abnormal bleeding, no significant developmental or other abnormalities were observed in homozygous PAI-1-deficient individuals. Heterozygous PAI-1 deficiency was not associated with abnormal bleeding, even after trauma or surgery. These observations define the clinical spectrum of PAI-1 deficiency and provide additional evidence to support the hypothesis that the primary function of plasminogen activator inhibitor-1 in vivo is to regulate vascular fibrinolysis.     

The influence of vascular space involvement on the prognosis of patients with stage IB cervical carcinoma: correlation of results from hematoxylin and eosin staining with results from immunostaining for factor VIII-related antigen

Factor VII is a trace protein required for normal haemostasis. Deficiency of factor VII comprises a highly heterogeneous disease group. Factor VII deficiency can cause bleeding, in particular if factor VII is extremely low, but a few cases lacking factor VII function entirely or subtotally may not present with a history of bleeding. Bleeding problems are not often reported in patients having a factor VII:C level at 10-15% of normal or more. Bleeding is frequently of mucocutaneous type, but the whole array of haemophilic bleeding may also occur. To control bleeding, during surgery in particular, substitution is required in the severe case of factor VII deficiency, but clinical studies documenting which correctional levels of factor VII:C to aim are lacking. It appears that a critical low level (trough) value at 10-15% may be anticipated, but clear documentation does not exist. Substitution programmes may include plasma or plasma derived factor IX concentrates of lower degrees of purity, so-called prothrombin complex concentrates that also are relatively impure, and pure factor VII concentrates. An alternative is a recombinant factor VIIa molecule. However, this concentrate has not received license in a number of countries. Thrombotic manifestations appear to occur more often than expected in the factor VII deficient patients, some have been linked to the use of impure concentrates, others to preexisting thrombophilic risk factors, but some are unexplained and may bear a relationship to the deficiency state of factor VII itself. Controlled clinical trials are highly warranted in this rare bleeding condition.     

Evaluation of solvent/detergent treated plasma in the management of patients with hereditary and acquired coagulation disorders

Haemostatic efficacy and pharmacokinetic analysis of solvent/detergent (S/D) treated, virus inactivated plasma (Octaplas, Germany) was evaluated in eight patients with hereditary factor VII, X and XI deficiency and in three patients with acquired coagulation disorders due to liver disease. The patients received the S/D plasma for treatment of haemarthrosis, menorrhagia or before surgical procedures. In all the patients the S/D plasma was sufficient to prevent or stop bleeding. Side effects included urticaria (one patient) and moderate anaphylactoid reaction (one patient). No evidence of plasma-born viral infections was observed up to 12 months after the treatment (95% confidence limits 0-22%). Calculated mean half-life of coagulation factors VII, X and XI was 4.36 h, 49.21 h and 44.5 h, respectively, similar to that observed with fresh-frozen plasma. Because of retained coagulation factor integrity and improved viral safety, S/D plasma could be considered a superior alternative to standard fresh-frozen plasma.     

An in vitro analysis of the combination of hemophilia A and factor V(LEIDEN)

The classification of factor VIII deficiency, generally used based on plasma levels of factor VIII, consists of severe (<1% normal factor VIII activity), moderate (1% to 4% factor VIII activity), or mild (5% to 25% factor VIII activity). A recent communication described four individuals bearing identical factor VIII mutations. This resulted in a severe bleeding disorder in two patients who carried a normal factor V gene, whereas the two patients who did not display severe hemophilia were heterozygous for the factor V(LEIDEN) mutation, which leads to the substitution of Arg506 --> Gln mutation in the factor V molecule. Based on the factor VIII level measured using factor VIII-deficient plasma, these two patients were classified as mild/moderate hemophiliacs. We studied the condition of moderate to severe hemophilia A combined with the factor V(LEIDEN) mutation in vitro in a reconstituted model of the tissue factor pathway to thrombin. In the model, thrombin generation was initiated by relipidated tissue factor and factor VIIa in the presence of the coagulation factors X, IX, II, V, and VIII and the inhibitors tissue factor pathway inhibitor, antithrombin-III, and protein C. At 5 pmol/L initiating factor VIIa x tissue factor, a 10-fold higher peak level of thrombin formation (350 nmol/L), was observed in the system in the presence of plasma levels of factor VIII compared with reactions without factor VIII. Significant increase in thrombin formation was observed at factor VIII concentrations less than 42 pmol/L (approximately 6% of the normal factor VIII plasma concentration). In reactions without factor VIII, in which thrombin generation was downregulated by the addition of protein C and thrombomodulin, an increase of thrombin formation was observed with the factor V(LEIDEN) mutation. The level of increase in thrombin generation in the hemophilia A situation was found to be dependent on the factor V(LEIDEN) concentration. When the factor V(LEIDEN) concentration was varied from 50% to 150% of the normal plasma concentration, the increase in thrombin generation ranged from threefold to sevenfold. The data suggested that the analysis of the factor V genotype should be accompanied by a quantitative analysis of the plasma factor V(LEIDEN) level to understand the effect of factor V(LEIDEN) in hemophilia A patients. The presented data support the hypothesis that the factor V(LEIDEN) mutation can increase thrombin formation in severe hemophilia A.     

Advances and dilemmas in factor XI

Factor XI is a key component of the intrinsic pathway of blood coagulation in vitro. The poor correlation between the clinical bleeding diathesis in factor XI deficiency and abnormalities in clotting assays that measure intrinsic coagulation brings into question the role of this serine protease in in vivo hemostasis. The characterizations of the point mutations responsible for the majority of cases of severe factor XI deficiency in Ashkenazi Jews and subsequent epidemiologic studies have provided insight into the perplexing hemostatic abnormalities in this disorder. It appears that excessive bleeding in factor XI deficiency depends on the severity of the deficiency in certain situations and on the location of the hemostatic challenge in others. Additional coexisting abnormalities of hemostasis, such as von Willebrand's disease, may also be responsible for variation in clinical presentation, particularly in those individuals with mild factor XI deficiency. The absence of abnormal bleeding in congenital deficiency of factor XII, the protease that activates factor XI in the intrinsic cascade, has stimulated a search for other mechanisms for factor XI activation. Recent studies have pointed to the serine protease thrombin and autoactivation by activated factor XI as possible alternatives to factor XII as activators of factor XI. These findings suggest that factor XI, rather than operating in a pathway for the initiation of hemostasis, may function in the consolidation of clot formation after the initiation of the hemostatic process by other mechanisms.     

Genetic deficiency of factor VII and hemorrhagic diathesis. A case report and literature review

FVII deficiency is a rather rare inherited hemocoagulation disorder that predisposes to hemorrhagic events, especially from mucous membranes, that are not predictable and severe as in hemophilia A. This defect produces prolonged prothrombin time (PT), reduced activity of FVII and normal activated partial thromboplastin time (aPTT). We report the case of a 43-year-old obese woman with severe deficiency of factor VII (FVII), probably genetic in nature, and meno-metrorrhagia associated with multiple fibromas of uterus. Our patient had no history of bleeding in infancy and young age, and in the past, before the disease was diagnosed, underwent major surgery operations (thyroidectomy and caesarian section) without hemorrhage. Patient's relatives with mild heterozygous deficiency of FVII (the father, a brother, a sister, a sister's daughter and the patient's son) did not show any bleeding tendency. This case report is discussed in the light of literature data ((source: Medline from 1964 to 1996). The different forms of congenital (isolated or combined with other clotting disorders) and acquired FVII deficiency, with the appropriate therapies, are reviewed. The clinician must consider FVII deficiency in cases of recurrent bleeding, and this disease, even if rather rare, should not be underestimated in clinical practice because it is potentially fatal.     

Successful hemostasis during a major orthopedic operation by using recombinant activated factor VII in a patient with severe hemophilia A and a potent inhibitor

The treatment of bleeding episodes and the provision of perioperative hemostasis in patients with hemophilia in whom coagulation factor inhibitors have developed are a major therapeutic challenge because ordinary replacement therapy is usually ineffective. Herein we report the use of recombinant activated factor VII (rFVIIa) in providing successful hemostasis in a patient with hemophilia A and a high-titer inhibitor to factor VIII during a major orthopedic operation. rFVIIa (102 micrograms/kg) was administered intravenously every 2 to 3 hours for a total of 9 days. No excessive bleeding occurred intraoperatively or postoperatively, and no adverse effects attributable to rFVIIa were observed. This surgical procedure probably represented a greater hemostatic challenge than any previously reported operation in which rFVIIa was used. Thus, this article adds considerably to the growing body of literature that suggests the safety and efficacy of rFVIIa in providing perioperative hemostasis and treating severe bleeding episodes in patients with hemophilia and inhibitors refractory to other treatment modalities.     

Azathioprine-induced myelosuppression due to thiopurine methyltransferase deficiency in a patient with autoimmune hepatitis

Azathioprine can cause severe myelosuppression. The inherited activity of the enzyme thiopurine methyltransferase has been recently recognised as a major factor in the susceptibility to myelosuppression. Thiopurine methyltransferase deficiency occurs at a frequency of one in 300 and is associated with profound myelosuppression after a short course of azathioprine. Very low thiopurine methyltransferase activity represents the TPMTL/TPMTL genotype, and can be detected before therapy with azathioprine is started. We describe the first documented case of azathioprine-induced severe myelosuppression due to thiopurine methyltransferase deficiency in autoimmune liver disease. The azathioprine dose was low (1 mg/kg) and pancytopenia occurred after 56 days therapy. It would be advisable to measure thiopurine methyltransferase activity before patients with autoimmune hepatitis are exposed to azathioprine.     

Protein phosphatases and the regulation of MAP kinase activity

A family with hereditary factor X deficiency is presented. One member, a 25-year-old man, showed a mild bleeding tendency. His factor X activity (extrinsic: 56%; intrinsic: 55%; Russell's viper venom: 57%) and his level of circulating factor X antigen (55% of normal) were markedly reduced. Analysis of his factor X gene revealed a single point mutation within exon II resulting in the substitution of +25 Gla (GAA) by Lys (AAA). The mutation was determined by gene analysis to be heterozygous in this patient, his mother and one of his brothers. Clotting assays of factor X purified from the plasma of the index patient revealed an activity of 89% of normal upon activation with Russell's viper venom, 77% of normal in the intrinsic and 81% of normal in the extrinsic coagulation pathway. The mutation responsible for the substitution of Lys for Gla+25 was introduced into an expression plasmid containing a wild type factor X cDNA and expressed in a mammalian cell line. Factor X antigen levels in the cell lysates and in the supernatant were identical in the mutant and wild type constructs. The specific activity of the factor X expressed from the mutant construct was 3% compared with the wild type construct. These data demonstrate that the substitution of Lys for Gla+25 results not only in a reduced level of factor X in the affected family members, but also in a substantial loss of specific factor X activity.     

Implantable venous access devices in children with hemophilia: a report of low infection rates

OBJECTIVE: The objective of this study was to define the efficacy and complications of implantable venous access devices (IVADs) in children with hemophilia. STUDY DESIGN: Records were reviewed on all patients with congenital blood coagulation disorders monitored at two children's hospitals in whom one or more central venous catheters had been placed. RESULTS: Since 1989 external and implantable central venous catheters have been inserted to enhance venous access for regular factor concentrate infusion in 45 patients with hemophilia ranging in age from 8 months to 19.5 years (median 7.4 years); 37 patients had factor VIII deficiency and 8 factor IX deficiency. Hemorrhagic complications of catheter placement were infrequent and minor. In the 41 patients having one or more IVADs in place for a median of 31 months, only six episodes of bacteremia occurred in 5 patients during 44,070 days of follow-up. The overall rate of bacteremia complicating IVADs in these patients was 0.14 episodes per 1000 catheter days. Other catheter-related complications were uncommon. Catheters are still in place in 33 patients for a median of 32 months. CONCLUSION: The low risk of infection and other complications associated with the use of IVADs makes the use of these devices attractive in the treatment of patients with hemophilia who require frequent venous access for factor concentrate infusions.     

Application of HUMF13A01 (AAAG)n STR polymorphism to the genetic diagnosis of coagulation factor XIII deficiency

Deficiency of the A subunit of coagulation factor XIII causes a severe bleeding disorder requiring life long replacement therapy. The mutations causing A subunit deficiency appear to be very heterogeneous, and it is impractical to identify each mutation before genetic counselling or prenatal diagnosis can be attempted. In this study we have shown that a highly polymorphic short tandem repeat element, HUMF13A01 (AAAG)n that occurs in the 5' flanking sequence of the factor XIII A subunit gene, can be used to follow the segregation of deficiency causing mutations. We studied 6 families with factor XIII A subunit deficiency from 5 different ethnic groups. All parents were heterozygous for the repetitive element and therefore all the families were informative. The linked polymorphism was used to carry out the first prenatal diagnosis of factor XIII A subunit deficiency. The analysis of this polymorphism by the polymerase chain reaction is rapid, reliable, requires little DNA and is ideal for the genetic analysis of factor XIII A subunit deficiency.     

Multiple angiodysplastic lesions of the colon--a therapeutic challenge

Colonic angiodysplasia is one of the most frequent causes of recurrent lower gastrointestinal tract bleeding, mainly in the elderly. In 50% of patients multiple angiodysplastic lesions were reported when they were the cause of rectal bleeding. Bleeding from angiodysplasia is more severe and less responsive to treatment in those with coagulation disorders. A 74-year-old woman with an artificial mitral valve who was treated with coumadine is reported. A few years after operation she began to develop severe recurrent rectal bleeding because of multiple angiodysplastic lesions along the right colon, proven by colonoscopy. She was frequently hospitalized for blood transfusions; endoscopic treatment was not feasible and the surgical risk of colectomy was very high. Treatment with estrogen and progesterone significantly decreased recurrent episodes of bleeding.     

Factor V Quebec revisited

Factor V Quebec has been described as a bleeding disorder that exhibits an autosomal dominant inheritance pattern and presents severe bleeding after trauma. Two members of a fourth-generation (IV.13 and IV.15) Canadian family have been studied in detail and are the subject of this report. Their clinical presentations and histories have been described previously (Tracy et al: J Clin Invest 74:1221, 1984). Persistent abnormalities include mild thrombocytopenia and defective platelet factor V. Plasma factor V is present at near normal concentration and is fully functional. Thus, the bleeding diathesis appears to reflect the absence of platelet factor V activity. The recent report (Hayward et al: Blood 84:110a, 1994 [suppl, abstr]) of multimerin deficiency in these individuals led us to reevaluate these patients. Western blot analyses of platelet lysates developed with a variety of monoclonal antibodies show that the alpha-granule proteins, fibrinogen, von Willebrand factor, factor V and osteonectin are decreased in concentration and significantly degraded in the platelets of these patients. Thrombospondin, while not degraded, is substantially decreased. In contrast, platelet factor 4 and beta-thromboglobulin do not appear to be affected. These observations suggest that the alpha-granules are correctly assembled but the contents are subsequently subjected to proteolytic degradation. The results indicate that factor V Quebec disorder is probably associated with a generalized defect that leads to degradation of most proteins of the alpha-granules.     

Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice

Matings of mice heterozygous for a protein C (PC) deficient allele, produced by targeted PC gene inactivation, yielded the expected Mendelian distribution of PC genotypes. Pups with a total deficiency of PC (PC-/-), obtained at embryonic day (E) 17.5 and at birth, appeared to develop normally macroscopically, but possessed obvious signs of bleeding and thrombosis and did not survive beyond 24 h after delivery. Microscopic examination of tissues and blood vessels of E17.5 PC-/- mice revealed their normal development, but scattered microvascular thrombosis in the brain combined with focal necrosis in the liver was observed. In addition, bleeding was noted in the brain near sites of fibrin deposition. The severity of these pathologies was exaggerated in PC-/- neonates. Plasma clottable fibrinogen was not detectable in coagulation assays in PC-/- neonatal mice, suggestive of fibrinogen depletion and secondary consumptive coagulopathy. Thus, while total PC deficiency did not affect the anatomic development of the embryo, severe perinatal consumptive coagulopathy occurred in the brain and liver of PC-/- mice, suggesting that a total PC deficiency is inconsistent with short-term survival.