Table of Contents

HK J Paediatr (New Series)
Vol 1. No. 1, 1996

HK J Paediatr (New Series) 1996;1:70-73

Case Report

Combined Factor V and Factor VIII Deficiency in a Girl with Haemarthrosis

DCC Wei, SY Ha, YL Lau


Abstract

Factor VIII and factor V are clotting proteins acting as cofactors respectively for factor IX in the intrinsic pathway and factor X in the common pathway of the coagulation cascade. Haemophilia A due to factor VIII deficiency is transmitted as an X-linked disease occurring in 1 in 10,000 males. Factor V deficiency alone is rare and is autosomal recessive with an estimated incidence of 1 in a million persons. Combined factor V and factor VIII deficiency is also rare but is the commonest of the inherited deficiencies of more than one coagulation factors. We describe a 5 year old Chinese girl who presented with haemarthrosis and diagnosed to have combined factor V and VIII deficiencies. She was found to have prolonged activated partial thromboplastin time and prolonged prothrombin time. Factor assays showed low factor V level of 0.14 u/ml and low factor VIII level of 0.20 u/ml. Her symptoms subsided with infusion of fresh frozen plasma. Over a 2 year follow up period, she has been free from further major bleeding.

Keyword : Clotting proteins; Factor V deficiency; Factor VIII deficiency; Haemarthrosis; Haemophilia


Introduction

Congenital bleeding disorders due to clotting factor deficiency present early in childhood, except for mild cases which may present only after major injury or surgery. The commonest disorders are von Willebrand disease (vWD), factor VIII deficiency or haemophilia A and factor IX deficiency or haemophilia B, the latter 2 disorders occurring in males as X-linked disorders. Congenital deficiencies of other clotting proteins are rare. Especially of interest are combined congenital factor deficiencies. Factor VIII and factor V are similar proteins acting respectively as cofactors for factor IX in the intrinsic clotting pathway and factor X in the common clotting pathway. The gene for factor V is on chromosome 11 and the gene for factor VIII is on chromosome X.2 Both genes belong to a family of related DNA sequences which also include caeruloplasmin gene and caeruloplasmin pseudogene. The genetic defect which causes combined factor V and factor VIII deficiency has not been elucidated to date.

Females presenting with haemarthrosis due to clotting factor deficiency is rare. This may occur in a female offspring of a haemophilia A or haemophilia B patient involved in a consanguineous marriage. Sporadic cases of female haemophilia A or B have been attributed to lyonization favouring expression of the abnormal gene, whilst double heterozygosity is very rare. Autosomal dominant vWD is a commoner disorder expressed in females, however haemarthrosis is uncommon in vWD whilst superficial bleeding, epistaxis, menorrhagia, immediate bleeding after dental extraction and surgery are more pronounced because of impairment of platelet adhesion. A recently described subtype of vWD, "Normandy Variant"3 involves mutations which impair von Willebrand factor (vWf) binding to factor VIII resulting in low levels of factor VIII. This is due to loss in protein stabilization that vWf imparts to factor VIII in the circulation. Some cases of vWD Normandy were initially misdiagnosed as haemophilia A. We report a case of a female patient presenting with haemarthrosis due to combined factor V and VIII deficiency.

Case Report

A 5-year-old Chinese girl presented with right knee pain. There was no history of trauma or recent illness. Small amount of blood was obtained during knee aspiration for bacterial culture. Over the next 2 weeks there were 3 episodes of right knee swelling and pain. The patient was afebrile and there was no evidence of other foci of infection. Examination showed limited range of joint movement and patellar tap sign was positive. The patient had a history of easy bruising and a few episodes of epistaxis for 2 years. She was the first child of a non-consanguineous marriage, born at term with an uneventful pregnancy. There was no family history of bleeding disorder. No drugs or Chinese medications had been taken. Investigations showed she had a deficiency of both factor V and factor VIII (see method and result).

The patient was treated with fresh frozen plasma (FFP) and factor VIII concentrate for 10 days after which her knee swelling improved. During her course of treatment she did suffer one episode of epistaxis which required packing and cautery. She was discharged with physiotherapy outpatient treatment with full knee recovery over 1 month. The patient was counselled and was active with restriction only on contact sports. There has been no further major bleeding episode after 2 years follow up.

The patient's response to the synthetic analogue of vasopressin, 1-deamino-8-D-arginine-vasopressin (DDAVP) was tested when she was well. DDAVP has been shown to raise factor VIII levels in haemophilia A4 and also increases vWf levels in vWD patients.5 The patient was administered 0.3 ug/kg DDAVP by I.V. infusion over 30 mins. There was a 3 to 4 fold increase in plasma factor VIII level and no rise in plasma factor V level.

Methods

Medical diagnosis of clotting protein deficiency is dependent on laboratory tests of the clotting system. The activated partial thromboplastin time (A.P.T.T.) tests the intrinsic pathway, whilst the prothrombin time (P.T.) tests the extrinsic pathway. Thrombin time (T.T.) and fibrinogen assay test for afibrinogenaemia and dysfibrinogenaemia. In addition laboratory tests should include assay of von Willebrand factor antigen (vWf:Ag) and a functional test for von Willebrand factor (vWf); commonly the ristocetin co-factor (RiCof) assay is used. Specific factor assay with single factor deficient plasma reagents, otherwise termed "one-stage" factor assays, are commonly used to measure the activity level of the deficient clotting factor.

Venous blood was obtained from the patient, her parents, and her younger brother for investigation on presentation. EDTA anticoagulated blood was used for blood count. Trisodium citrate was used to anticoagulate blood for coagulation studies.

During treatment plasma levels of factor V and factor VIII were measured after infusion of 30 ml/kg of FFP Pre and post-dose factor V and factor VIII levels were also measured to test the effect of DDAVP given by IV. infusion at 0.3 ug/kg when the patient was well.

Reagents

Commercial A.P.T.T. reagent, Thrombosil I was obtained from Ortho Diagnostics. Commercial P.T. reagent was obtained from Behring. Thrombin was obtained from Sigma. Control plasma reagent was obtained from Ortho Diagnostics.

Factor II, factor V, factor VIII, factor IX, factor X deficient plasma reagents prepared by an immunodepletion method was obtained from Stago. Factor VII and factor XI deficient plasma reagents were prepared from donors deficient in clotting factor and available from Hemolab and bioMerieux respectively. Rabbit anti-vWf polyclonal antibody was available from Behring. Lyophilized platelets for RiCof assay was obtained from Bio Data. Ristocetin sulphate was obtained from Lundbeck pharmaceuticals.

Blood counts were performed on the Technicon-H2 automated cell counter. Mixing of either control plasma or test plasmas with A.P.T.T. or P.T. reagents was performed on the ACL 1000 automated coagulation machine (Coulter Electronics) which uses a photosensor to determine time to fibrin clot formation. Thrombin time was performed by mixing control plasma or test plasmas with thrombin in the Cobas fibrinometer. Fibrinogen assay was performed by a functional method based on thrombin time (Clauss method).

Factor VIII, IX and XI assays were performed by the one stage method, mixing test plasma with factor deficient plasma reagent and using A.P.T.T.-based times performed on the ACL 1000. Each test plasma was serially diluted to create a 4 point A.P.T.T. graph and this was compared to a standardized graph using reference plasma with known levels of each coagulation factor (Reference Plasma, Immuno). Factor II, V, VII and X assays were also assayed by 1 stage method by P.T.-based times performed on the ACL 1000.

vWf

An assay was performed by antigen-antibody precipitation in agar gel enhanced by electrophoresis (Laurell rocket method).6 RiCof assay was performed by measuring the rate of aggregation of lyophilized platelets in the presence of ristocetin sulphate performed in a platelet aggregometer (Chrono-Log).

Results

On presentation, investigations showed the patient had a normal blood count with platelets numbering 348 x 109/l. The patient had a prolonged A.P.T.T. of 64 sec (n<34 sec) and a prolonged PT. of 18.6 sec (n = 9.5-12.5 sec). T.T. was 14.4 sec (n = 11.0-15.0 sec). Factor assays showed a mild deficiency of both factor V and factor VIII. Factor V assay was 0.14 u/ml and factor VIII assay was 0.20 u/ml (both n = 0.5-1.5 u/ml). Factor II, IX, X, XI, fibrinogen, vWf and RiCof assays were in the normal range.

The father, mother and brother had all normal results. Father showed a factor V level of 1.2 u/ml and factor VIII level of 1.4 u/ml. Mother showed factor V level of 0.7 u/ml and factor VIII level of 0.7 u/ml. Brother showed a factor V level of 1.2 u/mi and factor VIII level of 1.1 u/ml.

During treatment the plasma rise of factor V and factor VIII after one infusion of 30 ml/kg FFP showed factor V level 0.48 u/ml pre-infusion and 0.77 u/ml post infusion while factor VIII level was 0.32 u/ml pre-infusion and 0.49 u/mi post infusion.

DDAVP challenge showed factor VIII levels rose from a pre-dose level of 0.13 u/mi to 0.53 u/ml post-dose. Factor V levels did not change, being 0.17 u/mi both pre and post-dose.

Discussion

Females presenting with symptoms of haemophilia are rare. Haemophilia A and haemophilia B are the commoner disorders but are X-linked. Bleeding diathesis in females is more commonly due to vWD which has an incidence between 1%7 and 1 in 10,000 with equal sex incidence. In vWD spontaneous bleeding and bleeding after mild trauma is more pronounced in superficial and mucosal areas whilst spontaneous haemarthrosis is rare. Haemarthrosis in females therefore warrants further investigations for other rare clotting factor deficiency.

Combined factor V and factor VIII deficiency is an uncommon disorder with about 30 families described to date.8 Levels of V and VIII are commonly between 3 and 30 per cent of normal. Inheritance is autosomal recessive. The frequency of this disorder is more common than can be explained by independent chance expression of both disorders. This argues for a gene defect distinct from the factor V or factor VIII gene. Deficiency of protein C inhibitor which allows overactivity of protein C was quite logically proposed as a possible cause. Protein C is a naturally occurring vitamin K dependent protein which inhibits activated factors V and VIII. Its overactivity may be proposed for low plasma levels of factor V and VIII. Low levels of protein C inhibitor was reported in patients with combined factor V / factor VIII deficiency9 but has not been reproduced in studies by other authors.10 The cause of combined factor V / factor VIII deficiency remains unknown. The two proteins are similar in DNA sequence and protein structure. Some defect in post-translational processing step seems a likely explanation.

In our patient the deficiency of factor V and factor VIII is relatively mild. This accounts for her lack of major bleeding before and after the episode of haemarthrosis. Spontaneous haemarthrosis is uncommon in patients with mild deficiencies of single clotting factors. In combined factor deficiencies it may be possible that there is an additive effect that can result in spontaneous haemarthrosis.

Treatment of active bleeding in clotting factor deficiencies is clotting factor replacement. Dosage is calculated to bring clotting factor levels to at least 0.5 u/ml plasma in the patient. Dose frequency should be based on the in vivo half life of the clotting factor and treatment continued to be for several days after bleeding has stopped to avoid delayed bleeding.

Factor VIII concentrates, vitamin K dependent factor concentrates (II, VII, IX, X, Protein C), factor VII concentrates and factor XIII concentrate are also available for specific factor deficiencies. vWf may be replaced with cryoprecipitate and is also present in low and medium purity factor VIII concentrates. Cryoprecipitate is also a source for fibrinogen. FFP contains all clotting factors and is the only agent currently available for treatment of factor V and factor XI deficiency.

The half life of transfused factor V has been reported to vary between 4° to 36 hrs11 with an average of 12 hrs. The half life of factor VIII is 12 hrs. In our patient treatment with FFP at 30 ml/kg daily resulted in a measured rise of in factor V of 0.3 u/ml plasma. The rise in factor VIII was less at 0.17 u/ml. She was therefore treated with additional dose of factor VIII concentrate.

In agreement with other authors, treatment of combined factor V / factor VIII deficiency is by infusion of fresh frozen plasma with additional factor VIII concentrates replacement. Some authors advocate DDAVP as sufficient additional therapy to FFP instead of factor VIII concentrate. A rise in factor VIII to DDAVP was demonstrated in our patient and this may be a useful mode of therapy.


References

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6. Laurell CB. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Analyt Biochem 1966;15:45.

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8. Hultin MB, Eyster ME. Combined factor V / VIII deficiency: A case report with studies of factor V and VIII activation by thrombin. Blood 1981;58:983-5.

9. Marlar RA, Griffin JH. Deficiency of protein C inhibitor in combined factor V / VIII deficiency disease. J Clin Invest 1980;66:1186-9.

10. Canfield WM, Kisiel W. Evidence of normal functional levels of activated protein C inhibitor in combined factor V / factor VIII deficiency disease. J Clin Invest 1982;70:1260-72.

11. Melliger EJ, Duckert F. Major surgery in a subject with factor V deficiency : Cholecystectomy in a parahemophilic woman and review of the literature. Thromb Diath Haemorrh 1971;25:438-46.

 
 

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