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Postpartum cerebral venous thrombosis, congenital protein C deficiency, and activated protein C resistance due to heterozygous factor V Leiden mutation
  1. LAURENT DEREX,
  2. FREDERIC PHILIPPEAU,
  3. NORBERT NIGHOGHOSSIAN,
  4. PAUL TROUILLAS
  1. Service d’Urgences Neurovasculaires, Hôpital Neurologique, Lyon, France
  2. Laboratoire Central d’Hématologie et de Cytogénétique, Hôpital Cardio-Vasculaire et Pneumologique, Lyon, France
  1. Dr Laurent Derex, Service d’Urgences Neurovasculaires, Pr Paul Trouillas, Hôpital Neurologique, 59 Boulevard Pinel, 69003 Lyon, France
  1. MICHELINE BERRUYER
  1. Service d’Urgences Neurovasculaires, Hôpital Neurologique, Lyon, France
  2. Laboratoire Central d’Hématologie et de Cytogénétique, Hôpital Cardio-Vasculaire et Pneumologique, Lyon, France
  1. Dr Laurent Derex, Service d’Urgences Neurovasculaires, Pr Paul Trouillas, Hôpital Neurologique, 59 Boulevard Pinel, 69003 Lyon, France

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Activated protein C resistance (APC-R) due to factor V Leiden mutation is the most common thrombophilia associated with cerebral venous thrombosis. It is present in 10% to 20% of patients but usually in association with other constitutional or acquired prothrombotic conditions.1 We present a case of postpartum cerebral venous thrombosis in a patient with protein C deficiency and APC-R due to heterozygous factor V Leiden mutation. In addition to puerperium, the role of intravenous steroids is questioned in this case.

A 33 year old woman was admitted because of severe subacute headaches, nausea, and drowsiness. She was not taking oral contraceptives. Her medical history disclosed recent delivery of a second child 3 weeks before and an asthma attack 5 days before entry, treated with intravenous methylprednisolone (120 mg daily). Family history disclosed that the patient’s mother had had postpartum lower limb deep vein thrombosis. On admission, clinical examination disclosed papilloedema. There was no fever and no ear, nose, or throat infection. Brain CT showed a right temporal hypodensity, a delta sign, and small ventricles. Brain MRI (with MRA) demonstrated recent superior sagittal sinus, and right and left lateral sinus thrombosis. High dose intravenous heparin was immediately initiated. Heparin treatment was switched to warfarin after 10 days. At 3 months, neurological examination was normal. Follow up MRA showed complete recanalisation of the superior sagittal sinus and the right lateral sinus, and partial recanalisation of the left hypoplasic lateral sinus. Oral anticoagulation was maintained at International Normalized Ratio (INR)

between 2 and 3). One year later, the patient is still symptom free under this treatment. The proband investigations were performed twice: during acute phase thrombosis and seven months later when the patient had temporarily discontinued oral anticoagulation therapy. Four other family members (the father, the mother, and two sisters) were available for examination (figure and table). The proband (II.2) exhibited qualitative protein C deficiency and APC-R due to heterozygous factor V Leiden mutation. Protein S activity and antithrombin III concentrations were normal. Search for antinuclear antibodies, anticardiolipin antibodies, and lupus anticoagulant, dysfibrinogenaemia, or plasminogen deficiency was negative. Plasma homocysteine concentration was normal. The father (I.1) had APC-R due to heterozygous factor V Leiden mutation. The mother (I.2) had a qualitative protein C deficiency. The first sister (I.1) had no APC-R nor protein C deficiency. The second sister (II.3), who had one pregnancy without any thrombotic event, had both protein C deficiency and APC-R due to heterozygous factor V Leiden mutation.

Pedigree of the family. The three generations are indicated by roman numbers. Arabic numbers indicate the family members who have been investigated. Square=male; circle=female; no deficiency open; protein C deficiency hatched; factor V Leiden black; *positive thromboembolism history . The proband is indicated by an arrow.

Biological data of the proband (II.2) and her family

Our patient presented an extensive postpartum cerebral venous thrombosis with a double inherited coagulation defect: protein C deficiency and APC-R due to heterozygous factor V Leiden mutation. To our knowledge, the coexistence of these two thrombophilias has not been previously described in a patient with cerebral venous thrombosis. Genetic study showed that APC-R due to factor V Leiden mutation was transmitted by the patient’s father and that protein C deficiency was transmitted by the patient’s mother.

The protein C anticoagulant pathway is triggered when thrombin binds to the endothelial cell receptor thrombomodulin. This interaction converts thrombin into a potent protein C activator while blocking the fibrinogen clotting and platelet activating activity of thrombin. Activated protein C then serves as an anticoagulant by inactivating factors Va and VIIIa.2 In our patient, acquired causes of protein C deficiency could be excluded. We diagnosed a congenital protein C deficiency with an autosomal dominant mode of inheritance. A type I deficiency could be postulated according to the reduction of both antigen concentration and activity of protein C, reduction of activity but normal antigen concentration being present in type II. Only a few cases of cerebral venous thrombosis with congenital protein C deficiency have been reported so far.3 4 Inherited protein C deficiency seemed to be the sole risk factor for thrombosis in some cases4 whereas other prothrombotic conditions such as the postpartum period were present in other cases.3Additional risk factors for thrombosis might be necessary for thrombotic manifestations to appear in patients with protein C deficiency as the heterozygous state is usually asymptomatic with an estimated prevalence of 1 in 200 to 300.4

In 1993, Dahlbäck et al described a new pathological condition termed APC-R, characterised by a poor anticoagulant response to activated protein C. This coagulation disorder is often associated with a single point mutation in one or both alleles of the factor V gene (adenine substituted for guanine at nucleotide 1691, the so called Leiden mutation) at a site of cleavage by activated protein C which delays inactivation of coagulant factor Va. The prevalence of the factor V Leiden mutation varies by geography and ethnicity, ranging from 2% to 15% in healthy white people. Factor V Leiden mutation is inherited as an autosomal dominant trait and most heterozygous people do not have clinical thrombotic complications. The odds ratio for venous thrombosis has been calculated to be 3.8-fold for heterozygous patients.5 An important similarity of patients with APC-R and cerebral venous thrombosis is the frequency of other associated risk factors for thrombosis. Sixteen of 18 reported cases showed another genetic or acquired thrombosis risk factor: oral contraceptives in eight, pregnancy/puerperium in four, nephrotic syndrome in one, intravenous steroids in one, immobilisation in one, primary antiphospholipid antibody syndrome in one, and antithrombin III deficiency in one1 These data suggest that the association of APC-R with an other prothrombotic state is crucial in the occurrence of cerebral venous thrombosis. In our patient, APC-R was associated with congenital protein C deficiency and two other acquired prothrombotic risk factors, postpartum and intravenous steroid therapy. The prothrombotic risk of intravenous steroids is questioned in our patient as she had not experienced any thrombotic event during her first pregnancy and postpartum period. It is noticeable that the patient’s sister (II.3) with APC-R and protein C deficiency had had one child without venous thrombosis. The prothrombotic risk of intravenous steroids should be considered in patients with APC-R. This case report also points out that the presence of APC-R should not delay the search for other causes in patients with cerebral venous thrombosis. The detection of single or multiple inherited coagulation defects has major practical consequences for the secondary prevention of these patients and for the primary prevention of the other family members, as these abnormalities usually have an autosomal dominant inheritance pattern. Long term management to prevent further venous thrombotic events in patients with isolated APC-R is not well delineated up to now, particularly regarding the duration of anticoagulation. Patients with combinations of APC-R and protein C or protein S deficiency have a higher risk of thrombosis than those with APC-R alone.1 5 Lifelong oral anticoagulation may be advocated in patients with cerebral venous thrombosis and multiple inherited coagulation defects, such as protein C deficiency and APC-R.

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