Statistics from Altmetric.com
Predisposing factors can be identified in up to 80% of patients who develop cerebral venous thombosis (CVT).1 In many patients risk factors are acquired but 10 to 15% of patients may have inherited tendencies to thrombosis. Deficiencies of protein C, protein S, or antithrombin are reported in large series. The recently identified factor V Leiden mutation (FVR506Q) giving rise to activated protein C resistance is one of the most prevalent genetic mutations currently identified (10% to 15% of the white population),2 and it is now known to be an important risk factor for cerebral venous thrombosis.3-6 All of these thrombophilic tendencies, and particularly the factor V Leiden mutation, are compounded by other factors such as the oral contraceptive pill, pregnancy, pueperium, or immobility.
Prothrombin is a precursor of the serine protease thrombin and is a key enzyme in the process of haemostasis. Recently, a single nucleotide substitution (G to A) at position 20210 in the 3’ untranslated region of the gene encoding prothrombin has been identified.7 Its heterozygous state, 20210A, is a risk factor for the development of deep vein thromboses,7 8 and it has recently been implicated in the development of superior sagittal sinus thrombosis in a woman taking the oral contraceptive pill.9 We report the development of extensive cerebral venous thrombosis in a patient, without other risk factors, who was found to be heterozygous for this newly identified genetic mutation.
A 46 year old man had headaches for 2 weeks which became acutely worse and were associated with vomiting and dizziness. His conscious level fluctuated but was progressively deteriorating. He had a generalised tonic-clonic seizure and a history of a spontaneous deep vein thrombosis. There was no family history of thromboses.
He was obtunded with bilateral papilloedema. There were no focal signs except for a right extensor plantar. Unenhanced brain CT was normal but a lumbar puncture disclosed a pressure of 34 cm of CSF with 28 000 red blood cells, 40 white blood cells/mm3and a protein concentration of 1.5 g/l with normal glucose. A repeat brain CT with contrast showed diffuse swelling in the posterior fossa, with supratentorial and infratentorial haemorrhages and high attenuation around many of the venous sinuses. Brain MRI disclosed extensive thrombosis of the superior sagittal sinus, the straight sinus, and both transverse and sigmoid sinuses. There was haemorrhage in the left cerebellar hemisphere and haemorrhagic infarcts in the left parietal and both cerebellar hemispheres.
Full blood count and biochemistry were normal. The erythrocyte sedimentation rate was 24 mm in the first hour and C reactive protein was 24.1 mg/l (normal<8). Autoantibodies including antinuclear antibodies were negative. Treponemal pallidum haemagglutination test and rapid plasmin reagin tests were negative. The prothrombin time and activated partial thromboplastin time were normal. A thrombophilia screen was performed 24 hours after starting heparin (table). Initial antithrombin activity was reduced at 70% but was normal when repeated 4 months after the initial presentation; however, the patient was found to be heterozygous for the 20210A prothrombin gene mutation. This was identified using the polymerase chain reaction (PCR) of exon 14 and the 3’-untranslated region of the prothrombin gene, followed by restriction digestion by Hind III. The mutant allele then appeared as an extra DNA fragment on agarose gel electrophoresis. The presence of the 20210A allele was subsequently confirmed by DNA sequencing.
He was treated with intravenous heparin (APTT ratio 2 to 3) with the gradual introduction of warfarin which he will continue for life. His condition gradually improved; he had mild residual pyramidal signs, but no significant disability, and no further seizures.
The substitution of G to A at position 20210 of the prothrombin gene is a recently recognised risk factor for venous thrombosis. It has been found in 18% of selected patients with a family history of venous thrombosis, 6% to 7% of unselected patients with deep vein thrombosis, but only 1% to 2% of controls,7 8 making it the second most common hereditary thrombophilia after the factor V Leiden mutation.2 Prothrombin is encoded by a 21 kb gene located on chromosome 11p11 to q12. Patients with the mutation (20210A) have higher plasma prothrombin concentrations than controls with the normal genotype (20210G), suggesting that hypercoaguability is due to hyperactivity of the common coagulation pathway resulting in increased thrombin production.7
Our patient had reduced antithrombin concentrations at 70% on initial testing. Thrombotic tendencies arise when concentrations are less than 60% of normal. The initial concentration was probably secondary to the acute thrombosis or treatment with heparin. Repeat testing after 4 months showed normal concentrations, hence we think that antithrombin deficiency is unlikely to be implicated in this patient’s CVT. There were no other risk factors for venous thrombosis in our patient, unlike the recently reported patient with sagittal sinus thrombosis, who was taking the oral contraceptive pill.9
Activated protein C resistance due to the factor V Leiden mutation is the most common hereditary thrombophilia associated with CVT,3-6 although in most cases it is also associated with an acquired prothrombotic tendency,3 such as the oral contraceptive pill. In a recent study of 40 patients with CVT, Activated protein C resistance with the Leiden mutation was found in four patients, protein C deficiency in one, and protein S deficiency in another.3 Isolated hereditary thrombophilias as a cause of CVT seem to be rare in the absence of other factors, with only the patient with protein S deficiency in the series of Deschiens et al 3 and other occasional cases4 5having no other predisposing factor.
The identification of an inherited thrombophilia in a patient with CVT should not, therefore, preclude a search for other provoking factors. To the list of inherited thrombophilias should now be added the newly identified 20210A prothrombin gene mutation.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.