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Protein S is a vitamin K dependent plasma glycoprotein that inhibits blood coagulation through inactivating factors Va and VIIIa in cooperation with protein C. Deficiency of protein S, congenital or acquired, predisposes to thrombotic disease.
In postmortem studies, the prevalence of cerebrovascular disease in HIV infected patients has ranged from 11% to 34%. The causes are diverse, and include embolic and thrombotic stroke, cerebral vasculitis, and cerebral haemorrhage.1Decreased free protein S has been commonly found in HIV infected adults and has been associated with systemic venous thrombosis.2
To our knowledge, we report the first case of an HIV infected adult with intracranial dural sinuses and cerebral venous thrombosis due to protein S deficiency.
A 37 year old HIV infected woman was admitted with severe and persistent headache of two weeks duration in January 1994. She had no history of thrombotic events and there were no obvious precipitants of thrombosis. She had never received oral contraceptives or anticoagulants. On admission, vital signs were normal and physical and neurological examinations were unremarkable.
Laboratory studies showed a white blood cell count of 1.7 × 109/l, a CD4 cell count of 72/mm3, platelet count of 18.3 × 109/l, and erythrocyte sedimentation rate of 10 mm/h. Biochemical indices were within the normal range. Serological tests for syphilis were non-reactive. Tests for antinuclear, anti-DNA, anti-ENA, and antiphospholipid antibodies (anticardiolipin and lupus anticoagulant) were all negative. Prothrombin and partial thromboplastin times, and albumin, fibrinogen, antithrombin III, and protein C concentrations were normal. Protein S concentrations, measured by a crossed immunoelectrophoresis method, were 49% (normal 60% to 100%) and 28% (normal 65% to 125%), corresponding to free and functional protein S respectively. The family history was negative for thromboembolic disease and her parents’ protein S concentrations were normal.
A urinary monoclonal antibody test concentration of 2.3 hCG/ml (normal <10) excluded pregnancy.
Electrocardiography and two dimensional echocardiography did not disclose any abnormality.
Brain MRI disclosed hyperintense signals on T1 and T2 weighted images in the left venous sigmoid and lateral sinuses. Findings from MR angiography were consistent with obstruction of these sinuses and of the left jugular vein (figure). The patient was initially treated with heparin and when adequate anticoagulation was achieved, heparin was gradually discontinued and long term acenocumarol was started. No recurrence of thrombotic or neurological manifestations have occurred during two years.
Protein S is synthesised by endothelial cells, megakaryocytes, osteoblasts, neural derived tissues, and hepatocytes. Acquired decreases in protein S concentrations have been described in liver disease, nephrotic syndrome, systemic lupus erythematosus, disseminated intravascular coagulation, warfarin and oral contraceptive therapies, pregnancy, and HIV infection. The prevalence of decreased free protein S in HIV infected patients has ranged from 31% to 76%.2HIV has been found within endothelial cells of cerebral blood vessels.3 Thus it has been suggested that protein S deficiency can result from abnormal endothelial cell function during HIV infection.2 Although the mechanism responsible for the decrease in protein S is unknown, the proinflammatory cytokine tumour necrosis factor-α is increased in HIV infected patients and may induce a procoagulant state on the surface of endothelial cells, down regulating synthesis of protein S.2
Some authors have reported that HIV associated protein S deficiency may predispose to deep vein thrombosis and pulmonary embolism.2 Sagittal sinus thrombosis has been reported in a seronegative patient with hereditary protein S deficiency.4Although cerebrovascular disease is not uncommon in patients with AIDS, only a single case of dural sagittal venous thrombosis has been reported to date, in a four month old girl during pneumococcal sepsis.5
To our knowledge, the patient herein reported is the first case of intracranial venous and sinuses thrombosis secondary to acquired protein S deficiency in an HIV infected adult. The present case also suggets that long term anticoagulant therapy may prevent further thrombotic events in HIV infected patients with this disorder.