A CASE OF CEREBRAL VENOUS THROMBOSIS: ADVERSE EFFECT OF VALPROATE?

E. Pizzolato, M. Ulla, F. Giachino, S. Locatelli, F. Turvani, E. Lupia, M. L. Bonino, C. Moiraghi, S. Battista.

DAL CASO CLINICO ALLA DECISIONE Bologna, 15‐16 novembre 2013

Emergency Department, “Città della Salute e della Scienza” Hospital, Via Genova 3, 10126, Torino, Italy.

Background Several alterations of the blood picture in pro-bleeding sense are described during treatment with valproate: thrombocytopenia is the most common side effect. Less evidence exists about pro-thrombotic effect of valproate. These coagulopathies are reversible after discontinuation of valproic acid.

Case report A 42-year-old woman was admitted to the Emergency Department complaining of abdominal pain and diarrhea. Three months earlier she underwent the clipping of two cerebral aneurysms, the bandage of a third one and the emptying of an hematoma because of a subarachnoid hemmorhage: the postoperative period was complicated with tonic-clonic seizures so anticonvulsivant therapy with valproic acid was started. At the time of admission plasma sodium valproate levels were within the therapeutic range, routine laboratory tests showed hypokalemia and hypoalbuminemia, moderate thrombocytopenia (already present in recent outpatient controls), hypofibrinogemia with elongation of INR and protein C and S deficiencies (table below): in the suspicion of a valproate-induced coagulation disorder, the drug was discontinued and replaced with phenobarbital. In the second day of recovery a rapid deterioration of consciousness occurred: she complained of dizziness, confusion and pain in the right cervical region, where a jugular venous cannula were implanted. Urgent cranial CT scan showed cerebral venous thrombosis and anticoagulant therapy with intravenous heparin sodium was started. At discharge patient was in relatively good general conditions, alert and oriented, with a moderate dysarthria and dysphagia, already present at the admission. Indication to continue anticoagulation with low molecular weight heparin for at least three months was given. Rapid regressions of thrombocytopenia and fibrinogen, protein C and S deficiencies were obtained after withdrawal of valproate. CT and arteriographic controls run after two weeks showed the partial recanalization of venous sinuses.

Discussion and conclusion Elongation of INR, thrombocytopenia, fibrinogen, protein C and S deficiencies observed in our patient appear as side effects of valproic acid therapy rather than a secondary consumption to thrombosis and cerebral hematoma organization. This is suggested by the prompt normalization of the coagulative framework following the suspension of the drug. Deficiency of protein C and S induces an increased risk of stroke and cerebral or peripheral venous thrombosis but they need a concomitant thrombotic risk factor to cause a thrombosis event: venous stasis (due to dehydration and hypovolemia seconday to diarrhea), endothelial alterations (caused by neurosurgical intervention) and hypercoagulability/hyperviscosity (secondary to dehydration which acted by increasing coagulability). Therefore our patient fitted the familiar Virchow’s Triad about genesis of thrombosis.

PT-INR Augmented

PTT Normal

Fibrinogen Reduced

AT III Normal

D-dimer Normal

APC resistance Positive

Factor V Leiden Heterozygous mutation

(G1691A)

MTHFR Heterozygous mutation

(A1298C)

Prothrombin polymorphism Absent

Lupus Anticoagulant Absent

Protein C coagulation pathway Reduced (20; v.n. 70-140)

Protein S coagulation pathway Reduced (25; v.n. 50-100)

Anti-platelet Antibodies Absent

Anti-heparin Antibodies Absent

Anti-Transglutaminase and

Anti-Endomysial Antibodies

Positive

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