Cerebral Infarction in a Young Adult Associated with Protein C Deficiency A Case Report Hiroyuki Kato, M.D., Ph.D. Masashi Shirahama, M.D. Keizo Ohmori, M.D., Ph.D. and Toshiaki Sunaga, M.D., Ph.D., F.A.C.A. SAGA, JAPAN ABSTRACT Protein C deficiency is a cause of thromboembolic disease. Venous thrombosis is the most common clinical manifestation. Arterial thrombosis is unusual and involvement of the intracranial arteries is especially rare. Herein the authors describe a case of cerebellar infarction associated with protein C deficiency and review the relevant medical literature. A thirty-year-old man was hospitalized because of dysarthria, right limb ataxia, and a gait disturbance. Cranial computed tomography disclosed an infarction in the right cerebellar hemisphere and brachium pontis. Three months earlier the patient had had a transient ischemic attack with truncal ataxia and gait disturbances. On admission, the protein C antigen was 57% and protein C activity was 45%. Investigation of family members revealed protein C deficiency in an uncle. Literature review of stroke cases associated with protein C deficiency revealed that most had had a previous vascular event and/or a positive family history or had used oral contraceptives chronically. Protein C deficiency should be considered in young stroke patients with a positive family history of vasoocclusive disease, previous ischemic events, or chronic oral contraceptive use. From the Department of Internal Medicine and General Medicine, Saga Medical School, Saga, Japan. 169 Downloaded from ang.sagepub.com at OAKLAND UNIV on May 31, 2015 Introduction 120/70 mmHg, and the heart rate was 72 and Protein C is a vitamin K-dependent glycoprotein synthesized in the liver with a molecular weight of 62 kDa. It is activated by thrombin bound to thrombomodulin on the surface of endothelial cells. Activated protein C acts as an anticoagulant by inhibiting factors Va and Villa in the presence of protein S.1,2 The hereditary type of protein C deficiency is inherited primarily in an autosomal dominant pattern.3 Venous thrombosis is the most common clinical manifestation of this disease; 4-6 arterial thrombosis occurs rarely. 6.7 Strokes are rare relative to pulmonary embolism or deep vein throm- regular. Heart and respiratory sounds were normal, and hepatosplenomegaly was not detected. Neurologic examination revealed a clear sensorium with dysarthria (slurred, ataxic speech), right limb ataxia (incoordination), and a reeling tandem gait. Three months previously, the patient had had an episode of sudden truncal ataxia and a gait disturbance that disappeared completely within two hours. The patient was not taking medications at the time of admission. The family history was negative for thrombotic events. Cranial computed tomography disclosed an infarction in the right cerebellar hemisphere and brachium pontis (Figure 1). Two-dimensional and color Doppler echocardiography was negative for bosis. We describe the case of a thirty-year-old man with cerebral arterial thrombosis associated with protein C deficiency and review the relevant literature. Case Report A thirty-year-old man was admitted to the Saga Medical School Hospital on October 22, 1987, because of the sudden onset of neurologic symptoms including dysarthria and left facial dysesthesia. The blood pressure on admission was valvular disease, mural thrombi, and intracardiac shunting. Other potential sources of emboli were not detected. Laboratory tests revealed the following : the white blood cell count was 13,400/~L with a normal differential, the erythrocyte count was 530 x 104/ JLL, the hemoglobin concentration was 16.0 g/dL, the hematocrit was 48.0%, the platelet count was 27.2 x 104/jU.L, the prothrombin time was 13.0 seconds (control time 14.2 seconds), and the activated partial thromboplastin time was 38.0 seconds (control time 42.0 seconds). On hospital day 6, cerebral angiography (bilateral vertebral and common carotid arteries) showed no evidence of occlusive or malignant le- Figure 1. Cranial computed tomography on admission shows a lowdensity area in the right cerebellar hemisphere (arrow). 170 Downloaded from ang.sagepub.com at OAKLAND UNIV on May 31, 2015 Table I Results of Coagulation Studies sions. The patient’s neurologic abnormalities gradually improved, and he was discharged on hospital day 48 without neurologic deficits. As shown in Table I, a study of the patient and his uncle (paternal younger brother) disclosed protein C deficiency. The protein C antigen level was measured by the homogeneous enzyme immunoassay method,8 and protein C activity was measured by the coagulation test with inhibition of the activated partial thromboplastin time.9 We concluded that cerebral infarction was caused by protein C deficiency and started warfarin anticoagulant therapy in the outpatient department. As of December, 1992, the patient had had no recurrence of cerebral ischemic events. Discussion Protein C deficiency is an established risk factor for venous thrombosis.3,5,10 However, associated arterial thromboembolism is very rare, especially for intracranial arteries.7,11 Kohlerl2 described a thirty-two-year-old man with heterozygous protein C deficiency who developed a severe stroke due to thrombotic occlusion of the left middle cerebral artery. Matsushital3 described a thirtynine-year-old woman who developed a cerebral infarction in the right parietal lobe. In our patient, occlusion of the right superior cerebellar artery led to ischemic infarction and to the neurologic symptoms of dysarthria, right limb ataxia, and reeling tandem gait. Embolic infarction from a cardiac source or arterioarterial embolism due to preexisting carotid artery sclerosis was excluded. The patient’s protein C activity and antigen concentration were significantly decreased before anticoagulation was started. Prior to the stroke, the patient had an episode of transient ischemic attack with cerebellar symptoms. The family study revealed protein C deficiency in an uncle. Hypercoagulopathy due to inherited protein C deficiency likely caused the thrombosis of this patient’s right superior cerebellar artery. After six days of hospitalization, the occlusion was found by angiography to have recanalized. We reviewed all published stroke cases associated with protein C deficiency (Table II). The relevant database was reviewed in Medline. We uncovered 14 cases (6 men, 8 women) with a mean age of 34.4 ±14.8 years (mean ±SD). Diagnoses included ischemic infarction (6 cases), hemorrhagic infarction (3 cases), transient ischemic attack (2 cases), and others (3 cases). Various cerebral loci were susceptible to infarc- 171 Downloaded from ang.sagepub.com at OAKLAND UNIV on May 31, 2015 # o _ °# d ct 7~5 ~ 3 ~ cz 0 U >0 N 0 0 C,3 0ucll> 1 ct > 4-J ~ C 27#k ~ fj V 0 o z (D cuII q, Q £I##l . >~ v c~a E~ C,3 u e , r4 g l (VU C~40 c~. ~ II ^o ~ CL