The Japanese Journal of Psychiatry and Neurology, Vol. 47, No. 4, 1993 A Case of Protein C Deficiency Associated with Cerebral Infarction and Obstruction of Deep Leg and Inferior Mesenteric Veins Mitsunori Tsuda, M.D., Ph.D., Masao Miyazaki, M.D.,* Takahiro Takada, M.D., Yoshiyuki Uda, Ph.D. * * and Shigeki Kuzuhara, M.D. * * * Department of Neurology and Medical Information, Mie University Hospital, Tsu *Department of Neurology, Yamada Red Cross Hospital, Tsu * * Department of Information Center, Mie University Hospital, Tsu **t Department of Neurology, Mie University Hospital, Tsu Abstract: Protein C, a vitamin K-dependent protein, is a blood coagulation inhibitor. Its deficiency causes systemic thrombosis. A 31-year-old woman developed cerebral infarction followed by late psychomotor seizures, and thrombosis in the inferior mesenteric vein and bilateral crural veins. Her parents were first cousins. Her mother died of cerebral thrombosis in her 30’s. Her elder brother died of suspected purpura fulminans immediately after birth. Her protein C activity and protein C antigen level decreased markedly and were less than 5% of those of normal controls and 0.3 ,ug/ml, respectively. Her father, a paternal aunt and a maternal uncle also showed a low protein C activity and protein C antigen level. This patient seems to have congenital protein C deficiency which produced thrombosis in the leg veins and the mesenteric vein, probably cerebral infarction. Key Words: protein C deficiency, stroke, mesenteric venous thrombosis, psychomtor seizure, cerebral infarction Jpn J Psychiatr Neurol47: 887-892, 1993 INTRODUCTION Congenital protein C deficiency is transmitted in an autosomal dominant trait. The frequency of symptomatic venous thrombosis seems to be 6-896 in patients younger than 40 years old with heterozygous deficiency of protein C.’ * In homozygotes, a fulminant hemorrhagic condition occurs and victims Received for publication on April 16, 1993. Mailing address: Mitsunori Tsuda, M.D., Ph.D., Department of Neurology and Medical Information, Mie University Hospital, 2-174 Edobashi, Tsu, Mie 512, Japan. usually die withm the first m ~ n t h . ~Two -~ types of protein C deficiency are known. In type I, both the concentration and activity of protein C are reduced. On the other hand, type I1 shows a reduction only in the activity of protein C.6 Individuals with congenital protein C deficiency frequently develop systemic venous thrombosis, but a few cases of thrombosis of cerebral arteries have been reported.’ We experienced a patient with congenital protein C deficiency who presented with cerebral infarction, together with thrombosis in the inferior mesenteric vein and in the bilateral crural veins. M. Tsuda et al. 888 CASE REPORT On June 14, 1989, a 31-year-old woman was admitted to our hospital with a complaint of abdominal pain accompanied by vomiting and diarrhea. Her parents were first cousins. Her mother died of cerebral thrombosis in her 30's. Her elder brother died immediately after birth (Fig. 1). In 1986, the patient noted edema in her leg. She sometimes experienced the episodes of loss of consciousness while driving a car, which caused traffic accidents. In 1988, she developed episodes of unconsciousness for several seconds while doing housework, which were followed by bizarre behaviors of walking around in the kitchen for about one minute and subsequent mutism for several minutes. She had been healthy until 28 years old when she developed these episodes and had no risk factors for cerebral vascular disease including intoxication, drugs, alcohols and smoking. Based on a diagnosis of psychomotor seizure, she started taking carbamazepine (400 mg/day), which successfully relieved the attack. On her admission, a physical examination indicated acute abdominal pain. A subsequent laparotomy revealed sigmoid colon necrosis due to thrombosis in the inferior mesenteric vein. She was referred to our department for a I Fig. 1 : 0 : died. is the family line of this case. ,o:Thispropositus, heterozygote. 00: * : cerebral infarction (not studied), * * : purpura fulminans suspected. The numbers in this figure correspond to the numbers in Table 2. further examination. The physical examination revealed normal heart sounds and an arterial pulsation in all the limbs. There was edema in both legs. The Wechsler Adult Intelligence Scale (WAIS) was 61 in verbal IQ and 71 in performance IQ. A neurological examination was unremarkable except for a leftward nystagmus during gaze to the left. A muscle strength test disclosed mild weakness in the proximal muscles of the right arm. Deep tendon reflexes were hyperactive in the right extremities. Babinski sign was negative on both sides. Sensations were within the normal limits. A cardiologic investigation including electrocardiography, Holter electrocardiographic monitoring and echocardiography did not reveal any abnormality. Urinalysis was normal. Biochemical data for liver and kidney functions, glucose and lipid metabolism disclosed no abnormalities. Serum electrophoresis and immunoelectrophoresis showed a normal pattern. A rheumatoid factor determination test, antinuclear, anti-DNA and anti-ENA antibodies, lupus anticoagulant, anticardiolipin antibodies and serum analysis for syphilis were negative. Complement fractions, immunocomplex determinations and antistreptolysink titer were within the normal limits. The fractions of vitamin K were normal and vitamin K-dependent clotting factors 11, VII, IX, X and then V were measured in a standard one-stage clotting assay. These values were normal. Routine blood parameters and the hemostasiologic tests, bleeding time, coagulation time, thrombotest (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), hepaplastin test, fibrinogen, antithrombin 111, plasminogen activity, a 2 plasmin inhibitor (a2PI), a 2 plasmin inhibitor-plasmin complex (a 2 PI . Pm) and tissue plasminogen activator inhibitor (PAI-1) were within the normal ranges (Table 1). Chromatogenic assays were used to determine the concentrations of antithrombin III.9 The plasminogen activity was measured by the single radial immunodiffusion method and a 2 plasmin inhi- A Case of Protein C Deficiency bitor, a2 plasmin inhibitor-plasmin complex were measured by an enzyme immunoassay. The concentration of protein C antigen was determined by an enzyme immunoassay.lo The protein C activity was measured using a clotting method based on snake venom activation of protein C in plasma." The protein S activity was measured using immunoelectrophoresis. " The protein C activity and protein C antigen level for the patient were below 5% and below 0.3,ug/ml while the protein S activity was within the normal limits. These findings were obtained when the patient was under no medication. The protein C activity and protein C antigen level were 44% and 1.8,ug/ml in the father, and 44% and 2.0,ug/ml in one of the maternal uncles. Protein C abnormality was also noted in a paternal aunt (Fig. 1, Table 2 ) . 889 Table 1: Parameters of the Clotting System of the Propositus Bleeding time Coagulation time TT" PTb APTT' Hepaplastin test Fibrinogen Antithrombin 111 Plasminogen activity a 2PId a 2PI . Pm' PAI-1' Protein C activity Protein C antigen Protein S activity 3 min (1-5) 6.5 min (5-15) 100% (65-130) 79% (8Crl00) 32.4 S ~ C(25-35) 96% (65-120) 238 mg/dl (145-380) 115% (79121) 94% (79-121) 90% (85-115) 0.4 pg/ml (< 0.8) 4.2 pg/ml (< 50) < 5 % (7CF150) < 0 . 3 pg/ml (2.9-5.5) 86% (68-160) The values in parentheses indicate the values of normal control range. ': thromhotest, b: prothrombin time, ': activated partial thromboplastin time, d : a2 plasmin inhibitor, e : a2 plasmin inhibitor-plasmin complex, f : tissue plasminogen activator inhibitor. Fig. 2 : MRI image. The left side are T1-weight images and the right side are T2weight images, which show the cerebral infarction on the left temporal area. 890 M. Tsuda et al. Table 2 : Protein C of Normalities in the Present Family Propositus Family number case 1 case 2 case 3 case 4 case 5 case 6 (T) Antigen (,ug/ml) (2.9-5.5) * Activity (70- 150) <0.3 <5 1.8 1.7 2.8 2.0 2.6 4.4 44 47 73 44 60 170 * : The values in parentheses indicate the values of normal control range. The numbers of cases correspond to the numbers of Fig. 1. Brain CT revealed a slight atrophy of the frontal lobes and a low density area in the left temporal lobe. On MRI, dilatation of the inferior horn of the left lateral ventricle and low signal intensity in the surrounding region were observed on TI-weight images. T2weight images revealed a high signal intensity in the same areas indicative of an old infarct (Fig. 2). SPECT disclosed a reduced blood flow in the left temporal lobe, consistent with the abnormal region on CT and MRI. Electroencephalography showed 10 Hz alpha waves with poor continuity. Although slow waves were frequently observed, there were no laterality or paroxysmal abnormalities. A pulmonary blood flow and ventilation scintigrams disclosed no findings suggestive of a pulmonary embolism. A venography of both legs disclosed obstruction of the deep veins by old thrombi and new anastomosis. Cerebral angiography was not done. The patient was treated with heparin of 10,000 units/day, ticlopidine of 300 mg/day and aspirin of 300 mg/day. Heparin was discontinued when adequate anticoagulation was achieved. After that, she has never suffered from cerebrovascular disorder although she had several episodes of mild edema of the leg. DISCUSSION Protein C deficiency is well known as a major risk factor of venous thrombosis. In recent years, it has been noticed as a risk factor of thrombosis of cerebral arteries in young adults.' Protein C is a serine protease synthesized in the liver under the presence of vitamin K and is activated by thrombomodulin combined with thrombin on the endothelial cell. Therefore, it is necessary that both thrombin and protein C are bound to phospholipid, platelet or endothelial cell surface.I3l4 Activated protein C inactivates the clotting factor Va and VIIIa, and then it reacts with the tissue plasminogen activator inhibitor (PAI-1). The concentration of the tissue plasminogen activator inhibitor decreases and finally fibrinolysis is enhanced.6l 5 Furthermore, congenital protein C deficiency is an autosomal dominant trait with incomplete penetrance.' A diagnosis of protein C deficiency can be established when all the following criteria were satisfied: (1) constant fall of the protein C activity and antigen below the normal range, both at the moment of acute event and recovery; (2) the normal levels of protein S and other vitamin K-dependent clotting factors; (3) absence of recognized causes of acquired protein C deficiency; and (4) presence of protein C deficiency in at least one other family member.8 l6 In our case, these criteria were satisfied. The protein C activity and protein C antigen levels for the patient were below 5% and 0.3pg/ml, respectively, which were obtained when the patient was not in the hypercoagulation state. These findings seemed to be too low if these were not due to a consumption coagulopathy mechanism. Based on the family history and laboratory data this patient seems to be a late onset homozygous form of type I familial protein C deficiency. In homozygotes with a severe defect, a fulminant hemorrhagic condition occurs and they usually die within the first We must consider the reason why she was A Case of Protein C Deficiency asymptomatic until 28 years old. But homozygotes with a mild defect develop in the hypercoagulation state at an older age.’ Recently, it has been reported that the amount of protein C which is necessary to inactivate factor Va is very small and cannot be detected by the usual method on the study of lupus anticoagulant. l 3 We speculated that this patient was the late onset homozygote of protein C deficiency and that the small amount of protein C that could not be detected by the usual method prevented the hypercoagulated state, namely that the subtle balance in the coagulation system have been kept until 28 years old. However, the endothelial cell function changed slowly with aging and then the balance declined the hypercoagulation.l3 The first sign of the intracerebral lesion in this patient was the psychomotor seizures which were caused by an old infarction in the temporal lobe of probably arterial origin. Alternatively the cerebral infarction in this patient was produced by cerebral venous thrombosis. However, we could not find the evidence of thrombosis in the cerebral veins on the M R I study. Recently, cerebral ischemic vascular disorders in protein C deficiency have been reported. However, the incidence of cerebrovascular complications in patients with protein C deficiency seemed to be very low.’ * Sasaki et al. proposed that cerebral infarction is induced when an increased risk for cerebral arterial thrombosis due to protein C abnormality (low protein C activity and normal protein C antigen) is combined with circulatory insufficiency .23 The very low incidence of cerebrovascular complications in patients with protein C deficiency has been attributed to a poor distribution of thrombomodulin, a coenzyme that activates protein C in cerebral arteries. l 3 23 24 The protein C activity and protein C antigen levels for cases 1, 2, 4 and 5 in Table 2 were below the normal range and these for case 3 in Table 2 showed lower limit values of the normal range. We speculated that these cases were heterozygotes of type I familial protein C deficiency considering the family 89 1 history and laboratory data. These cases had no thromboembolic diseases. It is reported that protein C deficiency persons without thromboembolic diseases should not be treated with oral anticoagulants in the study on heterozygous protein C deficiency type I.2’ Therefore, we consider that antithrombotic treatment is only indicated in situations with a risk for thrombosis, such as surgery in these cases. REFERENCES 1. Broekmans, A.W. and Conard, J.: Hereditary protein C deficiency. In: Bertina, R.M. (Ed.), Protein C and Related Proteins. Churchill Livingstone, Edinburgh, London, Melbourne and New York, pp 160-181, 1988. 2. Miletich, J., Sherman, L. and Broze, G.J.: Absence of thrombosis in subjects with heterozygous protein C deficiency. N Eng J Med 317: 991-996, 1987. 3. Seligsohn, U., Berger, A., Abend, M., Rubin, L., Attias, D., Zivelin, A. and Rapaport, I.R.: Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Eng J Med 310: 559-562, 1984. 4. 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