815 Case Reports Progressing Ischemic Stroke in a Homozygote With Variant Antithrombin III Hidetsugu Ueyama, MD, Yoichiro Hashimoto, MD, Makoto Uchino, MD, Yasuto Sasaki, MD, Eiichiro Uyama, MD, Kenji Okajima, MD, and Shukuro Araki, MD A 31-year-old woman developed disturbance of consciousness and left hemiparesis. Cerebral computed tomograms showed a low-density area in the right temporal lobe that extended to the right parietal and left frontal lobes as her clinical symptoms worsened. The diagnosis of familial variant of antithrombin III (AT-III) was based on decreased biologic activity and a normal immunologic level of AT-III in this patient and in her family members. Transfusion of normal AT-III concentrate led to a striking clinical recovery. Blood coagulation studies revealed that nine of 13 family members had decreased biologic AT-III activity and that the patient herself was the only homozygote with variant AT-III. We conclude that variant AT-III, especially in a homozygote, seems to be one cause of ischemic stroke in young adults and that simultaneous measurement of both the biologic and immunologic activities of AT-III is necessary to detect it. (Stroke 1989;20:815-818) S ince cardiogenic, hematologic, or inflammatory diseases often predispose to thromboembolic stroke in young adults, both early diagnosis and early therapy of the predisposing disease are important, especially during the acute phase.1-3 We examined a young woman with progressing ischemic stroke associated with a familial variant of antithrombin III (AT-III). Cerebral thrombosis associated with AT-III deficiency is extremely rare, although some patients with cerebral venous thrombosis have been reported. Case Report A 31-year-old woman had a history of two transient ischemic attacks at ages 17 and 29 years and three episodes of deep-vein thrombosis of the extremities at ages 23 and 29 years. She had been given ticlopidine and pentoxifylline since she was 29 years old. On November 24,1987, she caught cold, and the next day she developed weakness of her left upper extremity that lasted for 20 minutes. On November 27, she became aware of numbness of her right palm and transient blurred vision of her right eye. She developed headache, nausea, and vomiting and subsequently discontinued her ticlopidine and pentoxiFrom the First Department of Internal Medicine (H.U., Y.H., M.U., Y.S., E.U., S.A.) and the Department of Laboratory Medicine (K.O.), Kumamoto University Medical School, Kumamoto, Japan. Address for reprints: Hidetsugu Ueya.na, MD, First Department of Internal Medicine, Kumamoto University Medical School, Honjo 1-1-1, Kumamoto 860, Japan. Received September 15, 1988; accepted November 23, 1988. fylline. On admission the next day, she was alert and had normal physical findings except for numbness of her right palm and an ulcer of her right leg due to an old case of thrombophlebitis. Routine laboratory examinations revealed normal values except for iron-deficiency anemia, elevated lactate dehydrogenase concentration, and presence of rheumatoid factor. Tests for coagulation and fibrinolysis showed prominent acceleration of fibrinolysis, such as E fraction of fibrinogen degradation product 2026 (normal 8.1-70) ng/ml, fibrin monomer test 2+, and D-dimer 2000 (normal <200) ng/ml. The biologic activity of AT-III was as low as 42% of control (heparin cofactor activity, incubation time 5 minutes; normal 81-121%), while its immunologic activity was as high as 37.1 (single radial immunodiffusion method; normal 27-33) mg/dl. The dissociation of the biologic and immunologic activities of AT-III in her plasma suggested the presence of a variant form of AT-III. The biologic activity of heparin cofactor-II was also as low as 48.5% (normal 70-150%).4 Bleeding, prothrombin, and activated partial prothrombin times and fibrinogen, a2-plasmin inhibitor, protein C, protein S, a r antitrypsin, and a2-macroglobulin concentrations were all normal. Electroencephalography revealed delta rhythmic activity, predominantly in the right temporal area. Chest x-ray film, electrocardiogram, and echocardiogram were all normal. On December 1 (Day 1), her nausea and headache increased and her level of consciousness gradually fell. That morning, transient generalized convulsions occurred. Neurologically, she was somnolent, Downloaded from http://stroke.ahajournals.org/ by guest on June 24, 2016 816 Stroke Vol 20, No 6, June 1989 FIGURE 1. Cerebral computed tomograms showed low-density area in right temporal lobe on Day 1 (A). By Day 2, low-density area had extended to right parietal lobe (B). By Day 3, low-density area had appeared in left frontal lobe (C). On Day 54, clear low-density area remained in right parietotemporal and left frontal lobes (D). her eyes showed horizontal roving movements, and there was hemiparesis with hemifacial paresis on her left side (upper limb dominant only detected by Barrels sign). We diagnosed ischemic stroke based on a low-density area in the right temporal lobe on a cerebral computed tomogram (CT scan) (Figure 1A). On Day 2, she became stuporous and her weakness worsened. The low-density area extended to the right parietal lobe (Figure IB). On enhanced CT scan, there were neither enhanced lesions nor empty delta signs. On Day 3, she developed a semicomatose state with left complete hemiplegia and transient Cheyne-Stokes respiration. A new low-density area appeared in the left frontal lobe (Figure 1C). At this time we found that her biologic AT-III activity was quite low, and we determined that her family members' activity was also depressed. Thus, we diagnosed familial AT-III deficiency.56 On Day 3, we started daily intravenous transfusions of normal AT-III concentrate (1500 units/day). As this treatment raised the biologic AT-III activity, her level of consciousness gradually improved to normal on Day 9 and her strength began to return. The low-density area stopped spreading. On Day 15, treatment with warfarin gave sufficient control to prevent thrombosis. By Day 54, her mentation, memory, and gait had recovered to normal and no new stroke was found on CT scan (Figure ID). Carotid angiography performed on Day 14 revealed branch occlusions of the right middle cerebral artery (Figure 2). There was neither atherosclerotic change of the cerebral arteries nor cerebral venous thrombosis. On hematologic examination of 13 members of her family, eight (including her parents) had decreased biologic activity and normal immunologic activity of AT-III, while one member showed a decrease in both. Thus, we diagnosed a familial variant of AT-III. 56 The mode of inheritance is suspected to be autosomal dominant. On crossed immunoelectrophoresis and affinity chromatography of their plasma, the patient was found to be a homozygote and the others (including her parents) were found to be heterozygotes.78 Discussion Familial AT-III deficiency is divided into two groups: quantitative AT-III deficiency and dysfunctional AT-III (variant of AT-III).1*-11 Although familial variant of AT-III is an extremely rare disorder, about 20 families have been reported.5-612-14 In Downloaded from http://stroke.ahajournals.org/ by guest on June 24, 2016 Ueyama et al Stroke in AT-m Variant 817 FIGURE 2. Lateral view of left internal carotid angiogram revealed branch occlusions of right middle cerebral artery (arrow). these families, a variant molecule of AT-III, immunologically detectable but biologically abnormal, is apparently produced. Although reduced AT-III activity occasionally produces venous thrombosis, reports of arterial thrombosis are rare. 671013 - 17 The clinical features of our case represented a progressing ischemic stroke,18 progression of clinical symptoms and extension of the low-density area for 3 days. At first we speculated a cerebral sinus thrombosis because of her severe headache and nausea, but this was later ruled out due to the absence of empty delta signs on the enhanced CT scan and good venous filling on the carotid angiogram.19 Whether she had developed a cerebral thrombosis or an embolism is a difficult clinical question. We speculated thrombosis because of the gradual onset, spread over several days, and absence of paradoxical embolism. The most important clinical point of our case is that we successfully diagnosed her as having a familial variant of AT-III during the acute period of her stroke and that concentrated AT-III infusion produced a striking clinical improvement.2021 Heparin by itself may be ineffective since its action largely depends on the presence of normal AT-III.22 It is still controversial whether reduced AT-III activity is the predisposing factor of stroke.23-26 Only six other cases of cerebral thrombosis associated with familial AT-III deficiency have been reported (Table 1). 10.12,15-17 Their common clinical Downloaded from http://stroke.ahajournals.org/ by guest on June 24, 2016 818 Stroke Vol 20, No 6, June 1989 TABLE 1. Reports of bcbcmk Stroke Associated With Familial Anttthrombin III Deficiency Case Author 1 2 3 4* 5* 6 7* Nagyetal 10 Nagyetal 1 0 Hirasawa et al13 Horieetal" Girolami et al12 Shinmyozu et al17 Current report Antithrombin III Obstructed Biologic Antigen Age Sex artery activity level 39 21 51 23 38 38 31 M R MCA M LICA M L MCA F R MCA F R MCA M L ICA F R MCA 28% 30% 54% 26% 50% 49% 42% Decreased Decreased Decreased Increased Normal Decreased Increased M, male; F, female; R, right; L, left; MCA, middle cerebral artery; ICA, internal carotid artery. •Variant of antithrombin III (dysfunctional AT-III). features were the occurrence in young adults and occlusion of the truncal arteries rather than the perforating arteries. Three of the seven cases (including ours) had a familial variant of AT-III, and two of the three were homozygotes. Since a homozygote is in a more hypercoagulable state than a heterozygote, arterial thrombosis is thought to be more frequent. Indeed, among her family, only our patient had recurrent thrombotic episodes. We conclude that variant AT-III, especially in the case of a homozygote, seems to be a cause of ischemic stroke even in young adults. Simultaneous measurement of both biologic and immunologic activities of AT-III is necessary for diagnosis of this disease. References 1. Natowicz M, Kelley RI: Mendelian etiologies of stroke. Ann Neurol 1987;22:175-192 2. Hart RG, Miller VT: Cerebral infarction in young adults: A practical approach. Stroke 1983;14:110-114 3. Hilton-Jones D, Warlow CP: The causes of stroke in the young. J Neurol 1985;232:137-143 4. Tollefsen DM, Majerus DW, Blank MK: Heparin cofactor II. Purification and properties of a heparin dependent inhibitor of thrombin in human plasma. J Biol Chem 1982; 257:2162-2169 5. Sas G, Blask6 G, Binhegyi D, Jak6 J, PSlos LA: Abnormal antithrombin III (antithrombin III 'Budapest') as a cause of a familial thrombophilia. Thromb Diath Haemorrh (Stuttg) 1974;32:105-115 6. Sakuragawa N, Takahashi K, Kondo S, Koide T: Antithrombin III Toyama: A hereditary abnormal antithrombin III of a patient with recurrent thrombophlebitis. Thromb Res 1983; 31:305-317 7. Sas G, Pepper DS, Cash JD: Plasma and serum antithrombinIII: Differentiation by crossed immunoelectrophoresis. Thromb Res 1975;6:87-91 8. Sas G, Peto I, Banhegyi D, Blask6 G, Domjan G: Heterogeneity of the "classical" antithrombin III deficiency. Thromb Haemost 1980;43:133-136 9. Egeberg O: Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965;13:516-530 10. Nagy I, Losonczy H, Szaksz I, Temesi C, Hergert K: An analysis of clinical and laboratory data in patients with congenital antithrombin III (AT-III) deficiency. Ada Med Acad Sci Hung 1979^6:53-60 11. Cosgriff TM, Bishop DT, Hershgold FJ, Skolnick MH, Martin BA, Baty BJ, Carlson KS: Familial antithrombin III deficiency: Its natural history, genetics, diagnosis and treatment. Medicine 1983 ;62:209-220 12. Girolami A, Marafioti F, Rubertelli M, Vicarioto MA, Cappellato G, Mazzuccato M: Antithrombin III Trento. A 'new' congenital AT III abnormality with a peculiar crossedimmunoelectrophoretic pattern in the absence of heparin. Ada Haematol 1984;72:73-82 13. Boyer C, Wolf M, Vedrenne J, Meyer D, Larrieu MJ: Homozygous variant of antithrombin III: AT III Fontainebleau. Thromb Haemost 1986^6:18-22 14. Fischer AM, Comu P, Sternberg C, Me'riane F, Dautzenberg MD, Chafa O, Beguin S, Desnos M: Antithrombin III Alger: A new homozygous AT III variant. Thromb Haemost 1986; 55:218-221 15. Hirasawa Y, Hayashi M, Nagaoka T, Kuto F, Tokuhiro H: Three families with hereditary antithrombin III deficiency: The use of antithrombin III concentrate in one of the patients through the course of mastectomy. Nippon Ketsueki Gakkai Z*m*i 1981;44:683-689 16. Hone Y, Koshu K, Endo S, Takaku A, Takahashi K, Sakuragawa N, Tomikawa M: A case of the occlusion of the right middle cerebral artery due to congenital antithrombin III (AT III) deficiency. Neurosurgery (Tokyo) 1982; 10:177-183 17. Shinmyozu K, Ohkatsu Y, Maruyama Y, Osame M, Igata A: A case of congenital antithrombin III deficiency complicated by an internal carotid artery occlusion. Rinsho Shinkeigaku 1986;26:162-165 18. Price TR: Progressing ischemic stroke, in Barnett HJM, Mohr JP, Stein BM, Yatsu FM (eds): Stroke: Pathophysiology, Diagnosis, and Management. Philadelphia, Churchill Livingstone Inc, 1986, vol 2, pp 1059-1068 19. Kalbag RM, Woolf AL: Thrombosis and thrombophlebitis of cerebral veins and dural sinuses, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, NorthHolland, 1972, pp 422-446 20. Winter JH, Fenech A, Bennett B, Douglas AS: Transfusion studies in patients with familial antithrombin III (AT III) deficiency: Half-disappearance time of infused AT III and influence of such infusion on platelet life-span. BrJ Haematol 1981;49:449-453 21. Mannucci PM, Boyer C, Wolf M, Tripodi A, Larrieu MJ: Treatment of congenital antithrombin III deficiency with concentrates. Br J Haematol 1982^0:531-535 22. Marciniak E, Gockerman JP: Heparin-induced decrease in circulating antithrombin-III. Lancet 1977;17:581-584 23. Fletcher AP, Alkjaersig N, Davies A, Lewis M, Brooks J, Hardin W, Landau W, Raichle ME: Blood coagulation and plasmafibrinolyticenzyme system pathophysiology in stroke. Stroke 1976;7:337-348 24. Panicucci F, Sagripanti A, Conte B, Pinori E, Vispi M, Lecchini L: Antithrombin III, heparin cofactor and antifactor Xa in relation to age, sex and pathological condition. Haemostasis 1980;9:297-302 25. Tengbom L, Larsson SA, Hedner U, Nilsson IM: Coagulation studies in children and young adults with cerebral ischemic episodes. Ada Neurol Scand 1981 ;63:351—361 26. Yamaguchi S, Kobayashi S, Tsunematsu T: The timecourse of antithrombin III (AT III) level in the ischemic cerebrovascular disease. Jpn J Stroke 1983;5:lll-116 KEY WORDS • young adults cerebrovascular disorders antithrombin III Downloaded from http://stroke.ahajournals.org/ by guest on June 24, 2016 Progressing ischemic stroke in a homozygote with variant antithrombin III. H Ueyama, Y Hashimoto, M Uchino, Y Sasaki, E Uyama, K Okajima and S Araki Stroke. 1989;20:815-818 doi: 10.1161/01.STR.20.6.815 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1989 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. 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