[nt J Clin Lab Res 23:212-214, 1993 9 Springer-Verlag 1993 Ischemic stroke in congenital (type II C) defective antithrombin III Ida Martinelli, Marco Moia, Arnaldo Arbini, Armando Tripodi, and Pier Mannuccio Mannucci Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Institute of Internal Medicine, University and [RCCS Maggiore Hospital, Milan, Italy Summary. Type II C is a subtype of defective antithrombin III deficiency in which there is a molecular defect in the heparin binding site. Usually, heterozygous patients with this defect have little or no thrombotic symptoms. Ischemic stroke has never been described. We report the case of a young woman who had an episode of right-sided hemiparesis. The computed tomographic scan showed an ischemic lesion in the left hemisphere. There were no previous thrombotic episodes in the patient's history and the sole risk factor for thrombosis was taking of an oral contraceptive. Her family history was mildly positive for thrombosis (superficial thrombophlebitis in two relatives). Laboratory tests showed normal antithrombin III antigen, low heparin cofactor activity and an increased slow-moving peak in crossed-immunoelectrophoresis with heparin. The same pattern was found in 7 of 20 relatives. Thus, a diagnosis of congenital type II C defective antithrombin III was made. This report suggests that young patients with ischemic stroke should be screened for defective antithrombin III. Key words: Cerebral ischemia - Antithrombin I I I - Oral contraceptives levels of AT III activity contrast with normal levels of AT III antigen. Type II is further subdivided into three phenotypes. One of these, type II C, consists of mutations of DNA encoding the protein domain responsible for binding heparin and heparin-like substances, which markedly accelerate inactivation of serine proteases [2]. Type II C leads to peculiar clinical features, being characterized by a much lower frequency of venous thromboembolic complications than in the other types of AT III defects in the heterozygous state [3]. That the type II C defect is less severe is also indicated by the fact that homozygotes with moderately severe clinical symptoms have been described, whereas homozygosity for other AT III defects has not been reported, probably because it is incompatible with life. There is no clear explanation for the fact that the type II C AT III defect is less severe, although it is surmised that the integrity of the AT III domain responsible for inactivation of coagulation enzymes minimizes the importance of the defect in acceleration by heparin-like substances. We describe the case of a young woman with heterozygous type II C AT III defect who developed an ischemic stroke. Stroke, and arterial thromboses in general, are rare in congenital AT III deficiency [6], and have not been reported for heterozygous type II C. Introduction Case report Antithrombin III (AT III) is the major protein that inhibits the serine proteases o f the intrinsic and common pathways of blood coagulation, mainly thrombin and activated factor X [1]. Congenital AT III deficiency, inherited as an autosomal dominant trait, predisposes to venous thromboembolism. Its relation to arterial thrombosis is not clearly established [1]. Two main phenotypes of congenital AT III defects have been recognized [14]: type I, in which there are concomitantly low levels of AT III activity and antigen; and type II, in which low Correspondence to: P. M. Mannucci, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Via Pace, 9, 1-20122 Milan, Italy On 23 March 1991 a previously healthy 34-year-old woman suddenly developed headache and paresthesia of her right side. Neurological examination revealed rightsided hemiparesis and right homonymous hemianopsia. Approximately 3 h after the onset of symptoms, a computed tomographic (CT) scan was normal. On day 2, two low-density areas became apparent: one about 2.5 cm in the left parieto-occipital hemisphere and a smaller one at the level of the left thalamus (Fig. 1). Left carotid and vertebral angiography performed on day 12 showed no significant abnormality. Chest X-ray, electrocardiogram and echocardiography were normal. I. Martinelli et al.: Stroke in type II C defective antithrombin III 213 Table I. Antithrombin III (AT III) in the propositus and her family members Gener- Relation to ation propositus Father Mother Maternal uncle Maternal aunt Maternal uncle Maternal aunt II Fig. 1. Computed tomographic scan shows two low-density areas, one in the left parieto-occipital hemisphere and one in the left talamus III f C O Fig. 2. Crossed-immunoetectrophoresis with heparin (25 IU/ml) of normal plasma (upper panel) and patient plasma (lower panel). Cathode is on the left In the patient's clinical history there were three operations under general anesthesia and two pregnancies without mishaps; there had been no prophylaxis against thrombosis. She did not s m o k e and had neither arterial hypertension n o r diabetes or dyslipidemia. Oral contraceptives (triphasic pill: levonorgestrel 0.05, 0.075, 0.125 mg; ethynyloestradiol 0.03, 0.04, 0.03 mg), taken for 4 years until the day o f the episode, were the only possible risk f a c t o r for thrombosis. The family history was mildly positive for thrombosis: her m o t h e r and maternal aunt h a d had recurrent superficial t h r o m bophlebitis. Propositus Brother Sister Sister Maternal cousin Maternal cousin Maternal cousin Maternal cousin Maternal cousin Maternal cousin Maternal cousin Maternal cousin Maternal cousin Son Daughter Normal laboratory range Heparin cofactor activity (%) Progressive AT III activity (%) AT III antigen concentration (%) 89 65 103 83 98 101 - - 110 - - 65 - 59 - 62 98 90 63 98 93 64 100 - 107 108 90 108 100 100 107 - - - 118 113 89 96 96 59 71 98 102 94 98 - 95 106 80-120 80-120 80-120 100 - D u r i n g hospitalization the patient was treated with subcutaneous heparin followed by aspirin; her condition gradually i m p r o v e d and on 9 April she was discharged, presenting only paresthesia o f her right side and right temporal hemianopsia. These s y m p t o m s still persist, 1 year after the stroke. A C T scan performed 9 weeks after the event confirmed the presence o f the two lowdensity areas in the left hemisphere. The patient was referred to the H e m o p h i l i a and T h r o m b o s i s Center 4 m o n t h s after the stroke. A laboratory examination gave n o r m a l values for h e m o c y t o m e try, liver and renal function; there was no evidence o f immunological diseases. C o a g u l a t i o n tests, including p r o t h r o m b i n time, activated partial t h r o m b o p l a s t i n time, t h r o m b i n time, fibrinogen, factor VII, protein C and protein S (both determined by i m m u n o l o g i c a l and functional methods), were within the n o r m a l range. The heparin cofactor activity o f AT III, which measures the capacity o f heparin to accelerate the inactivation o f t h r o m b i n [12], was low (62% o f normal); progressive AT I I I activity, which measures the capacity to inactivate t h r o m b i n with no heparin a d d e d [12], was n o r m a l (94% o f normal) and A T III antigen, which is a measure o f the total immunological protein c o n c e n t r a t i o n [10], was also n o r m a l (107%). The crossed-immunoelectrophoresis [15] pattern was n o r m a l in the absence o f heparin, b u t showed an a b n o r m a l slow-moving peak in the presence o f heparin, indicating that the molecule had p o o r heparin-binding capacity (Fig. 2). This pattern o f results is consistent with a diagnosis o f congenital type II C AT I I t defect. D a t a f r o m the propositus and all the family m e m b e r s studied 214 are s h o w n in Table 1. T h e s a m e a b n o r m a l i t i e s were present in 7 o f 20 relatives. Discussion W h e t h e r low A T III activity is a p r e d i s p o s i n g factor for cerebral arterial t h r o m b o s i s is still c o n t r o v e r s i a l . O n l y six cases o f ischemic s t r o k e a s s o c i a t e d with familial A T I I I defects have been p r e v i o u s l y r e p o r t e d . O f these, four patients h a d type II C A T I I I defects: three were hom o z y g o t e s [4, 13, 16], w h e r e a s the status o f the f o u r t h p a t i e n t c o u l d n o t be precisely e s t a b l i s h e d because she was an o r p h a n a n d childless [7]. T h e o t h e r two patients h a d type II A [5] a n d type I [8] A T III defects, c h a r a c t e r i z e d by defective t h r o m b i n i n a c t i v a t i o n b u t n o r m a l h e p a r i n c o f a c t o r activity. This is the first case o f ischemic s t r o k e as the sole t h r o m b o t i c episode in a y o u n g w o m a n h e t e r o z y g o t i c for type II C AT III defect. T h e case is peculiar, not only because arterial t h r o m b o s i s is rare in c o n g e n i t a l AT III defects, b u t also because t h r o m b o s i s is infrequent in type II C defect. In o u r patient, o r a l c o n t r a c e p t i v e s c o u l d have p l a y e d a causal role, as several studies have d e m o n s t r a t e d an a s s o c i a t i o n between oral c o n t r a c e p t i v e i n t a k e a n d s t r o k e o c c u r r i n g at a y o u n g age [9]. In conclusion, this r e p o r t suggests t h a t y o u n g patients with ischemic s t r o k e as the sole t h r o m b o t i c s y m p t o m s h o u l d be screened for A T III defect a n d s t r e n g t h e n s a previous suggestion [11] that the m e a s u r e m e n t o f h e p a r i n c o f a c t o r activity is the m e t h o d o f choice for screening t h r o m b o p h i l i c patients, since i m m u n o l o g i c a l assays m i g h t miss q u a l i t a t i v e defects. References 1. Beresford CH, Antithrombin Ill deficiency. Blood Rev 2:239, 1988 Martinelli et al.: Stroke in type II C defective antithrombin III Cooper DN, The molecular genetics of familial venous thrombosis. Blood Rev 5: 55, 1991 Finazzi G, Caccia R, Barbui T, Different prevalence of thromboembolism in the subtypes of congenital antithrombin III deficiency: review of 404 cases. Thromb Haemost 58: 1094, 1987 4. Fischer AM, Cornu I, Sternberg C, Meriane F, Dautzenberg MD, Chafa O, Beguin S, Desnos M, Antithrombin III Alger: a new homozygous AT III variant. Thromb Haemost 55:218, 1986 5. Girolami A, Marafioti F, Rubertelli M, Vicarioto MA, Cappellato G, Mazzuccato M, Antithrombin IIl Trento: a "new" congenital AT III abnormality with a peculiar crossed-immunoetectrophoretic pattern in the absence of heparin. Acta Haematol (Basel) 72: 73, 1984 6. Hart RG, Kanter MC, Haematologic disorders and ischemic stroke: a selective review. Stroke 21:1111, 1990 7. Imamura T, Yoshida T, Yamadori A, Matsuo T, Congenital antithrombin III abnormality and cerebral arterial thrombosis. Stroke 92: 1090, 1991 8. Johnson EJ, Prentice CRM, Parapia LA, Premature arterial disease associated with familial antithrombin II! deficiency. Thromb Haemost 63: 13, 1990 9. Longstreth WT, Swanson PD, Oral contraceptives and stroke. Stroke 15:747, 1984 10. Mancini G, Carbonara AO, Heremans JF, Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 2: 235, 1965 11. Mannucci PM, Tripodi A, Laboratory screening of inherited thrombotic syndromes. Thromb Haemost 57: 247, 1987 12. Odegard OR, Lie M, Abilgaard U, Heparin cofactor activity measured with an amidolytic method. Thromb Res 6: 287, 1975 13. Sakuragawa N, Takahashi K, Kondo S, Koide T, Antithrombin Ill Toyama: a hereditary abnormal antithrombin III of a patient with recurrent thrombophlebitis. Thromb Res 31:305, 1983 14. Sas G, Hereditary antithrombin IlI deficiency: biochemical aspects. Haematologica (Pavia) 17:81, 1984 15. Sas G, Pepper DS, Cash JD, Plasma and serum antithrombin III: differentiation by crossed immunoeleetrophoresis. Thromb Res 6:87, 1975 16. Ueyama H, Hashimoto Y, Uchino M, Sasaki Y, Uyama E, Okajima K, Araki S, Progressing ischemic stroke in a homozygote with variant antithrombin III. Stroke 20:815, 19