Ann Hematol (1992) 64:105-109

Annals of

Hematology 9 Springer-Verlag 1992

Case report Cerebral sinus thrombosis in a patient with hereditary protein S deficiency: case report and review of the literature M. Heistinger 1, E. Rumpl 1, H. Illiasch 2, H. Tiirck 3, P.A. Kyrle 4, K. Lechner 4, and I. Pabinger 4 Department of Neurology z Department of Radiology 3 Department of Medicine, Landeskrankenhaus Klagenfurt 4 First Department of Medicine, University Hospital of Vienna, Austria Received August 6, 1991/Accepted December 3, 1991

Summary. Hereditary protein S deficiency is an established risk factor for venous thrombosis. The c o m m o n sites o f thrombosis are the deep leg and pelvic veins. We report on a 38-year-old female patient with hereditary protein S deficiency and a previous history o f deep leg vein thrombosis, who developed thrombosis o f the cerebral straight and superior sagittal sinus while taking oral contraceptives. The diagnosis was established by computerized t o m o g r a p h y and carotid angiography. Lysis o f the t h r o m bus occurred during heparin treatment. The hereditary nature o f protein S deficiency was d o c u m e n t e d by family studies, since nine additional family members deficient in protein S were identified. Nineteen published cases o f cerebral vein thrombosis and a deficiency o f either antit h r o m b i n III, protein C, or protein S were reviewed. C o m p a r e d with patients without a deficiency state, the clinical features o f cerebral vein thrombosis were similar except for an earlier onset and a positive medical history o f venous t h r o m b o e m b o l i c events in a considerable number o f patients.

Key words: Cerebral sinus thrombosis - Protein S deficiency - T h r o m b o p h i l i a

Introduction Hereditary protein S (PS) deficiency is an autosomal d o m i n a n t disorder. Patients with this defect are, like those with antithrombin I I I (AT III) [311 and protein C (PC) deficiency [6, 17, 25], at a high risk for venous thrombosis [5,7,9, 10, 13, 14, 1 9 , 2 3 , 3 0 , 3 5 - 3 7 ] . The clinical manifestations have been reported to be deep leg vein t h r o m bosis, p u l m o n a r y embolism, and superficial t h r o m b o phlebitis, but other, u n c o m m o n sites o f venous thrombo-

Address for correspondence." I. Pabinger, Clinic of Internal Medicine I, University of Vienna, W~hringer Gfirtel 18-20, A-1090 Wien, Austria

sis have been described in rare cases. Cerebral vein t h r o m bosis was reported in a female patient with low n o r m a l plasma PS concentration from a family with hereditary PS deficiency [15]. Recently, two patients with t h r o m b o sis o f the sagittal sinus and decreased PS levels were reported [12,26]; however, the hereditary nature o f PS deficiency was not established in these two cases. We report on a patient with PS deficiency and t h r o m bosis o f the straight and superior sagittal sinus. Because o f her personal and family history o f venous thrombosis, a hereditary disorder was suspected to be the cause o f thrombophilia, and further laboratory tests o f the patient and 28 family members revealed hereditary PS deficiency.

Case report A 38-year-old woman, K.M., was admitted to the hospital because of generalized tonic-clonic seizures, severe frontal cephalalgia, nausea, and vomiting. On admission, the patient was somnolent. She showed meningism, anisocoria with the right pupil wider than the left, a reduced corneal reflex on the right, and weak central paresis of the right facial nerve and the right arm. The tendon reflexes were exaggerated on the right. Her cardiorespiratory system was normal. Blood cell count including platelet count and routine laboratory tests were within the normal range. Cerebrospinal fluid was normal. From a cranial computerized tomograph (CCT) cerebral vein thrombosis was suspected (Fig. 1) [32, 331. Bilateral carotid angiography confirmed the diagnosis of thrombosis of the straight and superior sagittal sinus (Fig. 2). Anticoagulant therapy with intravenous heparin was started immediately. The patient's condition improved very quickly, and 4 days after admission the neurological examination showed nearly complete normalization except for exaggerated tendon reflexes on the right. A control CCT revealed clear reduction of the thrombus. The anticoagulant treatment was subsequently switched to oral phenprocoumon therapy, and after 18 days of uncomplicated clinical course the patient was discharged from hospital in good health. She has been under continuous oral anticoagulant (OAC) treatment and has shown no further symptoms at all. The previous medical history of the patient was uneventful during childhood and youth. In 1973, phlebitis of the right arm occurred 3 days after delivery of her first child. The deliveries of her second and third child were also complicated by superficial thrombophlebitis of the arm.

106 In 1980, the patient spontaneously developed symptoms compatible with deep venous thrombosis (pain, swelling, and discoloration) of the right leg. The same symptoms recurrred approximately once a year. In 1986, deep venous thrombosis of both legs occurred after the delivery of her fourth child by cesarean section. This time the clinical diagnosis was confirmed by phlebography. Long-term OAC treatment was not introduced at that time. In 1987, the patient had to undergo an appendectomy, and there were no thromboembolic complications on that occasion. Until the recent thrombo-

tic event, the patient had been without complaints except for temporary swelling of the right leg. For regular medication the patient has been using oral contraceptives (Microgynon 30) since 1976, with interruptions during her pregnancies. She was accustomed to smoking 10-15 cigarettes per day. The family history was positive for thromboembolic episodes. Three of her brothers had experienced deep venous thrombosis (clinical diagnosis confirmed by phlebography); one of them died because of a pulmonary embolism, one is under continuous OAC treatment. The mother of the patient has suffered from recurrent deep venous thrombosis and thrombophlebitis of both legs since the age of 20. Two uncles and one aunt, as well as the maternal grandmother, were reported to have experienced symptoms compatible with deep venous thrombosis. A cousin had experienced pulmonary embolism after gastrectomy. The pedigree of the family is shown in Fig. 3.

Materials and methods Blood was collected by venipuncture with a 19-gauge single needle into natrium citrate (1 : 10 volume), the first 3 ml being discarded. Routine coagulation studies including prothrombin time (Thrombotest, Nyegaard, Oslo, Norway, for patients on OAC treatment and Normotest, Nyegaard, for patients without OAC treatment) were performed using fresh blood or plasma. For AT III and PC determination commercially available test kits were used (KabiVitrum, Stockholm, Sweden; Behring AG, Germany). Free PS was determined by Laurell rocket immunoelectrophoresis after polyethylene glycol (PEG) precipitation of complexed PS as previously described [111 (Anti-human PS antibody from American Diagnostica Inc., Greenwich, CN., USA). Total PS was determined by a commercially available ELISA (Boehringer, Mannheim, Germany).

Results

Fig. 1. Contrast CT scan showing bilateral parasagittal areas of enhancement and gyral enhancement due to venous congestion

At the time of the first investigation, the p a t i e n t was already o n oral oral a n t i c o a g u l a n t t r e a t m e n t with p h e n p r o c o u m o n (Thrombotest: 13%, i n t e r n a t i o n a l n o r m a l ized ratio 2.3). AT III activity (95.5%, n o r m a l range 80%-120~ a n d P C activity (37%, n o r m a l range for patients o n OAC t r e a t m e n t 3 0 % - 6 0 % ) were n o r m a l . Free PS was severely reduced (lower t h a n 12.5%, no visi-

Fig. 2. Right carotid angiography performed same day as CT scan showed no filling of the superior sagittal sinus during the delayed venous phase

107 v

Iv

Ill

-

1I

I

o

,,% /o

,/?/>-/2

I'~ L"I

14 15 16 17 7s 79 ~ 22 23 2~

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Fig. 3. Family pedigree: [], male; 9 female; 0, symptomatic; r~ ~, heterozygous deficiency state; [~ ~), decreased. Arrow denotes the proposita, asterisks denote individuals studied

k ~

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Table 1. Laboratory data of the proposita and nine additional family members with PS deficiency

Pedigree position (Fig. 3)

Age, sex

III-10a II-2 III-1 III-9 III-11 IV-3 IV-14 IV-15 IV-19 IV-24

39, 68, 49, 40, 32, 12, 14, 13, 15, 3,

OACT

(years) f f m m m m f f f f

+ + -

Free PS

Total PS

History of thrombosis

(070)

C48-binding protein (~

(~ < 12.5 31 23 18 35 15 11.3 18 17.6 18

26.5 41 66 37 45 48 46 56 42 57

124 112 122 80 84 88 87 110 94 84

Sinus thrombosis, DVT, STP DVT, STP DVT, PE DVT DVT None None None None None

a Proposita OACT, Oral anticoagulant treatment; PS, protein S; DVT, deep venous thrombosis; STP, superficial thrombophlebitis; PE, pulmonary embolism

ble peak on the Laurell plate; lower limit o f n o r m a l range for patients on OAC treatment 19~ as well as total PS (23.5%; lower limit o f n o r m a l range for patients on OAC treatment 35%). The C 4 B binding protein was 124% (Table 1). Twenty-eight relatives o f the patient were examined (Fig. 3) for PS deficiency, and nine additional affected individuals were found. Individual data o f the affected family members are listed in Table 1.

Discussion

A n association between hereditary PS deficiency and the development o f venous thrombosis is well established [5,7, 15, 19,23]. Thrombosis is mainly localized in the deep and superficial leg veins [5, 15] but m a y occasionally occur at unusual sites like the mesenteric [8] or portal veins [28]. Engesser et al. [15] reported on a female patient who had cerebral vein thrombosis and came f r o m a family with hereditary PS deficiency. However, total PS was within the lower n o r m a l range in this patient, and

neither i n f o r m a t i o n on the exact localization o f the cerebral vein thrombosis nor further clinical data were given. Recently, reports o f two patients with thrombosis o f the superior sagittal sinus associated with PS abnormalities were published [12,26], but the hereditary nature o f the deficiency state was not proven in either patient. One patient [26] had dysfibrinogenemia in addition to the decreased free PS level. We report on a young female patient with thrombosis o f the straight and superior sagittal sinus and a history o f recurrent deep vein thrombosis and a positive family history o f venous thrombosis. The sinus thrombosis occurred spontaneously without a recent history o f septicemia, a u t o i m m u n e disease, or trauma. At the time o f thrombosis the patient was on oral contraceptive medication, which is regarded as a risk factor for cerebral venous thrombosis [3, 14] and is known to influence PS concentration [2, 18], reducing total PS more t h a n free PS. One m a y speculate that a further reduction o f PS due to oral contraceptive treatment impairs the hemostatic equilibrium in PS-deficient patients, the

108 Table 2. Review of 19 published cases of patients with cerebral venous thrombosis and a deficiency of a natural coagulation inhibitor Reference

Deficiency state

Age (years)

Sex

Hereditary proven?

Previous TE events

Additional risk factors

Site of thrombosis

Ambruso et al. [1] Kobayashi et al. [20]

AT III AT III AT III AT II! AT III PC PC PC AT III PS (low normal PC AT III AT III PC AT III PS PS PC PS

15 32 16 47 17 27 38 34 46 35 19 2 weeks 40 25 27 24 30 18 38

m m m m m f f f m f m m m f f m m f f

yes yes yes yes yes yes yes yes n.m. "transmitter" yes yes yes no yes no no yes yes

STP n.m. none n.m. DVT, PE none DVT DVT n.m. DVT DVT none n.m. none n.m. none STP, DVT none STP, DVT

none surgery surgery none none oral contraception none none none n,m. none none none pregnancy delivery dysfibrinogenemia none delivery oral contraception

n.m. SSS SSS n.m. SSS SSS (frontal part) n.m. n.m. left LS, CV n.m. SSS, ISS SSS, SS CV SSS SSS SSS SSS SSS SSS,SS

Sauron et al. [29] Komiyama et al. [21] Wintzen et al. [38] Bousser et al. [3] Engesser et al. [15] Vogt et al. [34] Brenner et al. [4] Komiyama et al. [22] l~on et al. [16] Muramatsu et al. [24] Pasquale et al. [26] Cros et al. [26] Roos et al. [27] Heistinger (present case)

AT III, Antithrombin III; TE, thromboembolic; PC, protein C; PS, protein S; STP, superficial thrombophlebitis; DVT, deep venous thrombosis; PE, pulmonary embolism; SSS, superior sagittal sinus; ISS, inferior sagittal sinus; SS, straigt sinus; LS, lateral sinus; CV, cerebral veins; n.m., not mentioned

further r e d u c t i o n of PS eventually resulting in t h r o m b o sis. We c a n n o t c o m m e n t o n the c o n c e n t r a t i o n of free a n d total PS in the p a t i e n t at the time of sinus thrombosis, since the first d e t e r m i n a t i o n of PS was p e r f o r m e d w h e n the p a t i e n t was already o n OAC treatment. T h e medical history of the family m e m b e r s revealed a high frequency o f venous t h r o m b o e m b o l i s m . Nine relatives deficient in PS were identified, a n d all those who were older t h a n 20 years h a d experienced at least one t h r o m b o t i c episode. Two uncles of the proposita with n o r m a l total a n d free PS h a d s y m p t o m s suspicious for deep vein thrombosis, b u t they had never u n d e r g o n e any diagnostic procedure, n o r were they o n OAC treatment. T h e coincidence o f hereditary PS deficiency a n d sinus t h r o m b o s i s seems to be a rare finding; of more t h a n 100 published cases, o n l y o n e had a history of cerebral vein t h r o m b o s i s (CVT) [15]. However, the a u t h o r s do n o t provide detailed i n f o r m a t i o n o n this case. Several cases of C V T a n d deficiency of either AT III or P C were reported. Table 2 s u m m a r i z e s 19 published cases of C V T associated with a deficiency o f one o f the physiological c o a g u l a t i o n inhibitors: AT III, P C , or PS. C o m p a r e d with a review i n c l u d i n g 39 cases of C V T by Bousser et al. [3], the clinical picture of C V T in patients with AT III, PC, or PS deficiency seems to be similar to that in patients w i t h o u t such a n i n h i b i t o r deficiency, with the exception of a possibly earlier onset of the disease ( m e d i a n age of the 19 patients with a deficiency a n d of the 38 patients o f the review was 28 a n d 29 years, respectively) a n d a medical history o f venous t h r o m b o e m b o l i c events in a considerable n u m b e r of the patients with a n i n h i b i t o r deficiency. A l t h o u g h the coincidence of PS deficiency a n d sinus vein t h r o m b o s i s seems ot be rare, this clotting a b n o r m a l ity, like AT III a n d P C deficiency, should be considered

especially in patients who have a positive personal or family history of venous t h r o m b o e m b o l i s m . A n t i c o a g u lation seems to be beneficial especially in those patients with inherited t h r o m b o p h i l i a .

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36. 37. 38.

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