J Neurol (1992) 239 : 105-106
Journal of
Neurology © Springer-Verlag 1992
Hereditary protein S deficiency presenting with cerebral sinus thrombosis in an adolescent girl J. H . T . M . Koelman 1, C.M. Bakker 2' 3, W. C. G. Plandsoen 4, F. L. M. Peeters 5, and P. G. Barth 4 1Department of Neurology, 2Department of Haematology, 3Department of Paediatrics, 4Department of Paediatric Neurology, and 5Department of Neuroradiology, Academic Medical Centre, Meibergdreef 9, NL-1105 A Z Amsterdam, The Netherlands Received March 21, 1991 / Received in revised form June 3, 1991 / Accepted June 17, 1991
Summary. A 1 4 - y e a r - o l d girl, o n o r a l c o n t r a c e p t i v e s for 3 m o n t h s , p r e s e n t e d with c e r e b r a l sinus t h r o m b o s i s . Inv e s t i g a t i o n r e v e a l e d u n d e r l y i n g h e r e d i t a r y p r o t e i n S deficiency. This u n c o m m o n cause o f c e r e b r a l sinus t h r o m bosis a n d t h e p o s s i b l e a s s o c i a t i o n w i t h o r a l c o n t r a c e p tives a r e discussed.
Key words: C e r e b r a l sinus t h r o m b o s i s - P r o t e i n S - O r a l contraceptives
Introduction D e f i c i e n c i e s o f p r o t e i n S a n d p r o t e i n C can o c c u r as inh e r i t e d d i s e a s e s causing h y p e r c o a g u l a b l e states r e s p o n sible for m u l t i p l e e p i s o d e s of s u p e r f i c i a l a n d d e e p v e n ous t h r o m b o s i s a n d p u l m o n a r y e m b o l i . C e r e b r a l sinus t h r o m b o s i s is, h o w e v e r , a r a r e c o m p l i c a t i o n o f p r o t e i n C a n d p r o t e i n S deficiency. W e d e s c r i b e an a d o l e s c e n t girl w h o d e v e l o p e d c e r e b r a l sinus t h r o m b o s i s as the first manifestation of hereditary protein S deficiency, 3 months after s t a r t i n g to t a k e o r a l c o n t r a c e p t i v e s .
on second CT 1 week later. Lumbar puncture yielded an opening pressure of 50 cm water. The cerebrospinal fluid was xanthochromic with 1500 erythrocytes and 20 leucocytes, predominantly mononuclears, per mm3; protein content was 0.80 g/1 (normal < 0.50 g/l). Arterial cerebral Seldinger angiography showed venous congestion and collateral veins on the right side and an occluded right transverse sinus with irregular margins near the confluens sinuum (Fig. 1). The arterial phase was normal. Routine blood examination and serological tests for infectious and autoimmune disorders were negative. Coagulation studies performed within a week after presentation revealed normal values of activated partial thromboplastin time, prothrombin time, antithrombin III, lupus anticoagulant, protein C and fibrinogen. The level of total protein S was 41% (normal > 65 %) and of free protein S was 6% (normal > 30%). These levels, measured by an enzyme-linked immunoassay (Diagnostica Stago, Asnieres sur Seine, France), were unchanged when repeated 3 weeks later. In addition, protein S levels were measured in the family members and yielded reduced values in the father; his total protein S level was 47% and free protein S level was 15% (Fig. 2). On admission the oral contraceptives were discontinued. The patient was treated with anticonvulsants and low-dose subcutaneous heparin, as a prophylactic against deep venous thrombosis. After 6 weeks oral anticoagulants were prescribed. She made a complete recovery.
Case report In August 1989 a 14-year-old girl was referred with progressive, severe headache and drowsiness, which she had had for 3 days. On the day of admission she had a seizure. Prior to admission a urinary infection had been diagnosed for which cotrimoxazole had been prescribed. She had started to take oral contraceptives 3 months earlier. Otherwise her medical history was non-contributory. Family history was positive for thromboembolic events. The paternal grandfather suffered from spontaneous deep venous thrombosis at the age of 40 years and deep venous thrombosis probably occurred in three sibs of his at unknown ages. On examination the patient was photophobic. Nuchal rigidity was present and 2 diopters papilloedema was seen in both eyes. Otherwise examination was normal. Computed tomography (CT) of the brain showed an area of low attenuation in the right temporooccipital region with local high attenuation areas, more pronounced
Offprint requests to: J. H. T. M, Koelman
Fig. 1. Right carotid angiography, anteroposterior view, showing occlusion of right transverse sinus near the confluens sinuum with irregular margins (arrows)
106 I 2
[
*
*
2
.[
Fig. 2. Pedigree of family. Open square male, open circle female, square or circle with slash deceased, shaded square or circle history of thrombosis, black and white square or circle protein S deficiency, asterisk person studied, arrow proband
Discussion Protein S is a vitamin-K-dependent plasma protein functioning as a cofactor for the anticoagulant activity of activated protein C. Activated protein C inhibits fibrin formation by inactivation of the activated coagulation factors V and VIII, and it stimulates fibrinolysis, probably by decreasing the activity of plasminogen activator-inhibitor [7]. For both functions protein S is needed as a cofactor. In plasma 60% of protein S is bound. Only the free form of protein S can act as a cofactor for activated protein C. Until now only four patients with protein S deficiency and cerebral sinus thrombosis have been described [5, 7, 9, 10]. Two of these patients had a positive family history and suffered recurrent thromboembolic events prior to cerebral sinus thrombosis [5, 7]. In only one of these patients was the hereditary nature of the disease proven by low protein S levels in family members [7]. In our patient cerebral sinus thrombosis was not only the first manifestation of protein S deficiency, but it also led to the detection of a new, affected family. Hereditary protein S deficiency is transmitted as an autosomal dominant trait and so probably the paternal grandfather was also affected. Not all protein-S-deficient persons within a family necessarily develop clinical symptoms [7]. It is possible that additional risk factors like trauma, acute infection, pregnancy or use of oral contraceptives predispose to the clinical manifestation of the disease [1, 3, 4]. Oral contraceptives appear to decrease the plasma level of total and free protein S [1, 8]. Considering the recent use of oral contraceptives this may have been significant in our patient too. Unfortunately protein S levels were measured in our patient only when the oral contraceptives had been stopped. So far, we have been reluctant to prescribe therapeutic heparinization in cerebral sinus thrombosis especially
when signs of haemorrhage are present. Oral anticoagulant maintenance therapy, however, was prescribed later on to prevent recurrent venous thrombotic events. In protein C deficiency haemorrhagic skin necrosis has been seen during initial coumarin treatment [2]. This is probably caused by a dramatic fall of protein C concentration, due to the short half-life of the protein, compared with the relatively higher concentrations of factors II, IX and X. Although the half-life of protein S is longer, this complication has also been described in protein S deficiency [6]. As in protein C deficiency, use of heparin and, simultaneously, a start with low amounts of coumarin may prevent haemorrhagic skin necrosis [11]. In patients with unexplained cerebral sinovenous thrombosis, levels of anticoagulant factors, including protein S, should be determined. Oral contraceptives should not be considered as the sole explanation for the occurrence of cerebral sinovenous thrombosis without determining the levels of these factors.
References 1. Boerger LM, Morris PC, Thurnau GR, Esmon CT, Comp PC (1987) Oral contraceptives and gender affect protein S status. Blood 69 : 692-694 2. Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingemann HG (1983) Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 49: 251 3. Comp PC, Esmon CT (1984) Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 311 : 1525-1528 4. Comp PC, Thurnau GR, Welsh J, Esmon CT (1986) Functional and immunologic protein S levels are decreased during pregnancy. Blood 68 : 881-885 5. Cros D, Comp PC, Beltran G, Gum G (1990) Superior sagittal sinus thrombosis in a patient with protein S deficiency. Stroke 21 : 633-636 6. Dettori AG, Quintavalla R, Manotti C, Pini M (1989) Warfarininduced dermatitis and venous thrombosis in a patient with protein S deficiency. Thromb Haemost 62: 528 7. Engesser L, Broekmans AW, Bri~t E, Brommer EJP, Bertina RM (1987) Hereditary protein S deficiency: clinical manifestations. Ann Intern Med 106 : 677-682 8. Malta J, Laurell M, Dahlb~ck B (1988) Changes in the plasma levels of vitamin K-dependent proteins C and S and of C4bbinding protein during pregnancy and oral contraception. Br J Haematol 68 : 437-443 9. Pasquale LR, Moster ML, Schmaier A (1990) Dural sinus thrombosis with abnormalities of protein S and fibrinogen. Arch Ophthalmol 108 : 644 10. Sacco RL, Owen J, Mohr JP, Tatemichi TK, Grossman BA (1989) Free protein S deficiency: a possible association with cerebrovascular occlusion. Stroke 20 : 1657-1661 11. Samama M, Horellou MH, Soria J, Conard J, Nicolas G (1984) Successful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulant treatment. Thromb Haemost 51 : 132-133
Journal of
Neurology © Springer-Verlag 1992
Hereditary protein S deficiency presenting with cerebral sinus thrombosis in an adolescent girl J. H . T . M . Koelman 1, C.M. Bakker 2' 3, W. C. G. Plandsoen 4, F. L. M. Peeters 5, and P. G. Barth 4 1Department of Neurology, 2Department of Haematology, 3Department of Paediatrics, 4Department of Paediatric Neurology, and 5Department of Neuroradiology, Academic Medical Centre, Meibergdreef 9, NL-1105 A Z Amsterdam, The Netherlands Received March 21, 1991 / Received in revised form June 3, 1991 / Accepted June 17, 1991
Summary. A 1 4 - y e a r - o l d girl, o n o r a l c o n t r a c e p t i v e s for 3 m o n t h s , p r e s e n t e d with c e r e b r a l sinus t h r o m b o s i s . Inv e s t i g a t i o n r e v e a l e d u n d e r l y i n g h e r e d i t a r y p r o t e i n S deficiency. This u n c o m m o n cause o f c e r e b r a l sinus t h r o m bosis a n d t h e p o s s i b l e a s s o c i a t i o n w i t h o r a l c o n t r a c e p tives a r e discussed.
Key words: C e r e b r a l sinus t h r o m b o s i s - P r o t e i n S - O r a l contraceptives
Introduction D e f i c i e n c i e s o f p r o t e i n S a n d p r o t e i n C can o c c u r as inh e r i t e d d i s e a s e s causing h y p e r c o a g u l a b l e states r e s p o n sible for m u l t i p l e e p i s o d e s of s u p e r f i c i a l a n d d e e p v e n ous t h r o m b o s i s a n d p u l m o n a r y e m b o l i . C e r e b r a l sinus t h r o m b o s i s is, h o w e v e r , a r a r e c o m p l i c a t i o n o f p r o t e i n C a n d p r o t e i n S deficiency. W e d e s c r i b e an a d o l e s c e n t girl w h o d e v e l o p e d c e r e b r a l sinus t h r o m b o s i s as the first manifestation of hereditary protein S deficiency, 3 months after s t a r t i n g to t a k e o r a l c o n t r a c e p t i v e s .
on second CT 1 week later. Lumbar puncture yielded an opening pressure of 50 cm water. The cerebrospinal fluid was xanthochromic with 1500 erythrocytes and 20 leucocytes, predominantly mononuclears, per mm3; protein content was 0.80 g/1 (normal < 0.50 g/l). Arterial cerebral Seldinger angiography showed venous congestion and collateral veins on the right side and an occluded right transverse sinus with irregular margins near the confluens sinuum (Fig. 1). The arterial phase was normal. Routine blood examination and serological tests for infectious and autoimmune disorders were negative. Coagulation studies performed within a week after presentation revealed normal values of activated partial thromboplastin time, prothrombin time, antithrombin III, lupus anticoagulant, protein C and fibrinogen. The level of total protein S was 41% (normal > 65 %) and of free protein S was 6% (normal > 30%). These levels, measured by an enzyme-linked immunoassay (Diagnostica Stago, Asnieres sur Seine, France), were unchanged when repeated 3 weeks later. In addition, protein S levels were measured in the family members and yielded reduced values in the father; his total protein S level was 47% and free protein S level was 15% (Fig. 2). On admission the oral contraceptives were discontinued. The patient was treated with anticonvulsants and low-dose subcutaneous heparin, as a prophylactic against deep venous thrombosis. After 6 weeks oral anticoagulants were prescribed. She made a complete recovery.
Case report In August 1989 a 14-year-old girl was referred with progressive, severe headache and drowsiness, which she had had for 3 days. On the day of admission she had a seizure. Prior to admission a urinary infection had been diagnosed for which cotrimoxazole had been prescribed. She had started to take oral contraceptives 3 months earlier. Otherwise her medical history was non-contributory. Family history was positive for thromboembolic events. The paternal grandfather suffered from spontaneous deep venous thrombosis at the age of 40 years and deep venous thrombosis probably occurred in three sibs of his at unknown ages. On examination the patient was photophobic. Nuchal rigidity was present and 2 diopters papilloedema was seen in both eyes. Otherwise examination was normal. Computed tomography (CT) of the brain showed an area of low attenuation in the right temporooccipital region with local high attenuation areas, more pronounced
Offprint requests to: J. H. T. M, Koelman
Fig. 1. Right carotid angiography, anteroposterior view, showing occlusion of right transverse sinus near the confluens sinuum with irregular margins (arrows)
106 I 2
[
*
*
2
.[
Fig. 2. Pedigree of family. Open square male, open circle female, square or circle with slash deceased, shaded square or circle history of thrombosis, black and white square or circle protein S deficiency, asterisk person studied, arrow proband
Discussion Protein S is a vitamin-K-dependent plasma protein functioning as a cofactor for the anticoagulant activity of activated protein C. Activated protein C inhibits fibrin formation by inactivation of the activated coagulation factors V and VIII, and it stimulates fibrinolysis, probably by decreasing the activity of plasminogen activator-inhibitor [7]. For both functions protein S is needed as a cofactor. In plasma 60% of protein S is bound. Only the free form of protein S can act as a cofactor for activated protein C. Until now only four patients with protein S deficiency and cerebral sinus thrombosis have been described [5, 7, 9, 10]. Two of these patients had a positive family history and suffered recurrent thromboembolic events prior to cerebral sinus thrombosis [5, 7]. In only one of these patients was the hereditary nature of the disease proven by low protein S levels in family members [7]. In our patient cerebral sinus thrombosis was not only the first manifestation of protein S deficiency, but it also led to the detection of a new, affected family. Hereditary protein S deficiency is transmitted as an autosomal dominant trait and so probably the paternal grandfather was also affected. Not all protein-S-deficient persons within a family necessarily develop clinical symptoms [7]. It is possible that additional risk factors like trauma, acute infection, pregnancy or use of oral contraceptives predispose to the clinical manifestation of the disease [1, 3, 4]. Oral contraceptives appear to decrease the plasma level of total and free protein S [1, 8]. Considering the recent use of oral contraceptives this may have been significant in our patient too. Unfortunately protein S levels were measured in our patient only when the oral contraceptives had been stopped. So far, we have been reluctant to prescribe therapeutic heparinization in cerebral sinus thrombosis especially
when signs of haemorrhage are present. Oral anticoagulant maintenance therapy, however, was prescribed later on to prevent recurrent venous thrombotic events. In protein C deficiency haemorrhagic skin necrosis has been seen during initial coumarin treatment [2]. This is probably caused by a dramatic fall of protein C concentration, due to the short half-life of the protein, compared with the relatively higher concentrations of factors II, IX and X. Although the half-life of protein S is longer, this complication has also been described in protein S deficiency [6]. As in protein C deficiency, use of heparin and, simultaneously, a start with low amounts of coumarin may prevent haemorrhagic skin necrosis [11]. In patients with unexplained cerebral sinovenous thrombosis, levels of anticoagulant factors, including protein S, should be determined. Oral contraceptives should not be considered as the sole explanation for the occurrence of cerebral sinovenous thrombosis without determining the levels of these factors.
References 1. Boerger LM, Morris PC, Thurnau GR, Esmon CT, Comp PC (1987) Oral contraceptives and gender affect protein S status. Blood 69 : 692-694 2. Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingemann HG (1983) Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 49: 251 3. Comp PC, Esmon CT (1984) Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 311 : 1525-1528 4. Comp PC, Thurnau GR, Welsh J, Esmon CT (1986) Functional and immunologic protein S levels are decreased during pregnancy. Blood 68 : 881-885 5. Cros D, Comp PC, Beltran G, Gum G (1990) Superior sagittal sinus thrombosis in a patient with protein S deficiency. Stroke 21 : 633-636 6. Dettori AG, Quintavalla R, Manotti C, Pini M (1989) Warfarininduced dermatitis and venous thrombosis in a patient with protein S deficiency. Thromb Haemost 62: 528 7. Engesser L, Broekmans AW, Bri~t E, Brommer EJP, Bertina RM (1987) Hereditary protein S deficiency: clinical manifestations. Ann Intern Med 106 : 677-682 8. Malta J, Laurell M, Dahlb~ck B (1988) Changes in the plasma levels of vitamin K-dependent proteins C and S and of C4bbinding protein during pregnancy and oral contraception. Br J Haematol 68 : 437-443 9. Pasquale LR, Moster ML, Schmaier A (1990) Dural sinus thrombosis with abnormalities of protein S and fibrinogen. Arch Ophthalmol 108 : 644 10. Sacco RL, Owen J, Mohr JP, Tatemichi TK, Grossman BA (1989) Free protein S deficiency: a possible association with cerebrovascular occlusion. Stroke 20 : 1657-1661 11. Samama M, Horellou MH, Soria J, Conard J, Nicolas G (1984) Successful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulant treatment. Thromb Haemost 51 : 132-133
