Congenital protein S deficiency is an autosomal dominant disease, and the heterozygous state occurs in approximately 2% of unselected patients with VTE. Protein S deficiency is rare in a healthy population without abnormalities. The frequency is approximately 1 out of 700 based on extrapolations from a study of over 9000 blood donors who were tested for protein C deficiency. When looking at a selected group of patients with recurrent thrombosis or a family history of thrombosis, the frequency of protein S deficiency increases to 3-6%.9
Very rarely, protein S deficiency occurs as a homozygous state, and these individuals have a characteristic thrombotic disorder, purpura fulminans. Purpura fulminans is characterised by small vessel thrombosis with cutaneous and subcutaneous necrosis, and it appears early in life, usually during the neonatal period or within the first year of life.12
During physiological harmony, protein S (cofactor) combines with protein C (serine protease) which then binds to factor Va and VIIIa. Protein S/protein C complex splits factor Va and VIIIa preventing activation of factor X and thrombin, thus preventing thrombosis during the normal state. During deficiency the said mechanism fails, resulting in thrombosis.
In healthy individuals, approximately 30–40% of total protein S is in the free state. Only free protein S is capable of acting as a cofactor in the protein C system. This distinction between free and total protein S levels is important and gives rise to the current terminology regarding the deficiency states.
The congenital deficiencies of protein S are classified in three types:10
- type I deficiencies correspond to reduced antigen levels of both total and free protein S;
- type II deficiencies are characterised by reduced protein S activity but with normal antigen levels of both total and free protein S;
- type III deficiencies are defined by a reduced antigen level activity of free protein S but the antigen level of total protein S remains normal.
Acquired protein S deficiencies are associated with several clinical states:
- oral warfarin therapy;
- liver disease;
- disseminated intravascular coagulation;
- oral contraceptives;
- oestrogen therapy;
- acute phase inflammatory responses;
- sickle cell disease.
Venous thrombosis develops in 60–80% of patients who are heterozygous for protein S deficiency. The remaining patients are asymptomatic, and some heterozygous individuals never develop VTE. There is controversy regarding clear association between protein S deficiency and arterial thrombosis. Protein S deficiency is also associated with fetal loss in pregnant women.
Race-related variations exist in thrombophilic disorders as one may expect from genetic-based population traits. There is, a significant difference in the frequency of thrombophilic disorders between white, Japanese (Asian) and black African persons. The protein S deficiency is 5–10 times higher in Japanese populations compared with Caucasians. Protein C deficiency is estimated to be three times higher in Japanese populations. The factor V Leiden mutation is common in white populations. This mutation is rare and almost never found in Japanese or Asian populations. There is no difference between the male-to-female rate of occurrence.
Protein S deficiency is a hereditary disorder, but the age of onset of thrombosis is different in heterozygous or homozygous state. Most venous thrombosis events in heterozygous protein S deficiency occur in persons younger than 40–45 years. The rare homozygous patients have neonatal purpura fulminans, with onset in infancy.
The exact incidence of the protein S deficiency in the Indian population is not known. The association of Protein S deficiency and thromboembolic diseases was reported in several families by Comp, Brokemans, Batard and P K Lieu.13
On presentation, the patient had massive venous thrombosis involving the lungs and the leg veins. The duration between onset of symptoms and seeking medical attention was almost two months. Usually, the use of fibrinolytics in the treatment of pulmonary embolism is a controversial topic that has left many practicing physicians confused on how to best treat these patients. A rational approach to deciding whether fibrinolytic therapy is indicated should be based on an assessment of the benefit that each particular patient will derive from fibrinolytic therapy weighed against that patient’s risk for major bleeding and intracranial haemorrhage. The success of thrombolytic therapy decreases with the increase in duration from the onset, and only less than 50% success rate is reported after four weeks from the onset. We archived a good clinical response to the thrombolytic in spite of a long duration of almost eight weeks from the time of onset.
The patient is on regular follow-up with lifelong anticoagulation on warfarin and anti-platelets with monthly monitoring of target INR 2-3. The patient has no evidence of any haemorrhagic manifestations post dual anticoagulation. The patient has been advised coagulation studies of his siblings and kins.
The initial presentation of this case was an arterial ischaemic stroke involving the left middle cerebral artery ( and ).
Non-contrast CT brain showing left middle cerebral ischaemic infarction
MRI brain showing left middle cerebral ischaemic infarction
Two years later the patient developed massive thrombosis involving the pulmonary arteries and the leg veins in spite of being on anti-platelets. Later the evaluation revealed protein S deficiency. There was no evidence of chronic liver disease, hyperlipidemia, diabetes mellitus or smoking which predispose him for thrombosis. There is no clear association between protein S deficiency and arterial thrombosis. Ischaemic stroke has been reported as a rare manifestation of protein S deficiency. Girolami et al7
and Sie et al14
first reported the association of familial deficiency of protein S as a cause of ischaemic stroke in young. Wiesel et al15
studied 105 patients with protein S deficiency, showing relation with arterial events involving central nervous system and the cardiovascular system, while most studies revealed a weaker association between the two.16
Dovay et al17
reported that hereditary deficiencies of coagulation inhibitors are rare in ischaemic stroke patients under 45 years and their systematic detection seems to be of poor interest. Mayer et al16
also supported the fact that acquired deficiency of free protein S is not a major risk factor for ischaemic stroke. Lately Hooda et al18
described a case of recurrent stroke in a 16-year-old female with protein S deficiency. This case highlights a rare presentation and likely association and occurrence of arterial thrombosis in isolated protein S deficiency.