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Isolated protein S deficiency is an inherited condition having proven association with venous thromboembolism. There is controversy regarding clear association between protein S deficiency and arterial thrombosis. It is therefore necessary to bring focus to this uncommon clinical condition and highlight the probable association with arterial thrombosis facilitating timely diagnosis of this condition. We describe a 48-year-old male with stroke and pulmonary thromboembolism with chronic deep vein thrombosis secondary to isolated protein S deficiency, managed with thrombolysis and long-term anticoagulation.
In 1977, Di Scipio et al in Seattle first purified a new glycoprotein from human plasma which was named protein S, in reference to its isolation and characterisation in Seattle. Protein S is a vitamin K–dependent anticoagulant protein. Its major function is as a cofactor to facilitate the action of activated protein C on its substrates, activated factor V (F Va) and activated factor VIII (F VIIIa). Protein S deficiency usually manifests clinically as venous thrombo-embolism (VTE)1-3 although few researchers have also reported a relationship between protein S deficiency and arterial thrombosis.4-7
We describe a case with isolated protein S deficiency which experienced both arterial and venous thrombotic events sequentially in spite of being on long-term anti-platelets. Protein S deficiency is a rare cause which is frequently not considered in old patients with strokes on anti-platelets.
A 48-year-old male living in the plains, was on regular follow-up of two years for a cerebro-vascular accident (left middle cerebral artery infract) leading to right-sided hemiparesis (Grade IV) and aphasia. The patient was on prophylactic anti-platelets and statins when he presented with complaints of progressive breathlessness on exertion of two months duration. He denied any orthopnoea or paroxysmal nocturnal dyspnea. There was no history of cough, haemoptysis, chest pain, pedal oedema, prolonged immobilisation, angina or syncope. Clinical examination revealed a raised jugular venous pressure, loud pulmonary component of second sound and a grade 3/6 long systolic murmur in the tricuspid area. Electrocardiogram revealed normal sinus rhythm with normal axis. He was referred to cardiology for an urgent 2D Echo which showed a dilated Right Atrium/ Ventricle (RA/RV) with high Right Atrial Pressures (RAP 109 mmHg) and RV wall hypokinesia. A shortness of breath panel (SOB) showed increased Brain Natriuretic Peptide (BNP) levels 349 IU/L [>100] with normal CPK-MB 1.2 IU/L [0-4.3], Myoglobin 78.4[0-107], Trop I <0.05, D- Dimer 2420 [<400].
With a high D-Dimer value and a strong clinical suspicion of pulmonary thrombo-embolism, an urgent CT pulmonary angiography was ordered, which showed bilateral thrombosis of pulmonary arteries (Figure 1a) and complete obliteration of the descending branch of right pulmonary artery (Figure 1b), confirming the clinical diagnosis.
Colour Doppler flow imaging of both lower limbs was suggestive of chronic deep venous thrombosis involving the left popliteal and posterior tibial veins (Organised thrombus).
On presentation the lab parameters were as follows:
STACLOT protein assay kit was used for analysis of clotting factors.
The patient was immediately thrombolysed with Streptokinase 2.5 lakh units after sensitivity testing and 1 lakh units per hour infusion for 24 hours.8 No complications were observed during the thrombolysis. The patient was started on Enoxaparin 1mg/kg (60 mg) bid SC. After seven days of low molecular weight heparin therapy the patient was overlapped with warfarin 5 mg OD and ecosprin 150 mg OD. There was good response to therapy with improvement in dyspnoea and decreased RAP from 109mm of Hg to 34mm of Hg. His INR was 2.3 at discharge.
The patient became symptomatically better with a decrease in breathlessness from MRC grade III to grade II. There was no change in the motor deficit of the initial stroke, with a residual grade 4 hemiparesis and mild motor aphasia. Follow up 2D Echocardiography showed Right Atrium/Right Ventricle mildly dilated mild Tricuspid Regurgitation with a decrease in RAP from 109 mm of Hg to 34 mm of Hg. The patient was given adequate physiotherapy and deep breathing exercises and has been planned for lifelong anticoagulation with INR in the range of 2-3 with regular follow-up.
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.
Acquired protein S deficiencies are associated with several clinical states:
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.
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.16-17 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.
We thank the Department of Radiology, Base Hospital for providing us with the CT Reconstruction imaging.
Not commissioned. Externally peer reviewed.
CONFLICTS OF INTEREST
The authors declare that they have no competing interests
The authors, Wagh S, Anadure R, Dutta V, Sandhu MS, Trehan R, declare that:
Please cite this paper as: Wagh S, Anadure R, Dutta V, Sandhu MS, Trehan R, Isolated protein S deficiency presenting as catastrophic systemic arterial and subsequently venous thrombosis. AMJ 2012, 5, 8, 424-428. http//dx.doi.org/10.4066/AMJ.2012.1309.