342 Case report

Cerebral venous thrombosis in young adult with familial protein S deficiency Franciele M. Amarala,b, Caroline Ribeiro da Silvac, Michelle G. Bore´md and Ana L. Miranda-Vilelac,e Blood Coagul Fibrinolysis 26:342–345 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

Hereditary thrombophilia is the inherited predisposition to venous or, occasionally, arterial thrombosis. In most cases, it is because of changes related to physiological coagulation inhibitors or mutations in genes of coagulation factors. Protein S, a vitamin K-dependent plasma glycoprotein, is a natural anticoagulant and its deficiency is associated with familial venous thrombosis. We present a case study that brings together two rare diseases, cerebral venous thrombosis (CVT) and familial protein S deficiency, in a 21-year-old male patient with a positive family history of thrombosis. He developed a headache of moderate intensity lasting 30 days, followed by bizarre movements, which culminated in the patient’s death. This report discusses the importance of family history for the diagnosis of hereditary thrombophilia, as well as the request for brain imaging for diagnosis of CVT for an early appropriate intervention, and the importance of specialized medical guidance for family members, who must receive medical advice to prevent another fatal episode in a family member.

Received 26 February 2014 Revised 17 July 2014 Accepted 27 July 2014

Introduction

Case report

Hereditary thrombophilia is the inherited predisposition to venous or, occasionally, arterial thrombosis, owing to hematological changes, which induce blood hypercoagulability. In most cases, it is because of changes related to physiological coagulation inhibitors or mutations in genes of coagulation factors [1,2].

A 21-year-old male patient with a positive family history of thrombosis, whose mother had spontaneous deep vein thrombosis confirmed at the age of 41 and whose sister had spontaneous deep vein thrombosis confirmed at 15, developed a headache of moderate intensity, which lasted for 30 days. On consulting a general practitioner, no brain imaging was requested, nor was any family history of thrombosis, and the boy was treated for sinusitis after clinical examination. Besides experiencing a worsening headache, he began presenting bizarre movements, defined by his mother as the repetitive motion of opening and closing the zipper of his pants. The patient was then taken by his mother to the emergency room, where, at various times during the anamnesis, she was questioned by medical staff whether her son was using illegal drugs, but still without soliciting brain imaging or asking questions about family history of thrombosis. Although she reported that the patient was not a user of such drugs, he was referred to the psychiatrist. Next day, he had convulsions followed by coma, underwent mechanical ventilation and was transferred to the ICU, where computer tomography, MRI and magnetic resonance angiography (MRA) were finally performed.

Deficiency of the natural anticoagulant antithrombin was the first risk factor described for inherited venous thromboembolism [3]. Subsequently, protein C [4] and protein S [5] deficiencies have been associated with familial venous thrombosis. The latter is a vitamin Kdependent plasma glycoprotein that acts as a nonenzymatic cofactor of activated protein C in the inactivation of the coagulation factors Va and VIIIa [1]. Taken together, the deficiencies of antithrombin, protein C and protein S are found in only 0.2–1% of the world population [6]. Although venous thrombosis can occur anywhere in the venous system, the most common manifestation is deep vein thrombosis of the lower limbs with or without pulmonary embolism. Thrombosis may also involve unusual sites, as happens with cerebral venous thrombosis (CVT), considered a rare type of cerebrovascular disease that affects about five people per million [7]. This report discusses a case that combines two rare diseases: CVT and familial protein S deficiency. 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

Blood Coagulation and Fibrinolysis 2015, 26:342–345 Keywords: familial protein S deficiency, hereditary thrombophilias, magnetic resonance angiography, MRI, venous thrombosis a Fundac¸a˜o Hemocentro de Brası´lia, bNu´cleo de Hematologia e Hemoterapia do Hospital de Base do Distrito Federal, Brası´lia/DF, cFaculdades Integradas da Unia˜o Educacional do Planalto Central (Faciplac), Curso de Medicina, Campus Gama/DF, dClı´nica Villas Boas and eDepartamento de Gene´tica e Morfologia, Universidade Federal de Brası´lia, Brası´lia/DF, Brazil

Correspondence to Ana L. Miranda-Vilela, Departamento de Gene´tica e Morfologia, Instituto de Cieˆncias Biolo´gicas, Universidade de Brası´lia, Brası´lia/DF 70.910-900, Brazil Tel: +55 61 3107 3085; fax: +55 61 3107 2923; e-mail: [email protected] and [email protected]

Computer tomography showed a slightly hypodense area involving the right thalamus. The findings of brain MRI were indicative of superficial and deep venous DOI:10.1097/MBC.0000000000000206

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Cerebral venous thrombosis and protein S deficiency Amaral et al. 343

thrombosis, involving the two cerebral hemispheres, affecting the medial portion of the parietal lobes, medial portion of the right frontal lobe, the hippocampus, thalamus and the right midbrain (mesencephalon) as well as the right half of the pons (Fig. 1). MRA of the brain showed no arterial changes (Fig. 2). Despite full heparinization, the patient died on the seventh day of hospitalization in the ICU. A year after the son’s death, the mother and daughter decided to consult a hematologist. In the investigation of inherited thrombophilia, protein S deficiency was found in both.

Discussion Although CVT is characterized by a variety of symptoms, which include headache, lethargy, focal neurological signs, convulsions and coma [4], headache is the most

frequent symptom and occurs in 75–95% of all cases [8]. In most cases, this symptom precedes the development of other neurological deficits for days, weeks or even, exceptionally, months [8], as occurred with the patient in this report. Headache is a common symptom in the general population and present in a number of diseases, but when the patient was first seen by a doctor, he was treated for sinusitis despite presenting no other symptoms. With sinusitis, the pain is generally stronger in the affected sinus and the patient may present with fever, cough, nasal obstruction and secretion with drip at the back of the nasal cavity [9]. After a worsening of his headache, coupled with modified and unusual behavior, he was again taken for medical evaluation. His mother, who accompanied him, had already presented a framework of prior spontaneous thrombosis at a young age, as had his sister, suggesting the presence of hereditary thrombophilias, but this family history was not taken into account.

Fig. 1

(a)

(b)

(e)

(h)

(c)

(f)

(i)

(d)

(g)

(j)

Brain MRI. (a) Axial T2 fast spin echo (FSE), hypersignal area affecting the white matter and cortex of the right frontal lobe (white arrows); (b) Coronal T2 FSE, hypersignal area affecting the white matter and cortex of right (white arrow) and left (black arrow) parietal lobes; (c) Axial T2 FSE, hypersignal area affecting the white matter and cortex of right (white arrows) and left (black arrow) parietal lobes; (d) Coronal T2 FSE, hypersignal area affecting the right thalamus (white arrow); (e) Axial T2 FSE, hypersignal area affecting the right thalamus (white arrow); (f) Coronal T2 FSE, hypersignal area affecting the right midbrain (white arrow); (g) Axial T2 FSE, hypersignal area affecting the right midbrain (white arrow); (h) Coronal T2 FSE, hypersignal area affecting the right hippocampus (white arrow); (i) Axial T2 FSE, hypersignal area affecting the midbrain (white arrow) and the right hippocampus (black arrow); (j) Axial T2 FSE, small area of hypersignal affecting the right-hand posterior portion of the pons (white arrow).

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344 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 3

Fig. 2

(a)

(b)

Brain magnetic resonance angiography (MRA). (a) Axial three-dimensional time-of-flight (3D-TOF) MRA reconstruction; (b) Coronal 3D-TOF MRA reconstruction.

Given his family history, the patient should have undergone early imaging for investigation of CVT. This is usually a severe disease with improved outcome after the introduction of noninvasive and sensitive diagnostic techniques, such as MRI [4]. Once the thrombotic event has been diagnosed, anticoagulant treatment begins. Low-molecular-weight heparin given subcutaneously or intravenous heparin is used as first-line treatment [7]. If the patient’s situation worsens even after treatment has started and after excluding other causes of deterioration, other treatment methods should be considered, such as local venous thrombolysis or mechanical thrombectomy in selective centers with experienced interventional radiologists [8]. In this acute phase of thrombosis, plasma levels of antithrombin and occasionally proteins C and S can transiently decrease. Heparin therapy can reduce the levels of antithrombin, and warfarin therapy can reduce the vitamin K-dependent factors, including proteins C and S [7]. Thus, in the acute event and during anticoagulant therapy, performing the dosage of natural anticoagulants is not recommended. In addition to the deficiency of natural anticoagulants, several other risk factors should be investigated, wherein mutations in the genes of factor V (factor V Leiden) and prothrombin are the most common causes of inherited thrombophilia in patients with a family history of venous thrombosis [1,2,6]. Research into these mutations is performed by testing DNA, so it is not affected by anticoagulant therapy. The patient’s mother and sister were subjected to these tests, and change was found only in the dosage of protein S. At the time of dosing of S protein, they were not on anticoagulant therapy, and the examination was conducted in two different samples. The plasma protein S circulates 60% linked to the complement protein C4b, and 40% in the free form. Only free protein S acts as a nonenzymatic cofactor of activated

protein C. The dosage of total and free protein S can be performed with ELISA [10]. Bioassays based on coagulation (coagulometric method) are indirect and assess the activity of protein S. If a change in protein S is identified by this method, genetic research into factor V Leiden should be carried out, as it confers resistance to activated protein C. The enzyme immunoassay for determination of free protein S is preferable to using functional tests [11]. Although it comes too late for the patient, the diagnosis of hereditary thrombophilia after detection of protein S deficiency is very important for mother and daughter. Both should be advised against exposure to risk factors such as estrogen use. The mother’s age matches the climacteric period in which women can be subjected to hormone replacement therapy. The second is of childbearing age, a stage in which much of the female population uses oral contraceptives as birth control. If exposed to risk factors that cannot be avoided, such as surgery, they should use prophylaxis. Protein S deficiency is also associated with fetal loss [1], so heparin prophylaxis is recommended during pregnancy. Thus, the case of this patient that combines two rare diseases such as CVT and protein S deficiency reveals the importance of family history for the diagnosis of hereditary thrombophilia. It also reveals the importance of the request for brain imaging in cases of persistent headache, mainly in families with thrombosis history and when associated with neurological disorders. Moreover, after a thrombotic event in an uncommon site that evolved to the patient’s death and with the presence of first-degree kin with spontaneous venous thrombosis, inherited thrombophilia must be investigated. Family members should receive specialized medical advice to prevent another fatal episode among them.

Acknowledgements Written informed consent was obtained from the patient’s sister for publication of this case report and

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Cerebral venous thrombosis and protein S deficiency Amaral et al. 345

accompanying images. F.M.A. was responsible for the medical care of the mother and sister of the patient; C.R.S. and M.G.B. were responsible for the analysis and interpretation of images; F.M.A. and A.L.M.-V. wrote the manuscript and all authors read and approved the final manuscript. Conflicts of interest

The authors report no conflicts of interest.

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Cerebral venous thrombosis in young adult with familial protein S deficiency.

Hereditary thrombophilia is the inherited predisposition to venous or, occasionally, arterial thrombosis. In most cases, it is because of changes rela...
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