Cerebral venous thrombosis and pulmonary thromboembolism with thyrotoxicosis

LA Corry, NL Walker, J Byrne, ID Walker, B Kennon

Contact Details: Dr Lyn Corry
Department of Gastroenterology
Stobhill Hospital
Balornock Road
lyncorry@hotmail.com

Abstract

An elevated level of factor VIII is a recognised risk factor for thromboembolism. This case report describes a patient with elevated factor VIII levels secondary to hyperthyroidism. She presented with a triad of clinical hyperthyroidism, pulmonary emboli and cerebral venous thrombosis. This case highlights the importance of considering thromboprophylaxis in patients with clinical hyperthyroidism.

Keywords: Cerebral Venous Thrombosis
Thyrotoxicosis
Pulmonary Thromboembolism
Factor VIII levels

Introduction
Pulmonary embolism is a common disorder with an incidence in the general population of 1-2 per 1,000 per year. Cerebral venous thrombosis by contrast is a rare disorder with an incidence quoted at approximately 4 per 1,000,000 per year. Hyperthyroidism is five times more common in women than men, and the prevalence in women is estimated at 1%, but increases to 4-5% in post-menopausal women. We present a case of a woman with pulmonary emboli, cerebral venous thrombosis and hyperthyroidism.

History
A 42-year-old woman presented to the Emergency department with a two-week history of right-sided occipital headache and vomiting and a one-week history of dyspnoea on exertion without cough or haemoptysis.

On initial assessment she had a sinus tachycardia of 130bpm and borderline pyrexia of 37.6oC. She had no meningism, photophobia or focal neurology, however she was noted to have proptosis and lid lag. She also had a small smooth goitre with no bruit. She was not clinically dehydrated and her haematocrit, urea and creatinine were normal.

She denied any weight loss, appetite change or heat intolerance. She was a non-smoker. She had no past medical history of note but was taking regular co-codamol and naproxen since the onset of her headache. She was not taking any oral contraception. Her sister had had a postpartum deep vein thrombosis but there was no other family history of venous thrombosis. There was no family history of autoimmune disease.

An urgent CT scan of her brain showed a small right-sided occipital haemorrhage with localised oedema but no midline shift. She was transferred to the regional neurosurgical unit for further investigation. CT cerebral angiography revealed thrombus in her right jugular, sigmoid and transverse sinuses with intracranial haemorrhage. There was also evidence of cavernous sinus thrombosis (figure 1).

Figure 1:
CTPA showing filling defects “polo mint appearance” visible in right pulmonary vessels

Following transfer she became acutely short of breath and hypoxic. She complained of pleuritic chest pain. Blood pressure was 127/70mmHg. CT pulmonary angiography showed extensive bilateral pulmonary thromboemboli (figure 2). Thyroid function tests demonstrated thyrotoxicosis with free T4 level of >100pmol/l and a TSH of <0.05 IU/ml. Her ECG showed sinus rhythm with anterior T wave inversion. An echocardiogram demonstrated right ventricular dilatation and pulmonary hypertension.

Figure 2:
Initial cerebral venogram showing marked filing defect of the right transverse sinus

She was treated with intravenous crystalloids, beta-blocked with propranolol and started on anti-thyroid medication in the form of propylthiouracil. After discussion with the Neurosurgeons it was felt that the balance of risk justified full anticoagulation despite recent intracerebral haemorrhage. She was treated initially with low molecular weight heparin and then with warfarin.

A technetium thyroid uptake scan showed significantly elevated uptake of 14.5%. Thyroid peroxidase antibodies were positive. Thrombophilia tests including antithrombin activity, protein C activity, free protein S antigen, and lupus anticoagulant tests were normal, and she had no evidence of the factor V Leiden mutation or the G20210A prothrombin gene polymorphism. Clotting factor VIII activity was checked and found to be significantly elevated at 390iu/dl (normal range 46–189iu/dl).

She made a full recovery with the above treatment. She is currently euthyroid on propylthiouracil and the plan is to proceed to definitive treatment with radioactive iodine in the near future.

Discussion

Risk factors for pulmonary embolism are generally well described and include recent surgery or trauma, malignancy or other serious medical illness, immobility and pregnancy or oestrogen use. Specific thrombotic tendencies are associated with thrombophilic defects and these are present in up to half of patients with pulmonary thromboembolism1.

Cerebral venous thrombosis is also a multifactorial condition with risk factors including venous stasis, dehydration, central nervous system infection, heritable thrombophilia, pregnancy, oral contraceptives and vasculitis2. There are several case reports highlighting the additive thrombotic risk of multiple thrombophilic defects including factor V Leiden and the G20210A prothrombin gene polymorphism3. Approximately 25% of cerebral venous thromboses are thought to be idiopathic.

Through a MEDLINE search we found 13 case reports describing a possible association between hyperthyroidism and cerebral venous thrombosis. We were unable to find any case reports of the triad of cerebral venous sinus thrombosis, pulmonary thromboembolism and hyperthyroidism.

Hyperthyroidism is a hypercoagulable state and should be considered a risk factor for venous thromboembolism including cerebral venous thrombosis and pulmonary thromboembolism. The risk of arterial thromboembolism is also increased in hyperthyroidism. 10-15% of patients with thyrotoxicosis have atrial fibrillation4 (AF) which has been shown to be associated with an increased frequency of stroke and systemic embolism. Several mechanisms for the hypercoagulable state in thyrotoxicosis have been described, including vascular endothelial dysfunction, decreased fibrinolytic activity5 or increased plasma homocysteine levels induced by hyperthyroidism6. Erem et al5 demonstrated elevated levels of von Willibrand Factor, tissue plasminogen activator inhibitor-1 and antithrombin III along with decreased levels of tissue plasminogen activator when comparing 41 hyperthyroid patients with 20 euthyroid controls. The altered levels of these endothelial derived proteins could lead to the vascular endothelial dysfunction and decreased fibrinolytic activity described. In cerebral venous thrombosis, some case reports describe an association with a large goitre7 possibly causing stasis of venous blood flow, although this was not a contributory factor in our patient.

Publications have described a high factor VIII associated with hyperthyroidism8. Elevated factor VIII levels are associated with an increased incidence of venous thrombosis9. Koster et al looked at 301 patients under the age of 70 with a first diagnosis of venous thrombosis excluding patients with underlying malignancy. Their results showed that raised levels of factor VIII were associated with an increased risk of venous thrombosis (adjusted relative risk of 4.8 with factor VIII levels >150iu/dl) 10. Since then other publications have described an increase in factor VIII in association with hyperthyroidism6. The factor VIII level typically falls as the thyroid function normalises.

We believe our case is the first to report the triad of thyrotoxicosis, pulmonary embolism and cerebral venous thrombosis and highlights the increased risk of venous thromboembolism with hyperthyroidism. We conclude that in all patients with venous thromboembolic events there is a careful assessment for symptoms and signs of hyperthyroidism and where indicated thyroid function tests are checked. Hyperthyroidism is an under-recognised risk factor for venous thromboembolism. Its presence should prompt careful thrombosis risk assessment and lower the threshold for thromboprophylaxis.

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