Thyroid disease and haemostasis: a relationship with clinical implications? Squizzato, A.

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1 UvA-DARE (Digital Academic Repository) Thyroid disease and haemostasis: a relationship with clinical implications? Squizzato, A. Link to publication Citation for published version (APA): Squizzato, A. (2010). Thyroid disease and haemostasis: a relationship with clinical implications? General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 21 Apr 2018

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3 Chapter 15 Recurrent deep venous thrombosis during optimal anticoagulation and overt hyperthyroidism A case report Alessandro Squizzato, Josè Vitale, Victor EA Gerdes, Erica Romualdi, Harry R Büller, Walter Ageno Published in Blood Coagulation and Fibrinolysis 2007,18:

4 Abstract Recurrent deep venous thrombosis despite well-conducted anticoagulant treatment is an uncommon, but possible, event. It has been hypothesized that overt hyperthyroidism may increase thromboembolic risk. We present the case of an elderly man with a recurrent episode of deep venous thrombosis during optimal oral vitamin K antagonist treatment, associated with a new diagnosis of overt hyperthyroidism, with no evidence of occult cancer and normal levels of antiphosholipid antibodies. 184

5 Overt hyperthyroidism, DVT, and VKA Introduction Recurrent venous thromboembolism (VTE) despite well conducted anticoagulant treatment is an uncommon, but possible, event [1]. Overt or occult cancer and antiphospholipid syndrome are the main underlying disorders [2]. Overt hyperthyroidism is hypothesized to increase the risk of VTE: the occurrence of sinus and cerebral vein thrombosis during severe hyperthyroidism, and a number of coagulation abnormalities, such as increased activity of plasma factors VIII and IX, have been reported [3 5]. We present the case of an elderly man with a recurrent episode of deep venous thrombosis (DVT) during optimal vitamin K antagonist treatment, associated with a new diagnosis of overt hyperthyroidism, with no evidence of occult cancer after extensive screening and normal levels of antiphospholipid antibodies. Case report A 74-year-old Caucasian man, on chronic oral anticoagulation with warfarin because of a permanent atrial fibrillation, referred with an important oedema of the right leg during a follow-up visit at the Anticoagulation Clinic of the University of Insubria, in Varese, on 31 May After compression ultrasound, a femoral-popliteal DVT of the right leg was diagnosed. On the same day, the International Normalized Ratio was No International Normalized Ratios below 2.00 were detected during regular monitoring at the Anticoagulation Clinic for more than 1 year before DVT. A full therapeutic dose of low molecular weight heparin (enoxaparin IU twice daily for 10 days) was started, and the target International Normalized Ratio was elevated to 3.0. Neither temporary nor permanent thromboembolic risk factors were identified, but previous controlateral unprovoked proximal DVT was objectively diagnosed with a compression ultrasound on 4 June At that time, neither temporary nor permanent thromboembolic risk factors were identified. Thrombophilia screening had not been performed given the age of the patient. Until May 2006, neither thrombotic nor major bleeding complications had occurred. Other relevant concomitant diseases in the patient history included chronic obstructive pulmonary disease, obstructive sleeping apnoea syndrome, obesity, prostatic adenoma, and a surgically repaired aortic abdominal aneurysm. The patient was also on treatment with digoxin, alfuzosine, dutasteride, amiloride, and hydrochlorothiazide. At the time of recurrent DVT, anticardiolipin antibodies, antib2- glycoprotein I antibodies, and lupus anticoagulant were normal. In the suspicion of an occult cancer, chest/abdominal computed tomography was performed: an enlarged thyroid gland with a nodule in the right lobe, and a bilateral surrenalic adenoma were identified. Thyroid ultrasound confirmed a multinodular gland with a larger nodule of 43mm diameter in the right lobe; thyroid scintigraphy with 99mTc showed that the larger right lobe nodule was functionally autonomous. Thyrotropin (thyroid-stimulating hormone) was below 0.05mIU/ ml (reference range mIU/ml), free triiodothyronine was 6.67 pg/ml (reference range pg/ml), and serum free thyroxine was 1.72 ng/dl (reference range ng/dl); antithyroid peroxidase, antithyroglobulin, and antithyroid-stimulating hormone receptor antibodies were not elevated. The patient was temporarily started on thiamazole before 185 Chapter 15

6 definitive treatment with surgery or radiometabolic therapy could be performed. Hormonal dosages for detecting functional active surrenalic adenomas showed only a mild decrease in the bloodadrenocorticotropic hormone level at 0800 h (7 pg/ml, reference range 9 55 pg/ ml), a mild increase in blood cortisol level at 1600 h (103 ng/ml, reference range ng/ ml), with a normal free cortisol level in 24-h urine volume. Routine blood tests revealed a mild increase in erythrocyte sedimentation rate and in reactive C protein. Prostatic soluble antigen was 1.3 ng/ml (reference range <4ng/ml). The patient is still regularly followed at the Anticoagulation Clinic and no cancer has been diagnosed until now, April Discussion 186 VTE is a multicausal disease [6]. More than one acquired or environmental risk factors, as well as a genetic predisposition, often coincide to produce a vein thrombosis. Minor risk factors, therefore, may be relevant if other risk factors coexist: VTE occurs if a combination of these risk factors leads to crossing the thrombosis threshold [6]. At the time of the first DVT, three known minor risk factors were present: age, male sex, and obesity. No other potentially relevant conditions were identified. The same three risk factors still coexisted at the time of the second DVT, but this time the patient was on vitamin K antagonist treatment. For this reason, we believe that a new determinant event must have occurred. Cancer and antiphospholipid syndrome are the main reasons for VTE recurrence during adequate anticoagulation, but have been excluded [2]. Even the risk of cancer is increased for many months (even years) after the thrombotic event, our patient is apparently cancer-free after 9 months. No other relevant clinical events concomitantly occurred. Even if inherited thrombophilia tests could be theoretically advocated as necessary, natural coagulation factor inhibitor deficiency (antithrombin, protein C, and protein S) is improbable, given the old age of the patient [7]. Moreover, thrombophilias associated with increased levels of function of the coagulation factors (e.g. factor V Leiden, prothrombin gene mutation) are probably not relevant as they may not be risk factors for recurrent thrombosis, particularly under anticoagulant treatment [7]. Finally, if any congenital thrombophilic defects were present, these risk factors would have been present at the time of both the first and the second DVT, and therefore would have contributed the thrombotic risk in both episodes. Apparently a new risk factor increased the VTE risk at the time of the second DVT, given the optimal warfarin treatment. Overt hyperthyroidism may therefore have contributed to DVT recurrence on the top of the existing risk factors. While recognizing that the association of hyperthyroidism and venous thromboembolism may be purely coincidental, thyroid dysfunction was newly diagnosed and an extensive literature supports its potential role of this unusual VTE risk factor. The link between the haemostatic system and thyroid disease has been investigated since the beginning of the last century [5]. In particular, in-vitro studies showed that the effects of thyroid hormones on the coagulation system are mainly mediated by hormone/receptors interaction [5;8]. In-vivo studies on the effect of overt thyroid dysfunction on plasma coagulation

7 Overt hyperthyroidism, DVT, and VKA and fibrinolytic factors suggested a procoagulant state in overt hyperthyroid patients. Even if several methodological drawbacks obscure the real in-vivo effects of hyperthyroidism on the haemostatic system, these findings are further supported by two studies in which oral thyroid hormones were administered to healthy volunteers [9;10]. A few coagulation tests were performed, but a clear increase of factor VIII, von Willebrand antigen and activity, and tissue plasminogen activator antigen was observed (no statistically significant effect was shown on antithrombin activity). No clinical studies evaluating the relationship between thyroid dysfunction and VTE events have been published, but case reports confirmed the hypothesis that hyperthyroidism is associated with a hypercoagulable state [5]. Sinus and cerebral vein thrombosis have been reported in overt hyperthyroidism, in particular during thyrotoxic crisis: this association is relevant, since sinus and cerebral vein thrombosis is a rare disease (four per million inhabitants per year) [5]. To our knowledge, the present case is the first report of an association of overt hyperthyroidism with a recurrent episode of VTE. Only one case report [11] has described a DVT occurring in a patient with Graves disease after a long-haul flight. While recognizing that the association may be coincidental rather than causal, our case report reinforces the available evidence on the possible role of overt hyperthyroidism as VTE risk factor. Given that a definitive conclusion cannot be drawn, it seems worthwhile to prospectively measure thyroid hormones in aetiological clinical studies to definitively assess their causal role in VTE. Serum TSH measurement would be sufficient as a first screening test in order to avoid useless laboratory tests. References 1. Palareti G, Manotti C, D Angelo A, Pengo V, Erba N, Moia M, et al. Thrombotic events during oral anticoagulant treatment: results of the inception-cohort, prospective, collaborative ISCOAT study. Thromb Haemost 1997; 78: Ginsberg JA, Crowther MA, White RH, Ortel TL. Anticoagulation therapy. Hematol Am Soc Hematol Educ Program 2001; 1: Erem C, Ersoz H, Karti SS, Ukinc K, Hacihasanoglu A, Deger O, et al. Blood coagulation and fibrinolysis in hyperthyroidism. J Endocrinol Invest 2002;25: Marongiu F, Conti M, Mameli G, Murtas ML, Balzano S, Sorano G, et al. Fibrinogen and fibrinolytic activity in hyperthyroidism before and after antithyroid treatment. J Endocrinol Invest 1988; 11: Squizzato A, Gerdes VE, Brandjes DP, Buller HR, Stam J. Thyroid diseases and cerebrovascular disease. Stroke 2005; 36: Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999;353: Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med 2003; 138: Shih CH, Chen SL, Yen CC, Huang YH, Chen CD, Lee YS, et al. Thyroid hormone receptor dependent transcriptional regulation of fibrinogen and coagulation proteins. Endocrinology 2004; 145: Graninger W, Pirich KR, Speiser W. Effect of thyroid hormones on plasma protein concentrations in man. J Clin Endocrinol Metab 1986; 63: Rogers IIJS, Stanley RS. Factor VIII activity in normal volunteers receiving oral thyroid hormone. J Lab Clin Med 1983; 102: Morimoto S, Nemoto M, Han A, Katoh S, Kurata H, Utsunomiya K, et al. Economy class syndrome associated with diabetes and Graves disease. Nippon Naika Gakkai Zasshi 2003; 92: Chapter 15