The hormonal influence on the haemostatic system and the risk of thrombosis Stuijver, D.J.F.

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1 UvA-DARE (Digital Academic Repository) The hormonal influence on the haemostatic system and the risk of thrombosis Stuijver, D.J.F. Link to publication Citation for published version (APA): Stuijver, D. J. F. (2012). The hormonal influence on the haemostatic system and the risk of thrombosis. 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: 12 Apr 2019

2 CHAPTER 8 The prevalence of acquired von Willebrand syndrome in patients with overt hypothyroidism Submitted for publication Danka JF Stuijver, Eliana Piantanida, Bregje van Zaane, Luca Galli, Erica Romualdi, Maria L Tanda, Joost CM Meijers, Harry R Büller, Victor EA Gerdes, Alessandro Squizzato

3 chapter 8 Abstract Background Numerous case reports have been published on acquired von Willebrand syndrome (avws) in patients with hypothyroidism, but its frequency is unknown. We aimed to determine the prevalence of avws and occurrence of bleeding symptoms in patients with newly diagnosed overt hypothyroidism. Methods An observational cohort study was performed between May 2007 and February Consecutive hypothyroid patients were enrolled before or within the first 48 hours of start of replacement therapy. At inclusion, blood was sampled for coagulation tests and bleeding history was documented by means of a standardized bleeding questionnaire. Repeat-samples were obtained after restoration of euthyroidism. The prevalence of avws, defined as von Willebrand factor antigen (VWF:Ag) 50% and/or VWF ristocetin activity (VWF:RiCo) 50%, was calculated. Patients with avws were subsequently divided into severe (VWF:Ag and/or VWF:RiCo 10%), moderate (VWF:Ag and/or VWF:RiCo between 10 and 30%) or mild (VWF:Ag and/or VWF:RiCo between 30 and 50%). Results A total of 90 patients were included among whom a prevalence of avws of 33% was found. There were no patients with severe avws. Eight patients (9%) had moderate avws and 21 (23%) had mild avws. Bleeding score was negatively correlated to both VWF:Ag (β -0.32, p=0.03) and VWF:RiCo (β -0.32, p=0.02). After restoration of euthyroidism, VWF:Ag had increased by 44%, VWF:RiCo by 36%, factor VIII by 39%, endogenous thrombin potential by 10%, while prothrombin time and activated partial thromboplastin time had decreased by 4% and 8%, respectively; for all measurements a statistically significant difference was found between euthyroidism and hypothyroidism. Conclusions Acquired von Willebrand syndrome has a high prevalence in hypothyroid patients. Highest bleeding scores in patients with lower VWF levels suggest clinical relevance. 160

4 Hypothyroidism and acquired von Willebrand syndrome Introduction Thyroid hormones are potent mediators of numerous physiological processes in the human body, including blood coagulation. 1,2 Various coagulation abnormalities have been described in patients with thyroid disease. 3 The most common coagulation disorder in hypothyroid patients is thought to be acquired von Willebrand syndrome (avws), characterised by decreased levels of factor VIII (FVIII) and von Willebrand factor (VWF). 4-6 Presenting symptoms vary from mostly mild mucocutaneous bleeding (epistaxis, easy bruising or bleeding after dental extractions) to, rarely, major hemorrhage following surgery or trauma. 7,8 Suggested underlying mechanisms explaining the hypothyroidism- associated avws include downregulation of VWF synthesis in the endothelial cell, and autoimmunity, but the finding of a reversal of the hypothyroidism-associated avws after thyroid hormone replacement therapy, underlines the direct influence of thyroid deficiency on gene transcription of coagulation factors. 1,9-11 Although the association between hypothyroidism and acquired von Willebrand syndrome has frequently been described, albeit mostly in case reports and only a scarce number of observational studies, the prevalence of acquired von Willebrand syndrome in patients with hypothyroidism has not been studied prospectively. 6 In this observational cohort study, we aimed to determine the prevalence of acquired von Willebrand syndrome and the occurrence of bleeding symptoms in patients with newly diagnosed overt hypothyroidism, in order to shed light on the clinical relevance of this association. chapter 8 Methods Study population Between May 2007 and February 2011, consecutive patients with a new diagnosis of primary overt hypothyroidism, with a minimum age of 18 years, were enrolled before or within the first 48 hours of replacement therapy. Overt hypothyroidism was defined as a level of serum thyrotropin (TSH) above 10 mu/l, with serum free thyroxine (FT4) concentration below the lower limit of the reference range (10-23 pmol/l). Patients were excluded if they had any of the following: secondary hypothyroidism, subclinical hypothyroidism, more than 48 hours of thyroid hormone replacement therapy, known congenital von Willebrand syndrome, or presence of severe inflammatory disease (e.g. active inflammatory bowel disease, pneumonia). The study was performed at the department of Internal Medicine of the Slotervaart Hospital and the Academic Medical Center, Amsterdam, the Netherlands, and the Ospedale di Circolo, Varese Italy, and was approved by all institutional medical ethics committees. All participants provided written informed consent. 161

5 chapter 8 Study procedures At inclusion, subjects underwent a comprehensive assessment including documentation of medical history, measurement of body weight and height, and measurement of laboratory variables. Also, information about the type of hypothyroidism (autoimmune, postthyroidectomy, or other) and the presence of thyroid antibodies (AbTPO, AbTG), if available, were collected. Bleeding history was registered using the standardized bleeding questionnaire of Sadler and Rodeghiero, and is explained in Appendix A bleeding score of 3 in males and 5 in females was considered clinically significant. 13 The presence of thyroid antibodies was defined as positive when AbTPO > 75 IU/ML or AbTG > 150 IU/ML at the Slotervaart Hospital, the Netherlands, AbTPO 60 ku/l or AbTG 60 mmol/l at the Academic Medical Center, the Netherlands and AbTPO 60 U/ml or AbTG 60 U/ml at the Ospedale di Circolo, Varese Italy. Blood was sampled during hypothyroidism and after restoration of euthyroidism with thyroid hormone substition therapy. Definitions of acquired von Willebrand syndrome. Acquired von Willebrand syndrome was defined as either von Willebrand factor antigen (VWF:Ag) 50% and/or von Willebrand factor ristocetin cofactor activity (VWF:RiCo) 50%. 14,15 Patients were subsequently divided into three subgroups: - Severe avws: either VWF:Ag or VWF:RiCo of 10%. - Moderate avws: either VWF:Ag or VWF:RiCo of 10% to 30% (lowest value). - Mild avws: either VWF:Ag or VWF:RiCo of 30% to 50% (lowest value). Laboratory investigations. Blood samples were collected in 0.5 ml plain tubes for assessment of thyroid function, and in 5 ml trisodium citrated tubes for tests of coagulation and fibrinolysis (BD Vacutainer, Plymouth, UK). Citrated blood was immediately centrifuged, and the supernatant re-centrifuged, for 15 minutes at 2500x g at 15 C to obtain platelet-poor plasma. Plasma was aliquoted and stored at -80 C until further use. Serum levels of thyroid hormones were measured at the local laboratory on the day of sampling. Levels of FT4, tri-iodothyronine (T3) TSH and thyroid antibodies were assessed using commercially available assays (Slotervaart hospital, ADVIA Centaur immunoassay system, Siemens Healthcare Diagnostics, Marburg, Germany; Academic Medical Center, Perkin Elmer/Wallac, Turku, Finland; Varese, Brahms, Berlin, Germany). Coagulation tests were performed at the Academic Medical Center in batch after all participants had completed the study. Prothrombin time (PT), activated partial thromboplastin time (aptt), and 162

6 Hypothyroidism and acquired von Willebrand syndrome functional assays of coagulation factor VIII activity (FVIII:C) and VWF:RiCo were performed using an automated coagulation analyzer (Behring Coagulation System, Siemens Healthcare Diagnostics, Marburg, Germany) with reagents and protocols of the manufacturer. For the measurements of VWF:Ag, we used in-house enzyme-linked immunosorbent assays (ELISA) with antibodies from DAKO (Glostrup, Denmark). As the endogenous thrombin potential (ETP) has been found to be correlated to bleeding tendency previously, we decided to determine ETP levels as well. 16,17 ETP was determined with a calibrated automated thrombogram (CAT). The CAT assays the generation of thrombin in clotting plasma using a microtiter plate reading fluorometer (Fluoroskan Ascent, ThermoLab systems, Helsinki, Finland) and Trombinoscope software (Thrombinoscope BV, Maastricht, the Netherlands) as previously described. 18 Three parameters were derived from the thrombin generation curve: lag time, peak height and ETP (area under the curve). Reference values for thyroid hormones, and coagulation and fibrinolytic parameters are shown in Table 2 and 3. Statistical analysis Data for qualitative variables are presented as incidence rates (N, number and percent). The data of continuous variables were summarised using measures of central tendency (i.e. mean, median) and dispersion (i.e. standard deviation, range). The prevalence of avws was calculated as percentage with 95% confidence intervals (CI). Correlations between bleedings scores and VWF levels were calculated using log-transformed values linear regression analysis. Levels of coagulation parameters during hypothyroidism and after restoration of euthyroidism are presented as medians with interquartile range (IQR) and compared by Wilcoxon signed ranks test. Statistical analysis was performed using SPSS 18.0 (statistical software). chapter 8 Results Characteristics of patients are shown in Table 1. Ninety untreated hypothyroid patients (71 women and 19 men) with a mean age of 49 years (IQR 18-87) were included in the study. Each patient was biochemically overt hypothyroid: median FT4 was 5.0 pmol/l (IQR ) and median TSH 76.3 mu/l (IQR ). In approximately 60% of the patients, hypothyroidism was caused by Hashimoto thyroiditis. Three patients suffered from diabetes mellitus. Of these patients, one also had inactive rheumatoid arthritis, and one had monoclonal gammopathy of undetermined significance (MGUS). In 69 of the 90 patients, a second blood sample was obtained after euthyroidism was restored while on thyroid hormone replacement therapy, with a median of 5 months (IQR ) after the first visit. The remaining 21 patients were lost to follow-up due to relocation away from the study site, withdrawing of consent for further blood sampling, or death. 163

7 chapter 8 Table 1. Characteristics of participants. Hypothyroid (n=90) Age, years, mean (range) 48.8 (18-87) Female, n 71 (79) BMI, kg/m 2, mean (range) 27 (16-40) Creatinine, umol/l, mean (range) 92 (50-163) Hemoglobin, mmol/l, mean (range) 8.6 ( ) Etiology, n - Hashimoto thyroiditis 62 (63) - Thyroiditis 5 (6) - Post 131 I therapy 10 (10) - Post radiation therapy 2 (2) - Post surgery 2 (2) - Medically induced 4 (4) - Unknown 5 (5) N indicates number; BMI, body-mass index; 131 I therapy, radioactive iodine therapy Medically induced hypothyroidism includes overtreatment of hyperthyroidism and amiodarone treatment. Prevalence of acquired von Willebrand syndrome In 29 of the 90 patients, VWF:Ag and/or VWF:RiCo levels of 50% were found, resulting in a prevalence of avws of 33% (95% CI 23-42). Details on these patients are provided in Table 2 and 3. No patients with VWF levels below 10% were identified. Moderate avws with either VWF:Ag levels or VWF:RiCo levels between 10% to 30% was found in 8 patients (prevalence of 9%; 95% CI 5-17), whereas 21 patients had either VWF:Ag or VWF:RiCo levels between 30-50% (prevalence of mild avws of 23%; 95% CI 16-33). Of 23 of the 29 patients with avws, repeat-samples were obtained: 5 of these (7%) still had VWF:Ag or VWF:RiCo levels below 50% while euthyroidism was restored. The mean VWF:RiCo/VWF:Ag ratio was 1.1 (range ) indicating a quantitative VWF defect. After restoration of euthyroidism with thyroid hormone replacement therapy, a clear rise in VWF levels was observed in almost all patients (Figure 1). Levels of FT4 were positively correlated to VWF:Ag (regression coefficient β 0.23; 95%CI 0.1 to -0.5; p=0.03) and VWF:RiCo levels (regression coefficient β 0.23; 95%CI 0.03 to 0.4; p=0.03). Levels of TSH were not correlated to VWF levels (data not shown). 164

8 Hypothyroidism and acquired von Willebrand syndrome Figure 1. Individual change in von Willebrand levels before and after treatment. VWF indicates, von Willebrand factor; Ag, antigen; RiCo, ristocetin cofactor activity. Medians (and interquartile ranges) are shown Bleeding symptoms All 8 patients with moderate avws reported having, often mild, mucocutaneous bleeding symptoms, compared to about half of the cases with mild avws or cases without avws. A bleeding score of 3 in males and 5 in females was found in 2 patients (25%) with moderate avws, in 4 patients (19%) with mild avws and in 6 patients (10%) without avws. The average bleeding score in moderate avws was 3.5 compared to 2.0 in mild avws and 1.6 in patients without avws. Bleeding score was negatively correlated with both VWF:Ag (regression coefficient β -0.32; 95%CI -0.4 to -0.1; p=0.03) and VWF:RiCo (regression coefficient β -0.32; 95%CI -0.5 to -0.1; p=0.02). Thyroid hormone levels were not correlated to bleeding score (data not shown). chapter 8 165

9 chapter 8 Table 2. Clinical characteristics in hypothyroid patients with or without acquired von Willebrand syndrome. Moderate avws n=8 (9%) Mild avws n=21 (23%) No avws n=61 (68%) Age, years, mean (range) 38 (22-58) 43 (22-66) 52 (18-86) Female, n 8 (100) 18 (86) 45 (74) Body-mass index, kg/m 2, mean (range) 24.1 ( ) 28.0 ( ) 27.0 (16-40) TSH ( miu/l), median (IQR) FT4 (10-23 pmol/l), median (IQR) 83.6 (41.6;235.2) 3.2 (1.9;6.8) 84.3 (57.4;108.3) 4.0 (3.4;6.9) 75.7 (38.0;120.0) 5.7 (4.0;7.0) Bleeding symptoms (qualitative) n - Epistaxes 3 (38) 1 (5) 5 (8) - Cutaneous symptoms 5 (63) 5 (24) 9 (15) - Minor wounds 1 (13) 4 (19) 8 (13) - Oral cavity bleeding 5 (63) 3 (14) 10 (16) - Gastrointestinal Bleeding 0 3 (14) 5 (8) - Post partum haemorrhage 0 4 (19) 7 (11) - Muscle hematomas or haemarhrosis (2) - Toot extraction 0 1 (5) 4 (7) - Bleeding after surgery 1 (13) 3 (14) 7 (11) - Menorrhagia 5 (63) 4 (19) 9 (15) Bleeding score (quantitative), mean (range) 3.5 (2-6) 2.0 (0-7) 1.5 (0-9) avws indicates, acquired von Willebrand syndrome; IQR, interquartile range; n, number; TSH, thyroid stimulating hormone; FT4, free thyroxine. 166

10 Hypothyroidism and acquired von Willebrand syndrome Table 3. Hypothyroid patients with acquired von Willebrand syndrome. Hypothyroidism Euthyroidism FVIII VWF:RiCo Bleeding symptoms VWF:Ag Bleeding score FVIII VWF:RiCo Gender Age VWF:Ag F Mild epistaxis, petechiae and bruises, hysterectomy for menorrhagia Moderate avws F Petechiae and bruises, mild oral cavity bleeds, mild menorrhagia F Mild epistaxis, haematomas, mild menorrhagia F Severe bleeding after surgery needing transfusion, hysterectomy for menorrhagia F Oral cavity bleeding, mild menorrhagia F Petechiae and bruises, mild oral cavity bleeds F Mild epistaxis, minor wounds (1-5 episodes/year) F Petechiae and bruises, mild oral cavity bleeds Mild avws F F F Petechiae and bruises, minor wounds (1-5 episodes/ year), mild post-partum haemorrhage, mild bleeding after surgery not needing intervention F Petechiae and bruises, mild oral cavity bleeds F Petechiae and bruises, mild oral cavity bleeds F F Mild post-partum haemorrhage, severe bleeding after surgery needing transfusion, menorrhagia needing treatment (oral contraceptive) chapter 8 167

11 chapter 8 Hypothyroidism Euthyroidism Gender Age VWF:Ag VWF:RiCo FVIII Bleeding score Bleeding symptoms VWF:Ag VWF:RiCo FVIII Mild avws F M F F M F Post-partum menorrhagia, mild menorrhagia F Dubious gastrointestinal bleeding, mild post-partum haemorrhage, severe bleeding after surgery needing transfusion, menorrhagia needing treatment (oral contraceptive) F Minor wounds (1-5 episodes/year), gastrointestinal bleeding needing medical attention F Minor wounds (1-5 episodes/year), M Minor wounds (1-5 episodes/year), F F F Cutaneous symptoms needing medical consultation, gastrointestinal bleeding needing medical attention F Petechiae and bruises, mild oral cavity bleeds, mild menorrhagia F indicates female; M, male; VWF, indicates von Willebrand factor; Ag, antigen; RiCo, ristocetin cofactor activity; FVIII, indicates coagulation factor VIII. 168

12 Hypothyroidism and acquired von Willebrand syndrome Coagulation parameters Table 4 shows the median values of coagulation parameters during hypothyroidism and after restoring euthyroidism. After restoration of euthyroidism median levels of VWF:Ag increased by 44%, VWF:RiCo by 36%, FVIII by 39%, endogenous thrombin potential by 10%, whereas PT and aptt decreased by 3% and 8%, respectively. Values of these parameters were all statistically significantly different during euthyroidism compared to hypothyroidism. Table 4. Parameters of thyroid function and haemostasis during hypothyroidism and after restoring euthyroidism. Hypothyroid Euthyroid Change p-value Parameter (reference range) Thyroid function FT4 (10-23 pmol/l) 5.4 (3.8;7.0) 15.9 (13.0;17.0) 171 (112.5;352.1) <0.01 T3 ( nmol/l) 2.4 (1.1;3.2) 3.0 (2.5;3.8) 11.0 (4.1;177.2) <0.01 TSH ( miu/l) 75.1 (43.4 ;112.7) 1.9 (1.0;2.9) (-98.8;-95.5) <0.01 Coagulation Platelet count 235 (215;285) 0.5 (-5.0;10.7) 0.4 ( x10 9 /L) 233 (199;294) PT ( sec) 12.9 (11.8;14.3) 12.2 (11.6;13.4) -3.4 (-8.5;-0.0) <0.01 aptt ( sec) 38.2 (32.5;46.5) 33.6 (29.8;38.8) -7.9 (-16.3;-3.1) <0.01 VWF:Ag (50-150%) 65.0 (46.5;100.0) (65.0;142.0) 44.3 (20.3;78.4) <0.01 VWF:RiCo (58-172%) 69.0 (51.0;93.0) 96.0 (74.0;124.0) 35.7 (17.9;65.9) <0.01 Factor VIII (63-173%) 72.0 (46.5;101.0) (62.5; ) 38.5 (13.5;61.8) <0.01 Thrombin Generation Lag time of ETP 2.67 (2.17;3.00) 2.70 (2.33;3.00) 7.4 (0.0;14.5) 0.60 ( min) Peak height of ETP 254 (157;322) 295 (224;358) 14.3 (-2.6;33.2) <0.01 ( nm) ETP (area under curve) ( nm.min) 1526 (1101;1921) 1621 (1302;1960) 10.3 (-2.8;20.5) 0.02 chapter 8 FT4 indicates free thyroxine; T3, tri-iodothyronine; TSH, thyrotropin; PT, prothrombin time; aptt, activated partial thromboplastin time; VWF, von Willebrand factor; Ag, antigen; RiCo, ristocetin cofactor activity. Data are presented as medians (interquartile range). 169

13 chapter 8 Discussion In this prospective study, we found acquired von Willebrand syndrome in approximately 1 out of 3 patients with overt hypothyroidism. In 9% of all patients, the VWF antigen levels were below 30% corresponding with moderate avws, and bleeding scores were highest in patients with lower VWF levels. VWF levels were positively correlated to FT4 levels with lower levels of FT4 in patients with avws compared to hypothyroid patients without avws. Coagulation parameters all increased after restoration of euthyroidism with thyroid hormone replacement therapy. Thyroid hormones have been shown to directly influence the coagulation system by the interaction with its receptors In hypothyroidism, there is a quantitive deficiency of VWF, one of the major proteins of coagulation that acts as cofactor for platelet adhesion, ligand for platelet aggregation and carrier protein for FVIII, resulting from a decreased synthesis and/or release of VWF. 22,23 The first link between hypothyroidism and avws was described in the 1980s. 24,25 Since then, many case reports have emerged. 4,26,27 Also, a crosssectional study consisting of 131 individuals with low VWF levels reported a prevalence of subclinical hypothyroidism of approximately 6%, with normalisation of VWF levels after thyroid hormone replacement therapy. 28 However, both the frequency of laboratory diagnosis of avws and the occurrence of bleeding events in patients with hypothyroidism have not been previously investigated. We here provide evidence that avws does not only frequently occur in patients with hypothyroidism, but can also lead to a variety of bleeding episodes in some patients. Both laboratory and clinical data are in line with the hypothesis that avws is the main pathophysiological mechanism explaining the bleeding tendency found in hypothyroid patients: bleeding episodes are mainly mucocutaneous, and bleeding tendency is usually rather mild. Nevertheless, in clinical practice this bleeding tendency may remain largely unnoticed, because most patients with avws do not bleed until they are exposed to major trauma or surgery. 29 Bleeding symptoms in hypothyroid patients were found to be negatively correlated to VWF levels. However, these symptoms appear to be mild or even nonexistent in most cases with VWF levels between 30% and 50%. In comparison, in 9% of overt hypothyroid patients with VWF levels below 30%, bleeding symptoms were more severe. We therefore recommend that invasive treatment such as surgery or dental extractions in these patients should be postponed until euthyroidism has been achieved since the correction of thyroid hormones by thyroid hormone replacement therapy usually resolves both the bleeding diathesis and laboratory parameters. Also, DDAVP administration proved to be very useful in a small group of patients with avws associated with hypothyroidism undergoing thyroid surgery. 30,31 However, data on the therapeutic approaches in hypothyroid patients is not largely available. 170

14 Hypothyroidism and acquired von Willebrand syndrome Several limitations need to be addressed. First, we did not perform analysis of multimers to exclude other types of von Willebrand disease. However, none of the patients had discrepantly low VWF:RiCo, and inherited von Willebrand disease type 2 is rare. Second, in 3 of the 8 patients with the lowest VWF levels, we were unable to obtain repeat-samples after restoration of euthyroidism. We therefore can not confirm the temporality of its nature in these patients. However, in those patients with repeat-samples, treatment with thyroid hormone replacement therapy led to a significant rise in both VWF antigen and activity, which makes it likely to assume that the diagnosis of avws applies to these 3 patients as well. Third, information on blood group of our patients was not available, whereas blood group type O is associated with 25-30% lower levels of VWF. 32 However, bleeding tendency is driven by VWF levels, whatever the genetic cause is. Fourth, the definition of avws as used in this study could be debated. The quantitative defect of von Willebrand factor in avws in patients with hypothyroidism resembles the one found in the inherited form of the disease (type 1 von Willebrand disease), however, to date, there is considerable discussion about the cut-off levels for VWF used in the classification of this inherited defect. 30 Therefore, we feel the classification of our patients into those with VWF levels below 30% or between 30% and 50% is trivial. In conclusion, the 33% prevalence of acquired von Willebrand syndrome found in our study makes this a far from rare disorder in patients with overt hypothyroidism. Physicians should be aware of this association, especially since it may easily go unnoticed owing to the fact that most patients with avws do not bleed until they are exposed to trauma or surgery and further diagnostic tests are performed. 33 We suggest new cases of avws in hypothyroidism to be registered in the online International Registry on avws ( in order to determine the actual risk of bleeding in larger prospective cohort studies. chapter 8 Acknowledgments We thank the physicians of the outpatient clinic at the Slotervaart Hospital and Academic Medical centre in Amsterdam, the Netherlands, and the endocrinologists Ilaria Dalle Mule, Adriana Lai and Luigi Bartalena for the inclusion of the patients. We also thank Erik Endert, Yvonne van der Heide, Natasja Huisman, Huub Bout, Wil Kopatz, Marian Weijne and Lucy Leverink for their help in blood processing and laboratory procedures. 171

15 chapter 8 Reference List 1. Franchini M, Lippi G, Manzato F, Vescovi PP. Thyroid-associated autoimmune coagulation disorders. J Thromb Thrombolysis 2010;29: Squizzato A, Romualdi E, Buller HR, Gerdes VE. Clinical review: Thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review. J Clin Endocrinol Metab 2007;92: Vescovi PP, Favaloro EJ, Lippi G, Garofano M, Montagnana M, Manzato F, Franchini M. The spectrum of coagulation abnormalities in thyroid disorders. Semin Thromb Hemost 2011;37: Dalton RG, Dewar MS, Savidge GF, Kernoff PB, Matthews KB, Greaves M, Preston FE. Hypothyroidism as a cause of acquired von Willebrand s disease. Lancet 1987;1: Federici AB. Acquired von Willebrand syndrome associated with hypothyroidism: a mild bleeding disorder to be further investigated. Semin Thromb Hemost 2011;37: Manfredi E, van Zaane B, Gerdes VE, Brandjes DP, Squizzato A. Hypothyroidism and acquired von Willebrand s syndrome: a systematic review. Haemophilia 2008;14: Hofbauer LC, Heufelder AE. Coagulation disorders in thyroid diseases. Eur J Endocrinol 1997;136: Marongiu F, Barcellona D, Mameli A, Mariotti S. Thyroid disorders and hypocoagulability. Semin Thromb Hemost 2011;37: Erfurth EM, Ericsson UB, Egervall K, Lethagen SR. Effect of acute desmopressin and of long-term thyroxine replacement on haemostasis in hypothyroidism. Clin Endocrinol (Oxf) 1995;42: Gullu S, Sav H, Kamel N. Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism. Eur J Endocrinol 2005;152: Michiels JJ, Schroyens W, Berneman Z, van der Planken M. Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine. Clin Appl Thromb Hemost 2001;7: Sadler JE, Rodeghiero F. Provisional criteria for the diagnosis of VWD type 1. J Thromb Haemost 2005;3: Rodeghiero F, Castaman G, Tosetto A, Batlle J, Baudo F, Cappelletti A, Casana P, de Bosch N, Eikenboom JC, Federici AB, Lethagen S, Linari S, Srivastava A. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study. J Thromb Haemost 2005;3: Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008;14: Nichols WL, Rick ME, Ortel TL, Montgomery RR, Sadler JE, Yawn BP, James AH, Hultin MB, Manco-Johnson MJ, Weinstein M. Clinical and laboratory diagnosis of von Willebrand disease: a synopsis of the 2008 NHLBI/NIH guidelines. Am J Hematol 2009;84: Al Dieri R, Peyvandi F, Santagostino E, Giansily M, Mannucci PM, Schved JF, Beguin S, Hemker HC. The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding. Thromb Haemost 2002;88: Hemker HC, Beguin S. Phenotyping the clotting system. Thromb Haemost 2000;84: Hemker HC, Giesen P, Al Dieri R, Regnault V, de SE, Wagenvoord R, Lecompte T, Beguin S. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002;32: Baumgartner-Parzer SM, Wagner L, Reining G, Sexl V, Nowotny P, Muller M, Brunner M, Waldhausl W. Increase by tri-iodothyronine of endothelin-1, fibronectin and von Willebrand factor in cultured endothelial cells. J Endocrinol 1997;154: Shih CH, Chen SL, Yen CC, Huang YH, Chen CD, Lee YS, Lin KH. Thyroid hormone receptor-dependent transcriptional regulation of fibrinogen and coagulation proteins. Endocrinology 2004;145:

16 Hypothyroidism and acquired von Willebrand syndrome 21. van Zaane B, Squizzato A, Debeij J, Dekkers OM, Meijers JC, Van Zanten AP, Buller HR, Gerdes VE, Cannegieter SC, Brandjes DP. Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study. J Thromb Haemost 2011;9: Federici AB. Acquired von Willebrand syndrome: an underdiagnosed and misdiagnosed bleeding complication in patients with lymphoproliferative and myeloproliferative disorders. Semin Hematol 2006;43:S48-S Veyradier A, Jenkins CS, Fressinaud E, Meyer D. Acquired von Willebrand syndrome: from pathophysiology to management. Thromb Haemost 2000;84: Blesing NE, Hambley H, McDonald GA. Acquired von Willebrand s disease and hypothyroidism: report of a case presenting with menorrhagia. Postgrad Med J 1990;66: Smith SR AMMP. Hypothyroidism and von Willebrand s disease , Blesing NE, Hambley H, McDonald GA. Acquired von Willebrand s disease and hypothyroidism: report of a case presenting with menorrhagia. Postgrad Med J 1990;66: Concha R, Borzone MA, Castillo M, Rossle A, Quevedo I. [Acquired von Willebrand disease as an unusual manifestation of primary hypothyroidism: report of two cases]. Rev Med Chil 2005;133: Franchini M, Veneri D, Lippi G. Analysis of thyroid hormone status in 131 consecutive individuals with low von Willebrand factor levels. Thromb Haemost 2005;93: Mohri H, Motomura S, Kanamori H, Matsuzaki M, Watanabe S, Maruta A, Kodama F, Okubo T. Clinical significance of inhibitors in acquired von Willebrand syndrome. Blood 1998;91: Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006;4: Franchini M, de Gironcoli M, Lippi G, Manzato F, Brazzarola P, Bottura D, Aprili G, Gandini G. Efficacy of desmopressin as surgical prophylaxis in patients with acquired von Willebrand disease undergoing thyroid surgery. Haemophilia 2002;8: Castaman G, Eikenboom JC. ABO blood group also influences the von Willebrand factor (VWF) antigen level in heterozygous carriers of VWF null alleles, type 2N mutation Arg854GIn, and the missense mutation Cys2362Phe. Blood 2002;100: Federici AB. Acquired von Willebrand syndrome: is it an extremely rare disorder or do we see only the tip of the iceberg? J Thromb Haemost 2008;6: chapter 8 173

17 chapter 8 Appendix 1. Provisional criteria for the diagnosis of VWD type Bleeding clinical criteria for von Willebrand disease type 1 Bleeding score Epistaxis 0 = no or trivial; 1 = present; 2 = packing, cauterisation; 3= transfusion, replacement Cutaneous symptoms 0 = no or trivial; 1 = petecchiae or bruises; 2 = haematomas; 3 = medical consultation Minor wounds 0 = no or trivial; 1 = present (1-5episodes/year); 2 = medical attention; 3 = surgery/blood transfusion Oral cavity bleeding 0 = no or trivial; 1 = present; 2 = medical attention; 3 = surgery/blood transfusion Gastrointestinal bleeding 0 = no or trivial; 1 = present; 2 = medical attention; 3 = surgery/blood transfusion Post-partum hemorrhage 0 = no or trivial; 1 = present, iron therapy; 2 = blood transfusion, dilatation-curettage, suturing; 3 = hysterectomy Muscle hematomas or hemarthrosis 0 = no or trivial; 1 = present; 2 = medical attention; 3 = transfusion, intervention Tooth extraction (most severe episode) 0 = no or trivial; 1 = present; 2 = suturing or packing; 3 = transfusion Surgery (most severe episode) 0 = no or trivial; 1 = present; 2 = suturing or resurgery; 3 = transfusion Menorrhagia 0 = no or trivial; 1 = present; 2 = consultation, pill use, iron therapy; 3= transfusion, hysterectomy, dilatation-curettage, replacement therapy A bleeding score 3 in males and 5 in females was considered significant