Response to Letter Regarding Article, “Functional Impairment of von Willebrand Factor in Hypertrophic Cardiomyopathy: Relation to Rest and Exercise Obstruction”
We thank Drs Dimitrow and Undas for their interest and commentaries on our article regarding the impairment of von Willebrand factor (VWF) in the obstructive form of hypertrophic cardiomyopathy (HCM). We agree that spontaneous major bleedings were rare in our study despite the high frequency of acquired von Willebrand syndrome in patients with an obstructive form of HCM.1 In patients with aortic stenosis, cumulative evidence shows that VWF impairment (shear-stress-induced proteolysis of the largest multimers of VWF) favors or enhances spontaneous bleeding from a preexisting vascular lesion, mainly gastrointestinal angiodysplasia.2,3 In other words, spontaneous major bleedings in this setting are related to the association of VWF impairment and the presence of bleeding-prone lesions.2,3 Angiodysplasia and aortic stenosis are 2 diseases of the elderly. Aortic stenosis involves ≈2% of patients over age 65,4 and angiodysplasia affects ≈5% of patients over age 65.3 The association of these 2 diseases is therefore more frequent with age. Moreover, angiodysplasia is increasingly recognized as a major cause of bleeding in older people. By contrast to aortic stenosis, HCM involves younger patients (ages 42±17 in our series), and the association with gastrointestinal angiodysplasia is therefore less frequent and could account for the relative low risk of bleeding. However, the incidence of spontaneous major bleeding was 1.77% per year (95% confidence interval, 0.5% to 4.5%) in patients with the obstructive form of HCM, which could be compared with the bleeding risk in patients with a mitral or aortic mechanical valve (1% to 2% per year). Finally, because the potential link between obstruction and bleeding risk through VWF impairment was ignored in this setting, this pathological association has likely been underreported in the literature.
We have read with interest the recent article by Dimitrow et al.5 We agree with the authors that the balance between prothrombotic alterations and VWF impairment might also explain, in part, the relatively low incidence of spontaneous major bleedings in patients with an obstructive form of HCM. Nevertheless, the observed enhancement of thrombin generation in the systemic circulation does not necessarily signify that hemostasis is effective in high-shear-stress lesions because high-molecular-weight multimers of VWF are required in such a setting. Closure times of platelet function analyzer 100, a whole blood evaluation of primary hemostasis reflecting shear-induced platelet adhesion, were found to be impaired in patients with obstructive HCM.1 However, in a previous work in patients with aortic stenosis,2 we found no difference in the measured biological features between patients with and without a history of bleeding, suggesting that bleeding depends critically on the presence of bleeding-prone lesions. Thus, in HCM, primary hemostasis impairment may be clinically relevant only in the case of such lesions and independently of prothrombotic alterations.
Le Tourneau T, Caron C, Millaire A, Maréchaux S, Polge AS, Vincentelli A, Mouquet F, Ennezat PV, Lamblin N, de Groote P, Van Belle E, Deklunder G, Goudemand J, Bauters C, Jude B. Functional impairment of von Willebrand Factor in hypertrophic cardiomyopathy: relation to rest and exercise obstruction. Circulation. 2008; 118: 1550–1557.
Dimitrow PP, Undas A, Bober M, Tracz W, Dubiel JS. Obstructive hypertrophic cardiomyopathy is associated with enhanced thrombin generation and platelet activation. Heart. 2008; 94: e21.