Letter by Dimitrow and Undas Regarding Article, “Functional Impairment of von Willebrand Factor in Hypertrophic Cardiomyopathy: Relation to Rest and Exercise Obstruction”
To the Editor:
Recently, Le Tourneau et al1 demonstrated that in almost all patients with hypertrophic cardiomyopathy (HCM) and obstruction at rest, the von Willebrand factor (VWF) function is impaired through enhanced VWF proteolysis under high–shear-stress conditions. Importantly, a minimal resting left ventricular outflow tract (LVOT) gradient ranging from 13 to 17 mm Hg has also been shown to impair VWF function. The authors proposed an attractive cumulative effect hypothesis in HCM patients, with VWF impairment reflecting an average effect of daily nonobstructive and obstructive episodes. This hypothesis suggests that VWF impairment might become a marker of global obstruction burden useful in making decisions of intensity and strategy in (non)pharmacological treatment, especially in HCM patients with a latent or markedly labile LVOT gradient.
However, despite the high prevalence of VWF impairment in obstructive HCM, major spontaneous bleeds were rare.1 In our recent study,2 we demonstrated that LVOT obstruction is associated with increased thrombin generation and platelet activation, with the LVOT gradient being positively correlated with plasma levels of thrombin (thrombin-antithrombin complexes and prothrombin 1.2 fragments) and platelet markers (soluble CD40 ligand, β-thromboglobulin, and P-selectin). This finding suggests that LVOT obstruction might enhance the activation of blood coagulation in HCM patients by inducing high shear stress (due to turbulent flow) and hence compensate, to some extent, the hemostatic consequences of VWF-mediated hemostasis impairment. This discovery might explain, at least in part, the low annual incidence of major bleeds in HCM patients.1 In the literature, the coexistence of acquired prothrombotic risk factors, in some cases, may modulate thrombohemorrhagic balance, overcome the bleeding tendency, and lead to a milder clinical phenotype and, in rare cases, an increased probability of developing thrombotic complications.3–4 Moreover, we showed that C-reactive protein and interleukin-6 tend to be elevated in obstructive HCM, and their serum levels also correlate with the LVOT gradient.2 This result might contribute to increased thrombin formation because evidence suggests that enhanced inflammation activates blood coagulation.
In summary, overall hemostatic effects of LVOT obstruction in HCM should include procoagulant mechanisms of high shear stress. Both anatomic (systolic anterior motion of mitral leaflet with or without septal contact) and hemodynamic (pressure gradient) abnormalities generating turbulent flow might play a role in the prothrombotic state. It remains to be established to what extent these effects contribute to clinical phenotype (thrombohemorrhagic balance) of acquired VWF syndrome type 2A in this common genetic myocardial disease.
Le Tourneau T, Susen S, 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.