Increased bleeding risk in patients with aortic valvular stenosis: From ...

Thrombosis Research 139 (2016) 85–89

Contents lists available at ScienceDirect

Thrombosis Research journal homepage: www.elsevier.com/locate/thromres

Review Article

Increased bleeding risk in patients with aortic valvular stenosis: From new mechanisms to new therapies Joanna Natorska ⁎, Piotr Mazur, Anetta Undas a b

Institute of Cardiology, Jagiellonian University School of Medicine, Krakow, Poland John Paul II Hospital, Krakow, Poland

a r t i c l e

i n f o

Article history: Received 26 October 2015 Received in revised form 18 January 2016 Accepted 19 January 2016 Available online 21 January 2016 Keywords: Aortic stenosis Coagulation Bleeding von Willebrand factor Valve replacement Heyde syndrome

a b s t r a c t Aortic stenosis (AS), the most prevalent acquired valvular disease in the adults that requires invasive treatment, coexists with coagulopathy, resulting in bleeding in approximately 20% of patients. In the current review, we summarize the available knowledge on the mechanisms underlying the bleeding tendency observed in AS, and discuss potential compensatory mechanisms preventing most patients with severe AS from experiencing bleeding. We offer an update on Heyde's syndrome and other types of bleeding, and study extensively their pathobiology, providing insights into the new emerging concepts on coagulation regulation in AS. The focus is given to the impact of valvular interventions on coagulation abnormalities in AS. Both surgical valve replacement and transcatheter aortic valve implantation are discussed. Finally, we discuss current treatment recommendations in AS related bleeding. © 2016 Elsevier Ltd. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . 2. Heyde's syndrome . . . . . . . . . . . 3. von Willebrand factor and AS . . . . . . 4. Valvular interventions and bleeding in AS 5. Treatment recommendations . . . . . . 6. Conclusion . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

1. Introduction Aortic stenosis (AS) is the most common acquired valvular disease in adults that requires invasive treatment. In the United States alone almost 100,000 patients undergo surgical aortic valve replacement (SAVR) yearly, and the population requiring transcatheter valvular interventions is growing steadily. The prevalence of AS increases with age, and is 1.3% in subjects aged from 65 to 75 years, 2.4% in subjects from 75 to 85 years, and 4% in subjects N 85 years [1]. AS has repeatedly been reported to be associated with coagulation impairment related with bleeding

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

85 85 86 87 87 88 88 88 88

tendency (bleeding occurs approximately in 20% of AS patients [2]). Most commonly, mucous nasopharyngeal and cutaneous bleeds can be observed (Fig. 1). The incidence of 1–3% has been reported for gastrointestinal (GI) bleeding, the potentially most dangerous clinical scenario in severe AS [3]. In this review we discuss the clinical manifestations of ASrelated bleeding tendency and propose the molecular mechanisms that could underlie these pathologies. We also discuss the current concepts on potential compensatory mechanisms present in AS patients, in order to elucidate why most of them never experience bleeding episodes. 2. Heyde's syndrome

⁎ Corresponding author at: Institute of Cardiology, Jagiellonian University School of Medicine, 80 Pradnicka St., 31-202 Krakow, Poland. E-mail address: [email protected] (J. Natorska).

http://dx.doi.org/10.1016/j.thromres.2016.01.016 0049-3848/© 2016 Elsevier Ltd. All rights reserved.

In 1958, Edward C. Heyde described for the first time a series of 10 cases in which calcific AS coexisted with GI bleeding [4]. Most common

86

J. Natorska et al. / Thrombosis Research 139 (2016) 85–89

Fig. 1. Bleeding disorders in individuals with aortic stenosis who reported a spontaneous bleeding by Vincentelli et al. [2].

sites of GI bleeds were identified as angiodysplasia and the coexistence of AS and GI bleeding was termed the Heyde's syndrome (HS) [5]. The term angiodysplasia describes the most common, sporadic, acquired vascular abnormality found in the GI tract. Angiodysplastic vessels (thin, tortuous, with no internal elastic layer) may occur anywhere in the GI tract, but the most common locations are the right colon, caecum, and jejunum [6]. Although the prevalence of GI angiodysplasia in the general population is not well known, its incidence clearly rises with age. AS is an age-related lesion too, with increased prevalence in the elderly similarly to GI angiodysplasia [7]. Furthermore, compared to the normal aortic valve, jet-like flow and perturbed flow patterns are observed in patients with AS, resulting in increased shear stress [8]. Angiodysplasia, associated with progressive venular dilatation and concomitant incompetence of precapillary sphincters, results in arteriovenous malformation. The high rate of blood flow through these malformations can arguably result in shear rates higher than would usually be found in normal vessels [7]. The link between AS and GI bleeding in HS was questioned by several relatively small studies which found no relationship between angiodysplasia-related GI bleeding and AS. Nevertheless, compelling evidence supporting the HS existence derives from the complete resolution of GI bleeding commonly reported after SAVR. Recently, Thompson et al. reported 57 patients with HS treated with SAVR, of whom 79% were completely free from GI bleeding during median follow-up of 4.4 years, and in the remaining subjects the risk of this complication was reduced by half [6]. The present knowledge indicates that the common morphologic denominator of HS-underlying conditions is concurrent aortic valve and GI mucosa senile degeneration. Interestingly, however, although SAVR resolves GI bleeding, it does not cause regression of angiodysplasia, which remains visible during endoscopy after surgery [9]. This led to a conclusion that the molecular mechanism leading to bleeding must be AS related. 3. von Willebrand factor and AS In 1992 Warkentin et al. discovered acquired type 2A von Willebrand syndrome accompanying AS, characterized by an acquired qualitative defect of VWF associated with the loss of VWF high molecular weight multimers (HMWM) [7]. The loss of HMWM was proposed as a missing link and the major mechanism in the pathogenesis of GI bleeding in AS. VWF is a multimeric glycoprotein essential for normal hemostasis that is found in blood plasma, platelet α-granules and subendothelial

connective tissue. The half-life of VWF in circulation is 12–20 h and its plasma level ranges between 50 and 200 IU/dL in the general population [10]. Several other factors, besides blood type, also influence the VWF levels, including single-nucleotide polymorphisms in the VWF gene, age, thyroid status and stress. VWF is produced as a polypeptide and assembled from identical monomers into multimers that may range in size from 500 kDa to N 20,000 kDa. This HMWM are hyperactive in recruiting circulating platelets to the site of endothelial activation or injury. Once VWF is immobilized in subendothelial connective tissue, platelets recognize and adhere to it by interaction with platelet glycoprotein GpIb-IX-V complex, followed by platelets aggregation initiated by activated GpIIb-IIIa complex. Under normal conditions the VWF HMWM released into solution rapidly assume a “closed” conformation that is highly resistant to proteolysis by a specific metalloprotease ADAMTS13 (ADAMTS13; A, Disintegrin And Metalloproteinase with ThromboSpondin) in the absence of shear stress. This protein is probably constitutively secreted from cells as an active protease, and its amount is about 100-fold lower than that of VWF (100 ng/mL) produced in vitro under the same conditions [11]. Since there has been no inhibitor to ADAMTS13, it seems that ADAMTS13 function must be regulated at the substrate level. Under high shear stress the conformational structure of the VWF can be altered and regain its sensitivity to ADAMTS13, by exposure of the bond between Tyr842 and Met843, [12]. On one hand, ADAMTS13 released from endothelial cells may cleave newly formed HMWM on the cell surface, providing an additional mechanism to maintain a VWFfree surface [11]. On the other, under high fluid shear stress ADAMTS13 drives increased VWF proteolysis, leads to reduction of the plasma VWF activity to antigen ratio, and increases the risk of bleeding [13]. Such high shear conditions can be found in AS, where blood components pass the stenotic aortic orifice at greater than normal velocity. In patients with severe AS, ADAMTS13 activity was reported to decrease significantly after SAVR (generally, normal ranges for both ADAMTS13 antigen and activity are 50–150 IU/dL, however they depend on the method used and there is no international standardization), but not after balloon valvuloplasty [14]. This suggests that ADAMTS13 contributes to coagulation abnormalities in AS on one hand, and that ADAMTS13 decrease after the surgery is one of the mechanisms contributing to hematologic benefit of SAVR in severe AS. We previously reported that ADAMTS13 antigen, along with VWF ristocetin cofactor activity, predicted occurrence of elevated postoperative drainage in cardiosurgical patients [15]. However, in patients undergoing SAVR for severe AS there is no evidence on the influence of VWF multimers structure and platelet function on postoperative chest tube output volumes [16]. This might potentially be attributed to rapid recovery of VWF in the perioperative period after valve replacement. Also, clinically relevant bleeds reported by AS patients appear to be less common in clinical practice than would be expected. This may suggest the existence of mechanisms promoting efficient hemostasis despite the decreased levels of HMWM. These mechanisms might compensate, at least to some extent, VWF deficiency, and their identification may explain why majority of AS patients do not experience bleeding episodes (on one hand not all AS patients present decreased HMWM – this abnormality is observed in about 80% of the severe AS patients [2,16], on the other hand not all AS patients with decreased HMWM bleed). In addition to its effects on VWF, it is also known that shear stress induces tissue factor procoagulant activity [17], resulting in enhanced thrombin generation [18]. Another aspect of high shear stress conditions in AS is microparticles generation, likewise contributing to increased thrombin generation [19]. Moreover, the enhanced thrombin generation reported both in circulating blood [18] and within valve [20], as well as simultaneous increased platelet activation [18] might in part counterbalance the primary hemostasis impairment and in turn lead to faster formation of fibrin clots, additionally more resistant to lysis, as proved by prolonged clot lysis time [21]. Higher


concentrations of thrombin may potentiate platelet activation and aggregation, reducing the risk of bleeding from the bleeding-prone lesions (Fig. 2). The role of compensatory hemostatic mechanisms and their influence on the course of the disease, however, remains to be proven clinically. 4. Valvular interventions and bleeding in AS SAVR definitively stops GI bleeding in most HS patients [6] and VWF HMWM, preoperatively decreased, recover after SAVR [2,22]. Although only in two female HS patients, Warkentin et al. reported long-term recovery of HMWM, with no bleeding recurrence during the follow-up as long as 10 years [9]. Interestingly, in patients with the patientprosthesis mismatch (PPM), the hematological changes recur at 6 months after SAVR, despite the initial normalization [2]. Late recurrence of bleeding was also reported in valve bioprosthesis degeneration (with prompt bleeding cessation after re-do SAVR) [23]. This indicates that resolution of AS (either primary or secondary to prosthesis degeneration) treats the AS related von Willebrand syndrome is curative in AS related bleeding. Recently, a growing population of AS patients with high operative risk undergoes transcutaneous aortic valve intervention (TAVI). In the TAVI cohort, HS also occurs with incidence of 1.7%, increasing the periprocedural bleeding risk [24]. TAVI, similarly to SAVR, is an effective therapeutic method in the setting of HS [24]. The restoration of VWF multimer pattern after TAVI was confirmed by Spangenberg in 95 cases [25]. HMWM recover very quickly after the valvular intervention – Van Belle et al. recently reported that VWF HMWM are restored

87

only minutes after TAVI [26]. Interestingly, in the presence of a residual paravalvular leakage, the HMWM recovery is absent, making it potentially possible to monitor the correctness of valve implantation with VWF as a biomarker of restored linear flow and decreased shear stress [25,26]. These VWF HMWM alterations could be assessed, among others, using a platelet function analyzer-closure time adenine diphosphate (PFA-CADP), which makes it potentially possible to monitor VWF recovery in real-time during TAVI procedure (although it should be mentioned that PFA-CADP is not the diagnostic method of first choice in VWF defects) [26]. It must be highlighted that in the setting of ongoing GI bleeding the peri-procedural bleeding risk can still be high. Balloon aortic valvuloplasty (BAV) was reported to improve VWF (but not ADAMTS13) in AS patients [14], and in selected cases, the stepwise approach with initial BAV may be beneficial in terms of post-TAVI bleeding risk reduction (related to antiplatelet therapy in HS; TAVI is than performed after VWF normalization). It is not known, whether in HS secondary to aortic valve bioprosthesis degeneration a valve-in-valve TAVI procedures could be curative. 5. Treatment recommendations Treatment of VWD type 2A includes factor VIII, VWF concentrates and desmopressin [27]. In VWD diagnosis, the sensitivity of the screening tests is insufficient for exclusion of the disease and specific measurements of plasma VWF-Ag (vWF antigen), VWF-RCo (ristocetin cofactor activity), and factor VIII are the baseline [28]. The multimeric pattern of VWF is studied by gel electrophoresis [28]. Still, the PFA-CADP is a

Fig. 2. Ambivalent effects of aortic stenosis on (A) primary hemostasis impairment and (B) activation of coagulation. Under high fluid shear stress ADAMTS 13 ( ) drives increased von ) proteolysis, leading to reduction of the plasma VWF activity, resulting in reduced recruitment of circulating platelets ( ) to the site Willebrand high molecular weight multimers ( of endothelial activation and increased risk of bleeding. Shear stress induces tissue factor procoagulant activity and leads to the generation of tissue factor containing microparticles ( ) resulting in enhanced thrombin generation which in turn leads to the faster formation of fibrin clots (

), platelet activation and aggregation and limited bleeding.

88


sensitive way to screen for HMWM defects [29] and can be assessed by a small bed-side whole blood analyzer (PFA-100). [9]. Although screening of AS patients for VWD type 2A is not a routine practice in most cardiac surgery units, Steinlechner et al. demonstrated in a randomized doubleblind placebo-controlled trial that patients with severe AS undergoing SAVR, benefit from preoperative desmopressin infusion, particularly in the setting of impaired platelet function, as measured by PFA-100 (desmopressin treatment reduced the postoperative blood loss by 42%) [30]. HS is not included in the current AS treatment guidelines, however some authors, based on the resolution of GI bleeding following SAVR, support the recommendation for SAVR in severe HS [3,27]. It is not known whether the existence of preoperative AS-related bleeding syndrome should influence the choice of prosthesis. In the light of the current data, TAVI also appears to be a treatment option for HS patients [24]. If SAVR/TAVI is not considered an option, general rules of GI bleeding management in VWD should be applied, as outlined by Franchini et al. [31]. Briefly, in case of acute bleeding, if the location of angiodsyplasia causing bleeding is known, surgical, endoscopic (thermo-, electro- or photocoagulation) or angiographic embolization therapy should be sought. The conservative treatment includes supplementation of plasma-derived VWF/FVIII concentrates (40–60 U/ kg once daily) until bleeding stops as the first-choice strategy, however repeated blood product transfusions may be inevitable [31]. In the setting of GI bleeding complicating VWD and angiodysplasia, the treatment is difficult. Recurrence is frequent and bleeding severity tends to increase with patient's age. If the first line of treatment fails, the alternative approaches for refractory bleeding can be considered, including therapy with octreotide, estrogen-progesterone combination and thalidomide [31]. Octreotide (and somatostatin) are used based on their potential in decreasing blood pressure in portal venous system [5,9]. Combined treatment with estrogen and progesterone has been used to reduce bleeding from angiodysplasia, but the mechanism of action is not well understood. It could, speculatively, involve structural changes in blood vessels or other enhancement of hemostasis, as the improvement of VWF or multimer composition have not been observed [9]. Thalidomide inhibits angiogenesis and promotes vessel maturation [32]. The data on desmopressin or factor VIII and VWF concentrations use in patients with HS are lacking. In VWD related angiodysplasia, long term prophylaxis with VWF/FVIII concentrates appears to be a viable option, however there is no data to support this approach in case of AS. The decision on appropriate treatment has to be made on case-bycase basis, keeping in mind the valvular contribution to the pathophysiology of HS and other bleeding types in AS.

6. Conclusion This review summarizes the current knowledge on the associations between AS and coagulation abnormalities. We demonstrate the relationship of AS and VWF deficiency and correlate it to clinical findings. In the light of current evidence, HS is likely resulting from AS, VWF deficiency and GI angiodysplasia, but novel molecular mechanism might partially counterbalance the loss of VWF HMWM and normalize the bleeding risk in some AS patients. Valvular interventions, either surgical or percutaneous, may have a significant impact on bleeding and the underlying hematologic abnormalities found in AS, but other therapeutic approaches also discussed.

Funding The study was supported by the grant from the Polish Ministry of Science to AU (N N402 383338) and by a grant from the Jagiellonian University to PM (K/ZDS/005695).

Acknowledgements None.

References [1] P.G. Supino, J.S. Borer, J. Preibisz, A. Bornstein, The epidemiology of valvular heart disease: a growing public health problem, Heart Fail Clin 2 (2006) 379–393. [2] A. Vincentelli, S. Susen, T. Le Tourneau, I. Six, O. Fabre, F. Juthier, et al., Acquired von Willebrand syndrome in aortic stenosis, N. Engl. J. Med. 349 (2003) 343–349. [3] G.E. Pate, A. Mulligan, An epidemiological study of Heyde's syndrome: an association between aortic stenosis and gastrointestinal bleeding, J Heart Valve Dis 13 (2004) 713–716. [4] E. Heyde, Gastrointestinal bleeding in aortic stenosis (Letter), N. Engl. J. Med. 259 (1958) 196. [5] T.E. Warkentin, J.C. Moore, Heyde's syndrome: from controversy to mainstream, Thromb. Haemost. 103 (2010) 251–253. [6] J.L. Thompson 3rd, H.V. Schaff, J.A. Dearani, S.J. Park, T.M. Sundt 3rd, R.M. Suri, et al., Risk of recurrent gastrointestinal bleeding after aortic valve replacement in patients with Heyde syndrome, J. Thorac. Cardiovasc. Surg. 144 (2012) 112–116. [7] T.E. Warkentin, J.C. Moore, D.G. Morgan, Aortic stenosis and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand's disease the link? Lancet 340 (1992) 35–37. [8] M. Back, T.C. Gasser, J.B. Michel, G. Caligiuri, Biomechanical factors in the biology of aortic wall and aortic valve diseases, Cardiovasc. Res. 99 (2013) 232–241. [9] T.E. Warkentin, J.C. Moore, S.S. Anand, E.M. Lonn, D.G. Morgan, Gastrointestinal bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome, Transfus. Med. Rev. 17 (2003) 272–286. [10] J.E. Sadler, Low von Willebrand factor: sometimes a risk factor and sometimes a disease, Hematology Am Soc Hematol Educ Program 106-12 (2009). [11] N.A. Turner, L. Nolasco, Z.M. Ruggeri, J.L. Moake, Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage, Blood 114 (2009) 5102–5111. [12] H.M. Tsai, I.I. Sussman, R.L. Nagel, Shear stress enhances the proteolysis of von Willebrand factor in normal plasma, Blood 83 (1994) 2171–2179. [13] F.I. Pareti, A. Lattuada, C. Bressi, M. Zanobini, A. Sala, A. Steffan, et al., Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis, Circulation 102 (2000) 1290–1295. [14] J. Bander, S. Elmariah, L.M. Aledort, J. Dlott, P. Stelzer, J.L. Halperin, et al., Changes in von Willebrand factor-cleaving protease (ADAMTS-13) in patients with aortic stenosis undergoing valve replacement or balloon valvuloplasty, Thromb. Haemost. 108 (2012) 86–93. [15] P. Mazur, D. Plicner, J. Zdziarska, J. Sadowski, A. Undas, Decreased von Willebrand factor ristocetin cofactor activity and increased ADAMTS13 antigen increase postoperative drainage after coronary artery bypass grafting, Eur. J. Cardiothorac. Surg. 45 (2014) e26–e32. [16] D. Bolliger, S. Dell-Kuster, M.D. Seeberger, K.A. Tanaka, M. Gregor, U. Zenklusen, et al., Impact of loss of high-molecular-weight von Willebrand factor multimers on blood loss after aortic valve replacement, Br. J. Anaesth. 108 (2012) 754–762. [17] M.C. Lin, F. Almus-Jacobs, H.H. Chen, G.C. Parry, N. Mackman, J.Y. Shyy, et al., Shear stress induction of the tissue factor gene, J. Clin. Invest. 99 (1997) 737–744. [18] J. Natorska, K. Bykowska, M. Hlawaty, G. Marek, J. Sadowski, A. Undas, Increased thrombin generation and platelet activation are associated with deficiency in high molecular weight multimers of von Willebrand factor in patients with moderateto-severe aortic stenosis, Heart 97 (2011) 2023–2028. [19] P. Diehl, F. Nagy, V. Sossong, T. Helbing, F. Beyersdorf, M. Olschewski, et al., Increased levels of circulating microparticles in patients with severe aortic valve stenosis, Thromb. Haemost. 99 (2008) 711–719. [20] J. Breyne, F. Juthier, D. Corseaux, S. Marechaux, C. Zawadzki, E. Jeanpierre, et al., Atherosclerotic-like process in aortic stenosis: activation of the tissue factorthrombin pathway and potential role through osteopontin alteration, Atherosclerosis 213 (2010) 369–376. [21] J. Natorska, E. Wypasek, G. Grudzien, J. Sadowski, A. Undas, Impaired fibrinolysis is associated with the severity of aortic stenosis in humans, J. Thromb. Haemost. 11 (2013) 733–740. [22] A. Morishima, A. Marui, T. Shimamoto, Y. Saji, K. Tambara, T. Nishina, et al., Successful aortic valve replacement for Heyde syndrome with confirmed hematologic recovery, Ann. Thorac. Surg. 83 (2007) 287–288. [23] H. Soran, M. Lewis, P.J. Whorwell, Bleeding angiodysplasia: should we concentrate more on the aortic valve than on the bowel? Int. J. Clin. Pract. 56 (2002) 155–156. [24] C. Godino, L. Lauretta, A.G. Pavon, A. Mangieri, G. Viani, A. Chieffo, et al., Heyde's syndrome incidence and outcome in patients undergoing transcatheter aortic valve implantation, J. Am. Coll. Cardiol. 61 (2013) 687–689. [25] T. Spangenberg, U. Budde, D. Schewel, C. Frerker, T. Thielsen, K.H. Kuck, et al., Treatment of acquired von Willebrand syndrome in aortic stenosis with transcatheter aortic valve replacement, JACC Cardiovasc Interv 8 (2015) 692–700. [26] E. Van Belle, A. Rauch, A. Vincentelli, E. Jeanpierre, P. Legendre, F. Juthier, et al., von Willebrand factor as a biological sensor of blood flow to monitor percutaneous aortic valve interventions, Circ. Res. (2015). [27] G.E. Pate, M. Chandavimol, S.C. Naiman, J.G. Webb, Heyde's syndrome: a review, J Heart Valve Dis 13 (2004) 701–712. [28] A. Veyradier, E. Fressinaud, D. Meyer, Laboratory diagnosis of von Willebrand disease, Int J Clin Lab Res 28 (1998) 201–210.

J. Natorska et al. / Thrombosis Research 139 (2016) 85–89 [29] E. Fressinaud, A. Veyradier, F. Truchaud, I. Martin, C. Boyer-Neumann, M. Trossaert, et al., Screening for von Willebrand disease with a new analyzer using high shear stress: a study of 60 cases, Blood 91 (1998) 1325–1331. [30] B. Steinlechner, P. Zeidler, E. Base, B. Birkenberg, H.J. Ankersmit, M. Spannagl, et al., Patients with severe aortic valve stenosis and impaired platelet function benefit from preoperative desmopressin infusion, Ann. Thorac. Surg. 91 (2011) 1420–1426.

89

[31] M. Franchini, P.M. Mannucci, Gastrointestinal angiodysplasia and bleeding in von Willebrand disease, Thromb. Haemost. 112 (2014) 427–431. [32] M. Franchini, F. Frattini, S. Crestani, C. Bonfanti, Novel treatments for epistaxis in hereditary hemorrhagic telangiectasia: a systematic review of the clinical experience with thalidomide, J. Thromb. Thrombolysis 36 (2013) 355–357.