Continuous flow-left ventricular assist devices (CF-LVADs), including the frequently implanted centrifugal flow HeartWare ventricular assist device (HVAD), commonly serve as a bridge to orthotopic heart transplantation (OHT) for eligible candidates.1 Because exposure of blood to the foreign surface of the device may activate the coagulation cascade, systemic anticoagulation is recommended for all CF-LVAD recipients despite known bleeding risks in this population.2 A major contributor of perioperative and nonsurgical bleeding in CF-LVAD recipients is the loss of high molecular weight (HMW) von Willebrand factor (vWF) protein multimers and the effects this phenomenon has on platelet adhesion and aggregation. The presence of dysfunctional vWF protein characterizes a condition common to all CF-LVAD recipients known as acquired von Willebrand syndrome (AVWS).3
Emerging evidence suggests that AVWS is associated with increased blood product utilization at the time of CF-LVAD explantation and OHT.4 Perioperative bleeding related to AVWS has also recently been reported in a patient bridged with a short-term axial-flow Impella LVAD to a long-term CF-LVAD.5 The specific timing of AVWS recovery after OHT remains poorly characterized; however, recovery has been reported to occur between 2 and 34 months after transplantation.6 A temporal analysis of HMW multimer distribution at the time of CF-LVAD explantation and OHT is needed. We sought to determine the specific timing of HMW multimer recovery by serially quantifying vWF multimer ratios (vMRs) immediately after CF-LVAD explant and OHT. This case highlights the importance of understanding the mechanisms of AVWS-related perioperative bleeding, identifying methods of monitoring for AVWS resolution, and determining the precise timing of AVWS recovery after OHT in a patient bridged with a CF-LVAD.
Patient and Methods
Baseline plasma samples were collected and the following parameters were evaluated: fibrinogen, factor VIII activity, vWF antigen, ristocetin cofactor (vWF activity), and vWF multimer analysis. Citrated platelet poor plasma samples were collected immediately before OHT and at the following time points postoperatively: 0, 2, 4, 12, and 24 hours; 3, 7, and 14 days. Time 0 began upon the patient’s return to the intensive care unit. Plasma samples were size-fractionated by sodium dodecyl sulfate-agarose gel, in-gel immunostained with anti-vWF antibodies, and imaged. The images were then subjected to densitometric analysis (DA). von Willebrand factor multimer ratios were calculated by dividing the signal intensity of the 11 lowest multimer bands by the signal intensity of all remaining HMW bands. Ratios less than or equal to 20 were characterized as normal, whereas ratios greater than 20 indicated a loss of HMW multimers and were characterized as abnormal.7
A 45-year-old male sustained an acute myocardial infarction resulting in cardiogenic shock, despite successful revascularization, intraaortic balloon pump placement, and inotropic support. The patient underwent urgent evaluation for OHT and was deemed a suitable transplant candidate and underwent HVAD implantation. After 230 days of HVAD support without bleeding or thrombotic events, a suitable donor organ became available. Before OHT, the HVAD parameters (speed: 2,500 rpm, flow: 4.8 l/min, and pulsatility: 4) and hemodynamics (Doppler MAP 72 mmHg) were appropriate and stable. Preoperative vWF laboratory values and DA (Tables 1 and 2. and Figure 1.) indicated AVWS due to a loss of HWM multimers and a qualitative vWF dysfunction despite stable hematologic laboratory values. Intravenous 10 mg of vitamin K was given before OHT per institutional protocol. Intraoperatively, the patient required 8 units of red blood cells, 2 units of platelets, 2 units of cryoprecipitate, and 8 units of fresh frozen plasma due to generalized bleeding. Postoperative vWF laboratory values and DA were significantly improved compared with preoperative values, indicating rapid recovery of AVWS due to return of HMW multimers after CF-LVAD explantation. Densitometric analysis indicated that vMRs improved from a preoperative value of 197.8 (normal ≤20) to a postoperative value of 4.2 in less than 1 hour after sternal closure from CF-LVAD explantation and OHT. Routine hematologic laboratory parameters at these time points remained stable and were unable to indicate recovery of the HMW multimers as indicated by vWF-specific laboratory data and DA. vMRs remained within the normal range during the entire postoperative study period (14 days), indicating that HMW multimer recovery was durable. During the postoperative time period, the patient did not require further blood product transfusions and routine hematologic parameters remained within normal limits.
This case describes a detailed temporal analysis of HMW multimer recovery immediately after OHT in a patient who was bridged with a CF-LVAD. Despite an uncomplicated surgical course, the patient experienced significant intraoperative bleeding which may be related to CF-LVAD-induced AVWS. We observed an immediate and complete recovery of AVWS within the first few hours after CF-LVAD explantation and OHT. The recovery was confirmed by comparisons of vWF multimeric and DAs during the preoperative and immediate postoperative time periods indicating complete qualitative and quantitative HMW multimer recovery (Figure 2) despite normal hematologic laboratory parameters (Tables 1 and 2). Thus, standard hematologic measurements alone are not capable of indicating the presence or degree of AVWS. Understanding the mechanisms of CF-LVAD-related AVWS is critical for recognizing perioperative and postoperative bleeding diatheses in this patient population, especially in the context of increasing CF-LVAD implantation as a bridge to transplant.4
von Willebrand factor is a multimeric glycoprotein produced by endothelial cells. The ultra-large multimers of the protein are constitutively secreted into the plasma and must undergo cleavage by the metalloprotease a disintegrin and metalloproteinase with thrombospondin motifs (ADMATS)-13 to achieve the functional, physiologic multimer distribution. The HMW multimers normally circulate in plasma and are required to facilitate proper platelet adhesion and aggregation during hemostasis.3 Continuous flow-left ventricular assist devices induce both mechanical degradation (Figure 2A) and excessive proteolytic cleavage of vWF (Figure 2B) due to high shear stress from the CF-LVAD impeller and effects from continuous flow physiology causing unfolding and elongation of the vWF protein under nonphysiologic conditions. This process renders vWF more susceptible to cleavage by ADAMTS-13.3 Degradation of HMW multimers by either enzymatic or mechanical processes results in multimers that are of insufficient size to facilitate platelet adhesion and aggregation.6 Continuous flow-left ventricular assist device shear stress also activates platelets, which release additional ADAMTS-13 from their alpha granules and bind to HMW multimers, removing them from circulation (Figure 2C).3,6 Consequently, CF-LVAD recipients have qualitatively dysfunctional circulating plasma vWF which compromises platelet adhesion, aggregation, and clot formation, thus increasing bleeding risk (Figure 2).3,4
Our findings suggest that the recovery of HMW multimers was due to an immediate reduction in mechanical degradation and shear stress after CF-LVAD explant. This report does not account for removal of functional vWF from circulation as a result of unwarranted platelet activation and protein adsorption. A potential limitation of this study was the administration of two units of cryoprecipitate (a source of vWF) during surgery, approximately 2 hours before the first postoperative plasma collection. Although this may have increased circulating vWF levels, the vWF antigen level measured at time 0 hours was lower than any other postoperative time point (Tables 1 and 2), suggesting that the transfusions did not significantly impact our study conclusions.
This study has important clinical implications for cardiac transplant providers in this contemporary era of increased CF-LVAD utilization prior to OHT 1) intraoperative bleeding may be related to AVWS and should be treated accordingly; however postoperative bleeding is unlikely related to AVWS and therefore, alternative reasons for bleeding should be entertained; 2) routine assessment of preoperative and serial perioperative vWF profiles may assist clinicians in determining the degree of vWF dysfunction and therefore potential risk of bleeding, specifically at the time of CF-LVAD explantation and OHT. This study should be repeated in a larger cohort to definitively characterize the time to AVWS recovery and influence that this hemotologic abnormality has on perioperative bleeding in OHT recipients bridged with a CF-LVAD.
The authors thank the Vanderbilt Advanced Heart Failure Registry & Bio-repository (IRB# 131978), Vanderbilt Esoteric Coagulation for technical support, and Matthew C. Hackney, BSN, with the Vanderbilt Cardiovascular Intensive Care Unit.
1. Aaronson KD, Slaughter MS, Miller LW, et al.HeartWare Ventricular Assist Device (HVAD) Bridge to Transplant ADVANCE Trial Investigators. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation. 2012;125:3191–3200
2. Feldman D, Pamboukian SV, Teuteberg JJ, et al.International Society for Heart and Lung Transplantation. The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary. J Heart Lung Transplant. 2013;32:157–187
3. Dassanayaka S, Slaughter MS, Bartoli CR. Mechanistic pathway(s) of acquired von willebrand syndrome with a continuous-flow ventricular assist device: In vitro
findings. ASAIO J. 2013;59:123–129
4. Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol. 2010;56:1207–1213
5. Davis ME, Haglund NA, Tricarico NM, Keebler ME, Maltais S. Development of acquired von Willebrand syndrome during short-term micro axial pump support: Implications for bleeding in a patient bridged to a long-term continuous flow left ventricular assist device. ASAIO J. 2014;60(3):355–7
6. Klovaite J, Gustafsson F, Mortensen SA, Sander K, Nielsen LB. Severely impaired von Willebrand factor-dependent platelet aggregation in patients with a continuous-flow left ventricular assist device (HeartMate II). J Am Coll Cardiol. 2009;53:2162–2167
7. Pruthi RK, Daniels TM, Heit JA, Chen D, Owen WG, Nichols WL. Plasma von Willebrand factor multimer quantitative analysis by in-gel immunostaining and infrared fluorescent imaging. Thromb Res. 2010;126:543–549