Case report
Acquired von Willebrand Syndrome in a Child Following Berlin Heart EXCOR Pediatric Ventricular Assist Device Implantation: Case Report and Concise Literature Review
World Journal for Pediatric and Congenital Heart Surgery 2014, Vol. 5(4) 592-598 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2150135114539521 pch.sagepub.com
John P. Costello, MD1,2, Yaser A. Diab, MD3, Michael Philippe-Auguste, BS1, Melissa B. Jones, MSN, APRN, CPNP-AC4, Venkat Shankar, MD4, Kenneth D. Friedman, MD5, and Dilip S. Nath, MD1
Abstract The development of acquired von Willebrand syndrome (AVWS) after placement of a pulsatile-flow left ventricular assist device (LVAD) is rare and only recently recognized. We report the case of a young infant who was diagnosed with ventricular assist device (VAD)-related AVWS following implantation of a Berlin Heart EXCOR Pediatric Ventricular Assist Device (Berlin Heart Inc., The Woodlands, Texas, USA) for treatment of severe heart failure. Despite significant bleeding, the patient was successfully managed with von Willebrand factor-containing concentrate until VAD explantation led to definitive resolution of the AVWS. This case demonstrates that the possibility of this diagnosis should be considered in pediatric patients when extensive, nonsurgical bleeding is encountered after pulsatile-flow VAD implantation. Keywords circulatory assist devices, heart failure, hematology, blood Submitted February 20, 2014; Accepted May 19, 2014.
Introduction
Case Presentation
Pediatric and adult patients with severe heart failure often require mechanical circulatory support in order to provide adequate cardiac output for continued survival. Ventricular assist devices (VADs) are increasingly utilized in these critically ill patient populations to provide this ongoing cardiac support either as a bridge to transplantation or as destination therapy. Currently, two categories of VADs are available for clinical use: continuous-flow devices and pulsatile-flow devices. Although VADs have revolutionized the management of heart failure, their use is not free from potential complications. One of the unique complications associated with VAD support is acquired von Willebrand syndrome (AVWS). This acquired coagulopathy is known to occur infrequently following implantation of continuous-flow VADs; however, the development of AVWS in patients with pulsatile-flow devices is rarely reported.1 We present a case of severe AVWS that developed in a young infant following implantation of a pulsatile-flow left ventricular assist device (LVAD), which led to significant postoperative bleeding requiring multiple interventions.
A seven-month-old, 6.7-kg (body surface area: 0.35 m2) previously healthy female patient presented to our institution’s emergency department with labored breathing and cough of three days duration. Two days prior to presentation, the patient
1 Division of Cardiovascular Surgery, Children’s National Health System, Washington, DC, USA 2 The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Health System, Washington, DC, USA 3 Department of Hematology, Children’s National Health System, Washington, DC, USA 4 Department of Critical Care Medicine, Children’s National Health System, Washington, DC, USA 5 Hemostasis Reference Laboratory, Blood Center of Wisconsin, Milwaukee, WI, USA
Corresponding Author: Dilip S. Nath, Division of Cardiovascular Surgery, Children’s National Health System, 111 Michigan Avenue, NW, Washington, DC 20010, USA. Email: [email protected]
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Abbreviations and Acronyms ADAMTS-13 AVWS FVIII LV LVAD MW PFA VAD VWF
a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 acquired von Willebrand syndrome factor VIII left ventricular left ventricular assist device molecular weight platelet function analyzer ventricular assist device von Willebrand factor
was started on nebulized albuterol as an outpatient. Despite this therapy, her labored breathing continued to worsen. On presentation to the emergency department, she was found to be in severe respiratory distress requiring immediate transfer to the pediatric intensive care unit, endotracheal intubation, and mechanical ventilation. During intubation, she had cardiovascular collapse requiring a brief period of cardiopulmonary resuscitation. Subsequent echocardiography revealed severe left ventricular (LV) hypertrophy, LV dilation, severely decreased LV function (ejection fraction of 30%), and a moderate pericardial effusion. A diagnosis of cardiogenic shock of unclear etiology was made. The patient was started on intravenous dopamine and milrinone infusions resulting in improvement in her hemodynamics. An extensive diagnostic workup did not reveal any clear etiology for the severe and persistent heart failure. Repeat echocardiography continued to show persistent poor cardiac contractility without any evidence of improvement, despite maximal medical management. In order to support the patient’s circulatory system and wean off mechanical ventilation, a pulsatile-flow LVAD (Berlin Heart EXCOR Pediatric VAD; Berlin Heart Inc., The Woodlands, Texas, USA—10 mL pump, 6 mm inflow cannula, and 6 mm outflow cannula) was implanted. In order to place the inflow cannula, a small core of muscle was first sharply excised from the LV apex. The VAD inflow cannula was then placed into the LV through this opening and secured in place. Next, a Gore-Tex tube graft was anastomosed to the ascending aorta in an end-to-side fashion, and the VAD outflow cannula was placed into this graft and secured in place. Anticoagulation was initiated according to the Edmonton protocol.2 Initial pump settings were pulse rate: 100 beats/min, systolic drive pressure: 210 mm Hg, diastolic suction pressure: 45 mm Hg, and relative systolic duration: 35%. As expected, these settings were changed periodically throughout the hospitalization in response to the patient’s clinical status. Initial filling of the LVAD was found to be suboptimal, and the patient returned to the operating room on postoperative day 1 for revision of the VAD cannulae. Despite successful VAD implantation, the patient had extensive postoperative mediastinal bleeding and required eight chest re-explorations over the next 15 days. In addition, two complete pump changes were necessary due to formation of fibrin strands in the pump as a
result of interruption of anticoagulation and the significant blood product replacement, which included fresh frozen plasma, platelets, and cryoprecipitate, that was undertaken (Figures 1 and 2). No surgical source of bleeding was found despite multiple explorations, and the extent and persistence of the bleeding were disproportionate to the degree of anticoagulation that the patient was then receiving (subtherapeutic unfractionated heparin infusion). An extensive hemostatic laboratory evaluation was undertaken, which revealed an abnormal platelet function analyzer (PFA-100) assay, increased von Willebrand factor (VWF) propeptide, and reduced high-molecular-weight (MW) VWF multimers with absent ultrahigh-MW VWF multimers on quantitative VWF multimer analysis (Table 1 and Figure 3). These results were consistent with AVWS type 2A. Consequently, the patient was started on low-dose continuous infusion of the VWF/factor VIII (FVIII) concentrate (Humate-P; CSL Behring, King of Prussia, Pennsylvania) at 1.7 units/kg/h, which immediately led to a significant decrease in and ultimate cessation of bleeding. All laboratory testing for cardiomyopathy and myocarditis was negative. Unfortunately, a cardiac muscle specimen that was obtained from the LV apex at the time of initial VAD implantation was lost prior to histologic examination so no microscopic assessment of the cardiac muscle could be obtained. Once adequate hemostasis was achieved, unfractionated heparin infusion was restarted and successfully titrated up to a full therapeutic dose with a target antifactor Xa activity of 0.35 to 0.5 units/mL. Despite the patient’s clinical response to the Humate-P (CSL Behring, King of Prussia, Pennsylvania, USA) infusion, the PFA-100 assay remained persistently abnormal (Figure 1). In addition, FVIII activity became significantly elevated while on Humate-P infusion (Figure 2). The VAD pump remained free of any further visible fibrin deposits or thrombi. However, 12 days after initiation of Humate-P therapy, the patient was noted to have decreased movement of her left upper extremity. Head imaging revealed a subacute right middle cerebral artery embolic stroke, and no further intervention was taken. After 22 days of VAD support, follow-up echocardiography demonstrated significantly improved biventricular function, which continued to improve over the next week. The patient was placed on the Berlin Heart EXCOR Pediatric VAD weaning protocol 43 days after initial implantation, and the VAD was successfully explanted 52 days after implantation. Following explantation, the Humate-P infusion was immediately discontinued. Follow-up echocardiography after VAD explantation revealed the presence of a small left intraventricular cardiac thrombus, and, therefore, the patient was started on therapeutic anticoagulation with enoxaparin, which was well tolerated without any bleeding. The patient was subsequently discharged to an inpatient rehabilitation facility to continue her recovery. Echocardiography performed at the time of discharge revealed an LV ejection fraction of 51%. Repeat laboratory analysis one week after explantation showed normalization of the patient’s high-MW VWF multimer levels and PFA-100, confirming resolution of the AVWS (Table 1 and Figures 1 and 3). The patient
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Figure 1. Clinical course of patient and the effect of Humate-P infusion on platelet function analyzer 100 (PFA-100).
Figure 2. Clinical course of patient and the effect of Humate-P infusion on factor VIII (FVIII) activity levels.
remained at the inpatient rehabilitation facility following discharge secondary to (1) the inability to tolerate oral feeds and (2) concerns for a suboptimal home/family support system.
On outpatient follow-up three months after discharge, the patient had normal cardiac function, resolution of the LV thrombus, normal renal function, and improving motor
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Table 1. Summary of Hemostatic Laboratory Evaluation at Relevant Time Points.a Laboratory Test
Postimplantation #1
Hematocrit, % 32.1 Platelet count, K/mcl 142 PT (INR), seconds 13.9 (1.13) APTT, seconds 49.1 Fibrinogen, mg/dL 398 VWF:Ag, % 86 VWF:RCo, % 91 VWF:CB, % – FVIII, % 122 VWF propeptide, % – VWF:RCo/Ag ratio 1.05 VWF:CB/Ag ratio – VWF propeptide/Ag ratio – PFA-100 Col/Epi CT, seconds 219 Col/ADP CT, seconds >300 VWF quantitative multimer analysis High-MW multimers, % 12 (absent ultrahigh-MW multimers) Intermediate-MW multi60 mers, % Low-MW multimers, % 28
Postimplantation #2
Postexplantation
Normal Reference Range
30.9 172 12.7 (1.01) 39.3 581 236 214 237 235 246 0.9 1 1.04
30.4 350 11.7 (0.91) 27.5 497 223 218 – 507 – 0.98 – –
30.9-39.7 150-400 11.4-14 (0.88-1.14) 20.8-34 203-467 50-160 48-200 59-249 50-200 62-183 0.7 0.7 0.1-0.43
>300 >300
116 82
92.2-191.6 55.4-130.6
7 (absent ultrahigh-MW multimers) 67
23
19 (high-MW multimers)
26
20
57
Abbreviations: PT, prothrombin time; INR, international normalized ratio; APTT, activated partial thromboplastin time; VWF:Ag, VWF antigen; VWF:RCo, VWF ristocetin cofactor activity; VWF:CB, VWF collagen binding activity; FVIII, factor VIII; PFA-100, platelet function analyzer 100; Col/Epi CT, collagen/epinephrine closure time; Col/ADP CT, collagen/ADP closure time; MW, molecular weight; VWF, von Willebrand factor. a Postimplantation laboratories were obtained prior to initiation of Humate-P infusion, while postexplantation laboratories were obtained one week after stopping Humate-P infusion.
function of the left upper extremity. However, due to her persistent feeding issues, she was deemed to be a suitable candidate for Nissen fundoplication and gastric tube placement at our institution. This procedure was uneventful, and the patient’s postoperative echocardiogram was unchanged from baseline. Unfortunately, the patient had a rapid decline in renal function on postoperative day 5. Subsequently, she experienced sudden bradycardia, which progressed to cardiac arrest. Resuscitation was unsuccessful, and the family declined extracorporeal membrane oxygenation therapy. No autopsy was completed.
Comment Historically, VADs were used short term to support patients recovering from myocardial infarctions with reversible damage and in patients awaiting heart transplantation.5 As the technology of these devices has improved, VADs have been increasingly utilized to help sustain patients who need cardiac support for extended periods.5 Recently, pediatric patients have also benefited from the incorporation of VADs into the treatment strategy of heart failure requiring mechanical circulatory support. A recent study demonstrated the Berlin Heart EXCOR Pediatric VAD to be superior to extracorporeal membrane oxygenation for bridge-to-transplantation.6 Von Willebrand factor, a multimeric glycoprotein found in endothelial cells and platelets, plays key roles in hemostasis by facilitating platelet adhesion to damaged endothelium and
chaperoning FVIII to reduce its clearance.7 Specifically, the high-MW VWF multimers play a critical role in promoting platelet adhesion under conditions of high shear stress resulting from rapid blood flow.8 Acquired von Willebrand syndrome is a clinicopathologic syndrome caused by a variety of heterogeneous disorders and characterized by an acquired bleeding tendency and laboratory tests showing structural or functional defects of VW protein.9 Acquired von Willebrand syndrome type 2A associated with cardiovascular disorders with abnormally high shear stress is increasingly recognized in both children and adults.10,11 This form of AVWS results from a decrease in or loss of high- and ultrahigh-MW VWF multimers due to increased shear stress. This causes premature unfolding of VW protein in the circulation, which exposes specific cleavage sites and leads to subsequent enzymatic proteolysis by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13).10,11 Acquired von Willebrand syndrome type 2A has been reported in association with a variety of congenital heart lesions, including aortic stenosis, pulmonary stenosis, patent ductus arteriosus, ventricular, and atrial septal defects, and, more recently, continuous-flow LVADs.10,12 Nonsurgical bleeding is a frequent adverse event in patients supported with continuous-flow LVADs, which has been attributed to the development of AVWS in these patients.13 A study has demonstrated that blood samples from 37 patients with continuous-flow LVADs contained significantly reduced levels of high-MW
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Figure 3. Serial VWF multimer analysis (method described in4). Lane 1 is normal control; lanes 2 and 3 are postimplantation #1 and #2, respectively, showing decreased high-MW and absent ultrahigh-MW VWF multimers; and lane 4 is postexplantation and shows normal VWF multimer distribution.
VWF multimers.14 Of the 37 patients, 10 experienced bleeding symptoms. Another study has compared the incidence of nonsurgical bleeding in continuous-flow and pulsatile-flow LVADs.15 Laboratory tests included VWF antigen, VWF ristocetin cofactor activity, and VWF multimer analysis. The pulsatile-flow LVAD group had equivalent VWF ristocetin cofactor activity to VWF antigen ratios pre- and post-LVAD placement. However, patients in the nonpulsatile group had low VWF ristocetin cofactor activity to VWF antigen ratios 30 days following LVAD implantation. All patients in the continuousflow LVAD group were noted to have a decrease in high-MW VWF multimers. In addition, there were no bleeding events reported in the pulsatile-flow group, whereas 4 of the 11 patients with continuous-flow LVADs experienced nonsurgical bleeding. In another revealing clinical report,16 a patient received a HeartMate XVE (Thoratec Corporation, Pleasanton, California; a pulsatile-flow LVAD) that, due to mechanical dysfunction, required replacement one year after implantation. Prior to LVAD replacement, analysis of VWF in the patient’s blood revealed no qualitative or quantitative VWF abnormalities. The pulsatile-flow device was subsequently replaced with a continuous-flow LVAD (HeartMate II, Thoratec Corporation).
One week after this LVAD exchange, electrophoresis analysis demonstrated loss of high-MW VWF multimers, and PFA-100 showed prolonged closure times, thus highlighting the key distinction between these two VAD types as related to the development of AVWS. The diagnosis of AVWS type 2A associated with cardiovascular disorders, including VAD-related AVWS, can be difficult and requires a high index of suspicion. Von Willebrand factor antigen, VWF ristocetin cofactor activity, and VWF collagenbinding activity are often normal or even elevated.9 The ratios of VWF ristocetin cofactor activity to VWF antigen and VWF collagen-binding activity to WVF antigen can be reduced in some but not all patients.9 Additional tests, including PFA100 and VWF propeptide, can also be useful but have low sensitivity.9 Because loss or decrease in high-MW VWF multimers can be the only laboratory abnormality detected in this form of AVWS, analysis of VWF multimers should always be performed in patients with suspected AVWS even if other VWF studies are normal.9 Treatment can be particularly challenging, especially in patients with VAD-related AVWS, and is complicated by the administration of antithrombotic therapy that is required to prevent serious thromboembolic events. Device explantation is the only definitive therapy. However, this is often not possible until the patient’s cardiac function improves significantly or a heart transplant becomes available. Withdrawal or decreasing the intensity of antithrombotic therapy may be considered but could lead to an increased risk of thromboembolic events. 1-Deamino-8-D-arginine vasopressin has shown limited efficacy in AVWS associated with cardiovascular disorders and may not be safe due to its potential of causing fluid overload.17 Infusion of VWF-containing concentrates may be more effective for controlling bleeding in this form of AVWS.17 In the present case, our patient experienced severe recurrent nonsurgical bleeding following pulsatile-flow LVAD implantation. With multiple returns to the operating room being entirely unrevealing of a surgical source of bleeding, we immediately investigated a possible hemostatic defect, whether acquired or previously undiagnosed. We conducted a detailed laboratory evaluation that confirmed the presence of AVWS (Table 1). Not surprisingly, routine VWF studies (VWF antigen, VWF ristocetin cofactor activity, and VWF collagen-binding activity) were not decreased in our patient. However, the PFA-100 was significantly and persistently abnormal (Table 1). Interestingly, our patient also exhibited an increased VWF propeptide–antigen ratio (Table 1), suggesting rapid clearance and decreased halflife of VWF and indicating a severe phenotype. In our patient, the diagnosis of VAD-related AVWS type 2A was confirmed based on the results of quantitative VWF multimer analysis, which showed decreased high-MW VWF multimers and absence of ultrahigh-MW VWF multimers prior to initiation of Humate-P infusion as well as complete normalization of VWF multimer abnormities (and PFA-100) after VAD explantation (Table 1 and Figures 1 and 3). Since the degree of decrease in high-MW VWF multimers can vary and may be subtle in this form of AVWS, quantitative VWF multimer analysis was
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utilized, which offered improved sensitivity, precision, and a more rapid turn-around time compared to standard qualitative VWF multimer analysis.4,18 The initial suboptimal position of the inflow cannula may have been the causative factor in the development of AVWS in the present case. Although the inflow cannula position was revised on postoperative day 1, the shear stress likely caused by this suboptimal positioning could have led to the proteolytic cleavage of VWF, resulting in AVWS. Although the pump that was utilized was small, we speculate that it was more likely for the increased shear stress to have occurred at the site of the inflow cannula rather than in the blood pump or tubing. In addition, the patient did form small fibrin strands within her pump while she was off of all forms of anticoagulation and after receiving multiple blood product transfusions, including fresh frozen plasma and cryoprecipitate, all products that contain von Willebrand protein. We were concerned that these fibrin strands could progress and lead to thromboembolic complications once the AVWS was adequately controlled. As such, the pump changes were performed preemptively since we anticipated that we would need to continue withholding the patient’s anticoagulation for a prolonged period of time until hemostasis was secured. Treatment with VWF-containing concentrate was initiated once a diagnosis of AVWS was strongly suspected in order to achieve control of bleeding and to allow for reinitiation of antithrombotic therapy. Once the patient’s bleeding was controlled, antithrombotic therapy was resumed, given the significant risk of thromboembolic events during support with the Berlin Heart EXCOR Pediatric VAD.2 Humate-P is an intermediate purity plasma-derived VWF/FVIII concentrate. We chose Humate-P because, unlike other currently available VWF-containing concentrates, it contains less FVIII relative to VWF with an average ratio of 1:1.6 to 2.7.19 Moreover, the multimeric pattern between batches of Humate-P has been shown to be consistent and very similar to that of normal human plasma.20 A low-dose continuous infusion of HumateP was used to provide consistent replacement of high-MW VWF multimers, given the severity of AVWS in this patient with evidence of accelerated clearance. In addition, a significantly lower total dose of Humate-P was required with continuous infusion compared to intermittent dosing.21 Although Humate-P infusion provided rapid achievement of hemostasis, it is notable that the patient’s PFA-100 continued to be abnormal until the VAD was explanted, suggesting partial correction of AVWS (Figure 1). In addition, FVIII remained significantly elevated, which was likely the result of the Humate-P infusion and the VAD-related inflammatory response (Figure 2). Of note, the elevated FVIII resulted in shortened activated partial thromboplastin time, limiting its usefulness for monitoring of the effect of heparin, and, as a result, antifactor Xa activity was used predominantly for heparin dose titration. Despite intensive antithrombotic therapy, embolic stroke is still frequently encountered in children during support with the Berlin Heart EXCOR Pediatric VAD, especially in smaller patients.22 However, the elevated FVIII observed in this patient may have been a contributing factor to the occurrence of embolic stroke during VAD support.
In conclusion, we have reported a unique case of severe VAD-related AVWS and presented detailed information on its diagnostic workup and clinical management. Although exceedingly rare, with only one prior report in the literature,1 this case highlights for clinicians the importance of considering this diagnosis when excessive bleeding is encountered in pediatric patients following pulsatile-flow VAD implantation. Furthermore, this report provides the basis for continued study to evaluate the true incidence of AVWS in the setting of pulsatile-flow VADs. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Nubret K, Mauriat P, Roubertie F, James C, Tafer N, Ouattara A. Acquired von Willebrand disease in a child with a ventricular assist device. J Thorac Cardiovasc Surgery. 2013;146: e30-e32. 2. Fraser CD Jr, Jaquiss RD, Rosenthal DN, et al. Prospective trial of a pediatric ventricular assist device. N Engl J Med. 2012;367(6): 532-541. 3. Borchiellini A, Fijnvandraat K, ten Cate JW, et al. Quantitative analysis of von Willebrand factor propeptide release in vivo: effect of experimental endotoxemia and administration of 1-deamino-8-D-arginine vasopressin in humans. Blood. 1996;88(8): 2951-2958. 4. Flood VH, Gill JC, Friedman KD, et al. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clinical Chem. 2013;59(4): 684-691. 5. Haft JW. The heart: I. surgical treatment of acquired cardiac disease. In: Doherty GM, ed. Current Diagnosis & Treatment: Surgery. 13th ed. New York: McGraw-Hill; 2010; 359-391. 6. Almond CS, Morales DL, Blackstone EH, et al. Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children. Circulation. 2013;127(16): 1702-1711. 7. Nightingale T, Cutler D. The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story. J Thromb Haemost. 2013;11(suppl 1): 192-201. 8. Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis. 2014;25(3): 206-216. 9. Tiede A, Priesack J, Werwitzke S, et al. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study. J Thromb Haemost. 2008;6(4): 569-576. 10. Callaghan MU, Wong TE, Federici AB. Treatment of acquired von Willebrand syndrome in childhood. Blood. 2013;122(12): 2019-2022. 11. Tiede A, Rand JH, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome. Blood. 2011;117(25): 6777-6785.
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12. Meyer AL, Malehsa D, Bara C, et al. Acquired von Willebrand syndrome in patients with an axial flow left ventricular assist device. Circ Heart Fail. 2010;3(6): 675-681. 13. Geisen U, Heilmann C, Beyersdorf F, et al. Non-surgical bleeding in patients with ventricular assist devices could be explained by acquired von Willebrand disease. Eur J Cardiothorac Surg. 2008;33(4): 679-684. 14. Crow S, Chen D, Milano C, et al. Acquired von Willebrand syndrome in continuous-flow ventricular assist device recipients. Ann Thorac Surg. 2010;90(4): 1263-1269; discussion 9. 15. Crow S, Milano C, Joyce L, et al. Comparative analysis of von Willebrand factor profiles in pulsatile and continuous left ventricular assist device recipients. ASAIO J. 2010;56(5): 441-445. 16. Malehsa D, Meyer AL, Bara C, Struber M. Acquired von Willebrand syndrome after exchange of the HeartMate XVE to the HeartMate II ventricular assist device. Eur J Cardiothorac Surg. 2009;35(6): 1091-1093. 17. Federici AB, Rand JH, Bucciarelli P, et al. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost. 2000;84(2): 345-349.
18. 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(6): 543-549. 19. Nichols WL, Hultin MB, James AH, et al. 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(2): 171-232. 20. Metzner HJ, Hermentin P, Cuesta-Linker T, Langner S, Muller HG, Friedebold J. Characterization of factor VIII/von Willebrand factor concentrates using a modified method of von Willebrand factor multimer analysis. Haemophilia. 1998;4(suppl 3): 25-32. 21. Lubetsky A, Schulman S, Varon D, et al. Safety and efficacy of continuous infusion of a combined factor VIII-von Willebrand factor (vWF) concentrate (Haemate-P) in patients with von Willebrand disease. Thromb Haemost. 1999;81(2): 229-233. 22. Polito A, Netto R, Soldati M, et al. Neurological complications during pulsatile ventricular assistance with the Berlin Heart EXCOR in children: incidence and risk factors. Artif Organs. 2013;37(10): 851-856.
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Acquired von Willebrand Syndrome in a Child Following Berlin Heart EXCOR Pediatric Ventricular Assist Device Implantation: Case Report and Concise Literature Review
World Journal for Pediatric and Congenital Heart Surgery 2014, Vol. 5(4) 592-598 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2150135114539521 pch.sagepub.com
John P. Costello, MD1,2, Yaser A. Diab, MD3, Michael Philippe-Auguste, BS1, Melissa B. Jones, MSN, APRN, CPNP-AC4, Venkat Shankar, MD4, Kenneth D. Friedman, MD5, and Dilip S. Nath, MD1
Abstract The development of acquired von Willebrand syndrome (AVWS) after placement of a pulsatile-flow left ventricular assist device (LVAD) is rare and only recently recognized. We report the case of a young infant who was diagnosed with ventricular assist device (VAD)-related AVWS following implantation of a Berlin Heart EXCOR Pediatric Ventricular Assist Device (Berlin Heart Inc., The Woodlands, Texas, USA) for treatment of severe heart failure. Despite significant bleeding, the patient was successfully managed with von Willebrand factor-containing concentrate until VAD explantation led to definitive resolution of the AVWS. This case demonstrates that the possibility of this diagnosis should be considered in pediatric patients when extensive, nonsurgical bleeding is encountered after pulsatile-flow VAD implantation. Keywords circulatory assist devices, heart failure, hematology, blood Submitted February 20, 2014; Accepted May 19, 2014.
Introduction
Case Presentation
Pediatric and adult patients with severe heart failure often require mechanical circulatory support in order to provide adequate cardiac output for continued survival. Ventricular assist devices (VADs) are increasingly utilized in these critically ill patient populations to provide this ongoing cardiac support either as a bridge to transplantation or as destination therapy. Currently, two categories of VADs are available for clinical use: continuous-flow devices and pulsatile-flow devices. Although VADs have revolutionized the management of heart failure, their use is not free from potential complications. One of the unique complications associated with VAD support is acquired von Willebrand syndrome (AVWS). This acquired coagulopathy is known to occur infrequently following implantation of continuous-flow VADs; however, the development of AVWS in patients with pulsatile-flow devices is rarely reported.1 We present a case of severe AVWS that developed in a young infant following implantation of a pulsatile-flow left ventricular assist device (LVAD), which led to significant postoperative bleeding requiring multiple interventions.
A seven-month-old, 6.7-kg (body surface area: 0.35 m2) previously healthy female patient presented to our institution’s emergency department with labored breathing and cough of three days duration. Two days prior to presentation, the patient
1 Division of Cardiovascular Surgery, Children’s National Health System, Washington, DC, USA 2 The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Health System, Washington, DC, USA 3 Department of Hematology, Children’s National Health System, Washington, DC, USA 4 Department of Critical Care Medicine, Children’s National Health System, Washington, DC, USA 5 Hemostasis Reference Laboratory, Blood Center of Wisconsin, Milwaukee, WI, USA
Corresponding Author: Dilip S. Nath, Division of Cardiovascular Surgery, Children’s National Health System, 111 Michigan Avenue, NW, Washington, DC 20010, USA. Email: [email protected]
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Abbreviations and Acronyms ADAMTS-13 AVWS FVIII LV LVAD MW PFA VAD VWF
a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 acquired von Willebrand syndrome factor VIII left ventricular left ventricular assist device molecular weight platelet function analyzer ventricular assist device von Willebrand factor
was started on nebulized albuterol as an outpatient. Despite this therapy, her labored breathing continued to worsen. On presentation to the emergency department, she was found to be in severe respiratory distress requiring immediate transfer to the pediatric intensive care unit, endotracheal intubation, and mechanical ventilation. During intubation, she had cardiovascular collapse requiring a brief period of cardiopulmonary resuscitation. Subsequent echocardiography revealed severe left ventricular (LV) hypertrophy, LV dilation, severely decreased LV function (ejection fraction of 30%), and a moderate pericardial effusion. A diagnosis of cardiogenic shock of unclear etiology was made. The patient was started on intravenous dopamine and milrinone infusions resulting in improvement in her hemodynamics. An extensive diagnostic workup did not reveal any clear etiology for the severe and persistent heart failure. Repeat echocardiography continued to show persistent poor cardiac contractility without any evidence of improvement, despite maximal medical management. In order to support the patient’s circulatory system and wean off mechanical ventilation, a pulsatile-flow LVAD (Berlin Heart EXCOR Pediatric VAD; Berlin Heart Inc., The Woodlands, Texas, USA—10 mL pump, 6 mm inflow cannula, and 6 mm outflow cannula) was implanted. In order to place the inflow cannula, a small core of muscle was first sharply excised from the LV apex. The VAD inflow cannula was then placed into the LV through this opening and secured in place. Next, a Gore-Tex tube graft was anastomosed to the ascending aorta in an end-to-side fashion, and the VAD outflow cannula was placed into this graft and secured in place. Anticoagulation was initiated according to the Edmonton protocol.2 Initial pump settings were pulse rate: 100 beats/min, systolic drive pressure: 210 mm Hg, diastolic suction pressure: 45 mm Hg, and relative systolic duration: 35%. As expected, these settings were changed periodically throughout the hospitalization in response to the patient’s clinical status. Initial filling of the LVAD was found to be suboptimal, and the patient returned to the operating room on postoperative day 1 for revision of the VAD cannulae. Despite successful VAD implantation, the patient had extensive postoperative mediastinal bleeding and required eight chest re-explorations over the next 15 days. In addition, two complete pump changes were necessary due to formation of fibrin strands in the pump as a
result of interruption of anticoagulation and the significant blood product replacement, which included fresh frozen plasma, platelets, and cryoprecipitate, that was undertaken (Figures 1 and 2). No surgical source of bleeding was found despite multiple explorations, and the extent and persistence of the bleeding were disproportionate to the degree of anticoagulation that the patient was then receiving (subtherapeutic unfractionated heparin infusion). An extensive hemostatic laboratory evaluation was undertaken, which revealed an abnormal platelet function analyzer (PFA-100) assay, increased von Willebrand factor (VWF) propeptide, and reduced high-molecular-weight (MW) VWF multimers with absent ultrahigh-MW VWF multimers on quantitative VWF multimer analysis (Table 1 and Figure 3). These results were consistent with AVWS type 2A. Consequently, the patient was started on low-dose continuous infusion of the VWF/factor VIII (FVIII) concentrate (Humate-P; CSL Behring, King of Prussia, Pennsylvania) at 1.7 units/kg/h, which immediately led to a significant decrease in and ultimate cessation of bleeding. All laboratory testing for cardiomyopathy and myocarditis was negative. Unfortunately, a cardiac muscle specimen that was obtained from the LV apex at the time of initial VAD implantation was lost prior to histologic examination so no microscopic assessment of the cardiac muscle could be obtained. Once adequate hemostasis was achieved, unfractionated heparin infusion was restarted and successfully titrated up to a full therapeutic dose with a target antifactor Xa activity of 0.35 to 0.5 units/mL. Despite the patient’s clinical response to the Humate-P (CSL Behring, King of Prussia, Pennsylvania, USA) infusion, the PFA-100 assay remained persistently abnormal (Figure 1). In addition, FVIII activity became significantly elevated while on Humate-P infusion (Figure 2). The VAD pump remained free of any further visible fibrin deposits or thrombi. However, 12 days after initiation of Humate-P therapy, the patient was noted to have decreased movement of her left upper extremity. Head imaging revealed a subacute right middle cerebral artery embolic stroke, and no further intervention was taken. After 22 days of VAD support, follow-up echocardiography demonstrated significantly improved biventricular function, which continued to improve over the next week. The patient was placed on the Berlin Heart EXCOR Pediatric VAD weaning protocol 43 days after initial implantation, and the VAD was successfully explanted 52 days after implantation. Following explantation, the Humate-P infusion was immediately discontinued. Follow-up echocardiography after VAD explantation revealed the presence of a small left intraventricular cardiac thrombus, and, therefore, the patient was started on therapeutic anticoagulation with enoxaparin, which was well tolerated without any bleeding. The patient was subsequently discharged to an inpatient rehabilitation facility to continue her recovery. Echocardiography performed at the time of discharge revealed an LV ejection fraction of 51%. Repeat laboratory analysis one week after explantation showed normalization of the patient’s high-MW VWF multimer levels and PFA-100, confirming resolution of the AVWS (Table 1 and Figures 1 and 3). The patient
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Figure 1. Clinical course of patient and the effect of Humate-P infusion on platelet function analyzer 100 (PFA-100).
Figure 2. Clinical course of patient and the effect of Humate-P infusion on factor VIII (FVIII) activity levels.
remained at the inpatient rehabilitation facility following discharge secondary to (1) the inability to tolerate oral feeds and (2) concerns for a suboptimal home/family support system.
On outpatient follow-up three months after discharge, the patient had normal cardiac function, resolution of the LV thrombus, normal renal function, and improving motor
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Table 1. Summary of Hemostatic Laboratory Evaluation at Relevant Time Points.a Laboratory Test
Postimplantation #1
Hematocrit, % 32.1 Platelet count, K/mcl 142 PT (INR), seconds 13.9 (1.13) APTT, seconds 49.1 Fibrinogen, mg/dL 398 VWF:Ag, % 86 VWF:RCo, % 91 VWF:CB, % – FVIII, % 122 VWF propeptide, % – VWF:RCo/Ag ratio 1.05 VWF:CB/Ag ratio – VWF propeptide/Ag ratio – PFA-100 Col/Epi CT, seconds 219 Col/ADP CT, seconds >300 VWF quantitative multimer analysis High-MW multimers, % 12 (absent ultrahigh-MW multimers) Intermediate-MW multi60 mers, % Low-MW multimers, % 28
Postimplantation #2
Postexplantation
Normal Reference Range
30.9 172 12.7 (1.01) 39.3 581 236 214 237 235 246 0.9 1 1.04
30.4 350 11.7 (0.91) 27.5 497 223 218 – 507 – 0.98 – –
30.9-39.7 150-400 11.4-14 (0.88-1.14) 20.8-34 203-467 50-160 48-200 59-249 50-200 62-183 0.7 0.7 0.1-0.43
>300 >300
116 82
92.2-191.6 55.4-130.6
7 (absent ultrahigh-MW multimers) 67
23
19 (high-MW multimers)
26
20
57
Abbreviations: PT, prothrombin time; INR, international normalized ratio; APTT, activated partial thromboplastin time; VWF:Ag, VWF antigen; VWF:RCo, VWF ristocetin cofactor activity; VWF:CB, VWF collagen binding activity; FVIII, factor VIII; PFA-100, platelet function analyzer 100; Col/Epi CT, collagen/epinephrine closure time; Col/ADP CT, collagen/ADP closure time; MW, molecular weight; VWF, von Willebrand factor. a Postimplantation laboratories were obtained prior to initiation of Humate-P infusion, while postexplantation laboratories were obtained one week after stopping Humate-P infusion.
function of the left upper extremity. However, due to her persistent feeding issues, she was deemed to be a suitable candidate for Nissen fundoplication and gastric tube placement at our institution. This procedure was uneventful, and the patient’s postoperative echocardiogram was unchanged from baseline. Unfortunately, the patient had a rapid decline in renal function on postoperative day 5. Subsequently, she experienced sudden bradycardia, which progressed to cardiac arrest. Resuscitation was unsuccessful, and the family declined extracorporeal membrane oxygenation therapy. No autopsy was completed.
Comment Historically, VADs were used short term to support patients recovering from myocardial infarctions with reversible damage and in patients awaiting heart transplantation.5 As the technology of these devices has improved, VADs have been increasingly utilized to help sustain patients who need cardiac support for extended periods.5 Recently, pediatric patients have also benefited from the incorporation of VADs into the treatment strategy of heart failure requiring mechanical circulatory support. A recent study demonstrated the Berlin Heart EXCOR Pediatric VAD to be superior to extracorporeal membrane oxygenation for bridge-to-transplantation.6 Von Willebrand factor, a multimeric glycoprotein found in endothelial cells and platelets, plays key roles in hemostasis by facilitating platelet adhesion to damaged endothelium and
chaperoning FVIII to reduce its clearance.7 Specifically, the high-MW VWF multimers play a critical role in promoting platelet adhesion under conditions of high shear stress resulting from rapid blood flow.8 Acquired von Willebrand syndrome is a clinicopathologic syndrome caused by a variety of heterogeneous disorders and characterized by an acquired bleeding tendency and laboratory tests showing structural or functional defects of VW protein.9 Acquired von Willebrand syndrome type 2A associated with cardiovascular disorders with abnormally high shear stress is increasingly recognized in both children and adults.10,11 This form of AVWS results from a decrease in or loss of high- and ultrahigh-MW VWF multimers due to increased shear stress. This causes premature unfolding of VW protein in the circulation, which exposes specific cleavage sites and leads to subsequent enzymatic proteolysis by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13).10,11 Acquired von Willebrand syndrome type 2A has been reported in association with a variety of congenital heart lesions, including aortic stenosis, pulmonary stenosis, patent ductus arteriosus, ventricular, and atrial septal defects, and, more recently, continuous-flow LVADs.10,12 Nonsurgical bleeding is a frequent adverse event in patients supported with continuous-flow LVADs, which has been attributed to the development of AVWS in these patients.13 A study has demonstrated that blood samples from 37 patients with continuous-flow LVADs contained significantly reduced levels of high-MW
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Figure 3. Serial VWF multimer analysis (method described in4). Lane 1 is normal control; lanes 2 and 3 are postimplantation #1 and #2, respectively, showing decreased high-MW and absent ultrahigh-MW VWF multimers; and lane 4 is postexplantation and shows normal VWF multimer distribution.
VWF multimers.14 Of the 37 patients, 10 experienced bleeding symptoms. Another study has compared the incidence of nonsurgical bleeding in continuous-flow and pulsatile-flow LVADs.15 Laboratory tests included VWF antigen, VWF ristocetin cofactor activity, and VWF multimer analysis. The pulsatile-flow LVAD group had equivalent VWF ristocetin cofactor activity to VWF antigen ratios pre- and post-LVAD placement. However, patients in the nonpulsatile group had low VWF ristocetin cofactor activity to VWF antigen ratios 30 days following LVAD implantation. All patients in the continuousflow LVAD group were noted to have a decrease in high-MW VWF multimers. In addition, there were no bleeding events reported in the pulsatile-flow group, whereas 4 of the 11 patients with continuous-flow LVADs experienced nonsurgical bleeding. In another revealing clinical report,16 a patient received a HeartMate XVE (Thoratec Corporation, Pleasanton, California; a pulsatile-flow LVAD) that, due to mechanical dysfunction, required replacement one year after implantation. Prior to LVAD replacement, analysis of VWF in the patient’s blood revealed no qualitative or quantitative VWF abnormalities. The pulsatile-flow device was subsequently replaced with a continuous-flow LVAD (HeartMate II, Thoratec Corporation).
One week after this LVAD exchange, electrophoresis analysis demonstrated loss of high-MW VWF multimers, and PFA-100 showed prolonged closure times, thus highlighting the key distinction between these two VAD types as related to the development of AVWS. The diagnosis of AVWS type 2A associated with cardiovascular disorders, including VAD-related AVWS, can be difficult and requires a high index of suspicion. Von Willebrand factor antigen, VWF ristocetin cofactor activity, and VWF collagenbinding activity are often normal or even elevated.9 The ratios of VWF ristocetin cofactor activity to VWF antigen and VWF collagen-binding activity to WVF antigen can be reduced in some but not all patients.9 Additional tests, including PFA100 and VWF propeptide, can also be useful but have low sensitivity.9 Because loss or decrease in high-MW VWF multimers can be the only laboratory abnormality detected in this form of AVWS, analysis of VWF multimers should always be performed in patients with suspected AVWS even if other VWF studies are normal.9 Treatment can be particularly challenging, especially in patients with VAD-related AVWS, and is complicated by the administration of antithrombotic therapy that is required to prevent serious thromboembolic events. Device explantation is the only definitive therapy. However, this is often not possible until the patient’s cardiac function improves significantly or a heart transplant becomes available. Withdrawal or decreasing the intensity of antithrombotic therapy may be considered but could lead to an increased risk of thromboembolic events. 1-Deamino-8-D-arginine vasopressin has shown limited efficacy in AVWS associated with cardiovascular disorders and may not be safe due to its potential of causing fluid overload.17 Infusion of VWF-containing concentrates may be more effective for controlling bleeding in this form of AVWS.17 In the present case, our patient experienced severe recurrent nonsurgical bleeding following pulsatile-flow LVAD implantation. With multiple returns to the operating room being entirely unrevealing of a surgical source of bleeding, we immediately investigated a possible hemostatic defect, whether acquired or previously undiagnosed. We conducted a detailed laboratory evaluation that confirmed the presence of AVWS (Table 1). Not surprisingly, routine VWF studies (VWF antigen, VWF ristocetin cofactor activity, and VWF collagen-binding activity) were not decreased in our patient. However, the PFA-100 was significantly and persistently abnormal (Table 1). Interestingly, our patient also exhibited an increased VWF propeptide–antigen ratio (Table 1), suggesting rapid clearance and decreased halflife of VWF and indicating a severe phenotype. In our patient, the diagnosis of VAD-related AVWS type 2A was confirmed based on the results of quantitative VWF multimer analysis, which showed decreased high-MW VWF multimers and absence of ultrahigh-MW VWF multimers prior to initiation of Humate-P infusion as well as complete normalization of VWF multimer abnormities (and PFA-100) after VAD explantation (Table 1 and Figures 1 and 3). Since the degree of decrease in high-MW VWF multimers can vary and may be subtle in this form of AVWS, quantitative VWF multimer analysis was
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utilized, which offered improved sensitivity, precision, and a more rapid turn-around time compared to standard qualitative VWF multimer analysis.4,18 The initial suboptimal position of the inflow cannula may have been the causative factor in the development of AVWS in the present case. Although the inflow cannula position was revised on postoperative day 1, the shear stress likely caused by this suboptimal positioning could have led to the proteolytic cleavage of VWF, resulting in AVWS. Although the pump that was utilized was small, we speculate that it was more likely for the increased shear stress to have occurred at the site of the inflow cannula rather than in the blood pump or tubing. In addition, the patient did form small fibrin strands within her pump while she was off of all forms of anticoagulation and after receiving multiple blood product transfusions, including fresh frozen plasma and cryoprecipitate, all products that contain von Willebrand protein. We were concerned that these fibrin strands could progress and lead to thromboembolic complications once the AVWS was adequately controlled. As such, the pump changes were performed preemptively since we anticipated that we would need to continue withholding the patient’s anticoagulation for a prolonged period of time until hemostasis was secured. Treatment with VWF-containing concentrate was initiated once a diagnosis of AVWS was strongly suspected in order to achieve control of bleeding and to allow for reinitiation of antithrombotic therapy. Once the patient’s bleeding was controlled, antithrombotic therapy was resumed, given the significant risk of thromboembolic events during support with the Berlin Heart EXCOR Pediatric VAD.2 Humate-P is an intermediate purity plasma-derived VWF/FVIII concentrate. We chose Humate-P because, unlike other currently available VWF-containing concentrates, it contains less FVIII relative to VWF with an average ratio of 1:1.6 to 2.7.19 Moreover, the multimeric pattern between batches of Humate-P has been shown to be consistent and very similar to that of normal human plasma.20 A low-dose continuous infusion of HumateP was used to provide consistent replacement of high-MW VWF multimers, given the severity of AVWS in this patient with evidence of accelerated clearance. In addition, a significantly lower total dose of Humate-P was required with continuous infusion compared to intermittent dosing.21 Although Humate-P infusion provided rapid achievement of hemostasis, it is notable that the patient’s PFA-100 continued to be abnormal until the VAD was explanted, suggesting partial correction of AVWS (Figure 1). In addition, FVIII remained significantly elevated, which was likely the result of the Humate-P infusion and the VAD-related inflammatory response (Figure 2). Of note, the elevated FVIII resulted in shortened activated partial thromboplastin time, limiting its usefulness for monitoring of the effect of heparin, and, as a result, antifactor Xa activity was used predominantly for heparin dose titration. Despite intensive antithrombotic therapy, embolic stroke is still frequently encountered in children during support with the Berlin Heart EXCOR Pediatric VAD, especially in smaller patients.22 However, the elevated FVIII observed in this patient may have been a contributing factor to the occurrence of embolic stroke during VAD support.
In conclusion, we have reported a unique case of severe VAD-related AVWS and presented detailed information on its diagnostic workup and clinical management. Although exceedingly rare, with only one prior report in the literature,1 this case highlights for clinicians the importance of considering this diagnosis when excessive bleeding is encountered in pediatric patients following pulsatile-flow VAD implantation. Furthermore, this report provides the basis for continued study to evaluate the true incidence of AVWS in the setting of pulsatile-flow VADs. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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