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Anticoagulation strategy in a patient on the HeartMate III® left ventricular assist device with acquired von Willebrand syndrome and recurring gastrointestinal bleeding episodes: sometimes less is more

Anticoagulation strategy in a patient on the HeartMate III® left ventricular assist device with... Abstract Acquired von Willebrand syndrome is a frequently encountered complication of continuous flow ventricular assist devices, which may lead to clinically relevant bleeding in up to 30% of patients after continuous flow ventricular assist device implantation. As standard anticoagulation strategies may be detrimental, individualized treatment is called for, as described in our patient on the HeartMate III® left ventricular assist device. Acquired von Willebrand syndrome, Left ventricular assist device, Gastrointestinal bleeding, Individualized anticoagulation INTRODUCTION Clinically relevant bleeding episodes after left ventricular assist device (LVAD) implantation occurs in up to 30% of patients [1]. These events are considered to be due to high target international normalized ratio (INR) between 2.5 and 3.5, hyper-physiological LVAD induced shear stress [2, 3] and routinely administered antiplatelet therapy. Recently another causative factor, acquired von Willebrand syndrome (AVWS), has been identified and is thought to be a result of the loss in large multimers of von Willebrand factor. AVWS causes significant platelet dysfunction [3] and aggravates bleeding tendency in an already highly endangered patient collective. A lower target INR, temporary cessation of vitamin K antagonists, as well as cessation of antiplatelet therapy may be a viable strategy to suppress bleeding in such cases. CASE REPORT A HeartMate III® (thoratec.com) LVAD was implanted into a 72-year old female patient with end stage ischaemic heart disease as a destination therapy. Prior to surgery, no bleeding events was reported in the patient. Intraoperatively, the patient rapidly developed severe diffuse bleeding despite ROTEM® delta (werfen.com)-guided coagulation factor substitution and surgical haemostasis. After arrival at the critical care unit, the patient was requiring multiple packed blood units as well as further factor substitution, followed by haemodynamically compromising pericardial tamponade. After surgical revision, which did not reveal the origin of bleeding, the patient stabilized and continuous low dose anticoagulation treatment with unfractioned heparin infusion was established as shown in Fig. 1. On postoperative day (POD) 8, the patient developed significant melaena. Neither gastroscopy nor colonoscopy revealed any sources of bleeding. Since standard coagulation tests were inconspicuous, screening for von Willebrand syndrome (VWS) was performed, which disclosed a lack of high molecular weight multimers, suggesting severe aVWS associated platelet dysfunction. Figure 1: View largeDownload slide Left Y axis: number of packed blood units, right Y scale: daily cumulative dosage of UFH × 102 and of LMWH. LMWH: low molecular weight heparin; UFH: unfractioned heparin. Figure 1: View largeDownload slide Left Y axis: number of packed blood units, right Y scale: daily cumulative dosage of UFH × 102 and of LMWH. LMWH: low molecular weight heparin; UFH: unfractioned heparin. Discontinuation of anticoagulation therapy after POD 8 resulted in the cessation of bleeding. On POD 24 a prophylactic dosage (20 mg) of low molecular weight heparin (LMWH) resulted in the recurrence of gastrointestinal bleeding. Another gastroscopy showed two clippable sources of arrosion haemorrhages. LMWH therapy was, once again, discontinued and the bleeding ceased. Considering the patients bleeding diathesis and the absence of thrombotic events as well as the coagulation test history (Fig. 2 and Table 1), low dose LMWH was re-established and after a period of four weeks without bleeding, anticoagulant therapy with a vitamin K antagonist was initiated with a lowered target INR of 1.5–2.0. Acetylsalicylic acid-based anti-platelet therapy (as indicated in patients on the HeartMate III LVAD device) was ruled out in view of the AVWS diagnosis. Table 1: Coagulation tests Postoperative day 7 8 10 20 22 41 42 aPTT (s) 37 36 34 38 41 36 36 Prothrombin time (%) 63 61 78 85 81 70 75 Fibrinogen (mg/dl) 473 534 564 558 566 552 572 PFA/Epi (s) >300 >300 >300 299 PFA/ADP (s) >300 >300 211 177 vWF antigen (%) 369 379 220 vWF activity (%) 201 140 129 vW-Ristocetin cofactor activity (%) 190 161 81 vWF collagen-binding activity (%) >320 >320 vWF multimers Reduced multimers Reduced multimers Multiplate/ADP (U) <20 <20 <20 76 Multiplate/ASPI (U) 34 <20 50 106 Multiplate/TRAP (U) 39 <20 30 84 Free haemoglobin (mg/dl) 3.4 2.9 4.2 4.2 2.2 3.8 2.2 LDH (U/l) 266 247 323 217 177 198 193 Postoperative day 7 8 10 20 22 41 42 aPTT (s) 37 36 34 38 41 36 36 Prothrombin time (%) 63 61 78 85 81 70 75 Fibrinogen (mg/dl) 473 534 564 558 566 552 572 PFA/Epi (s) >300 >300 >300 299 PFA/ADP (s) >300 >300 211 177 vWF antigen (%) 369 379 220 vWF activity (%) 201 140 129 vW-Ristocetin cofactor activity (%) 190 161 81 vWF collagen-binding activity (%) >320 >320 vWF multimers Reduced multimers Reduced multimers Multiplate/ADP (U) <20 <20 <20 76 Multiplate/ASPI (U) 34 <20 50 106 Multiplate/TRAP (U) 39 <20 30 84 Free haemoglobin (mg/dl) 3.4 2.9 4.2 4.2 2.2 3.8 2.2 LDH (U/l) 266 247 323 217 177 198 193 aPTT: activated partial thromboplastin time; ADP: adenosine diphosphate; ASPI: aspirin; LDH: lactate dehydrogenase; PFA: platelet function analyser; TRAP: thrombin receptor activating peptide; vWF: von Willebrand factor. View Large Table 1: Coagulation tests Postoperative day 7 8 10 20 22 41 42 aPTT (s) 37 36 34 38 41 36 36 Prothrombin time (%) 63 61 78 85 81 70 75 Fibrinogen (mg/dl) 473 534 564 558 566 552 572 PFA/Epi (s) >300 >300 >300 299 PFA/ADP (s) >300 >300 211 177 vWF antigen (%) 369 379 220 vWF activity (%) 201 140 129 vW-Ristocetin cofactor activity (%) 190 161 81 vWF collagen-binding activity (%) >320 >320 vWF multimers Reduced multimers Reduced multimers Multiplate/ADP (U) <20 <20 <20 76 Multiplate/ASPI (U) 34 <20 50 106 Multiplate/TRAP (U) 39 <20 30 84 Free haemoglobin (mg/dl) 3.4 2.9 4.2 4.2 2.2 3.8 2.2 LDH (U/l) 266 247 323 217 177 198 193 Postoperative day 7 8 10 20 22 41 42 aPTT (s) 37 36 34 38 41 36 36 Prothrombin time (%) 63 61 78 85 81 70 75 Fibrinogen (mg/dl) 473 534 564 558 566 552 572 PFA/Epi (s) >300 >300 >300 299 PFA/ADP (s) >300 >300 211 177 vWF antigen (%) 369 379 220 vWF activity (%) 201 140 129 vW-Ristocetin cofactor activity (%) 190 161 81 vWF collagen-binding activity (%) >320 >320 vWF multimers Reduced multimers Reduced multimers Multiplate/ADP (U) <20 <20 <20 76 Multiplate/ASPI (U) 34 <20 50 106 Multiplate/TRAP (U) 39 <20 30 84 Free haemoglobin (mg/dl) 3.4 2.9 4.2 4.2 2.2 3.8 2.2 LDH (U/l) 266 247 323 217 177 198 193 aPTT: activated partial thromboplastin time; ADP: adenosine diphosphate; ASPI: aspirin; LDH: lactate dehydrogenase; PFA: platelet function analyser; TRAP: thrombin receptor activating peptide; vWF: von Willebrand factor. View Large Figure 2: View largeDownload slide Course of standard coagulation tests. Left Y axis: prothrombin time, fibrinogen, LDH, right Y axis: free haemoglobin and aPTT. aPTT: activated partial thromboplastin time; fHB: free haemoglobin; LDH: lactate dehydrogenase. Figure 2: View largeDownload slide Course of standard coagulation tests. Left Y axis: prothrombin time, fibrinogen, LDH, right Y axis: free haemoglobin and aPTT. aPTT: activated partial thromboplastin time; fHB: free haemoglobin; LDH: lactate dehydrogenase. DISCUSSION According to protocol, anticoagulant treatment is started after about 24 hours when bloody chest tube output remains below a certain hourly rate. It is initiated as continuous unfractioned heparin (UFH) infusion with target activated partial thromboplastin time (aPTT) values depending on bleeding intensity. If bleeding conditions remain stable or bleeding has stopped, low molecular weight heparin (LMWH) in therapeutical dosages is used intermittently. Finally, Vitamin K antagonists are used after a prolonged bleeding free period. Routine laboratory findings in our patient did not reflect the clinical course of bleeding episodes nor hint at aVWS and platelet dysfunction (Figs 1 and 2). Diagnosis of aVWS was achieved using a platelet function analyser PFA-100® (healthcare.siemens.de) with increased closure times indicating platelet dysfunction. Moreover, VWF multimers were assessed revealing decreased large molecular weight multimers. Additionally, Multiplate® (roche.de) analysis provided evidence of impaired platelet function. Decreased VWF multimers are found in nearly all LVAD patients but only a fraction of them exhibit clinically relevant bleeding. Loss of large multimers might be compensated by procoagulant pathways such as an increase in thrombin production [4, 5]. SUMMARY In light of the growing evidence suggesting lower target INR values and the routine availability of platelet function tests, a careful risk assessment of (very rare) thrombotic events and frequently occurring bleeding events in patients on LVAD support, suggests a re-evaluation of established anticoagulation strategies. In particular, cessation of anticoagulant treatment might be beneficial in certain cases. Conflict of interest: none declared. REFERENCES 1 Cushing K , Kushnir V. Gastrointestinal bleeding following LVAD placement from top to bottom . Dig Dis Sci 2016 ; 61 : 1440 . Google Scholar Crossref Search ADS PubMed 2 Susen S , Rauch A , Van Belle E , Vincentelli A , Lenting PJ. Circulatory support devices: fundamental aspects and clinical management of bleeding and thrombosis . J Thromb Haemost 2015 ; 13 : 1757 – 67 . Google Scholar Crossref Search ADS PubMed 3 Chen Z , Mondal NK , Ding J , Gao J , Griffith BP , Wu ZJ et al. Shear-induced platelet receptor shedding by non-physiological high shear stress with short exposure time: glycoprotein Ibα and glycoprotein VI . Thromb Res 2015 ; 135 : 692 – 8 . Google Scholar Crossref Search ADS PubMed 4 Zayat R , Khattab MA , Grottke O , Honickel M , Goetzenich A , Moza A et al. Survival of HeartMate II patients despite cessation of anticoagulation—outcomes and hemostatic analysis . Circ J 2018 ; 82 : 1309 – 18 . Google Scholar Crossref Search ADS PubMed 5 Uriel N , Pak SW , Jorde UP , Jude B , Susen S , Vincentelli A 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 – 13 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

Anticoagulation strategy in a patient on the HeartMate III® left ventricular assist device with acquired von Willebrand syndrome and recurring gastrointestinal bleeding episodes: sometimes less is more

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Publisher
Oxford University Press
Copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
ISSN
1010-7940
eISSN
1873-734X
DOI
10.1093/ejcts/ezz165
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Abstract

Abstract Acquired von Willebrand syndrome is a frequently encountered complication of continuous flow ventricular assist devices, which may lead to clinically relevant bleeding in up to 30% of patients after continuous flow ventricular assist device implantation. As standard anticoagulation strategies may be detrimental, individualized treatment is called for, as described in our patient on the HeartMate III® left ventricular assist device. Acquired von Willebrand syndrome, Left ventricular assist device, Gastrointestinal bleeding, Individualized anticoagulation INTRODUCTION Clinically relevant bleeding episodes after left ventricular assist device (LVAD) implantation occurs in up to 30% of patients [1]. These events are considered to be due to high target international normalized ratio (INR) between 2.5 and 3.5, hyper-physiological LVAD induced shear stress [2, 3] and routinely administered antiplatelet therapy. Recently another causative factor, acquired von Willebrand syndrome (AVWS), has been identified and is thought to be a result of the loss in large multimers of von Willebrand factor. AVWS causes significant platelet dysfunction [3] and aggravates bleeding tendency in an already highly endangered patient collective. A lower target INR, temporary cessation of vitamin K antagonists, as well as cessation of antiplatelet therapy may be a viable strategy to suppress bleeding in such cases. CASE REPORT A HeartMate III® (thoratec.com) LVAD was implanted into a 72-year old female patient with end stage ischaemic heart disease as a destination therapy. Prior to surgery, no bleeding events was reported in the patient. Intraoperatively, the patient rapidly developed severe diffuse bleeding despite ROTEM® delta (werfen.com)-guided coagulation factor substitution and surgical haemostasis. After arrival at the critical care unit, the patient was requiring multiple packed blood units as well as further factor substitution, followed by haemodynamically compromising pericardial tamponade. After surgical revision, which did not reveal the origin of bleeding, the patient stabilized and continuous low dose anticoagulation treatment with unfractioned heparin infusion was established as shown in Fig. 1. On postoperative day (POD) 8, the patient developed significant melaena. Neither gastroscopy nor colonoscopy revealed any sources of bleeding. Since standard coagulation tests were inconspicuous, screening for von Willebrand syndrome (VWS) was performed, which disclosed a lack of high molecular weight multimers, suggesting severe aVWS associated platelet dysfunction. Figure 1: View largeDownload slide Left Y axis: number of packed blood units, right Y scale: daily cumulative dosage of UFH × 102 and of LMWH. LMWH: low molecular weight heparin; UFH: unfractioned heparin. Figure 1: View largeDownload slide Left Y axis: number of packed blood units, right Y scale: daily cumulative dosage of UFH × 102 and of LMWH. LMWH: low molecular weight heparin; UFH: unfractioned heparin. Discontinuation of anticoagulation therapy after POD 8 resulted in the cessation of bleeding. On POD 24 a prophylactic dosage (20 mg) of low molecular weight heparin (LMWH) resulted in the recurrence of gastrointestinal bleeding. Another gastroscopy showed two clippable sources of arrosion haemorrhages. LMWH therapy was, once again, discontinued and the bleeding ceased. Considering the patients bleeding diathesis and the absence of thrombotic events as well as the coagulation test history (Fig. 2 and Table 1), low dose LMWH was re-established and after a period of four weeks without bleeding, anticoagulant therapy with a vitamin K antagonist was initiated with a lowered target INR of 1.5–2.0. Acetylsalicylic acid-based anti-platelet therapy (as indicated in patients on the HeartMate III LVAD device) was ruled out in view of the AVWS diagnosis. Table 1: Coagulation tests Postoperative day 7 8 10 20 22 41 42 aPTT (s) 37 36 34 38 41 36 36 Prothrombin time (%) 63 61 78 85 81 70 75 Fibrinogen (mg/dl) 473 534 564 558 566 552 572 PFA/Epi (s) >300 >300 >300 299 PFA/ADP (s) >300 >300 211 177 vWF antigen (%) 369 379 220 vWF activity (%) 201 140 129 vW-Ristocetin cofactor activity (%) 190 161 81 vWF collagen-binding activity (%) >320 >320 vWF multimers Reduced multimers Reduced multimers Multiplate/ADP (U) <20 <20 <20 76 Multiplate/ASPI (U) 34 <20 50 106 Multiplate/TRAP (U) 39 <20 30 84 Free haemoglobin (mg/dl) 3.4 2.9 4.2 4.2 2.2 3.8 2.2 LDH (U/l) 266 247 323 217 177 198 193 Postoperative day 7 8 10 20 22 41 42 aPTT (s) 37 36 34 38 41 36 36 Prothrombin time (%) 63 61 78 85 81 70 75 Fibrinogen (mg/dl) 473 534 564 558 566 552 572 PFA/Epi (s) >300 >300 >300 299 PFA/ADP (s) >300 >300 211 177 vWF antigen (%) 369 379 220 vWF activity (%) 201 140 129 vW-Ristocetin cofactor activity (%) 190 161 81 vWF collagen-binding activity (%) >320 >320 vWF multimers Reduced multimers Reduced multimers Multiplate/ADP (U) <20 <20 <20 76 Multiplate/ASPI (U) 34 <20 50 106 Multiplate/TRAP (U) 39 <20 30 84 Free haemoglobin (mg/dl) 3.4 2.9 4.2 4.2 2.2 3.8 2.2 LDH (U/l) 266 247 323 217 177 198 193 aPTT: activated partial thromboplastin time; ADP: adenosine diphosphate; ASPI: aspirin; LDH: lactate dehydrogenase; PFA: platelet function analyser; TRAP: thrombin receptor activating peptide; vWF: von Willebrand factor. View Large Table 1: Coagulation tests Postoperative day 7 8 10 20 22 41 42 aPTT (s) 37 36 34 38 41 36 36 Prothrombin time (%) 63 61 78 85 81 70 75 Fibrinogen (mg/dl) 473 534 564 558 566 552 572 PFA/Epi (s) >300 >300 >300 299 PFA/ADP (s) >300 >300 211 177 vWF antigen (%) 369 379 220 vWF activity (%) 201 140 129 vW-Ristocetin cofactor activity (%) 190 161 81 vWF collagen-binding activity (%) >320 >320 vWF multimers Reduced multimers Reduced multimers Multiplate/ADP (U) <20 <20 <20 76 Multiplate/ASPI (U) 34 <20 50 106 Multiplate/TRAP (U) 39 <20 30 84 Free haemoglobin (mg/dl) 3.4 2.9 4.2 4.2 2.2 3.8 2.2 LDH (U/l) 266 247 323 217 177 198 193 Postoperative day 7 8 10 20 22 41 42 aPTT (s) 37 36 34 38 41 36 36 Prothrombin time (%) 63 61 78 85 81 70 75 Fibrinogen (mg/dl) 473 534 564 558 566 552 572 PFA/Epi (s) >300 >300 >300 299 PFA/ADP (s) >300 >300 211 177 vWF antigen (%) 369 379 220 vWF activity (%) 201 140 129 vW-Ristocetin cofactor activity (%) 190 161 81 vWF collagen-binding activity (%) >320 >320 vWF multimers Reduced multimers Reduced multimers Multiplate/ADP (U) <20 <20 <20 76 Multiplate/ASPI (U) 34 <20 50 106 Multiplate/TRAP (U) 39 <20 30 84 Free haemoglobin (mg/dl) 3.4 2.9 4.2 4.2 2.2 3.8 2.2 LDH (U/l) 266 247 323 217 177 198 193 aPTT: activated partial thromboplastin time; ADP: adenosine diphosphate; ASPI: aspirin; LDH: lactate dehydrogenase; PFA: platelet function analyser; TRAP: thrombin receptor activating peptide; vWF: von Willebrand factor. View Large Figure 2: View largeDownload slide Course of standard coagulation tests. Left Y axis: prothrombin time, fibrinogen, LDH, right Y axis: free haemoglobin and aPTT. aPTT: activated partial thromboplastin time; fHB: free haemoglobin; LDH: lactate dehydrogenase. Figure 2: View largeDownload slide Course of standard coagulation tests. Left Y axis: prothrombin time, fibrinogen, LDH, right Y axis: free haemoglobin and aPTT. aPTT: activated partial thromboplastin time; fHB: free haemoglobin; LDH: lactate dehydrogenase. DISCUSSION According to protocol, anticoagulant treatment is started after about 24 hours when bloody chest tube output remains below a certain hourly rate. It is initiated as continuous unfractioned heparin (UFH) infusion with target activated partial thromboplastin time (aPTT) values depending on bleeding intensity. If bleeding conditions remain stable or bleeding has stopped, low molecular weight heparin (LMWH) in therapeutical dosages is used intermittently. Finally, Vitamin K antagonists are used after a prolonged bleeding free period. Routine laboratory findings in our patient did not reflect the clinical course of bleeding episodes nor hint at aVWS and platelet dysfunction (Figs 1 and 2). Diagnosis of aVWS was achieved using a platelet function analyser PFA-100® (healthcare.siemens.de) with increased closure times indicating platelet dysfunction. Moreover, VWF multimers were assessed revealing decreased large molecular weight multimers. Additionally, Multiplate® (roche.de) analysis provided evidence of impaired platelet function. Decreased VWF multimers are found in nearly all LVAD patients but only a fraction of them exhibit clinically relevant bleeding. Loss of large multimers might be compensated by procoagulant pathways such as an increase in thrombin production [4, 5]. SUMMARY In light of the growing evidence suggesting lower target INR values and the routine availability of platelet function tests, a careful risk assessment of (very rare) thrombotic events and frequently occurring bleeding events in patients on LVAD support, suggests a re-evaluation of established anticoagulation strategies. In particular, cessation of anticoagulant treatment might be beneficial in certain cases. Conflict of interest: none declared. REFERENCES 1 Cushing K , Kushnir V. Gastrointestinal bleeding following LVAD placement from top to bottom . Dig Dis Sci 2016 ; 61 : 1440 . Google Scholar Crossref Search ADS PubMed 2 Susen S , Rauch A , Van Belle E , Vincentelli A , Lenting PJ. Circulatory support devices: fundamental aspects and clinical management of bleeding and thrombosis . J Thromb Haemost 2015 ; 13 : 1757 – 67 . Google Scholar Crossref Search ADS PubMed 3 Chen Z , Mondal NK , Ding J , Gao J , Griffith BP , Wu ZJ et al. Shear-induced platelet receptor shedding by non-physiological high shear stress with short exposure time: glycoprotein Ibα and glycoprotein VI . Thromb Res 2015 ; 135 : 692 – 8 . Google Scholar Crossref Search ADS PubMed 4 Zayat R , Khattab MA , Grottke O , Honickel M , Goetzenich A , Moza A et al. Survival of HeartMate II patients despite cessation of anticoagulation—outcomes and hemostatic analysis . Circ J 2018 ; 82 : 1309 – 18 . Google Scholar Crossref Search ADS PubMed 5 Uriel N , Pak SW , Jorde UP , Jude B , Susen S , Vincentelli A 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 – 13 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Apr 1, 2020

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