Ulrich Geisen

Non-surgical bleeding in patients with ventricular assist devices could be explained by acquired von Willebrand disease.

OBJECTIVE Outcomes after ventricular assist device (VAD) implantation have significantly improved during the last decade. However, bleeding episodes remain a serious complication of VAD support. This cannot be explained by the individual anticoagulation regimen alone in several cases, but may be symptomatic of acquired von Willebrand disease (VWD). The leading finding in acquired VWD (AVWD) is the loss of large multimers which results in diminished binding to collagen and to the platelets. We, therefore, analysed patients with two VAD types for laboratory parameters of VWD and compared them with patients after heart transplantation (HTX). MATERIALS AND METHODS Seven patients with a HeartMate II left-ventricular assist device and five patients who received a Thoratec biventricular assist device were included in this study. Eight HTX recipients served as controls. Analysis included international normalized ratio (INR), partial thromboplastin time (PTT), platelet count, von Willebrand factor (VWF) antigen, collagen binding capacity, ristocetin cofactor activity, the ratios of the latter two to the VWF antigen and presence of large VWF multimers. RESULTS The VAD and HTX groups did not differ with regard to age or time-point of analysis after surgery. INR and number of platelets were comparable in both groups, PTT was prolonged in VAD patients. Both VAD and HTX patients had elevated but comparable amounts of VWF antigen. However, large multimers were missing in all of 10 tested VAD patients. In contrast, five of six tested HTX recipients displayed normal multimer pattern. Indeed, collagen binding capacity and ristocetin cofactor activity (which measures binding of VWF to platelets) were lower in VAD patients compared to HTX recipients. Impaired coagulation associated with VADs was also reflected by the diminished ratios of collagen binding capacity and ristocetin cofactor activity to VWF antigen. A pathologic collagen binding ratio was found in all 10 tested VAD patients and one of the eight HTX patients, a reduced ristocetin cofactor activity ratio in 10 of 12 VAD and one of eight HTX patients. CONCLUSION Non-surgical postoperative bleeding after VAD implantation could be explained by an AVWD. Several pharmacologic treatment options (tranexamic acid, desmopressin, VWF-factor VIII concentrate, recombinant factor VIIa) may arise from our data. Improved VAD design could prevent this problem in the future.

Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women.

Women with a history of venous thromboembolism (VTE), thrombophilia or both may be at increased risk of thrombosis during pregnancy, but the optimal management strategy is not well defined in clinical guidelines because of limited trial data. A strategy of risk assessment and heparin prophylaxis was evaluated in pregnant women at increased risk of VTE. In a prospective trial (Efficacy of Thromboprophylaxis as an Intervention during. Gravidity [EThIG]), 810 pregnant women were assigned to one of three management strategies according to pre-defined risk factors related to history of VTE and thrombophilic profile. Low-risk women (group I), received 50-100 IU dalteparin/kg body weight/day for 14 days postpartum, or earlier when additional risk factors occurred. Women at high (group II) or very high risk (group III) received dalteparin from enrollment until six weeks postpartum (50-100 IU and 100-200 IU/kg/day, respectively). Objectively confirmed, symptomatic VTE occurred in 5/810 women (0.6%; 95% confidence interval [CI], 0.2 to 1.5%) (group I, 0 of 225; II, 3/469; III, 2/116). The rate of serious bleeding was 3.0% (95 % CI, 1.9 to 4.4%); 1.1% (95 % CI, 0.5 to 2.2%) was possibly dalteparin-related. There was no evidence of heparin-induced thrombocytopenia, one case of osteoporosis, and rates of miscarriage and stillbirth were similar to previous, retrospective studies. Risk-stratified heparin prophylaxis was associated with a low incidence of symptomaticVTE and few clinically important adverse events. Antepartum heparin prophylaxis is, therefore, warranted in pregnant women with idiopathic thrombosis or symptomatic thrombophilia.

Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS)

PurposeExtracorporeal life support (ECLS) is used for patients with refractory heart failure with or without respiratory failure. This temporary support is provided by blood pumps which are connected to large vessels. Bleeding episodes are a typical complication in patients with ECLS. Recently, several studies illustrated that acquired von Willebrand syndrome (AVWS) can contribute to bleeding tendencies in patients with long-term ventricular assist devices (VAD). AVWS is characterized by loss of the high molecular weight (HMW) multimers of von Willebrand factor (VWF) as a result of high shear stress and leads to impaired binding of VWF to platelets and to subendothelial matrix. Since ECLS and VAD share several features, we investigated patients with ECLS for AVWS.MethodsWe analyzed 32 patients with ECLS and 19 of them without support. To diagnose AVWS, ratios of ristocetin cofactor activity (VWF:RCo) and collagen binding capacity (VWF:CB) to VWF antigen (VWF:Ag) were employed in conjunction with multimeric analysis.ResultsReduced VWF:RCo/VWF:Ag ratios were identified in 28 ECLS patients. Furthermore, VWF:CB/VWF:Ag ratios were decreased in 31 patients. HMW multimers of VWF were missing in the same 31 patients. Thus, 31 of 32 ECLS patients presented with AVWS. Twenty-two of the 32 patients suffered from bleeding complications. Without support, AVWS was not detectable in any analyzed patient.ConclusionOur data indicate that AVWS is a typical disorder in patients with ECLS. We hypothesize that AVWS could contribute to aggravation of bleeding tendencies in ECLS patients.

Acquired von Willebrand syndrome in patients with ventricular assist device or total artificial heart.

Unexplained bleeding episodes are associated with ventricular assist devices (VAD) and can occur in part due to acquired von Willebrand syndrome (AVWS). AVWS is characterised by loss of high molecular weight (HMW) multimers of von Willebrand factor (VWF) and decreased ratios of collagen binding capacity and ristocetin cofactor activity to VWF antigen. Loss of multimers can occur as VWF is subjected to increased shear stress, which occurs in presence of VADs. We studied 12 patients who required mechanical support of their native heart for terminal cardiac insufficiency. Nine patients underwent placement of a VAD, while three underwent placement of a total artificial heart (TAH), which is connected directly to heart and large cardiac vessels without cannulas. Within one day of VAD implantation, four of five patients evaluated demonstrated loss of HMW multimers and impaired VWF function. AVWS was present within two weeks of implantation in eight of nine patients, and in all seven tested patients after >/=3 months. Patients with different VAD types developed varying severities of AVWS. After VAD explantation, HMW multimers were detectable and VWF function normalised in all patients. AVWS was not observed in the TAH patients studied. Our findings demonstrate that patients with an implanted VAD experience a rapid onset of AVWS that is quickly and completely reversed after device explantation. In addition, TAH patients do not develop AVWS. These results suggest that shear stress associated with exposure of blood to VAD cannulas and tubes may contribute to the development of AVWS.

Haemolysis in patients with ventricular assist devices: major differences between systems

INTRODUCTION Implantation of a ventricular assist device (VAD) is a seminal therapeutic option for patients with terminal cardiac failure. However, haemolysis remains a clinically relevant adverse effect of several VAD types. Lysed erythrocytes release lactate dehydrogenase (LDH) and haemoglobin. Free haemoglobin in plasma is bound by haptoglobin with high affinity. The complex is internalised by monocytes/macrophages and degraded. Any more released free haemoglobin is captured by haemopexin. This complex also undergoes lysosomal degradation in various cells. Only now, the excessive free haemoglobin can be measured in plasma. Here, we investigated haemolysis in patients supported by different VAD types. METHODS Five patients with an intracorporeal centrifugal left ventricular VAD (LVAD), 10 patients with an axial LVAD and seven patients with a paracorporeal biventricular assist device (BVAD) were analysed preoperatively and 3 days (3.0+/-0.4 days, early), 2 weeks (14+/-1 days, intermediate) and 2 months (62+/-5 days, later) after VAD implantation for haptoglobin, haemopexin, free haemoglobin in plasma, LDH, total haemoglobin, haematocrit and transfusion requirements. RESULTS Patients with a centrifugal LVAD displayed normal haptoglobin and haemopexin, low free haemoglobin and moderately increased LDH. In comparison, axial LVADs were accompanied by lower haptoglobin and haemopexin and higher free haemoglobin and LDH values. In contrast, BVADs led to an almost complete loss of haptoglobin and haemopexin and to high levels of free haemoglobin and LDH at each analysed time point. CONCLUSIONS While severe haemolysis accompanies BVAD support, erythrocyte damage is less pronounced in the axial LVAD examined and only slight in the intracorporeal centrifugal LVAD. Haemopexin, a scavenger of free haemoglobin, can be used, in combination with haptoglobin and free haemoglobin, to assess erythrocyte damage.

Acquired Von Willebrand syndrome is an early-onset problem in ventricular assist device patients,

OBJECTIVE Acquired Von Willebrand syndrome (AVWS) can contribute to bleeding complications in patients with ventricular assist devices (VADs). AVWS results from shear stress, which causes unfolding of the high-molecular-weight (HMW) multimers of Von Willebrand factor (VWF) with subsequent cleavage. Loss of the HMW multimers of VWF is the leading finding in AVWS. In consequence, binding of VWF to collagen and to platelets is impaired. The onset of AVWS after VAD implantation is not yet determined. We examined VAD patients for presence of an AVWS in the early, intermediate, and late phase after VAD implantation. METHODS Patients with a biventricular Thoratec-PVAD(®) (BVAD, n = 6) or a left-ventricular HeartMateII(®) (HMII, n = 11) were analyzed prior to VAD implantation and after 1, 3, 14, 30, and 60 days. Diagnosis of AVWS based on VWF:ristocetin cofactor activity/VWF:VWF antigen (VWF:RCo/VWF:Ag), collagen-binding capacity:VWF antigen (VWF:CB/VWF:Ag), and multimeric analysis. In addition, we analyzed the number of bleeding episodes, which required surgical intervention. RESULTS No patient had an AVWS prior to VAD implantation. An AVWS was identified already in the very early postoperative period, that is, in almost all patients on the first day and in all patients on the third day. The AVWS was also detected in the majority of patients in the further course. Nine of all 17 patients suffered bleeding complications and required a total of 25 interventions due to hemorrhages. Forty percent of re-interventions were carried out within the first 10 days after implantation; five of these were necessary within the first 24h. CONCLUSION The AVWS is present already in the early postoperative phase after VAD implantation. Therefore, reduced shear stress has to be an important feature of newly developed assist devices in the future.

Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study

Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ≥1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within ≤21 days was more common in patients with FVIII ≥1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA.

Platelet dysfunction and acquired von Willebrand syndrome in patients with left ventricular assist devices

OBJECTIVES Unexplained bleeding events are a severe complication in patients with left ventricular assist devices (LVADs). Platelet dysfunction and acquired von Willebrand syndrome (AVWS) may contribute to bleeding tendencies. Yet, comprehensive data with respect to platelet function and AVWS in LVAD patients in terms of bleeding events are scarce. METHODS Thirty-nine HeartMate II patients were included in this study. Data of at least two time points were available for each patient. Platelet function was analysed via light transmission aggregometry in 19 patients without LVAD, 28 in early (≤14 days) and 30 in late postimplantation states (≥30 days). Von Willebrand factor (VWF) antigen, VWF collagen binding capacity and VWF multimeric analyses were performed in 26 patients without LVAD, 39 in early and 33 in late postimplantation states to diagnose AVWS. Bleeding complications were recorded for 39 patients in the early and 33 in the late postoperative period. RESULTS Platelet dysfunction was detectable in 18 of 19 without LVAD and in all patients following LVAD implantation. Platelet aggregation values did not change over time (without-early, P = 0.27, n = 14; early-late, P = 0.17, n = 21). AVWS was not diagnosed in patients without LVAD, except for one. On LVAD, 33 of 39 patients had AVWS in the early and all in the late period (n = 33). Bleeding events occurred in 44% of patients in the early and in 64% of patients in the late period. CONCLUSIONS According to our data, platelet aggregation is often impaired in LVAD patients even without an implanted LVAD. Additionally, appearance of AVWS seems to be closely linked to LVAD implantation.

Comparison of Von Willebrand factor (VWF) activity VWF:Ac with VWF ristocetin cofactor activity VWF:RCo

INTRODUCTION Ristocetin cofactor activity of Von Willebrand factor (VWF:RCo) and the ratio VWF:RCo to its antigen VWF:Ag are used as routine screening to estimate VWF function and to detect types of Von Willebrand disease (VWD) caused by loss of high molecular weight multimers. However, the VWF:RCo test is prone to analytic imprecisions due to various reasons. We compared an assay for VWF activity (VWF:Ac) with VWF:RCo putting emphasis on the ratios to VWF:Ag. MATERIALS AND METHODS We evaluated 942 samples from 432 patients and evaluated three groups in detail: normal patients (normal multimers, VWF:Ag and VWF:RCo >0.5 U/ml, VWD type 1 excluded; n=258), VWD type 1 (n=76) and acquired Von Willebrand syndrome (AVWS, n=326). In addition, 30 healthy subjects were analysed. RESULTS VWF:Ac and VWF:RCo correlated well (Pearson´s r=0.96, p<0.01), so did their ratios to VWF:Ag (Pearson´s r=0.82, p<0.01). We calculated the normal range of VWF:Ac/VWF:Ag for healthy subjects as 0.8-1.16. In comparison, the reference range (mean±2std) derived from normal patient samples was 0.73-1.14. The corresponding ranges for VWF:RCo/VWF:Ag came to 0.74-1.23 (healthy) and 0.62-1.25 (normal patients). The ratios showed similar results regarding VWD type 1. The sensitivity for AVWS was higher with VWF:Ac/VWF:Ag than with VWF:RCo/VWF:Ag (97.5% versus 84.7%). CONCLUSIONS The data suggest that the results obtained with the VWF:Ac assay are comparable to that of the VWF:RCo assay. An AVWS was more reliably detected by VWF:Ac/VWF:Ag. We assume that the VWF:Ac assay could replace VWF:RCo for routine screening for AVWS, especially when prompt evaluation is required.

TRAP-induced platelet aggregation is enhanced in cardiovascular patients receiving dabigatran

BACKGROUND/OBJECTIVES Novel (or non-vitamin K antagonist) oral anti-coagulants (NOACs) are antagonists of coagulation factors (F) Xa (rivaroxaban) or IIa (dabigatran), and their non-inferiority compared with vitamin K antagonists has been demonstrated in patients with non-valvular atrial fibrillation. However, it is still not fully understood if and how dabigatran and rivaroxaban impact platelet function. This observational study aimed to assess platelet function in patients receiving dabigatran or rivaroxaban. METHODS/RESULTS This was a single centre, observational study quantifying platelet aggregation in 90 patients treated with NOACs by multiple electrode aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly higher in 35 patients receiving dabigatran (d) compared with control (c) patients (d 108±31 vs. c 85±30arbitrary units [AU]∗min, p<0.001). Patients receiving rivaroxaban (r) showed no differences compared with the control group (r 88±32 vs. c 85±30AU∗min, p=0.335). In intraindividual time courses of 16 patients, a significantly higher aggregation was found after the administration of dabigatran (before vs. after; 83±29 vs. 100±31AU∗min, p=0.009). CONCLUSION In this observational study, the TRAP-induced platelet aggregation was enhanced in cardiovascular patients receiving dabigatran. This might be explained by a change in the expression profile of thrombin receptors on the surface of platelets. Rivaroxaban had no influence on platelet aggregation.