Michael Berchtold-Herz

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

OBJECTIVEnOutcomes 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).nnnMATERIALS AND METHODSnSeven 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.nnnRESULTSnThe 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.nnnCONCLUSIONnNon-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.

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

INTRODUCTIONnImplantation 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.nnnMETHODSnFive 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.nnnRESULTSnPatients 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.nnnCONCLUSIONSnWhile 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,

OBJECTIVEnAcquired 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.nnnMETHODSnPatients 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.nnnRESULTSnNo 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.nnnCONCLUSIONnThe 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.

Effects of Donor Pre-Treatment With Dopamine on Survival After Heart Transplantation A Cohort Study of Heart Transplant Recipients Nested in a Randomized Controlled Multicenter Trial

OBJECTIVESnWe determined the outcome of cardiac allografts from multiorgan donors enrolled in a randomized trial of donor pre-treatment with dopamine.nnnBACKGROUNDnTreatment of the brain-dead donor with low-dose dopamine improves immediate graft function after kidney transplantation.nnnMETHODSnA cohort study of 93 heart transplants from 21 European centers was undertaken between March 2004 and August 2007. We assessed post-transplant left ventricular function (LVF), requirement of a left ventricular assist device (LVAD) or biventricular assist device (BVAD), need for hemofiltration, acute rejection, and survival of recipients of a dopamine-treated versus untreated graft.nnnRESULTSnDonor dopamine was associated with improved survival 3 years after transplantation (87.0% vs. 67.8%, p = 0.03). Fewer recipients of a pre-treated graft required hemofiltration after transplant (21.7% vs. 40.4%, p = 0.05). Impaired LVF (15.2% vs. 21.3%, p = 0.59), requirement of a LVAD (4.4% vs. 10.6%, p = 0.44), and biopsy-proven acute rejection (19.6% vs. 14.9%, p = 0.59) were not statistically different between groups. Post-transplant impaired LVF (hazard ratio [HR]: 4.95; 95% confidence interval [CI]: 2.08 to 11.79; p < 0.001), requirement of LVAD (HR: 6.65; 95% CI: 2.40 to 18.45; p < 0.001), and hemofiltration (HR: 2.83; 95% CI: 1.20 to 6.69; p = 0.02) were predictive of death. The survival benefit remained (HR: 0.33; 95% CI: 0.12 to 0.89; p = 0.03) after adjustment for various risks affecting mortality, including pre-transplant LVAD/BVAD, inotropic support, and impaired kidney function.nnnCONCLUSIONSnTreatment of brain-dead donors with dopamine of 4 μg/kg/min will not harm cardiac allografts but appears to improve the clinical course of the heart allograft recipient. (Prospective Randomized Trial to Evaluate the Efficacy of Donor Preconditioning With Dopamine on Initial Graft Function After Kidney Transplantation; NCT00115115).

Double tunnel technique for the LVAD driveline: improved management regarding driveline infections

A driveline exit site infection is a serious and common complication in long-term left ventricular assist device (LVAD) support. To reduce the incidence and severity of late driveline infections, we modified our surgical technique (double tunnel), and compared it to the conventional short and straight driveline tunnel technique (conventional). We analyzed 43 consecutive patients (37 HeartMate II; 6 Ventrassist) regarding late onset driveline exit site infections after using the surgical driveline tunnel technique after successful LVAD implantation. Of these 43 patients, 11 were treated with the conventional short and straight driveline tunnel technique (conventional), while 32 patients were treated with the modified long subfascial, C-shaped technique (double tunnel). We observed slightly fewer superficial driveline exit site infections in the double tunnel group, even though the difference was not statistically significant (0.638 vs. 1.148 infections/1,000 patient-days; Pxa0=xa00.22). There were also insignificantly fewer surgical interventions because of exit site infections in the double tunnel group (0.159 vs. 0.581 revisions/1,000 patient-days; Pxa0=xa00.18). The double tunnel technique offers more surgical options in the case of driveline exit site infections. Due to the long subfascial tunnel, the infected site can be separated from the new driveline exit site, and vacuum-assisted closure therapy can be applied to the infected area. In conclusion, we recommend using the double tunnel driveline technique because of the low infection rate and better treatment options in the case of driveline exit site infection.

Successful treatment of pulmonary hypertension with inhaled nitric oxide after pulmonary embolectomy

Inhaled nitric oxide is an agent known to reduce pulmonary vascular resistance and prevent right heart failure. Pulmonary embolism is frequently followed by right heart failure and cardiogenic shock. Although successful treatment of patients with right ventricular failure caused by pulmonary embolism has been reported, clinical use of inhaled nitric oxide as an adjunct to surgical treatment is not in widespread use. We present a case of a 69-year-old woman with massive pulmonary embolism followed by right ventricular failure. After emergency operation, weaning from ventilation was prolonged. Pulmonary hypertension was decreased with low-dose inhaled nitric oxide, although pulmonary gas exchange did not improve. The patient was weaned successfully from ventilation 52 hours after operation and recovered completely. In a follow-up examination after 9 months, the patient is in healthy constitution with good cardiopulmonary function.

Regression of ''fixed'' pulmonary vascular resistance in heart transplant candidates after unloading with ventricular assist devices

Pulmonary hypertension is a risk factor for early and late mortality after heart transplantation. An increase in pulmonary artery pressure secondary to long-standing elevations in left atrial pressures is observed in 33% to 72% of all patients with end-stage heart failure. This increase is disproportionate to the increase in left atrial pressure, thus causing an increased transpulmonary gradient and an increased pulmonary vascular resistance (pulmonary vascular resistance [Wood units] ¼ transpulmonary gradient/cardiac output) over time. All patients with increased pulmonary vascular resistance greater than 3 Wood units or transpulmonary gradients greater than 10 mm Hg are subjected to a standardized protocol testing the reversibility of the elevated pulmonary artery pressure by pharmacologic interventions before cardiac transplantation. Pulmonary vascular resistance that cannot be lowered pharmacologically is termed ‘‘fixed’’ pulmonary vascular resistance. It has been shown that ventricular assist devices are able to reduce pulmonary vascular resistance even in patients who are unresponsive to pharmacologic reduction of pulmonary vascular resistance, thus allowing a listing for transplantation after a relatively short period of mechanical support (ie, 3–6 months). SIGNIFICANCE OF PULMONARY HYPERTENSION IN PATIENTS WITH END-STAGE HEART FAILURE Pulmonary hypertension (PHT) is a risk factor for early and late mortality after heart transplantation (HTX) with mortality rates up to 40%. 1,2 Moreover, Erickson and associates 2 stated that right ventricular dysfunction accounts for approximately 50% of all cardiac complications and 20% of early mortality after HTX. In the initial phase of heart failure, increases in pulmonary artery pressure (PAP) occur in proportion to an increase of left atrial pressures that can be determined indirectly by measuring the pulmonary capillary wedge pressure (PCWP). Therefore, in this early stage with initially normal pulmonary vascular resistance (PVR), no elevated transpulmonary

Outcomes in HeartMate II Patients With No Antiplatelet Therapy: 2-Year Results From the European TRACE Study

BACKGROUNDnCurrent recommendations of antithrombotic therapy for HeartMate II (HMII) patients include the use of both an anticoagulant and an antiplatelet agent. Because bleeding is still the most frequent adverse event, the TRACE (STudy of Reduced Anti-Coagulation/Anti-platelet Therapy in Patients with the HeartMatE II) study was initiated to evaluate the incidence of adverse events in HMII patients on reduced antithrombotic (RT) therapy.nnnMETHODSnHMII patients (nxa0= 101) from nine centers were enrolled in the European arm of TRACE and were managed on a single anticoagulant (vitamin K antagonist) with no antiplatelet agents. An analysis of bleeding and thrombotic adverse events from all 101 patients with 2-year follow-up after initiation of RT therapy is reported here.nnnRESULTSnMedian age was 56 years (range, 18 to 72 years), 93% were men, 70% had an Interagency Registry for Mechanically Assisted Circulatory Support profile 1xa0toxa03, and 82% received the HMII as a bridge to transplantation. Ninety-two percent were placed on RT therapy as a center standard of care or due to physician preference and 6% as a response to bleeding. Median HMII support duration on RT therapy was 25 months (range, 1 to 93 months). Median international normalized ratio was 2.31 [quartile 1 to quartile 3: 2.07 to 2.60]. At 2 years, freedom from bleeding, ischemic stroke, hemorrhagic stroke, and pump thrombosis after initiation of RT therapy was 81% ± 6%, 96% ± 2%, 94% ± 3%, and 94% ± 3%, respectively.nnnCONCLUSIONSnThe 2-year analysis of the observational European TRACE study suggests that managing HMII patients with a vitamin K antagonist with a target international normalized ratio of 2.3 without antiplatelet therapy may help to reduce the incidence of major bleeding without increasing the risk of thromboembolic events, including ischemic stroke and pump thrombosis.