Table 5 - uploaded by Rashad Zayat
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Objectives
Acquired von Willebrand syndrome (AvWS) is associated with postoperative bleeding complications in patients with continuous flow left ventricular assist devices (CF-LVADs). The aim of this study is to analyze the perioperative vWF profile comparing an axial pump (HMII) to a centrifugal pump (HVAD) regarding the correlation between periop...
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Context 1
... patients presented with normal baseline vWF:ratio (0.87 ± 0.23) which decreased sig- nificantly during the postoperative period. Beginning at the 6hr postoperative point, this significant decrease continued until 24hr postoperatively (0.64±0.17) and values normalized after two months (0.80 ± 0.13, Table 5). Despite that, we could detect a loss of HMWM of vWF via multimer analysis two months after surgery in all patients from HMII group (one patient died during the first 60 days after implantation). ...
Citations
... Clinical reports from other groups do not follow the same trend of declining vWF observed in our patient cohort. [36][37][38] This is potentially due to variations in CF-VAD support level affecting pulsatility and the use of ELISA in our study to quantify levels of vWF, whereas the other clinical studies used different functional assays. Despite these limitations, the VPPM provides a controlled, high throughput platform that can enable the identification of biomarkers, investigate mechanisms, and evaluate future therapies. ...
Nonsurgical bleeding occurs in a significant proportion of patients implanted with continuous-flow ventricular assist devices (CF-VADs) and is associated with nonphysiologic flow with diminished pulsatility. An in vitro vascular pulse perfusion model seeded with adult human aortic endothelial cells (HAECs) was used to identify biomarkers sensitive to changes in pulsatility. Diminished pulsatility resulted in an ~45% decrease in von Willebrand factor (vWF) levels from 9.80 to 5.32 ng/ml (n = 5, p < 0.05) and a threefold increase in angiopoietin-2 (ANGPT-2) levels from 775.29 to 2471.93 pg/ml (n = 5, p < 0.05) in cultured HAECs. These changes are in agreement with evaluation of patient blood samples obtained pre-CF-VAD implant and 30-day postimplant: a decrease in plasma vWF level by 50% from ~45.59 to ~22.49 μg/ml (n = 15, p < 0.01) and a 64% increase in plasma ANGPT-2 level from 7,073 to 11,615 pg/ml (n = 8, p < 0.05). This study identified vWF and ANGPT-2 as highly sensitive to changes in pulsatility, in addition to interleukin-6 (IL-6), IL-8, and tumor necrosis-α (TNF-α). These biomarkers may help determine the optimal level of pulsatility and help identify patients at high risk of nonsurgical bleeding.
... This causes a large number of erythrocytes to rupture, which initiates the release of hemoglobin from the cells into the plasma, provoking hemolysis [15]. This also induces acquired vascular hemophilia and platelet activation [16,17], which can be life-threatening in severe cases. In addition, prolonged contact between the blood and foreign surfaces can cause platelets to activate and aggregate, forming clots [18]. ...
The centrifugal blood pump is a commonly used ventricular assist device. It can replace part of the heart function, pumping blood throughout the body in order to maintain normal function. However, the high shear stress caused by the impeller rotating at high speeds can lead to hemolysis and, as a consequence, to stroke and other syndromes. Therefore, reducing the hemolysis level while ensuring adequate pressure generation is key to the optimization of centrifugal blood pumps. In this study, a screw centrifugal blood pump was used as the research object. In addition, pressure generation and the hemolysis level were optimized simultaneously using a coupled algorithm composed of random forest (RF) and multi-objective gray wolf optimization (MOGWO). After verifying the prediction accuracy of the algorithm, three optimized models were selected and compared with the baseline model in terms of pressure cloud, 2D streamline, SSS distribution, HI distribution, and vortex distribution. Finally, via a comprehensive evaluation, the optimized model was selected as the final optimization design, in which the pressure generation increased by 24% and the hemolysis value decreased by 48%.
... 9 However, a recent study also reported a pre-existing AvWS in patients with HeartWare implants. 10 Similarly, the ratios of vWF:RCo/Ag and vWF:CBA/Ag were already reduced on postoperative day 1 in a study in patients with different MCS implants. 11 Despite the preoperatively reduced ratios of 13 and it has been shown that neurohormone levels remain elevated prior to and following cf-LVAD implantation. ...
Background
The associations between mechanical circulatory support (MCS), acquired von Willebrand syndrome (AvWS), and clinical outcome are incompletely understood.
Methods
In 128 heart failure patients with pulsatile MCS implants (65 total artificial heart or biventricular assist device implants, 63 left ventricular assist device [LVAD] implants) and 76 patients with continuous flow LVAD implants, we analyzed the von Willebrand factor (vWF) profile before (≤24 h) and 17.5 (standard deviation: 5.1) days after device implant. We determined vWF concentrations, vWF activity, and vWF collagen binding capacity and calculated ratios of vWF activity/binding capacity with vWF concentration. The relation of the vWF profile with clinical outcomes such as stroke, gastrointestinal bleeding, and survival was also evaluated. Events were assessed up to 1 year of device implant.
Results
All entities of vWF were already significantly elevated preoperatively and remained high after MCS implantation. The ratios of vWF activity/concentration (vWF:RCo/Ag) and collagen binding capacity/concentration (vWF:CBA/Ag) were significantly reduced preoperatively and remained low postoperatively, indicating AvWS. The preoperative alterations in the vWF profile were already present in patients without intra‐aortic balloon pump and/or extracorporeal circulatory membrane oxygenation implants. The vWF profile was unrelated to postoperative stroke. However, a higher postoperative ratio of vWF:CBA/Ag was independently associated with increased gastrointestinal bleeding. In addition, a postoperative increase in vWF concentrations and activity were independent predictors of increased 1‐year mortality.
Conclusions
Our data indicate that AvWS is present in heart failure patients before device implantation, and is independently associated with clinical outcomes, especially with 1‐year mortality.
... It has been shown that acute heart failure patients show increased levels of interleukin-6, which might contribute to the prothrombotic state of these patients (40). At the same time, some patients suffer from avWs already before VAD implantation, which might predispose them to bleeding events (41). ...
Ventricular assist devices (VADs), among which the HeartMate 3 (HM3) is the latest clinically approved representative, are often the therapy of choice for patients with end‐stage heart failure. Despite advances in the prevention of pump thrombi, rates of stroke and bleeding remain high. These complications are attributed to the flow field within the VAD, among other factors. One of the HM3′s characteristic features is an artificial pulse that changes the rotor speed periodically by 4000 rpm, which is meant to reduce zones of recirculation and stasis. In this study, we investigated the effect of this speed modulation on the flow fields and stresses using high‐resolution computational fluid dynamics. To this end, we compared Eulerian and Lagrangian features of the flow fields during constant pump operation, during operation with the artificial pulse feature and with the effect of the residual native cardiac cycle. We observed good washout in all investigated situations, which may explain the low incidence rates of pump thrombosis. The artificial pulse had no additional benefit on scalar washout performance, but it induced rapid variations in the flow velocity and its gradients. This may be relevant for the removal of deposits in the pump. Overall, we found that viscous stresses in the HM3 were lower than in other current VADs. However, the artificial pulse substantially increased turbulence, and thereby also total stresses, which may contribute to clinically observed issues related to hemocompatibility.
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... However, computational fluid dynamics comparison of the HVAD with other continuous blood flow pumps revealed the exposure of larger blood volume to shear stresses above 9 Pa in the HVAD (indicating higher propensity for von Willebrand factor cleavage), comparable platelet activation and hemolysis (19). While blood residence times in the HVAD were higher, clinical observations showed similar von Willebrand factor profiles to other pumps (HeartMate II), suggesting similar general blood trauma tendencies in the tested pumps (20,21). The maximum hemodynamic damage was observed in the gap regions at the volute tongue in the HVAD. ...
... Due to reduced surgical complications, patient survival rates and quality of life are likely to improve. A minimally invasive approach for HVAD implantation was first developed at the Hannover Medical School in Hannover, Germany in 2011 (20,21). Modifications of this approach also exist and long-term follow up studies were performed to evaluate the safety of the procedure (7,(21)(22)(23)(24). ...
Growing worldwide incidences of end-stage heart failure and declining rates of cardiac transplants have given rise to the need for alternative treatment options, based on mechanical circulatory support (MCS) devices such as left ventricular assist devices (LVADs). Technologically advanced LVADs such as the HVAD® (HeartWare®, Medtronic) facilitate safe and efficient treatment of heart failure patients with reduced post-operative complications, which is attributed to their considerably miniaturized size. This also facilitates the development and implementation of novel, minimally-invasive surgical techniques. The HVAD is a centrifugal pump, manufactured by HeartWare Inc., (Framingham, MA, USA) and subsequently by Medtronic Inc., (Minnesota, MN, USA), and has been approved for clinical application after receiving the CE Mark approval in 2008 and the FDA approval in 2012. Current research efforts are focused on further miniaturization alongside optimization of electronic and software controllers as well as implementation of the transcutaneous energy transfer (TET) technology. Salient features of the HVAD pump technology, clinical applications and future optimization strategies have been discussed in this article.
... The development of acquired von Willebrand syndrome (AvWS) is one of the most discussed factor in which patients experienced with mechanical destruction and proteolysis of high-molecular weight multimers of vWF, induced by CF-LVADs-generated nonphysiological high shear stress. [37][38][39][40] Although the CF-LVAD patients with AvWS may result in reduced vWF-associated platelet activity and aggregation, not all of them experience major bleeding. [40][41][42] The key function of platelets is to prevent bleeding; subsequently, it stands to reason that abnormal platelet function may be a contributing factor to NSB events. ...
Nonsurgical bleeding (NSB) in heart failure (HF) patients with continuous-flow left ventricular assist device (CF-LVAD) support is the most common clinical complication. The aim of this study was to investigate the association between oxidative stress and platelet glycoproteins GPIbα and GPVI shedding on the incidence of NSB in CF-LVAD patients. Fifty-one HF patients undergoing CF-LVAD implantation and 11 healthy volunteers were recruited. Fourteen patients developed NSB (bleeder group) during 1 month follow-up duration, while others were considered nonbleeder group (n = 37). Several biomarkers of oxidative stress were quantified at baseline and weekly intervals in all patients. Surface expression and plasma elements of platelet receptor glycoproteins GPIbα and GPVI were measured. Oxidative stress biomarkers and platelet GPIbα and GPVI receptor-shedding (decreased surface expression and higher plasma levels) were found to be preexisting conditions in baseline samples of both groups of HF patients when compared with healthy volunteers. Significantly elevated oxidative stress biomarkers and platelet glycoprotein receptor shedding were observed in postimplant bleeder group temporarily when compared with nonbleeder group. Strong significant associations between biomarkers of oxidative stress and platelet glycoprotein receptor shedding were observed, suggesting a possible role of oxidative stress in platelet integrin shedding leading to NSB in CF-LVAD patients. Receiver operating characteristic analyses of GPIbα and GPVI indicated that the likelihood of NSB had a predictive power of bleeding complication in CF-LVAD patients. In conclusion, elevated oxidative stress may play a role in GPIbα and GPVI shedding in the event of NSB. Thus, oxidative stress and GPIbα and GPVI shedding may be used as potential biomarkers for bleeding risk stratification in those patients.
Introduction and Importance
Acquired von Willebrand disease (AvWD) is a rare underdiagnosed bleeding disorder caused by alterations in the levels of the major blood clotting protein von Willebrand factor (vWF). The clinical and laboratory parameters of AvWD are similar to congenital vWD, but it is found in individuals with no positive family history with no underlying genetic basis. The disease remains multifactorial and incompletely understood. Proposed mechanisms include the development of autoantibodies to vWF, absorption of high molecular weight vWF multimers that impair normal function, shear stress induced vWF cleavage and increased proteolysis.
The etiology of the disease is variable, the most common being hematoproliferation, lymophoproliferation, myeloproliferation and autoimmune and cardiovascular disorders. Consensus and protocols for AvWD patients that require major surgery are currently lacking. Patients with AvWD can experience thrombotic events during surgery as a result of therapeutic interactions with pro-thrombotic risk factors.
Case Presentation
Here, we report a patient with AvWD requiring a knee prosthesis implantation due to chronic pain, limited range of motion and functional impairment. The patient had a high risk of bleeding during surgery and was at risk of thrombosis due to age and obesity.
Clinical Discussion
Perioperative care required a collaborative approach and the management of bleeding. The patient was administered vWF concentrate Willfact ® lacking Factor VIII to prevent haemorrhage and to minimize the risk of thrombosis.
Conclusion
The treatment was effective and well-tolerated. We use this information to provide recommendations for AvWD patients for whom major surgery is indicated.
BACKGROUND
Continuous-flow LVADs cause an acquired VWF deficiency and bleeding. Models to risk-stratify for bleeding are urgently needed. We developed a model of continuous-flow left ventricular assist device (LVAD) bleeding risk from patient-specific severity of von Willebrand factor (VWF) degradation.
METHODS
In a prospective, longitudinal cohort study, paired blood samples were obtained from continuous-flow LVAD patients (n=67) before and during support. After 640±395 days, patients were categorized as all-cause bleeders, gastrointestinal (GI) bleeders, or non-bleeders. VWF multimers and VWF clotting function were evaluated to determine bleeding risk.
RESULTS
Of 67 patients, 34 (51%) experienced bleeding, 26 (39%) experienced GI bleeding, and 33 (49%) did not bleed. In all patients, LVAD support significantly reduced high-molecular-weight VWF multimers (P<.001). Bleeders exhibited greater loss of high-molecular-weight VWF multimers (mean±SD, -10±5% vs. -7±4%, P=.008) and reduced VWF function versus non-bleeders (median [IQR], -12% [-31-4%] vs. 0% [-9-26%], P=.01). A combined metric of VWF multimers and VWF function generated the All-Cause Bleeding Risk Score, which stratified bleeders versus non-bleeders (86±56% vs. 41±48%, P<.001) with a positive predictive value (PPV) of 86% (95% CI, 66-95%) and diagnostic odds ratio of 11 (95% CI, 2.9-44). A separate GI Bleeding Risk Score stratified GI bleeders versus non-bleeders (202±114 vs. 120±86, P=.003) with a PPV of 88% (64-97%) and diagnostic odds ratio of 18 (3.1-140).
CONCLUSIONS
The severity of loss of VWF multimers and VWF clotting function generated Bleeding Risk Scores with high predictive value for LVAD-associated bleeding. This model may guide personalized antithrombotic therapy and patient surveillance.
Bleeding is a common complication of cardiac surgery associated with the derangements of the hemostatic system related to cardiopulmonary bypass and the effects and consequences of the disease state. The cause of post-operative bleeding is often multifactorial and minimizing bleeding requires not only the correction of deficiencies, but also balancing of the different blood components that contribute to clot formation. The standard coagulation tests (SCTs) frequently used by clinicians to assess coagulation capacity do not reflect the complexity of the coagulation system and typically do not provide timely information, resulting in empirical management of bleeding. Point-of-care viscoelastic hemostasis assays (VHA) are tests that monitor the different phases from clot formation to clot lysis in whole blood and provide the clinician with more complete information about imbalances in the coagulation system. Coupled with transfusion algorithms, the information provided by VHAs allows clinicians to better identify coagulation defects and improve therapeutic decision-making.
Critically ill patients undergo numerous laboratory tests to better understand their disease processes and track their illnesses. Many critically ill patients have a variety of conditions such as anemia, sepsis, multiorgan failure, coagulopathies, and/or infection. For the patient to receive the correct diagnosis and treatment, laboratory tests must be carefully ordered and interpreted. Laboratory testing pertaining to anemia, thrombocytopenia, sepsis, bleeding, and hypercoagulability will be discussed in this chapter. Testing interferences as well as caveats that are important to recognize in test result interpretation will be addressed. Moreover, recent advances in hematologic testing of critically ill patients for anemia and coagulopathies such as the reticulocyte hemoglobin, chromogenic factor Xa assay, chromogenic factor VIII assay, TEG platelet mapping, and anti-Xa assay will be discussed in detail.
