Non-surgical Bleeding Research Articles

Efficacy and safety of a recombinant von Willebrand factor treatment in acquired von Willebrand syndrome in case of bleeding and surgical procedures.

Acquired von Willebrand syndrome (AVWS) is a rare haemorrhagic disorder. The prophylaxis and treatment of bleeding before surgery are complex. Since 2018, a new recombinant VWF (rVWF) concentrate that contains no factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France. To describe the real-world experience of using rVWF in non-surgical bleeding and surgical procedures in patients with AVWS. Fifteen bleeding episodes in seven patients and 16 surgeries in 10 patients were retrospectively analysed in t French haemostasis centres. During bleeding, the median number of infusions was only 1 (range 1-27) with a median loading dose of 58IU/kg (range 17-116) rVWF and a total median dose of 65IU/kg (range 35-1488) rVWF. Bleeding control was rated markedly effective in 73% (11/15) of the cases and ineffective in 27% (4/15). During surgeries, the median number of infusions was 3 (range 1-8) with a preoperative loading dose of 60IU/kg (range 23-118) rVWF and a total median dose of 123IU/kg (range 31-542). The overall clinical efficacy was qualified as excellent, good and poor (ISTH criteria) in respectively 7 (43%), 6 (38%) and 3 (19%) procedures. There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events nor adverse events were reported. This French 'real-world' experience shows that rVWF could be of interest in the treatment and prophylaxis of bleeding in patients with AVWS, with no clinically significant safety concern.

Higher soluble thrombomodulin and angiogenic markers in continuous flow left ventricular assist device–supported patients associated with arteriovenous malformation and nonsurgical bleeding

Higher soluble thrombomodulin and angiogenic markers in continuous flow left ventricular assist device–supported patients associated with arteriovenous malformation and nonsurgical bleeding

Incidence and Outcomes of Re-Exploration in Adult Cardiac Surgery at A Tertiary Care Hospital

Introduction: Postoperative bleeding is a significant complication following cardiac surgery, with a global re-exploration incidence of 2-5%. This study aims to investigate re-exploration rates, risk factors, and outcomes within the unique context of a tertiary care center in Nepal. Methods: In this retrospective, single-center study, we analyzed all consecutive adult patients (≥18 years) who underwent cardiac surgery with cardiopulmonary bypass (CPB) at the Manmohan Cardiothoracic Vascular and Transplant Centre (Nepal) between 2018-2021. Data on demographics, clinical characteristics, operative details, re-exploration, and outcomes were extracted from medical records. Statistical analysis included descriptive statistics, chi-square tests, independent samples t-tests, and logistic regression. Results: Of 720 patients, 56 (7.8%) required re-exploration for bleeding. Emergency procedures were strongly associated with higher re-exploration (p<0.05). Non-surgical bleeding was the primary cause in 42.9% of cases. Independent risk factors included preoperative deranged LFTs (OR=2.1, 95% CI: 1.2-3.7), elevated creatinine (>1.5 mg/dL, OR= 3.2, 95% CI: 1.8-5.6), prolonged CPB time (>120 min), and substantial transfusion requirements. Modified Bentall's procedures had the highest re-exploration rate (21.4%). Re-explored patients experienced higher AKI rates (87.5%), longer hospitalizations (13.6 vs. 7.2 days, p<0.001), and increased in-hospital mortality confined to emergency cases (1.94%). Conclusion: Emergency procedures had higher rate of re-exploration. Preoperative deranged LFTs, elevated creatinine, prolonged CPB time, and substantial transfusion requirements were independent risk factors for re-exploration. Re-explored cases experienced higher complication. In-hospital mortality were confined to emergency cases only.

Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure

Left ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety. To determine whether excluding aspirin as part of the antithrombotic regimen with a fully magnetically levitated LVAD is safe and decreases bleeding. This international, randomized, double-blind, placebo-controlled study of aspirin (100 mg/d) vs placebo with VKA therapy in patients with advanced heart failure with an LVAD was conducted across 51 centers with expertise in treating patients with advanced heart failure across 9 countries. The randomized population included 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD (314 in the placebo group and 314 in the aspirin group), of whom 296 patients in the placebo group and 293 in the aspirin group were in the primary analysis population, which informed the primary end point analysis. The study enrolled patients from July 2020 to September 2022; median follow-up was 14 months. Patients were randomized in a 1:1 ratio to receive aspirin (100 mg/d) or placebo in addition to an antithrombotic regimen. The composite primary end point, assessed for noninferiority (-10% margin) of placebo, was survival free of a major nonsurgical (>14 days after implant) hemocompatibility-related adverse events (including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism) at 12 months. The principal secondary end point was nonsurgical bleeding events. Of the 589 analyzed patients, 77% were men; one-third were Black and 61% were White. More patients were alive and free of hemocompatibility events at 12 months in the placebo group (74%) vs those taking aspirin (68%). Noninferiority of placebo was demonstrated (absolute between-group difference, 6.0% improvement in event-free survival with placebo [lower 1-sided 97.5% CI, -1.6%]; P < .001). Aspirin avoidance was associated with reduced nonsurgical bleeding events (relative risk, 0.66 [95% confidence limit, 0.51-0.85]; P = .002) with no increase in stroke or other thromboembolic events, a finding consistent among diverse subgroups of patient characteristics. In patients with advanced heart failure treated with a fully magnetically levitated LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes VKA, is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events. ClinicalTrials.gov Identifier: NCT04069156.

Real-World Experience with a Human Fibrinogen Concentrate: Clinical Data from Adult and Pediatric Patients Requiring Fibrinogen for Bleeding Control and Prevention.

Human fibrinogen concentrate (Fibryga) received temporary approval for fibrinogen replacement therapy in France (2017), with subsequent full approval for congenital and acquired hypofibrinogenemia. We evaluated real-world use for on-demand treatment of bleeding and prophylaxis to enhance our knowledge on fibrinogen concentrate as an option for fibrinogen replacement. Data were retrospectively collected from adult and pediatric patients with fibrinogen deficiency. The primary end point was indication for fibrinogen concentrate use; the secondary end point was treatment success for on-demand treatment/perioperative prophylaxis. The study included 150 adult (median age, 62years; range, 18-94years) and 50 pediatric (median age, 3years; range, 0.01-17years) patients with acquired fibrinogen deficiency. Fibrinogen concentrate was administered to 47.3% for nonsurgical bleeding, 22.7% for surgical bleeding, and 30.0% for perioperative prophylaxis in adult patients, and to 4.0% for surgical bleeding and 96.0% for perioperative prophylaxis in pediatric patients. Cardiac surgeries accounted for 79.5%/75.0% perioperative prophylaxis and 82.4%/100.0% surgical bleeding cases in adult/pediatric patients, respectively. The mean±standard deviation (SD, median) total fibrinogen doses were 3.06±1.69g (32.61mg/kg), 2.09±1.36g (22.99mg/kg), and 2.36±1.25g (29.67mg/kg) for adult nonsurgical bleeding, surgical bleeding, and perioperative prophylaxis, respectively; doses of 0.75±0.35g (47.64mg/kg) and 0.83±0.62g (55.56mg/kg) were used for pediatric surgical bleeding and perioperative prophylaxis, respectively. Treatment success was 85.7%/97.1/93.3% in adults and 50.0%/87.5% in pediatrics for nonsurgical bleeding (adults only), surgical bleeding, and perioperative prophylaxis, respectively. Fibrinogen concentrate demonstrated favorable effectiveness and safety across the age groups. This study contributes to evidence supporting fibrinogen concentrate for bleeding control/prevention in real-world clinical practice, particularly for patients with acquired fibrinogen deficiency.

Association of Angiopoetin-2 and TNF-α With Bleeding During Left Ventricular Assist Device Support: Analysis from the PREVENT Biorepository.

The purpose of this study was to describe the changes in plasma levels of angiogenic and inflammatory biomarkers, specifically Ang-2 and TNF-α, in patients receiving HeartMate II (HMII) left ventricular assist device (LVAD) and correlate them with nonsurgical bleeding. It has been shown that angiopoietin-2 (Ang-2) and tissue necrosis factor-α (TNF-α) may be linked to bleeding in LVAD patients. This study utilized biobanked samples prospectively collected from the PREVENT study, a prospective, multicenter, single-arm, nonrandomized study of patients implanted with HMII. Paired serum samples were obtained in 140 patients before implantation and at 90 days postimplantation. Baseline demographics were as follows: age 57 ± 13 years, 41% had ischemic etiology, 82% male, and 75% destination therapy indication. In the 17 patients with baseline elevation of both TNF-α and Ang-2, 10 (60%) experienced a significant bleeding event within 180 days postimplant compared with 37 of 98 (38%) patients with Ang-2 and TNF-α below the mean (p = 0.02). The hazard ratio for a bleeding event was 2.3 (95% CI: 1.2-4.6) in patients with elevated levels of both TNF-α and Ang-2. In the PREVENT multicenter study, patients with elevations in serum Angiopoietin-2 and TNF-α at baseline before LVAD implantation demonstrated increased bleeding events after LVAD implantation.

(135) Glycoprotein (GP)Ibα Protein Expression is Reduced in HeartMate 3 Patients with Non-Surgical Bleeding Complications Within the First 3 Months

(135) Glycoprotein (GP)Ibα Protein Expression is Reduced in HeartMate 3 Patients with Non-Surgical Bleeding Complications Within the First 3 Months

The Glycoprotein (GP)Ib-IX-V Complex on Platelets: GPIbα Protein Expression Is Reduced in HeartMate 3 Patients with Bleeding Complications within the First 3 Months.

Non-surgical bleeding (NSB) remains the most critical complication in patients under left ventricular assist device (LVAD) support. It is well known that blood exposed to high shear stress results in platelet dysfunction. Compared to patients without NSB, decreased surface expression of platelet receptor GPIbα was observed in LVAD patients with NSB. In this study, we aimed to compare the expression level of glycoprotein (GP)Ib-IX-V platelet receptor complex in HeartMate 3 (HM 3) patients with and without bleeding complications to investigate the alterations of the platelet transcriptomic profile on platelet damage and increased bleeding risk. Blood samples were obtained from HM 3 patients with NSB (bleeder group, n = 27) and without NSB (non-bleeder group, n = 55). The bleeder group was further divided into patients with early NSB (bleeder ≤ 3 mo, n = 19) and patients with late NSB (bleeder > 3 mo, n = 8). The mRNA and protein expression of GPIbα, GPIX and GPV were quantified for each patient. Non-bleeder, bleeder ≤ 3 mo and bleeder > 3 mo were comparable regarding the mRNA expression of GPIbα, GPIX and GPV (p > 0.05). The protein analysis revealed a significantly reduced expression level of the main receptor subunit GPIbα in bleeders ≤ 3 mo (p = 0.04). We suggest that the observed reduction of platelet receptor GPIbα protein expression in patients who experienced their first bleeding event within 3 months after LVAD implantation may influence platelet physiology. The alterations of functional GPIbα potentially reduce the platelet adhesion capacities, which may lead to an impaired hemostatic process and the elevated propensity of bleeding in HM 3 patients.

For people who have coagulopathic non-surgical bleeding and who undergo cardiac surgery, how does prothrombin complex concentrate (PCC) compare with fresh frozen plasma (FFP) or recombinant factor VIIa (rFVIIa)?

For people who have coagulopathic non-surgical bleeding and who undergo cardiac surgery, how does prothrombin complex concentrate (PCC) compare with fresh frozen plasma (FFP) or recombinant factor VIIa (rFVIIa)?

Von Willebrand Factor and Angiopoietin-2 are Sensitive Biomarkers of Pulsatility in Continuous-Flow Ventricular Assist Device Patients.

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.

Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding.

Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding.

Loss of pulsatility with continuous-flow left ventricular assist devices and the significance of the arterial endothelium in von-Willebrand factor production and degradation.

Patients on continuous flow ventricular assist devices (CF-VADs) are at high risk for the development of Acquired von-Willebrand Syndrome (AVWS) and non-surgical bleeding. von Willebrand Factor (vWF) plays an essential role in maintaining hemostasis via platelet binding to the damaged endothelium to facilitate coagulation. In CF-VAD patients, degradation of vWF into low MW multimers that are inefficient in facilitating coagulation occurs and has been primarily attributed to the supraphysiological shear stress associated with the CF-VAD impeller. In this review, we evaluate information from the literature regarding the unraveling behavior of surface-immobilized vWF under pulsatile and continuous flow pertaining to: (A) the process of arterial endothelial vWF production and release into circulation, (B) the critical shear stress required to unravel surface bound versus soluble vWF which leads to degradation, and (C) the role of pulsatility in on the production and degradation of vWF. Taken together, these data suggests that the loss of pulsatility and its impact on arterial endothelial cells plays an important role in the production, release, unraveling, and proteolytic degradation of vWF into low MW multimers, contributing to the development of AVWS. Restoration of pulsatility can potentially mitigate this issue by preventing AVWS and minimizing the risk of non-surgical bleeding.

Decreased Platelet Specific Receptor Expression of P-Selectin and GPIIb/IIIa Predict Future Non-Surgical Bleeding in Patients after Left Ventricular Assist Device Implantation.

Non-surgical bleeding (NSB) is one of the major clinical complications in patients under continuous-flow left ventricular assist device (LVAD) support. The increased shear stress leads to an altered platelet receptor composition. Whether these changes increase the risk for NSB is unclear. Thus, we compared the platelet receptor composition of patients with (bleeder group, n = 18) and without NSB (non-bleeder group, n = 18) prior to LVAD implantation. Blood samples were obtained prior to LVAD implantation and after bleeding complications in the post-implant period. Platelet receptor expression of GPIbα, GPIIb/IIIa, P-selectin and CD63 as well as intra-platelet oxidative stress levels were quantified by flow cytometry. Bleeders and non-bleeders were comparable regarding clinical characteristics, von Willebrand factor diagnostics and the aggregation capacity before and after LVAD implantation (p > 0.05). LVAD patients in the bleeder group suffered from gastrointestinal bleeding (33%; n = 6), epistaxis (22%; n = 4), hematuria or hematoma (17%; n = 3, respectively) and cerebral bleeding (11%; n = 2). Prior to LVAD implantation, a restricted surface expression of the platelet receptors P-selectin and GPIIb/IIIa was observed in the bleeder group (P-selectin: 7.2 ± 2.6%; GPIIb/IIIa: 26,900 ± 13,608 U) compared to non-bleeders (P-selectin: 12.4 ± 8.1%, p = 0.02; GPIIb/IIIa: 36,259 ± 9914 U; p = 0.02). We hypothesized that the reduced platelet receptor expression of P-selectin and GPIIb/IIIa prior to LVAD implantation may be linked to LVAD-related NSB.

Identification of Biomarkers Sensitive to Pulsatile and Continuous Flow for Identification of Promising Continuous Flow VAD Modulation Protocols to Mitigate Non-Surgical Bleeding Events

Identification of Biomarkers Sensitive to Pulsatile and Continuous Flow for Identification of Promising Continuous Flow VAD Modulation Protocols to Mitigate Non-Surgical Bleeding Events

Acquired platelet defects are responsible for nonsurgical bleeding in left ventricular assist device recipients.

Left ventricular assist devices (LVADs) have been used as a standard treatment option for patients with advanced heart failure. However, these devices are prone to adverse events. Nonsurgical bleeding (NSB) is the most common complication in patients with continuous flow (CF) LVADs. The development of acquired von Willebrand syndrome (AVWS) in CF-LVAD recipients is thought to be a key factor. However, AVWS is seen across a majority of LVAD patients, not just those with NSB. The purpose of this study was to examine the link between acquired platelet defects and NSB in CF-LVAD patients. Blood samples were collected from 62 CF-LVAD patients at pre- and 4 post-implantation timepoints. Reduced adhesion receptor expression (GPIbα and GPVI) and activation of platelets (GPIIb/IIIa activation) were used as markers for acquired platelet defects. Twenty-three patients experienced at least one NSB episode. Significantly higher levels of platelet activation and receptor reduction were seen in the postimplantation blood samples from bleeders compared with non-bleeders. All patients experienced the loss of high molecular weight monomers (HMWM) of von Willebrand Factor (vWF), but no difference was seen between the two groups. Multivariable logistic regression showed that biomarkers for reduced platelet receptor expression (GPIbα and GPVI) and activation (GPIIb/IIIa) have more predictive power for NSB, with the area under curve (AUC) values of 0.72, 0.68, and 0.62, respectively, than the loss of HMWM of vWF (AUC: 0.57). The data from this study indicated that the severity of acquired platelet defects has a direct link to NSB in CF-LVAD recipients.

Rate of thromboembolic and bleeding events in patients undergoing concomitant aortic valve surgery with left ventricular assist device implantation

BackgroundSignificant aortic regurgitation at the time of left ventricular assist device (LVAD) implantation, requires concomitant aortic valve (AoV) replacement or repair. However, the impact of concomitant AoV surgery on morbidity remains unknown. Therefore, our aim is to determine the impact of concomitant AoV surgery on thromboembolic and bleeding events. MethodsA retrospective IMACS registry study, including patients implanted from 2013 until September 2017. Differences between different concomitant AoV surgery modalities were analyzed. ResultsIn total, 785 (5.1%) out of 15.267 patients (median age 58 IQR 49–66 years, 79% male) underwent concomitant AoV surgery (median age 63 IQR 54–69 years, 84% male); 386 (49%) patients received biological prostheses, 71 (9%) mechanical prostheses and 328 (42%) AoV repairs. In total, 54 (8%) patients with AoV surgery experienced a thromboembolic event and 1016 (9%) patients with no AoV surgery. Furthermore, concomitant AoV surgery was associated with an increased rate of all and nonsurgical bleedings. Following a multivariable Cox regression, concomitant AoV surgery remained an independent predictor for bleeding events. ConclusionsIn LVAD patients undergoing concomitant AoV surgery, thromboembolic event rates were not higher, however both all and nonsurgical bleeding event rates were higher.

Gastrointestinal Bleeding After LVAD Implantation: Is It Predictable?

Purpose Non-surgical bleeding (NSB) is one of the major clinical complications in patients under continuous-flow left ventricular assist device (LVAD) support. Previous studies showed an altered platelet receptor composition in response to increased shear stress and bleeding events in LVAD patients. We investigated if the platelet receptor composition of patients with bleeding complications differs from patients without bleeding complications prior to LVAD implantation. Methods Blood samples were obtained prior to LVAD implantation and at regular follow up-visits after LVAD implantation. The bleeder group consisted of 18 consecutive LVAD patients with postoperative NSB that were matched by age and gender with LVAD patients without NSB (non-bleeder group, n=18). Platelet receptor expression of GPIbα, GPIIb/IIIa, P-selectin and CD63 as well as intra-platelet oxidative stress levels were quantified by flow cytometry. Further we documented clinical characteristics, aggregation capacity and von Willebrand factor (vWF) diagnostic of all patients. Results Bleeders and non-bleeders were comparable regarding their age at study begin, gender, LVAD type, vWF antigen, vWF activity, vWF collagen-binding activity, and the aggregation capacity before and after LVAD implantation (p>0.05). LVAD patients in the bleeder group suffered from gastrointestinal bleeding (44%; n=8), epistaxis (28%; n=5), hematuria (28%; n=5), and from cerebral bleeding (11%; n=2). The analysis of platelet receptor expression showed that the percentage of P-selectin-positive platelets and the relative quantity of GPIIb/IIIa molecules on platelets were decreased in bleeders (GPIIb/IIIa: 26.900 ± 13.608 U; P-selectin: 7.2 ± 2.6%) compared to non-bleeders (GPIIb/IIIa: 36.259 ± 9.914 U; p = 0.024; P-selectin: 12.4 ± 8.1%; p = 0.016) prior to LVAD implantation. Conclusion In this pilot study, we observed a restricted surface expression of the two platelet receptors P-selectin and GPIIb/IIIa prior to LVAD implantation in patients who suffer from NSB during LVAD support. We hypothesized that P-selectin and GPIIb/IIIa may be suitable markers to identify patients at risk for LVAD-related NSB prior to LVAD implantation. Non-surgical bleeding (NSB) is one of the major clinical complications in patients under continuous-flow left ventricular assist device (LVAD) support. Previous studies showed an altered platelet receptor composition in response to increased shear stress and bleeding events in LVAD patients. We investigated if the platelet receptor composition of patients with bleeding complications differs from patients without bleeding complications prior to LVAD implantation. Blood samples were obtained prior to LVAD implantation and at regular follow up-visits after LVAD implantation. The bleeder group consisted of 18 consecutive LVAD patients with postoperative NSB that were matched by age and gender with LVAD patients without NSB (non-bleeder group, n=18). Platelet receptor expression of GPIbα, GPIIb/IIIa, P-selectin and CD63 as well as intra-platelet oxidative stress levels were quantified by flow cytometry. Further we documented clinical characteristics, aggregation capacity and von Willebrand factor (vWF) diagnostic of all patients. Bleeders and non-bleeders were comparable regarding their age at study begin, gender, LVAD type, vWF antigen, vWF activity, vWF collagen-binding activity, and the aggregation capacity before and after LVAD implantation (p>0.05). LVAD patients in the bleeder group suffered from gastrointestinal bleeding (44%; n=8), epistaxis (28%; n=5), hematuria (28%; n=5), and from cerebral bleeding (11%; n=2). The analysis of platelet receptor expression showed that the percentage of P-selectin-positive platelets and the relative quantity of GPIIb/IIIa molecules on platelets were decreased in bleeders (GPIIb/IIIa: 26.900 ± 13.608 U; P-selectin: 7.2 ± 2.6%) compared to non-bleeders (GPIIb/IIIa: 36.259 ± 9.914 U; p = 0.024; P-selectin: 12.4 ± 8.1%; p = 0.016) prior to LVAD implantation. In this pilot study, we observed a restricted surface expression of the two platelet receptors P-selectin and GPIIb/IIIa prior to LVAD implantation in patients who suffer from NSB during LVAD support. We hypothesized that P-selectin and GPIIb/IIIa may be suitable markers to identify patients at risk for LVAD-related NSB prior to LVAD implantation.

Quality of life metrics in LVAD patients after hemocompatibility-related adverse events.

Hemocompatibility-related adverse events (HRAE) negatively influence survival. However, no study has examined the impact of these events on health-related quality of life (HRQOL) and functional outcomes following continuous-flow left ventricular assist device implantation (CF-LVAD). We assessed the impact of HRAE events on HRQOL and hypothesized that HRAE's adversely impact HRQOL and functional outcomes. INTERMACS database identified patients undergoing primary CF-LVAD implantation from 2008 to 2017. HRAEs included stroke, non-surgical bleeding, hemolysis, and pump thrombosis and were identified as defined in the literature. HRAEs were further stratified as Tier 1-2 and disabling stroke events. Time-series analysis was executed for HRAE patients with values pre-HRAE, post-HRAE, and closest to 12 months follow up. Local polynomial regression curves modeling individual patients were superimposed into "spaghetti" plots. All HRQOL and functional metrics improved in patients over time, despite HRAE complications. However, these patient metrics were significantly reduced compared to the non-HRAE cohort. Advanced data visualization techniques noted a decline after experiencing an HRAE with a subsequent recovery to baseline levels or higher. Six-minute walk test (6MWT) was noted to be most affected in the post-HRAE period but recovered similar to other metrics. The burden of HRAE following CF-LVAD implantation did not negatively impact the quality of life. However, the 6MWT did not increase in the post-HRAE period in all HRAE patients. Improvement of heart failure symptoms after CF-LVAD coupled with optimal management following the HRAE act to preserve the enhanced quality of life.

Prognostic Value of Pressure-Volume Measures in Hemocompatibility-Related Clinical Adverse Events

<h3>Purpose</h3> Continuous-flow left ventricular assist device (cf-LVADs) can lead to hemocompatibility-related clinical adverse events (HRAEs) which are largely determined by mechanisms that underpin the pump-patient interaction. We assessed the association of pressure-volume (PV) measures [stroke work (SW) & pump arterial elastance (E_A)] with incidence of HRAEs. <h3>Methods</h3> Using a validated algorithm, brachial-pressure waveforms from oscillometric blood pressure cuff (SphygmoCor Xcel), echocardiography measures and Medtronic HVAD controller data were collected for estimation PV measures within the first 3 months. Patients (all Bridge-To-Transplantation) were divided into low, intermediate and high tertiles for each of SW (n=13, 14, 9) and E_A (n=12, 12, 12). HRAEs, including nonsurgical bleeding (NB), neurological (NE) and thromboembolic events (TE), was followed through a 12-month period post-implant. Hemocompatibility score (HCS) was calculated based on HRAEs in the 1^st year. Comparison between groups were conducted with one-way ANOVAs and Kruskal-Wallis analyses. Kaplan Meier survival analyses determined time-to-event. <h3>Results</h3> 36 HVAD patients (mean age 57±10, 83% males, 69% non-ischemic cardiomyopathy) were included. Baseline demographics and clinical parameters were comparable between SW and E_A tertile groups. Low E_A group had significantly higher rates of HRAEs in the 1^st year compared to intermediate and high groups (p=0.004). HRAE rates were marginally higher in the low SW group (p=0.080). There were no differences in HCS. Survival analysis showed significant differences in distribution of 1-year cumulative HRAE-free probabilities according to E_A tertiles (33.3%, 83.3% and 91.7% for low, intermediate and high E_A respectively, log-rank=0.003). <h3>Conclusion</h3> PV measures offer value in prognostication of LVAD patients. This study highlights the potential importance of assessing afterload and native ventricular contractility in circumventing HRAEs in cf-LVAD patients.

Effect of pulsatility on shear-induced extensional behavior of Von Willebrand factor.

Patients with continuous flow ventricular assist devices (CF-VADs) are at high risk for non-surgical bleeding, speculated to associate with the loss of pulsatility following CF-VAD placement. It has been hypothesized that continuous shear stress causes elongation and increased enzymatic degradation of von Willebrand Factor (vWF), a key player in thrombus formation at sites of vascular damage. However, the role of loss of pulsatility on the unravelling behavior of vWF has not been widely explored. vWF molecules were immobilized on the surface of microfluidic devices and subjected to various pulsatile flow profiles, including continuous flow and pulsatile flow of different magnitudes, dQ/dt (i.e., first derivative of flow rate) of pulsatility and pulse frequencies to mimic in vivo shear flow environments with and without CF-VAD support. VWF elongation was observed using total internal reflection fluorescence (TIRF) microscopy. Besides, the vWF level is measured from the patients' blood sample before and after CF-VAD implantation from a clinical perspective. To our knowledge, this work is the first in providing direct, visual observation of single vWF molecule extension under controlled-pulsatile shear flow. Unravelling of vWF (total sample size n~200 molecules) is significantly reduced under pulsatile flow (p<0.01) compared to continuous flow. An increase in the magnitude of pulsatility further reduces unravelling lengths, while lower frequency of pulsatility (20 vs. 60 pulses per min) does not have a major effect on the maximum or minimum unravelling lengths. Evaluation of CF-VAD patient blood samples (n=13) demonstrates that vWF levels decreased by ~40% following CF-VAD placement (p<0.01), which correlates to single-molecule observations from a clinical point of view. Pulsatile flow reduces unfolding of vWF compared to continuous flow and a lower pulse frequency of 20 pulses/minute yielded comparable vWF unfolding to 60 pulses/minute. These findings could shed light on non-surgical bleeding associated with the loss of pulsatility following CF-VAD placement.