[Biology of von Willebrand factor and pathogenesis of von Willebrand disease].

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative and qualitative abnormalities of von Willebrand factor (VWF), a multimeric glycoprotein that is the largest of its kind in plasma and is also found in platelet alpha granules and Weibel-Palade bodies of endothelial cells. VWF plays two roles in hemostasis: (1) primary hemostasis via adhesion of platelet GPIb to subendothelial connective tissue and (2) stabilization of coagulation factor VIII. The pathological classification proposed by the International Society of Thrombosis and Haemostasis (ISTH) in 1994 divided VWF into three major categories based on the results of VWF:RCo, VWF:Ag, and multimer analysis. Recent genetic analysis and molecular and cellular analysis of abnormal VWF have revealed a molecular basis for the dominant inheritance form of VWD.

Converging pathways: acquired von Willebrand disease in systemic lupus erythematosus with antiphospholipid antibodies presenting with persistent menstrual bleeding.

We present a case of a woman in her 20s with inadequately treated systemic lupus erythematosus (SLE). She presented with heavy menstrual bleeding, along with nasal and gum bleeding worsening over 3 months. There was no bleeding history in her family, childhood, dental procedures or childbirth. Evaluation ruled out structural causes, revealing prolonged activated partial thromboplastin time (incomplete correction on mixing studies), normal prothrombin time, moderate thrombocytopenia, and lupus anticoagulant and anti-phosphatidylserine/prothrombin antibody positivity twice, 12 weeks apart. Further evaluation showed very low von Willebrand factor (vWF) levels (<5%). She was treated with pulse methylprednisolone for 3 days, resulting in complete symptom resolution and improvement in vWF levels to 130%. The absence of bleeding history, family history, presence of very low vWF and its response to corticosteroids led to a diagnosis of acquired vWF syndrome as the cause of mucosal bleeding in an SLE patient with concomitant positive antiphospholipid antibody. She was discharged on hydroxychloroquine, mycophenolate mofetil and tapering oral corticosteroids.

Retrospectively diagnosed autoimmune VWF deficiency in a patient with repeated hemorrhagic events after two common colds.

Autoimmune von Willebrand factor (VWF) deficiency (AiVWFD) caused by anti-VWF autoantibodies is a rare bleeding disorder, whereas "non-immune" acquired von Willebrand syndrome (AVWS) caused by other etiologies is more common. Therefore, only 40 patients with AiVWFD have been identified in Japan through an ongoing nationwide survey on autoimmune coagulation factor deficiencies. This may be due to the inability to efficiently detect anti-VWF antibodies, as anti-VWF antibody testing is not routine. An 80-year-old Japanese woman developed AVWS and experienced bleeding after two separate common colds. She took the same cold medicine each time and recovered spontaneously after discontinuation of the medicine. Severe VWF deficiency normalized each time. Initial immunological tests did not detect anti-VWF autoantibodies, and thus a diagnosis of "non-immune" AVWS of unknown origin was made. However, after 6 years, new ELISA assays using purified VWF proteins detected free anti-VWF autoantibodies, which led to a retrospective diagnosis of AiVWFD. It is probable that the cold medicine (and/or cold virus infection) induced the autoantibodies, as the recurrence and normalization of the same coagulation abnormality and the clinical course (including drug administration and discontinuation) were completely synchronized. If AiVWFD is suspected, highly sensitive autoantibody tests should be performed.

Surprise diagnosis of acquired von Willebrand syndrome in a patient previously thought to have type III von Willebrand disease: evaluation and periprocedural management.

Acquired von Willebrand syndrome (AVWS) is a rare disorder that is characterised by an acquired deficiency of von Willebrand factor. AVWS was suspected in a patient with type III von Willebrand disease (VWD) who did not respond to factor replacement therapy. Given the crucial implications for management, we describe this patient's clinical presentation, diagnosis and periprocedural management. To facilitate pericardiocentesis, periprocedural management included steroids, intravenous immunoglobulin and factor replacement therapy. In other patients with suspected immune-mediated AVWS, a similar approach may be effective. This case also highlights the importance of distinguishing AVWS from inherited VWD.

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.

Successful and safe response to ibrutinib alone in treating relapsed Waldenström macrogobulinemia and related acquired von Willebrand syndrome: an option to consider.

Ibrutinib, a first-class Bruton tyrosine kinase inhibitor, is known to be associated with adverse bleeding events and has been recently approved for the treatment of relapse Waldenström macroglobulinemia (WM). Here, we report the exhaustive clinical and biological follow-up of 2 patients treated by ibrutinib alone in the context of relapsed WM with an acquired von Willebrand syndrome (AVWS) complication. In two cases, ibrutinib has been shown to be quickly efficient and safe for treating both AVWS and its underlying condition the WM, without bleeding complications. Interestingly, ibrutinib treatment brings a rapid and extended over time normalization of von Willebrand factor clearance. These observations show that ibrutinib is a valuable therapeutic option in relapsed WM patients associated with AVWS and highlighting the need for further cohort studies with long-term follow-up of patients to confirm the efficacy and safety of a treatment by ibrutinib for WM patients with AVWS complication.

The impact of bicuspid aortic valve morphology on von Willebrand factor function in patients with severe aortic stenosis and its change after TAVI.

BACKGROUND: Aortic stenosis (AS) can cause acquired von Willebrand syndrome (AVWS) and valve replacement has been shown to lead to von Willebrand factor (vWF) recovery. The aim of the current study was to investigate the prevalence of AVWS in different severe AS phenotypes and its course after transcatheter aortic valve implantation (TAVI). METHODS: 143 patients with severe AS undergoing TAVI were included in the study. vWF function was assessed at baseline, 6 and 24 h after TAVI. AVWS was defined as a reduced vWF:Ac/Ag ratio ≤ 0.7. Phenotypes were classified by tricuspid (TAV) and bicuspid (BAV) valve morphology, mean transvalvular gradient (Pmean), stroke volume index (SVI), ejection fraction (EF) and indexed effective orifice area (iEOA). RESULTS: AVWS was present in 36 (25.2%) patients before TAVI. vWF:Ac/Ag ratio was significantly lower in high gradient compared to low-gradient severe AS [0.78 (IQR 0.67-0.86) vs. 0.83 (IQR 0.74-0.93), p < 0.05] and in patients with BAV compared to TAV [0.70 (IQR 0.63-0.78) vs. 0.81 (IQR 0.71-0.89), p < 0.05]. Normalization of vWF:Ac/Ag ratio was achieved in 61% patients 24 h after TAVI. As in the overall study cohort, vWF:Ac/Ag ratio increased significantly in all severe AS subgroups 6 h after TAVI (each p < 0.05). Regarding binary logistic regression analysis, BAV was the only significant predictor for AVWS. CONCLUSIONS: BAV morphology is a strong predictor for AVWS in severe AS. TAVI restores vWF function in most patients with severe AS independently of AS phenotype and valve morphology.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: The data from this study indicated that the severity of acquired platelet defects has a direct link to NSB in CF-LVAD recipients.

Individual Variability in von Willebrand Factor Fragility in Response to Shear Stress: A Possible Clue for Predicting Bleeding Risk.

Acquired von Willebrand syndrome (AVWS), characterized by reduced von Willebrand factor (VWF) large multimers, has recently been implicated as the principal mechanism underlying bleeding in patients implanted with left ventricular assist devices (LVADs). Hematological severity of AVWS varies among patients, even if an identical device is implanted. We investigated whether this diversity in hematological severity is due to individual variability in VWF fragility, according to responses to incremental shear stress. Whole-blood samples were sheared at 20,000-40,000 s -1 shear rate, an index of shear stress, using a custom-made shear stressor that could generate shear stress compatible with that produced by an LVAD. The degree of VWF large multimers degradation was evaluated using the VWF large multimer index. A significant inverse correlation was observed between the VWF large multimer index and LVAD-compatible magnitudes of shear stress: the VWF large multimer indices were 68.5 ± 18.3, 48.0 ± 13.9, 33.9 ± 12.1, 23.7 ± 7.9, and 18.7% ± 8.7% at 20,000, 25,000, 30,000, 35,000, and 40,000 s -1 of shear rates, respectively ( P < 0.0001). Furthermore, experimental VWF large multimer index values were compatible with those derived from patients with implanted LVADs (median; 28.9%). Finally, reduction in the VWF large multimer index corresponding to shear stress showed individual variation. We demonstrated that the combined use of a novel high shear stress loading device and quantitative evaluation of VWF large multimers may predict risk of bleeding before LVAD implantation.

Bleeding in patients with continuous-flow left ventricular assist devices: acquired von Willebrand disease or antithrombotics?

OBJECTIVES: To evaluate the competing pro-haemorrhagic contribution of acquired von Willebrand (vW) disease and antithrombotic therapy in patients implanted with continuous-flow left ventricular assist devices (LVADs). METHODS: We compared the extent of vW factor (vWf) degradation [vWf antigen (vWf:Ag)] and a decrease of functional activity of large vWf multimers [vWf collagen binding (vWf:CB)] in LVAD patients who did and did not suffer from bleeding. Data were measured pre-implant, at short-term (t1: <3 months) and long-term (t2: >12 months) follow-up. The occurrence of primary bleeding events, as well as bleeding recurrence, was correlated with patient-specific vWf profile and antithrombotic regimen. Indeed, patients were discharged on warfarin (international normalized ratio: 2-2.5) and aspirin, with the latter withhold after a first bleeding episode. RESULTS: Fifty-three patients were enrolled. The median follow-up was 324 (226-468) days. We recorded 25 primary bleeding events (47% of patients). All primary events occurred in patients on warfarin and aspirin. Both vWf:Ag and vWf:CB decreased significantly post-implant (P = 0.0003 and P < 0.0001), and patients showing pathological vWf:CB/vWf:Ag ratio (<0.7) increased progressively over the time of support (pre-implant = 26%, t1 = 58%, t2 = 74%; P < 0.0001). Of note, activity of large vWf multimers of bleeders was significantly lower at t2 with respect to non-bleeders (vWf:CB: 61 (36-115) vs 100 (68-121), P = 0.04; vWf:CB/vWf:Ag ratio: 0.36 (0.26-0.61) vs 0.58 (0.33-0.96), P = 0.04). Despite these marked differences in the vWf profile, following aspirin discontinuation only 3 patients had bleeding recurrence. CONCLUSIONS: Aspirin contributes significantly to haemorrhagic events in the background of acquired vW disease; its discontinuation significantly reduces bleeding recurrence. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03255928; ClinicalTrials.gov Identifier: NCT03255928.

Role of acquired von Willebrand syndrome in the development of bleeding complications in patients treated with Impella RP devices.

Axial flow pumps are standard treatment in cases of cardiogenic shock and high-risk interventions in cardiology and cardiac surgery, although the optimal anticoagulation strategy remains unclear. We evaluated whether laboratory findings could predict bleeding complications and acquired von Willebrand syndrome (avWS) among patients who were treated using axial flow pumps. We retrospectively evaluated 60 consecutive patients who received Impella devices (Impella RP: n = 20, Impella CP/5.0: n = 40; Abiomed Inc., Danvers, USA) between January 2019 and December 2020. Thirty-two patients (53.3%) experienced major or fatal bleeding complications (Bleeding Academic Research Consortium score of > 3) despite intravenous heparin being used to maintain normal activated partial thromboplastin times (40-50 s). Extensive testing was performed for 28 patients with bleeding complications (87.5%). Relative to patients with left ventricular support, patients with right ventricular support were less likely to develop avWS (87.5% vs. 58.8%, p = 0.035). Bleeding was significantly associated with avWS (odds ratio [OR]: 20.8, 95% confidence interval [CI]: 3.3-128.5; p = 0.001) and treatment duration (OR: 1.3, 95% CI 1.09-1.55; p = 0.003). Patients with avWS had longer Impella treatment than patients without avWS (2 days [1-4.7 days] vs. 7.3 days [3.2-13.0 days]). Bleeding complications during Impella support were associated with avWS in our cohort, while aPTT monitoring was not sufficient to prevent bleeding complications. A more targeted anticoagulation monitoring might be needed for patients who receive Impella devices.

Estudio de la relación entre el grupo sanguíneo eritrocitario ABO con los niveles del factor von Willebrand en pacientes diagnosticados con la enfermedad / Study of the relationship between the ABO erythrocyte blood group with the von Willebrand factor levels in patients diagnosed with the disease

Resumen La presencia o ausencia de los antígenos del sistema ABO entre otros factores se han relacionado con los niveles plasmáticos del factor von Willebrand (VWF) debido a su influencia en la proteólisis por la ADAMTS 13; la actividad de este sistema eritrocitario puede incidir en eventos trombóticos o hemorrágicos. El propósito de este estudio fue determinar si los pacientes diagnosticados con la enfermedad de von Willebrand pertenecían al grupo sanguíneo O y si los niveles de VWF y FVIII eran más bajos que los de los grupos no-O. El grupo sanguíneo fue identificado por un método directo en tubo y el VWF y FVIII se midieron mediante ensayos de coagulación. Se analizó un total de 64 pacientes, el 29,4% eran mayores de 40 años, el 100% presentaron valores más bajos del VWF que los grupos no-O, el 64% de los pacientes presentaron una concentración del FVIII de 6-49% inferior al rango normal establecido y el 78,51% fueron tipificados como del grupo sanguíneo O. El análisis estadístico demostró una relación estadísticamente significativa entre los niveles de VWF y el grupo sanguíneo. Se determinó que existe una relación entre el sistema ABO y el VWF-FVIII (p<0,05); sin embargo, esto no significa que sea la única causa de la existencia de un nivel bajo del factor. Estos datos indican la necesidad de mayores estudios en la población de pacientes con la enfermedad y la necesidad de determinar los tipos de von Willebrand y su relación con el grupo sanguíneo.

Abstract The presence or absence of antigens of the ABO system, among other factors, have been related to plasma levels of von Willebrand factor (VWF) due to its influence on proteolysis by ADAMTS 13. The activity of this erythrocyte system may influence on thrombotic or hemorrhagic events. The purpose of this study was to determine if the patients diagnosed with von Willebrand disease belonged to the O blood group and the VWF and FVIII levels were lower than those of the other blood groups. The blood group was identified by direct tube method and the VWF and FVIII were measured by coagulation tests. A total of 64 patients were analised, 29.4% were older than 40, 100% presented lower values of VWF than the non-O groups. A total of 64% of the patients presented a lower concentration of 6-49% in FVIII at the established normal range and 78.51% were typified as blood group O. Statistical analysis showed a statistically significant relationship between VWF levels and blood group. It was determined that there is a relationship between the ABO system and the VWF-FVIII (p<0.05). However, this does not mean that is the only cause of the existence of a low level of these factors. These data indicate the need for further studies in the population of patients with von Willebrand disease in order to determine the von Willebrand types and their relationship with the blood group.

Resumo A presença ou ausência dos antígenos do sistema ABO, entre outros fatores, tem sido relacionada aos níveis plasmáticos do fator de von Willebrand (VWF) devido à sua influência na proteólise pelo ADAMTS 13; a atividade desse sistema eritrocitário pode afetar eventos trombóticos ou hemorrágicos. O objetivo deste estudo foi determinar se os pacientes com diagnóstico de doença de von Willebrand pertenciam ao grupo sanguíneo O e se os níveis de VWF e FVIII eram inferiores aos dos grupos não-0. O grupo sanguíneo foi identificado por um método direto em tubo e o VWF e o FVIII foram medidos por testes de coagulação. Foram analisados 64 pacientes, 29,4% tinham idade superior a 40 anos, 100% apresentaram valores mais baixos do VWF que os grupos não-O e 64% dos pacientes apresentaram concentração de FVIII 6-49% menor à faixa normal estabelecida, e 78,51% foram tipificados como do grupo sanguíneo O. A análise estatística mostrou uma relação estatisticamente significativa entre os níveis de VWF e o grupo sanguíneo. Foi determinado que existe uma relação entre o sistema ABO e o VWF-FVIII (p<0,05), no entanto, isso não significa que seja a única causa da existência de um baixo nível do fator. Esses dados indicam a necessidade de novos estudos na população de pacientes com a doença e a necessidade de determinar os tipos de von Willebrand e sua relação com o grupo sanguíneo.

Characteristics, complications, and sites of bleeding among infants and toddlers less than 2 years of age with VWD.

Data on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were <2 years of age. In 68% of the patients, the reason for diagnostic testing was a family history of a bleeding disorder. The mean age at diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history were diagnosed ∼4 months earlier than those with none (P < .001). Among the patients who experienced a bleeding event (70%), oral mucosa was the most common site of the initial bleeding episode (32%), followed by circumcision-related (12%) and intracranial/extracranial bleeding (10%). Forty-one percent of the initial bleeding events occurred before 6 months of age, and 68% of them occurred before the age of 1 year. Approximately 5% of the cohort experienced an intracranial hemorrhage; however, none was associated with delivery at birth. Bleeding patterns and rates were similar by sex (P = .40) and VWD type (P = .10). Forty-seven percent were treated with plasma-derived von Willebrand factor VIII concentrates. The results of this study indicate that a high percentage of ITs diagnosed with VWD and receiving care within the multidisciplinary structure of the USHTCN have a family history of VWD. In addition, bleeding events such as circumcision-related, oropharyngeal, and intracranial or extracranial episodes are common and are leading indicators for treatment.

Acquired von Willebrand syndrome in association with multiple myeloma: remission after stem cell transplant.

Acquired von Willebrand syndrome is a rare bleeding disorder characterised by a later age of onset without a personal or family history of bleeding diathesis. It is vital to discern acquired von Willebrand syndrome from inherited von Willebrand disease and other acquired bleeding disorders as management differs significantly. Acquired von Willebrand syndrome is usually secondary to an underlying disorder such as lymphoproliferative disorder, myeloproliferative neoplasm, solid tumour, cardiovascular disorder, autoimmune disorders or hypothyroidism. Diagnosis is often delayed with a significant risk of morbidity and even mortality. Here we present a case of a 74-year-old man with an acquired bleeding disorder and work up suggestive of acquired von Willebrand syndrome secondary to immunoglobulin G kappa multiple myeloma. He was treated successfully with intravenous immunoglobulin, von Willebrand Factor/Coagulation Factor VIII Complex (human), myeloma directed chemotherapy and autologous stem cell transplantation. We also discuss the management strategies that are largely based on retrospective studies and case reports.

Assessment of von Willebrand disease and pregnancy outcomes at regional Australian hospitals.

BACKGROUND: von Willebrand disease (vWD) is a heterogeneous hereditary bleeding disorder and is associated with risk of primary postpartum haemorrhage (PPH). DESIGN AND METHODS: An observational study at a tertiary referral centre in Australia of 16 women with 23 deliveries with a median age of 27.5 years (range, 21-39; IQR = 9). Median gestational age at delivery was 39 weeks (range, 35-41; IQR = 1.1). RESULTS: All cases had type 1 vWD, apart from one case with type 2. Patients were managed in combined obstetrics and haematology clinics. PPH occurred in ten deliveries (44%). Intravenous desmopressin was administered in 6 cases, and IV human vWF was administered in 4 cases. Two cases with mild vWD had received oral tranexamic acid. The median Apgar score at 1 and 5 min was 9 (IQR = 1.0), while the median Apgar score at 10 min was 10.0 (IQR = 0.0). One case required transfusion of blood products postdelivery. There were no other significant complications observed. CONCLUSIONS: vWD was associated with a high incidence of primary PPH. Individualised treatment to restore haemostasis, according to the severity of the disease, could achieve as possible, normal haemostasis with favourable outcomes for both mothers and their infants. Further studies to confirm our findings are warranted.

Shear Stress-Induced Activation of von Willebrand Factor and Cardiovascular Pathology.

The von Willebrand factor (vWF) is a plasma protein that mediates platelet adhesion and leukocyte recruitment to vascular injury sites and carries coagulation factor VIII, a building block of the intrinsic pathway of coagulation. The presence of ultra-large multimers of vWF in the bloodstream is associated with spontaneous thrombosis, whereas its deficiency leads to bleeding. In cardiovascular pathology, the progression of the heart valve disease results in vWF deficiency and cryptogenic gastrointestinal bleeding. The association between higher plasma levels of vWF and thrombotic complications of coronary artery disease was described. Of note, it is not the plasma levels that are crucial for vWF hemostatic activity, but vWF activation, triggered by a rise in shear rates. vWF becomes highly reactive with platelets upon unfolding into a stretched conformation, at shear rates above the critical value (more than 5000 s-1), which might occur at sites of arterial stenosis and injury. The activation of vWF and its counterbalance by ADAMTS-13, the vWF-cleaving protease, might contribute to complications of cardiovascular diseases. In this review, we discuss vWF involvement in complications of cardiovascular diseases and possible diagnostic and treatment approaches.

Decreased RPM reduces von Willebrand factor degradation with the EVAHEART LVAS: implications for device-specific LVAD management.

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) produces supraphysiologic shear stress that causes von Willebrand factor (VWF) degradation and a bleeding diathesis. Reduction of revolutions per minute (RPM) with axial-flow LVADs does not decrease shear stress enough to reduce VWF degradation and bleeding. However, it is unknown if RPM reduction with centrifugal flow LVADs may minimize VWF degradation. We tested the hypothesis that RPM reduction preserves VWF multimers in the centrifugal-flow EVAHEART left ventricular assist system (LVAS), which is designed to minimize shear stress and blood trauma. METHODS: Whole blood samples were collected from humans (n = 28). Blood was circulated in ex vivo mock circulatory loops for 6 hours with an EVAHEART LVAS at 2300 (n = 12), 2100 (n = 8), or 1800 RPM (n = 8). Immunoblotting was used to resolve and quantify VWF multimers and degradation fragments. RESULTS: RPM reduction from 2300 to 2100 to 1800 RPM significantly decreased EVAHEART blood flow from 5.8 ± 0.4 to 4.3 ± 0.6 to 4.1 ± 0.5 L/min (analysis of variance [ANOVA], P = .03). RPM reduction protected VWF from pathologic degradation. At lower RPMs, significantly greater levels of VWF multimers were observed (ANOVA, P = .001). Similarly, at lower RPMs, significantly fewer VWF fragments, a product of VWF degradation, were observed (ANOVA, P = .007). CONCLUSIONS: RPM reduction significantly reduced VWF degradation with the centrifugal-flow EVAHEART LVAS, an LVAD specifically designed with low shear stress. Different LVADs have unique hematologic footprints and should be managed with device-specific protocols. Adjustment of RPM to minimize blood trauma while still maintaining physiologic hemodynamics has the potential to decrease complications related to LVAD-associated von Willebrand's disease, such as gastrointestinal bleeding and hemorrhagic stroke.