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Von Willebrand factor multimer quantitation for assessment of cardiac lesion severity and bleeding risk.

ABSTRACT: Background:von Willebrand factor (VWF) multimer quantitation has been utilized in the assessment of valvular heart disease, however, there is no standardized method for quantitation. We compared three methods of assessment which utilized a normal plasma control. Methods:We analyzed 476 samples and their control plasma from 368 patients with valvular heart disease, hypertrophic cardiomyopathy, or LVAD therapy, and 27 normal subjects. VWF multimers were assessed as normalized VWF multimer ratios (NMR) of gel bands >15/2-15 (NMR15) or gel bands >10/2-10 (NMR10). Associations of VWF laboratory and multimeric assessments with cardiac lesion severity and acquired bleeding were investigated. Results:Abnormal multimers were present in 78% of patients with moderate to severe hemodynamic abnormalities compared to 19% of patients with normal or mildly abnormal hemodynamics. NMR showed strong association with severe cardiac lesions (NMR15: OR 15.29, CI 9.04-27.18; NMR10: OR 14.18, CI 8.88-23.21). PFA-CADP was strongly associated with moderate to severe cardiac lesions (OR 14.91, CI 9.08-24.50). PFA-CADP and NMR15 showed excellent ability to discriminate ?moderate (AUC 0.86, CI 0.83-0.89 and 0.83, CI 0.79-0.87 respectively) and severe cardiac lesions (AUC 0.84, CI 0.81-0.88 and 0.85, CI 0.81-0.88 respectively). NMR was less strongly associated with bleeding (OR 4.01 for NMR10, CI 2.49-6.58). Conclusion:Quantification of VWF multimers may provide clinical utility in circumstances where clinical estimation of cardiac lesion severity is challenging, such as with dysfunctional prosthetic valves. The presence of abnormal VWF multimers is associated with bleeding, however further quantitation provided only modest improvement in risk stratification.

SUBMITTER: Austin CO

PROVIDER: S-EPMC6055563 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Von Willebrand factor multimer quantitation for assessment of cardiac lesion severity and bleeding risk.

Austin Christopher O CO Chen Dong D Thomas Colleen S CS Safford Robert E RE Shapiro Brian P BP Bryan Justin A JA Ray Jordan C JC Blackshear Joseph L JL

Research and practice in thrombosis and haemostasis 20171221 1

<h4>Background</h4>von Willebrand factor (VWF) multimer quantitation has been utilized in the assessment of valvular heart disease, however, there is no standardized method for quantitation. We compared three methods of assessment which utilized a normal plasma control.<h4>Methods</h4>We analyzed 476 samples and their control plasma from 368 patients with valvular heart disease, hypertrophic cardiomyopathy, or LVAD therapy, and 27 normal subjects. VWF multimers were assessed as normalized VWF mu ...[more]

PMID: 30046716

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Project description:The formation of hemostatic plugs at sites of vascular injury crucially involves the multimeric glycoprotein von Willebrand factor (VWF). VWF multimers are linear chains of N-terminally linked dimers. The latter are formed from monomers via formation of the C-terminal disulfide bonds Cys2771-Cys2773', Cys2773-Cys2771', and Cys2811-Cys2811'. Mutations in VWF that impair multimerization can lead to subtype 2A of the bleeding disorder von Willebrand Disease (VWD). Commonly, the multimer size distribution of VWF is assessed by electrophoretic multimer analysis. Here, we present atomic force microscopy (AFM) imaging as a method to determine the size distribution of VWF variants by direct visualization at the single-molecule level. We first validated our approach by investigating recombinant wildtype VWF and a previously studied mutant (p.Cys1099Tyr) that impairs N-terminal multimerization. We obtained excellent quantitative agreement with results from earlier studies and with electrophoretic multimer analysis. We then imaged specific mutants that are known to exhibit disturbed C-terminal dimerization. For the mutants p.Cys2771Arg and p.Cys2773Arg, we found the majority of monomers (87 ± 5% and 73 ± 4%, respectively) not to be C-terminally dimerized. While these results confirm that Cys2771 and Cys2773 are crucial for dimerization, they additionally provide quantitative information on the mutants' different abilities to form alternative C-terminal disulfides for residual dimerization. We further mutated Cys2811 to Ala and found that only 23 ± 3% of monomers are not C-terminally dimerized, indicating that Cys2811 is structurally less important for dimerization. Furthermore, for mutants p.Cys2771Arg, p.Cys2773Arg, and p.Cys2811Ala we found 'even-numbered' non-native multimers, i.e. multimers with monomers attached on both termini; a multimer species that cannot be distinguished from native multimers by conventional multimer analysis. Summarizing, we demonstrate that AFM imaging can provide unique insights into VWF processing defects at the single-molecule level that cannot be gained from established methods of multimer analysis.

Project description:BackgroundVon Willebrand factor (vWF) is an important part of blood coagulation since it binds platelets to each other and to endothelial cells. In traumatic and surgical haemorrhage, both blood cells and plasmatic factors are consumed, leading to consumption coagulopathy and fluid resuscitation. This often results in large amounts of crystalloids and blood products being infused. Additional administration of vWF complex and platelets might mitigate this problem. We hypothesize that administration of vWF concentrate additionally to platelet concentrates reduces blood loss and the amount of blood products (platelets, red blood cells [RBC], fresh frozen plasma [FFP]) administered.MethodsWe conducted a monocentric 6-year retrospective data analysis of cardiac surgery patients. Included were all patients receiving platelet concentrates within 48 h postoperatively. Patients who additionally received vWF concentrates were allocated to the intervention group and all others to the control group. Groups were compared in mixed regression models correcting for known confounders, based on nearest neighbour propensity score matching. Primary endpoints were loss of blood (day one and two) and amount of needed blood products on day one and two (platelets, RBC, FFP). Secondary endpoints were intensive care unit (ICU) and in-hospital length of stay, ICU and in-hospital mortality, and absolute difference of platelet counts before and after treatment.ResultsOf 497 patients analysed, 168 (34%) received vWF concentrates. 121 patients in both groups were considered for nearest neighbour matching. Patients receiving additional vWF were more likely to receive more blood products (RBC, FFP, platelets) in the first 24 h after surgery and had around 200 mL more blood loss at the same time.ConclusionIn this retrospective analysis, no benefit in additional administration of vWF to platelet concentrates on perioperative blood loss, transfusion requirement (platelets, RBC, FFP), length of stay, and mortality could be found. These findings should be verified in a prospective randomized controlled clinical trial (www.clinicaltrials.gov identifier NCT04555785).

Dataset Information

Von Willebrand factor multimer quantitation for assessment of cardiac lesion severity and bleeding risk.

Publications

Von Willebrand factor multimer quantitation for assessment of cardiac lesion severity and bleeding risk.

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