The purpose of this study was to analyze the results of Cytosorb (CytoSorbents, Monmouth Junction, NJ) adsorption during emergency open heart operations in patients at high risk of bleeding due to ...treatment with coagulation-active substances.
We investigated 55 consecutive patients (median age 70 years; interquartile range: 60 to 77) who underwent emergency cardiac surgery at our institution between June 2016 and June 2018. All patients were receiving therapy with either ticagrelor (n = 43) or rivaroxaban (n = 12). In 39 of 55 cases, we routinely installed standardized Cytosorb adsorption into the heart-lung machine. Bleeding complications during and after surgery were analyzed in detail and compared with 16 patients without adsorption.
In the Cytosorb adsorption group, no rethoracotomies had to be performed. Drainage volumes in 24 hours were only 350 mL (interquartile range: 300 to 450 mL) after ticagrelor administration and 390 mL (interquartile range: 310 to 430 mL) after rivaroxaban therapy. In the majority of patients, transfusions of blood products were not needed. Compared with that group, among the group of patients without adsorption, multiple bleeding complications occurred. These were associated with longer total operation (p = 0.0042), higher drainage volumes (p = 0.0037), more transfusions of red blood cells (p = 0.0119) and platelets (p = 0.0475), a significantly higher rethoracotomy rate (p = 0.0003), significantly prolonged stay in the intensive care unit (p = 0.0141), and a longer hospital stay (p = 0.0244).
The intraoperative use of Cytosorb adsorption of ticagrelor and rivaroxaban in emergency open heart operations is reported for the first time. The data show that the strategy is safe and is an effective method to reduce bleeding complications. We recommend the use for safety in patients with ticagrelor or rivaroxaban undergoing emergency cardiac surgery.
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The acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is frequently unrecognized or is misdiagnosed as von Willebrand disease. AVWS is characterized by structural or functional ...defects of von Willebrand factor (VWF) that are secondary to autoimmune, lymphoproliferative or myeloproliferative, malignant, cardiovascular, or other disorders. VWF abnormalities in these disorders can result from (1) antibody-mediated clearance or functional interference, (2) adsorption to surfaces of transformed cells or platelets, or (3) increased shear stress and subsequent proteolysis. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AVWS. Furthermore, there are no evidence-based guidelines for management. Treatments of the underlying medical condition, including chemo/radiotherapy, surgery, or immunosuppressants can result in remission of AVWS, but is not always feasible and successful. Because of the heterogeneous mechanisms of AVWS, more than one therapeutic approach is often required to treat acute bleeds and for prophylaxis during invasive procedures; the treatment options include, but are not limited to, desmopressin, VWF-containing concentrates, intravenous immunoglobulin, plasmapheresis or recombinant factor VIIa. Here, we review the management of AVWS with an overview on the currently available evidence and additional considerations for typical treatment situations.
Background
Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID‐19. The multimeric size and ...function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS‐13)‐‐mediated proteolysis.
Objectives
This study investigated the hypothesis that ADAMTS‐13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) infection contributing to the observed microvascular thrombosis.
Patients and Methods
Patients with COVID‐19 (n = 23) were recruited from the Beaumont Hospital Intensive Care Unit (ICU) in Dublin. Plasma VWF antigen, multimer distribution, ADAMTS‐13 activity, and known inhibitors thereof were assessed.
Results
We observed markedly increased VWF collagen‐binding activity in patients with severe COVID‐19 compared to controls (median 509.1 versus 94.3 IU/dl). Conversely, plasma ADAMTS‐13 activity was significantly reduced (median 68.2 IU/dl). In keeping with an increase in VWF:ADAMTS‐13 ratio, abnormalities in VWF multimer distribution were common in patients with COVID‐19, with reductions in high molecular weight VWF multimers. Terminal sialylation regulates VWF susceptibility to proteolysis by ADAMTS‐13 and other proteases. We observed that both N‐ and O‐linked sialylation were altered in severe COVID‐19. Furthermore, plasma levels of the ADAMTS‐13 inhibitors interleukin‐6, thrombospondin‐1, and platelet factor 4 were significantly elevated.
Conclusions
These findings support the hypothesis that SARS‐CoV‐2 is associated with profound quantitative and qualitative increases in plasma VWF levels, and a multifactorial down‐regulation in ADAMTS‐13 function. Further studies will be required to determine whether therapeutic interventions to correct ADAMTS‐13‐VWF multimer dysfunction may be useful in COVID‐microvascular thrombosis and angiopathy.
A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to ...microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock.
We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4 μg/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma.
Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41-61) vs. 63% (48-70), p = 0.029; protein C, 47% (38-60) vs. 62% (54-69), p = 0.029). Median ADAMTS13 activity was increased by TPE from 27 (21-42) % before to 47 (38-62) % after TPE (p < 0.001). In contrast, vWF:Ag was elevated and could be reduced by TPE (353 (206-492) IU/dL vs. 170 (117-232) IU/dL, p < 0.001). Regression analysis yielded a correlation between ADAMTS13 activity and platelet count (p = 0.001, R
= 0.316).
Septic shock was associated with activation of pro-coagulant pathways and simultaneous depletion of anti-coagulant factors. TPE partially attenuated this dysbalance by removing pro- and by replacing anti-coagulant factors.
ClinicalTrials.gov, NCT03065751. Retrospectively registered on 28 February 2017.
Thromboembolic and bleeding events in patients with a left ventricular assist device (LVAD) are still a major cause of complications. Therefore, the balance between anti-coagulant and pro-coagulant ...factors needs to be tightly controlled. The principle hypothesis of this study is that different pump designs may have an effect on hemolysis and activation of the coagulation system. Referring to this, the HeartMate II (HMII; Thoratec Corp, Pleasanton, CA) and the HeartWare HVAD (HeartWare International Inc, Framingham, MA) were investigated.
For 20 patients with LVAD support (n = 10 each), plasma coagulation, full blood count, and clinical chemistry parameters were measured. Platelet function was monitored using platelet aggregometry, platelet function analyzer-100 system ( Siemens, Marburg, Germany), vasodilator-stimulated phosphoprotein phosphorylation assay, immature platelet fraction, platelet-derived microparticles, and von Willebrand diagnostic.
Acquired von Willebrand syndrome could be detected in all patients. Signs of hemolysis, as measured by lactate dehydrogenase levels (mean, 470 U/liter HMII, 250 U/liter HVAD; p < 0.001), were more pronounced in the HMII patients. In contrast, D-dimer analysis indicated a significantly higher activation of the coagulation system in HVAD patients (mean, 0.94 mg/liter HMII, 2.01 mg/liter HVAD; p < 0.01). The efficacy of anti-platelet therapy using clopidogrel was not sufficient in more than 50% of the patients.
Our results support the finding that all patients with rotary blood pumps suffered from von Willebrand syndrome. In addition, a distinct footprint of effects on hemolysis and the coagulation system can be attributed to different devices. As a consequence, the individual status of the coagulation system needs to be controlled in long-term patients.
Proteolysis of the multimeric blood coagulation protein von Willebrand Factor (VWF) by ADAMTS13 is crucial for prevention of microvascular thrombosis. ADAMTS13 cleaves VWF within the mechanosensitive ...A2 domain, which is believed to open under shear flow. In this study, we combine fluorescence correlation spectroscopy (FCS) and a microfluidic shear cell to monitor real-time kinetics of full-length VWF proteolysis as a function of shear stress. For comparison, we also measure the Michaelis-Menten kinetics of ADAMTS13 cleavage of wild-type VWF in the absence of shear but partially denaturing conditions. Under shear, ADAMTS13 activity on full-length VWF arises without denaturing agent as evidenced by FCS and gel-based multimer analysis. In agreement with Brownian hydrodynamics simulations, we find a sigmoidal increase of the enzymatic rate as a function of shear at a threshold shear rate γ˙1/2 = 5522/s. The same flow-rate dependence of ADAMTS13 activity we also observe in blood plasma, which is relevant to predict hemostatic dysfunction.
Objectives The aim of this study was to determine whether differences in continuous flow left ventricular assist devices (LVADs) may lead to differences in the von Willebrand profile and the ...occurrence of bleeding and thromboembolic events. Background The HeartMate II (Thoratec Corp., Pleasanton, California) and HeartWare Ventricular Assist Device (HVAD) (HeartWare, Inc., Framingham, Massachusetts) systems are the most frequently implanted LVADs worldwide. In all patients with an axial-flow HeartMate II, acquired von Willebrand syndrome (AvWS) due to the loss of large molecular weight multimers was found. The large molecular weight multimers of the von Willebrand factor (vWF) play a key role in primary hemostasis through interactions with platelets. Methods This was a retrospective study of the vWF profile and incidence of bleeding and thromboembolic events in 102 patients receiving the HeartMate II (n = 51) and HVAD (n = 51). Between January 2003 and December 2010, vWF testing was performed in 102 of 175 consecutive patients after LVAD implantation. Results AvWS was found in all patients, demonstrated by a decrease in the high molecular weight multimers of vWF to 30 ± 14% in HeartMate II patients and 34 ± 13% in patients with an HVAD. Significant predictors of vWF antigen included age (p = 0.011), number of days on the device (p = 0.035), C-reactive protein (p < 0.001), and blood group (p = 0.007). Bleeding and thromboembolic event rates were similar. However, lower fractions of vWF antigen and high molecular weight multimers did not correlate with the rate of bleeding complications or thromboembolic events. Conclusions AvWS developed in all patients after centrifugal or axial flow pump implantation. Different patterns of AvWS were seen between the devices as well as individually. However, the complication rates after implantation were similar.
Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of ...clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy.
In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE.
A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004).
Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 ).
Abstract Objectives This study sought to investigate the prevalence of abnormal von Willebrand multimers (AbM) in patients undergoing transcatheter aortic valve replacement (TAVR) and the impact of ...TAVR on the underlying factor variances. Background An association between the acquired von Willebrand syndrome (aVWS) and valvular aortic stenosis (AS) has been established in the past and surgical aortic valve replacement (SAVR) shown to lead to factor recovery. Prevalence and course of AbM in patients treated with TAVR though has not yet been described comprehensively. Methods Ninety-five consecutive patients underwent TAVR at our institution. Hemostaseologic testing was performed before and up to 1 week after TAVR. Transvalvular and right heart hemodynamics as well as bleeding episodes were recorded and analyzed with descriptive statistics. Results Baseline prevalence of AbM was 42% with an average high-molecular-weight multimer (HMWM) count of 16.2 ± 3.3%. Pressure gradients correlated significantly with the extent of HMWM deficiency (r = –0.63 p < 0.0001). Following valve implantation, HMWM increased proportional to the drop in mean pressure gradient and normalized in most of the patients. However, residual aortic regurgitation/leakage led to inferior HMWM recovery but prosthesis-patient mismatch (PPM) was rare and left HMWM uninfluenced. We saw no association of transfusion with AbM and 1-year mortality was unaffected by AbM. Conclusions AbM in patients with AS undergoing TAVR is frequent. However, TAVR is capable of correcting AbM and therefore possibly aVWS in patients with AS. As opposed to SAVR, bleeding and transfusion requirement in TAVR patients was not associated with severe HMWM deficiency; PPM was rare and HMWM were uninfluenced by the procedure. Aortic regurgitation after TAVR adversely influenced HMWM recovery.
During posttranslational modifications of von Willebrand factor (VWF), the VWF propeptide (VWFpp) is cleaved. The ratio between VWFpp and VWF antigen (VWF:Ag) and the ratio between factor VIII ...(FVIII:C) and VWF:Ag may be used to assess synthesis and clearance of VWF. We analyzed the contribution of VWFpp and ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag in the pathophysiological characterization of type 1 von Willebrand disease (VWD) in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD (MCMDM-1VWD) study. The VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were increased among patients compared with unaffected family members and healthy controls. The VWFpp/VWF:Ag ratio was higher in individuals heterozygous for missense mutations than in those heterozygous for null alleles. In contrast, the FVIII:C/VWF:Ag ratio was highest among heterozygotes for VWF null alleles. The ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag indicate that the pathophysiological mechanisms of type 1 VWD include reduced production and accelerated clearance of VWF, but that often a combination of both mechanisms is implicated.
•VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios define the pathophysiological mechanisms that play a role in VWD and various VWF mutations.•A high VWFpp/VWF:Ag ratio indicates increased clearance of VWF and a high FVIII:C/VWF:Ag ratio decreased synthesis of VWF.
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