Moderate Severe Thrombocytopenia Research Articles

Fibrinogen binding to histones in circulation protects against adverse cellular and clinical outcomes

BackgroundCirculating histones are released by extensive tissue injury or cell death and play important pathogenic roles in critical illnesses. Their interaction with circulating plasma components and the potential roles in the clinical setting are not fully understood. ObjectivesWe aimed to characterize the interaction of histones with fibrinogen and explore its roles in vitro, in vivo, and in patient samples. MethodsHistone–fibrinogen binding was assessed by electrophoresis and enzyme-linked immunosorbent assay-based affinity assay. Functional significance was explored using washed platelets and endothelial cells in vitro and histone-infusion mouse models in vivo. To determine clinical translatability, a retrospective single-center cohort study was conducted on patients requiring intensive care admission (n = 199) and validated in a cohort of hospitalized patients with COVID-19 (n = 69). ResultsFibrinogen binds histones through its D-domain with high affinity (calf thymus histones, KD = 18.0 ± 5.6 nM; histone 3, KD = 2.7 ± 0.8 nM; and histone 4, KD = 2.0 ± 0.7 nM) and significantly reduces histone-induced endothelial damage and platelet aggregation in vitro and in vivo in a histone-infusion mouse model. Physiologic concentrations of fibrinogen can neutralize low levels of circulating histones and increase the cytotoxicity threshold of histones to 50 μg/mL. In a cohort of patients requiring intensive care, a histone:fibrinogen ratio of ≥6 on admission was associated with moderate–severe thrombocytopenia and independently predicted mortality. This finding was validated in a cohort of hospitalized patients with COVID-19. ConclusionFibrinogen buffers the cytotoxic properties of circulating histones. Detection and monitoring of circulating histones and histone:fibrinogen ratios will help identify critically ill patients at highest risk of adverse outcomes who might benefit from antihistone therapy.

Absolute and Relative Risks of Hematologic Disease and Cause-Specific Death in Individuals with Incidentally Discovered Thrombocytopenia: A Prospective Study of Two Independent General Population Cohorts Including 486,782 Individuals from the United Kingdom and Denmark

Background: Incidentally discovered thrombocytopenia in asymptomatic individuals often result in a referral to hematology. Clinical decisions for these individuals are mostly based on local practice, as little evidence exists on their risk of hematologic disease and death. We aim to lay ground for an evidence-based clinical approach to incidental thrombocytopenia with or without concurrent anemia by studying relative and absolute risk of being diagnosed with hematologic disease, death from hematologic disease and death from any cause. Methods: We studied 382,424 general population individuals from the United Kingdom (UK) Biobank aged 40-70 years, of whom 9,151 had thrombocytopenia with or without anemia. Individuals with leukocytosis, neutropenia or prior hematologic disease were excluded. As a validation cohort, we studied 104,358 Danish general population individuals. All individuals attended a health examination and had platelets, hemoglobin, leukocyte and differential count measured at study enrolment. Individuals were followed prospectively for up to 16 years for hematologic disease and cause-specific death using national registries, covering all deaths and almost all cancer cases in the UK and Denmark. Results: Among 382,424 individuals from the UK, 6,044 had hematologic disease during follow-up, 28,403 died from any cause and 1,213 died due to hematologic disease. For all analyses, the reference group was individuals with normal platelet count and normal hemoglobin. Individuals with isolated mild thrombocytopenia (platelets 100-149 x 10 9/L) or isolated moderate-severe thrombocytopenia (<100 x 10 9/L) had increased relative risk of hematologic disease (multivariable adjusted Cox regression hazard ratios [HR] 2.19; 95% CI:1.94-2.47 and HR 7.68; 6.35-9.29, respectively), death from hematologic disease (HR 1.81; 1.37-2.38 and HR 2.80; 1.45-5.39, respectively) and death from any cause (HR 1.30; 1.22-1.39 and HR 1.84; 1.58-2.16, respectively). Individuals with mild thrombocytopenia combined with mild anemia (hemoglobin 11-11.8 g/dL for women; 11.9-13.4 for men) also had increased risk of hematologic disease (HR 5.36; 3.82-7.52), death from hematologic disease (4.99; 2.49-10.04), and death from any cause (2.57; 2.14-3.10). Relative risk estimates were increased to a similar or higher extent in individuals having moderate-severe thrombocytopenia with mild anemia, mild thrombocytopenia with severe anemia (hemoglobin <11 g/dL for women; <11.9 for men) or moderate-severe thrombocytopenia with severe anemia. When studying absolute risk (Figure 1), the 10-year risk of death from any cause was especially high (23-53%) in individuals aged 60-70 years with combined thrombocytopenia and anemia. However, 10-year risk of death from hematologic disease was below 5% for all combinations of sex, age, platelet count and hemoglobin, except for women (5.0%) and men (7.9%) aged 60-70 years having moderate-severe thrombocytopenia with mild anemia. For risk of hematologic disease, absolute 10-year risk was below 5% for all age and sex-groups with isolated mild thrombocytopenia, while 10-year risk was as high as 21% in 60-70 year-old men having mild anemia combined with moderate-severe thrombocytopenia. For individuals with thrombocytopenia with or without anemia, the most common hematologic diseases were lymphoid malignancies (41% of diagnoses; HR 1.73; 1.49-2.01), ITP (34%; HR 22.85; 18.56-28.13), and myeloid malignancies (25%; HR 2.90; 2.39-3.52). Among causes of death in individuals with thrombocytopenia were non-hematologic cancer (35% of deaths; HR 1.21; 1.10-1.33), heart disease (21%; HR 1.43; 1.27-1.62), infections (4%; HR 1.84; 1.36-2.49), and bleeding (2%; HR 1.37; 0.94-1.99). In the independent Danish validation cohort, results were generally similar to those presented in Figure 1. Conclusion: Individuals with thrombocytopenia with or without anemia had increased relative risk of hematologic disease, death from hematologic disease and death from any cause. However, 10-year absolute risk of death from hematologic disease was below 5% for most combinations of sex, age, platelet count and hemoglobin. Our absolute 10-year risk estimates can help clinicians to identify low and high-risk individuals and guide decisions on which individuals with incidentally discovered thrombocytopenia that should undergo investigations for possible hematologic disease.

PB0259 Diagnostic Utility of Full Blood Count Screening in Neonates Born to Mothers with Moderate-Severe Thrombocytopenia

PB0259 Diagnostic Utility of Full Blood Count Screening in Neonates Born to Mothers with Moderate-Severe Thrombocytopenia

Thrombocytopenia is associated with a dysregulated host response in severe COVID-19

BackgroundThrombocytopenia is associated with increased mortality in COVID-19 patients. ObjectiveTo determine the association between thrombocytopenia and alterations in host response pathways implicated in disease pathogenesis in patients with severe COVID-19. Patients/methodsWe studied COVID-19 patients admitted to a general hospital ward included in a national (CovidPredict) cohort derived from 13 hospitals in the Netherlands. In a subgroup, 43 host response biomarkers providing insight in aberrations in distinct pathophysiological domains (coagulation and endothelial cell function; inflammation and damage; cytokines and chemokines) were determined in plasma obtained at a single time point within 48 h after admission. Patients were stratified in those with normal platelet counts (150-400 × 109/L) and those with thrombocytopenia (<150 × 109/L). Results6.864 patients were enrolled in the national cohort, of whom 1.348 had thrombocytopenia and 5.516 had normal platelets counts; the biomarker cohort consisted of 429 patients, of whom 85 with thrombocytopenia and 344 with normal platelet counts. Plasma D-dimer levels were not different in thrombocytopenia, although patients with moderate-severe thrombocytopenia (<100 × 109/L) showed higher D-dimer levels, indicating enhanced coagulation activation. Patients with thrombocytopenia had lower plasma levels of many proinflammatory cytokines and chemokines, and antiviral mediators, suggesting involvement of platelets in inflammation and antiviral immunity. Thrombocytopenia was associated with alterations in endothelial cell biomarkers indicative of enhanced activation and a relatively preserved glycocalyx integrity. ConclusionThrombocytopenia in hospitalized patients with severe COVID-19 is associated with broad host response changes across several pathophysiological domains. These results suggest a role of platelets in the immune response during severe COVID-19.

Non-heparin-induced thrombocytopenia in patients after open-heart surgery.

Thrombocytopenia (platelet count below 150 x 103/μL) is a common finding after open-heart surgery and can lead to various complications, including patient death. This study aimed to determine the extent of non-heparin-induced thrombocytopenia in open-heart surgery and to highlight the associated factors. In this cohort study, 842 patients who underwent valve and/or coronary bypass surgery over a 5-year period were retrospectively analyzed. After open-heart surgery, patients whose platelet count was less than 150 x 103/μL on a complete blood count 12 and 24h after surgery were classified as thrombocytopenic. Three hundred twenty patients without thrombocytopenia and 21 patients with a high probability of heparin-induced thrombocytopenia were excluded from the study. Logistic regression analysis was used to assess the association of independent variables in moderate-severe thrombocytopenia: Age groups, sex, underlying disease, symptoms, type of surgery, pump time, pulsatile or non-pulsatile duration, degree of hypothermia, hemodilution, oxygenator type, use of an intra-aortic balloon, and erythrocyte transfusion counts were included in the analysis. A total of 501 patients were diagnosed as having non-heparin-induced thrombocytopenia, and 64.3% were male. Three hundred seventy-seven (75.2%) patients had mild thrombocytopenia and 124 (24.7%) had moderate-severe thrombocytopenia. The postoperative platelet count was significantly lower than the preoperative platelet count (213 x 103 vs.117 x 103/μL; p < 0.001). Moderate-severe thrombocytopenia was associated with age ≥80years odds (OR = 9.026, 95% CI: [1.757-46.363]; p = 0.008), isolated valve surgery (OR = 3.090, 95% CI: [1.867-5.114]; p < 0.001), and valve surgery with coronary bypass (OR = 4.938, 95% CI: [1.638-14.889]; p = 0.005) compared to isolated coronary bypass, type of oxygenator (Nipro vital compared with Affinity OR = 11.097, 95% CI: [1.923-64.023]; p = 0.007), erythrocyte transfusion count (OR = 1.219, 95%CI: [1.046-1.420]; p = 0.011). Age 80years or older, surgical procedures including heart-valve surgery, and the number of red blood cell transfusions are associated with the risk of moderate-to-severe thrombocytopenia. This study provides a guide in terms of risk factors that may lead to moderate-to-severe thrombocytopenia after open-heart surgery. However, future multicentre prospective randomized studies may provide more detailed information on this subject.

Impact of severity of baseline thrombocytopenia on outcomes after percutaneous coronary interventions: Analysis from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) Program.

The aim of this study was to evaluate the effect of the degree of severity of baseline thrombocytopenia (TCP) on outcomes after percutaneous coronary intervention (PCI) BACKGROUND: The association of TCP with clinical outcomes among patients undergoing coronary intervention has not been previously evaluated. Using data from the US Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) Program, we identified patients undergoing PCI between October 1, 2007, to September 30, 2017. The cohort was then stratified by platelet count, as no TCP (platelet count >150,000/mcl), mild TCP (100-150,000/mcl), or moderate-severe TCP (<100,000/mcl) and this was associated with clinical outcomes. The cohort included 80,427 patients (98% male), of which 14.9% (13.2% mild, 1.7% moderate-severe) suffered from TCP at the time of PCI. Compared with mild or no TCP, moderate-severe TCP was associated with increased risk of post-PCI pericardiocentesis (0.6% vs. 0.2% vs. 0.2%, p = 0.018) and in-hospital mortality (1.5% vs. 0.7% vs. 0.7%) without a difference in postprocedure stroke (0.5% vs. 0.3% vs. 0.3%, p = 0.6). Over a median follow-up of 1729 days, time-to-repeat revascularization was significantly shorter in moderate-severe TCP (1080 vs. 1347 vs. 1467 days, p < 0.001) despite lower risk of revascularization. Both mild (adjusted HR: 1.11, 95% CI: 1.07-1.15, p < 0.001) and moderate-severe TCP (HR: 1.55, 95% CI: 1.43-1.69, p < 0.001) were associated with increased all-cause mortality compared with those without TCP. Thrombocytopenia was associated with increased short- and long-term adverse events among patients undergoing PCI. Any degree of TCP was associated with increased long-term all-cause mortality while moderate-severe TCP was also associated with increased risk of periprocedural adverse events.

Baseline thrombocytopenia in acute coronary syndrome: The lower, the worse

BackgroundPatients with baseline thrombocytopenia can have increased mortality and morbidity, but are typically excluded from randomized clinical trials studying acute coronary syndromes (ACS). We sought to better define the effect thrombocytopenia on clinical outcomes in ACS patients. MethodsPatients identified from the NCDR Chest Pain registry at Mayo Clinic Arizona from Oct 2015 to Sep 2018 were retrospectively classified into two groups: TP (platelet <150 × 103 μL) and control (platelet ≥150 × 103 μL). The groups were analyzed for the clinical outcome (all-cause mortality, major adverse cardiac events (MACE), and bleeding events). The TP group was divided into moderate-severe thrombocytopenia (TPmod; platelet 50–100 × 103 μL) and mild thrombocytopenia (TPmild; platelet 100–150 × 103 μL) for further analysis. P-value <0.05 is considered significant. ResultsFive hundred and thirty-six patients were identified, and 72 patients (13%) had thrombocytopenia. The median follow-up time was 1.1 years. The TP group was older (TP vs. control: mean age 73 ± 13 years vs. 70 ± 13 years; P = 0.026). In patients discharged on dual-antiplatelet therapy, the TP group had higher all-cause mortality (23% vs. 7.3%; P = 0.007) but not major bleeding events (11% vs. 5.0%; P = 0.123). Only all-cause mortality increased with the severity of thrombocytopenia (TPmod vs. TPmild vs. control: 33% vs. 24% vs. 7.3%; P = 0.007). ConclusionsIn patients with ACS, baseline thrombocytopenia is associated with increased all-cause mortality and all bleeding events without net MACE benefit. Further study is needed to identify the optimal antiplatelet strategy in this higher risk population.

Impact of preoperative thrombocytopenia on the outcome after coronary artery bypass grafting

The impact of thrombocytopenia on postoperative bleeding and other major adverse events after cardiac surgery is unclear. This issue was investigated in a series of patients who underwent isolated coronary artery bypass grafting (CABG) from the prospective, multicenter E-CABG registry. Preoperative thrombocytopenia was defined as preoperative platelet count <150 × 109/L and it was considered moderate-severe when preoperative platelet count was <100 × 109/L. Multilevel mixed-effects regression analysis was performed to adjust the effect of thrombocytopenia on outcomes for baseline and operative covariates as well as for interinstitutional differences in patient-blood management. Among 7189 patients included in this analysis, 599 (8.3%) had preoperative thrombocytopenia. Patient with preoperative thrombocytopenia had an increased chest drainage output at 12 h (mean, 519 vs. 456 mL, adjusted coeff. 39, 95%CI 18–60) and rates of severe-massive bleeding (Universal Definition of Perioperative Bleeding (UDPB) severity grades 3–4: 12.7% vs. 8.1%, adjusted OR 1.47, 95%CI 1.11–1.93; E-CABG bleeding severity grades 2–3: 10.4% vs. 6.1%, adjusted OR 1.78, 95%CI 1.30–2.43). Thrombocytopenia was associated with an increased risk of hospital/30-day death (3.2% vs. 1.9%, adjusted OR 2.02, 95%CI 1.20–3.42), 1-year death (5.7% vs. 3.4%, adjusted HR 1.68, 95%CI 1.16–2.44), deep sternal wound infection (3.5% vs. 2.4%, adjusted OR 1.65, 95%CI 1.02–2.66), acute kidney injury (28.1% vs. 22.2%, OR 1.45, 1.18–1.78), and prolonged stay in the intensive care unit (mean, 3.6 vs 2.8 days, adjusted coeff. 0.74, 95%CI 0.40–1.09). Similar results were observed in a subset of patients with moderate-severe thrombocytopenia (51 patients, 0.7%). In particular, these patients had a markedly higher rate of acute kidney injury (40%, adjusted OR, 1.94, 95%CI 1.05–3.57), resternotomy for bleeding (7.8%, adjusted OR 3.49, 95%CI 1.20–10.21), and severe-massive bleeding (UDPB severity grades 3–4: 23.5%, adjusted OR 3.08, 95%CI 1.52–6.22; E-CABG bleeding severity grades 2–3: 23.5%, adjusted OR 4.43, 95%CI 2.15–9.15) compared to patients with normal preoperative platelet count. Mild preoperative thrombocytopenia is associated with increased risk of severe-massive bleeding, mortality, and other major adverse events after CABG. Such risks are markedly increased in patients with moderate-severe preoperative thrombocytopenia.

Predictors and clinical impact of pre-existing and acquired thrombocytopenia following transcatheter aortic valve replacement.

Data are limited regarding transcatheter aortic valve replacement (TAVR)-related thrombocytopenia (TP). We sought to thoroughly characterize the presence, clinical impact, and severity of TP associated with TAVR. Data were collected from 90 patients who underwent TAVR using the Edwards SAPIEN valve (59 TF, 29 TA, 2 Tao). Platelet counts were evaluated peri-procedurally and for 8 days following TAVR. Platelet levels were compared and patients were divided into a no TP (No-TP) group 1, acquired (new) TP (NTP) group 2, pre-existing (pre-TAVR) TP (PTP) group 3, and further stratified based on the severity of TP: mild (M) TP (100-149 × 10(3) cell/µL) and moderate-severe (MS) TP (<100 × 10(3) cell/µL). Pre-TAVR point prevalence and post-TAVR incidence of TP were 40% and 79%, respectively (P < 0.001); nadir platelet count in all groups occurred day 4 post-TAVR. Baseline predictors for developing MS TP in groups 2-3 included baseline TP, leaner body mass, smaller pre-procedural aortic valve area, higher peak aortic jet velocity, and worsening baseline renal function. Development of "major" TP (nadir platelet count <100 × 103 cell/µL, ≥50% decrease) predicted a higher risk of major vascular complications (OR 2.78 [95% CI, 1.58-3.82]) and major bleeding (OR 3.18 [95% CI, 1.33-5.42]) in group 3. TAVR-related TP is predictable and classification by PTP and TP severity prior to TAVR allows for better risk stratification in predicting in-hospital clinical outcomes. Major TP in the presence of worsening TP is predictable and is associated with worse clinical outcomes. © 2014 Wiley Periodicals, Inc.

Abstract P195: Long-Term Outcomes Associated with Hospital-Acquired Thrombocytopenia Among Patients with Acute Coronary Syndrome

Background Prior studies demonstrated that the development of thrombocytopenia (platelet count drop to &lt;100x10 9 /L) during an ACS hospitalization is associated with adverse outcomes. The long-term prognosis associated with thrombocytopenia of milder severity (100-149x10 9 /L) is less clear. Methods We examined 7,435 ACS patients enrolled in the SYNERGY trial (a randomized comparison between unfractionated and low molecular weight heparin) who had normal platelet counts (≥150x10 9 /L) at admission. Mild thrombocytopenia was defined as a platelet count drop to a nadir of 100-149x10 9 /L; moderate-severe thrombocytopenia was defined as &lt;100x10 9 /L. Patients with nadir platelet counts occurring after in-hospital CABG were excluded. Cox models were used to compare risks of 30-day GUSTO moderate-severe bleeding and 1 year mortality between groups after adjusting for baseline clinical factors. Results Overall, 720 patients (9.7%) developed mild thrombocytopenia and 83 (1.1%) developed moderate-severe thrombocytopenia. Nadir platelet counts occurred at a median of 1.4 days (interquartile range 0.7 - 2.5) after admission. Patients who developed thrombocytopenia were older (median age 71 vs. 67 years, p&lt;0.001) and more often male (71% vs. 63%, p&lt;0.001). Compared with non-thrombocytopenic patients, patients with mild thrombocytopenia were as likely to be prescribed aspirin (90.6% vs. 90.1%) and clopidogrel (65.2% vs. 64.9%) at discharge, whereas patients with moderate-severe thrombocytopenia were less likely to receive aspirin (66.2%) and clopidogrel (44.6%) therapy (both p&lt;0.001). Thrombocytopenia was associated with increased 30-day GUSTO moderate-severe bleeding and 1-year mortality risks (Table) compared with no thrombocytopenia. Conclusions Thrombocytopenia occurs in more than 1 of 10 ACS patients. Our findings suggest that even mild thrombocytopenia is clinically relevant and associated with increased downstream bleeding and mortality risks. Risks of Adverse Events Unadjusted Rate Adjusted Hazard Ratio (95% confidence interval) 30-day GUSTO mod-severe bleeding No thrombocytopenia 5.9% Reference Mild thrombocytopenia 10.0% 1.83 (1.34 - 2.51) Mod-severe thrombocytopenia 34.3% 6.88 (4.08 - 11.59) 1-year Mortality No thrombocytopenia 6.5% Reference Mild thrombocytopenia 9.8% 1.30 (1.00 - 1.69) Mod-severe thrombocytopenia 27.7% 5.02 (3.22 - 7.84)