Thrombocytopenia in COVID-19: Focused Summary of Current Understanding of Mechanisms and Clinical Implications.

Thrombocytopenia is noted in corona virus disease-2019 (COVID-19) with a prevalence of 5% to 41%, and has been observed to be associated with inferior outcomes. The pathogenesis of thrombocytopenia in COVID-19 is unique and differs from other viral syndromes in terms of clinical presentation and causative mechanisms. Platelets act as both targets and the initial defense against severe acute respiratory syndrome-coronavirus 2 and work in concert with the underlying thrombophilic mechanisms to modulate the final disease phenotype. Understanding these mechanisms may possibly allow targeting of a key component of COVID-19 pathogenesis. We provide a focused review of the current mechanisms implicated in development of thrombocytopenia in COVID-19 and therapeutic implications of the same.

Intracerebral Hemorrhage due to Thrombosis with Thrombocytopenia Syndrome after Vaccination against COVID-19: the First Fatal Case in Korea.

Vaccination with an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in the rare development of thrombosis with thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4). This is a life-threating condition that may be accompanied by bleeding due to thrombocytopenia with thrombosis of the cerebral venous sinus or splanchnic vein. Herein, we describe the first fatal case of thrombosis with thrombocytopenia syndrome in Korea, presenting with intracranial hemorrhage caused by cerebral venous sinus thrombosis. A 33-year-old Korean man received the first dose of the ChAdOx1 nCoV-19 vaccination. He developed severe headache with vomiting 9 days after the vaccination. Twelve days after vaccination, he was admitted to the hospital with neurological symptoms and was diagnosed with cerebral venous sinus thrombosis, which was accompanied by intracranial hemorrhage. Thrombocytopenia and D-dimer elevation were observed, and the result of the PF4 enzyme-linked immunosorbent assay antibody test was reported to be strongly positive. Despite intensive treatment, including intravenous immunoglobulin injection and endovascular mechanical thrombectomy, the patient died 19 days after vaccination. Physicians need to be aware of thrombosis with thrombocytopenia syndrome (TTS) in adenoviral vector-vaccinated patients. Endovascular mechanical thrombectomy might be a useful therapeutic option for the treatment of TTS with cerebral venous sinus thrombosis.

Interactions of Spike-RBD of SARS-CoV-2 and Platelet Factor 4: New Insights in the Etiopathogenesis of Thrombosis.

The rare but dangerous adverse events evidenced after massive vaccination against SARS-CoV-2 are represented by thrombosis and thrombocytopenia. The patients diagnosed with severe COVID-19 may develop a pro-thrombotic state with a much higher frequency, thus we decided to investigate the role of Spike protein (the only common product of the two conditions) or the anti-Spike antibodies in the etiopathogenesis of thrombosis. A pathogenic Platelet Factor 4 (PF4)-dependent syndrome, unrelated to the use of heparin therapy, has been reported after the administration of vaccines in the patients manifesting acute thrombocytopenia and thrombosis. Thus, we aimed at shedding light on the structural similarities of Spike of SARS-CoV-2 and PF4 on their eventual biochemical interactions and on the role of their specific antibodies. The similarities between PF4 and Spike-RBD proteins were evaluated by a comparison of the structures and by testing the cross-reactivity of their specific antibodies by ELISA assays. We found that the anti-Spike antibodies do not recognize PF4, on the contrary, the anti-PF4 antibodies show some cross-reactivity for Spike-RBD. More interestingly, we report for the first time that the PF4 and Spike-RBD proteins can bind each other. These data suggest that the interaction of the two proteins could be involved in the generation of anti-PF4 antibodies, their binding to Spike-RBD, which could lead to platelets aggregation due also to their high expression of ACE2.

Thromboembolism after COVID-19 vaccine in patients with preexisting thrombocytopenia.

While vaccination is the single most effective intervention to drastically reduce severe disease and death following SARS-CoV-2 infection, as shown in UK and Israel, some serious concerns have been raised for an unusual adverse drug reaction (ADR), including vaccine-induced immune thrombotic thrombocytopenia (VITT) with concurrent low platelets as well as capillary leak syndrome. In fact, the overall safety of the vaccine is highlighted by the low frequency of ADR considering that in UK, by the early June, 40 million first doses and 29 million second doses have been injected; nonetheless, 390 thrombotic events, including 71 fatal events have been reported. Interestingly, the cases reported low platelet counts with the presence of anti-platelet factor-4 (PF4) antibodies, indicating an abnormal clotting reaction. Here, out of three referred cases, we report a post-vaccine clinical case of fatal thrombosis with postmortem examination and whole exome sequencing (WES) analysis, whose pathogenesis appeared associated to a preexisting condition of thrombocytopenia due to myelodysplasia.

Patient hematology during hospitalization for viral pneumonia caused by SARS-CoV-2 and non-SARS-CoV-2 agents: a retrospective study.

BACKGROUND: Hematological comparison of coronavirus disease (COVID-19) and other viral pneumonias can provide insights into COVID-19 treatment. METHODS: In this retrospective case-control single-center study, we compared the data of 126 patients with viral pneumonia during different outbreaks [severe acute respiratory syndrome (SARS) in 2003, influenza A (H1N1) in 2009, human adenovirus type 7 in 2018, and COVID-19 in 2020]. RESULTS: One of the COVID-19 characteristics was a continuous decline in the hemoglobin level. The neutrophil count was related to the aggravation of COVID-19 and SARS. Thrombocytopenia occurred in patients with SARS and severe COVID-19 even at the recovery stage. Lymphocytes were related to the entire course of adenovirus infection, recovery of COVID-19, and disease development of SARS. CONCLUSIONS: Dynamic changes in hematological counts could provide a reference for the pathogenesis and prognosis of pneumonia caused by respiratory viruses in clinics.

Cytokine storm in severe COVID-19 pneumonia.

In this study, laboratorial parameters of hospitalized novel coronavirus (COVID-19) patients, who were complicated with severe pneumonia, were compared with the findings of cytokine storm developing in macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH). Severe pneumonia occurred as a result of cytokine storm in some patients who needed intensive care unit (ICU), and it is aimed to determine the precursive parameters in this situation. Also in this study, the aim is to identify laboratory criteria that predict worsening disease and ICU intensification, as well as the development of cytokine storm. This article comprises a retrospective cohort study of patients admitted to a single institution with COVID-19 pneumonia. This study includes 150 confirmed COVID-19 patients with severe pneumonia. When they were considered as severe pneumonia patients, the clinic and laboratory parameters of this group are compared with H-score criteria. Patients are divided into two subgroups; patients with worsened symptoms who were transferred into tertiary ICU, and patients with stable symptoms followed in the clinic. For the patients with confirmed COVID-19 infection, after they become complicated with severe pneumonia, lymphocytopenia (55.3%), anemia (12.0%), thrombocytopenia (19.3%), hyperferritinemia (72.5%), hyperfibrinogenemia (63.7%) and elevated lactate dehydrogenase (LDH) (90.8%), aspartate aminotransaminase (AST) (31.3%), alanine aminotransaminase (ALT) (20.7%) are detected. There were no significant changes in other parameters. Blood parameters between the pre-ICU period and the ICU period (in which their situation had been worsened and acute respiratory distress syndrome [ARDS] was developed) were also compared. In the latter group lymphocyte levels were found significantly reduced (p = 0.01), and LDH, highly sensitive troponin (hs-troponin), procalcitonin, and triglyceride levels were significantly increased (p < 0.05). In addition, there was no change in hemoglobin, leukocyte, platelet, ferritin, and liver function test levels, including patients who developed ARDS, similar to the cytokine storm developed in MAS/sHLH. COVID-19 pneumonia has similar findings as hyperinflammatory syndromes but does not seem to have typical features as in cytokine storm developed in MAS/sHLH. In the severe patient group who has started to develop ARDS signs, a decrease in lymphocyte level in addition to the elevated LDH, hs-troponin, procalcitonin, and triglyceride levels can be a predictor in progression to ICU admission and could help in the planning of anti-cytokine therapy.

Platelets: "multiple choice" effectors in the immune response and their implication in COVID-19 thromboinflammatory process.

Although platelets are traditionally recognized for their central role in hemostasis, the presence of chemotactic factors, chemokines, adhesion molecules, and costimulatory molecules in their granules and membranes indicates that they may play an immunomodulatory role in the immune response, flanking their capacity to trigger blood coagulation and inflammation. Indeed, platelets play a role not only in the innate immune response, through the expression of Toll-like receptors (TLRs) and release of inflammatory cytokines, but also in the adaptive immune response, through expression of key costimulatory molecules and major histocompatibility complex (MHC) molecules capable to activate T cells. Moreover, platelets release huge amounts of extracellular vesicles capable to interact with multiple immune players. The function of platelets thus extends beyond aggregation and implies a multifaceted interplay between hemostasis, inflammation, and the immune response, leading to the amplification of the body's defense processes on one hand, but also potentially degenerating into life-threatening pathological processes on the other. This narrative review summarizes the current knowledge and the most recent updates on platelet immune functions and interactions with infectious agents, with a particular focus on their involvement in COVID-19, whose pathogenesis involves a dysregulation of hemostatic and immune processes in which platelets may be determinant causative agents.

Thrombocytopenia as a prognostic marker in COVID-19 patients: diagnostic test accuracy meta-analysis.

This systematic review and meta-analysis aimed to evaluate thrombocytopenia as a prognostic biomarker in patients with coronavirus disease 2019 (COVID-19). We performed a systematic literature search using PubMed, Embase and EuropePMC. The main outcome was composite poor outcome, a composite of mortality, severity, need for intensive care unit care and invasive mechanical ventilation. There were 8963 patients from 23 studies. Thrombocytopenia occurred in 18% of the patients. Male gender (P = 0.037) significantly reduce the incidence. Thrombocytopenia was associated with composite poor outcome (RR 1.90 (1.43-2.52), P < 0.001; I2: 92.3%). Subgroup analysis showed that thrombocytopenia was associated with mortality (RR 2.34 (1.23-4.45), P < 0.001; I2: 96.8%) and severity (RR 1.61 (1.33-1.96), P < 0.001; I2: 62.4%). Subgroup analysis for cut-off <100 × 109/l showed RR of 1.93 (1.37-2.72), P < 0.001; I2: 83.2%). Thrombocytopenia had a sensitivity of 0.26 (0.18-0.36), specificity of 0.89 (0.84-0.92), positive likelihood ratio of 2.3 (1.6-3.2), negative likelihood ratio of 0.83 (0.75-0.93), diagnostic odds ratio of 3 (2, 4) and area under curve of 0.70 (0.66-0.74) for composite poor outcome. Meta-regression analysis showed that the association between thrombocytopenia and poor outcome did not vary significantly with age, male, lymphocyte, d-dimer, hypertension, diabetes and CKD. Fagan's nomogram showed that the posterior probability of poor outcome was 50% in patients with thrombocytopenia, and 26% in those without thrombocytopenia. The Deek's funnel plot was relatively symmetrical and the quantitative asymmetry test was non-significant (P = 0.14). This study indicates that thrombocytopenia was associated with poor outcome in patients with COVID-19.PROSPERO ID: CRD42020213974.

A Novel Use of Romiplostim for SARS-CoV-2-induced Thrombocytopenia.

The literature regarding coronavirus disease of 2019 (COVID-19) infection in pediatrics indicates that children have less severe clinical presentations and lower mortality rates. There remains limited data regarding hematologic sequelae in pediatric patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Romiplostim has shown a platelet response in pediatric patients with chronic immune thrombocytopenic purpura, and eltrombopag is proven to increase platelet counts in patients with inherited thrombocytopenia. We review SARS-CoV-2-associated thrombocytopenia and present a pediatric patient with acute on chronic thrombocytopenia in the setting of COVID-19 with subsequent platelet recovery using romiplostim.

Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), also known as coronavirus disease 2019 (COVID-19)-induced infection, is strongly associated with various coagulopathies that may result in either bleeding and thrombocytopenia or hypercoagulation and thrombosis. Thrombotic and bleeding or thrombotic pathologies are significant accompaniments to acute respiratory syndrome and lung complications in COVID-19. Thrombotic events and bleeding often occur in subjects with weak constitutions, multiple risk factors and comorbidities. Of particular interest are the various circulating inflammatory coagulation biomarkers involved directly in clotting, with specific focus on fibrin(ogen), D-dimer, P-selectin and von Willebrand Factor (VWF). Central to the activity of these biomarkers are their receptors and signalling pathways on endothelial cells, platelets and erythrocytes. In this review, we discuss vascular implications of COVID-19 and relate this to circulating biomarker, endothelial, erythrocyte and platelet dysfunction. During the progression of the disease, these markers may either be within healthy levels, upregulated or eventually depleted. Most significant is that patients need to be treated early in the disease progression, when high levels of VWF, P-selectin and fibrinogen are present, with normal or slightly increased levels of D-dimer (however, D-dimer levels will rapidly increase as the disease progresses). Progression to VWF and fibrinogen depletion with high D-dimer levels and even higher P-selectin levels, followed by the cytokine storm, will be indicative of a poor prognosis. We conclude by looking at point-of-care devices and methodologies in COVID-19 management and suggest that a personalized medicine approach should be considered in the treatment of patients.

Influenza-induced thrombocytopenia is dependent on the subtype and sialoglycan receptor and increases with virus pathogenicity.

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.

Thrombocytopenia Is Associated with COVID-19 Severity and Outcome: An Updated Meta-Analysis of 5637 Patients with Multiple Outcomes.

The COVID-19 pandemic is persistent worldwide. A prior meta-analysis suggested the association of thrombocytopenia (TCP) with more severe COVID-19 illness and high mortality. Considering newly published studies, we updated the previous meta-analysis to confirm and explain the association of TCP with COVID-19 severity and multiple outcomes. Twenty-four studies with 5637 patients with COVID-19 were included in this study. The weighted incidence of TCP in COVID-19 was 12.4% (95% confidence interval [CI], 7.9%-17.7%). Data synthesis showed that the platelet number was lower in patients with either more severe illness or poor outcomes and even lower in nonsurvivors, with weighted mean differences of -24.56 × 109/L, -22.48 × 109/L, and -49.02 × 109/L, respectively. The meta-analysis of binary outcomes (with and without TCP) indicated the association between TCP and 3-fold enhanced risk of a composite outcome of intensive care unit admission, progression to acute respiratory distress syndrome, and mortality (odds ratio [OR], 3.49; 95% CI, 1.57-7.78). Subgroup analysis by endpoint events suggested TCP to be significantly associated with mortality (OR, 7.37; 95% CI, 2.08-26.14). Overall, the present comprehensive meta-analysis indicated that approximately 12% of hospitalized patients with COVID-19 have TCP, which also represents a sign of more severe illness and poor outcomes.

Paradoxical effect of SARS-CoV-2 infection in patients with immune thrombocytopenia.

Thrombocytopenia has been identified as a common complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the general population. In an attempt to determine the impact of coronavirus disease 2019 (COVID-19) in patients with immune thrombocytopenia (ITP), a retrospective single-centre study was performed. Thrombocytosis was observed in patients with chronic ITP after SARS-CoV-2 infection, frequently needing treatment adjustment or even discontinuation of therapy. Relapses and newly diagnosed cases showed a fast response after initial treatment compared to ITP. Reduced immune activity due to lymphopenia during COVID-19 could explain this paradoxical effect, although further studies are needed.

Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study.

BACKGROUND: COVID-19 is an ongoing global pandemic. Changes in haematological characteristics in patients with COVID-19 are emerging as important features of the disease. We aimed to explore the haematological characteristics and related risk factors in patients with COVID-19. METHODS: This retrospective cohort study included patients with COVID-19 admitted to three designated sites of Wuhan Union Hospital (Wuhan, China). Demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records and compared between patients with moderate, severe, and critical disease (defined according to the diagnosis and treatment protocol for novel coronavirus pneumonia, trial version 7, published by the National Health Commission of China). We assessed the risk factors associated with critical illness and poor prognosis. Dynamic haematological and coagulation parameters were investigated with a linear mixed model, and coagulopathy screening with sepsis-induced coagulopathy and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation scoring systems was applied. FINDINGS: Of 466 patients admitted to hospital from Jan 23 to Feb 23, 2020, 380 patients with COVID-19 were included in our study. The incidence of thrombocytopenia (platelet count <100 × 109 cells per L) in patients with critical disease (42 [49%] of 86) was significantly higher than in those with severe (20 [14%] of 145) or moderate (nine [6%] of 149) disease (p<0·0001). The numbers of lymphocytes and eosinophils were significantly lower in patients with critical disease than those with severe or moderate disease (p<0·0001), and prothrombin time, D-dimer, and fibrin degradation products significantly increased with increasing disease severity (p<0·0001). In multivariate analyses, death was associated with increased neutrophil to lymphocyte ratio (≥9·13; odds ratio [OR] 5·39 [95% CI 1·70-17·13], p=0·0042), thrombocytopenia (platelet count <100 × 109 per L; OR 8·33 [2·56-27·15], p=0·00045), prolonged prothrombin time (>16 s; OR 4·94 [1·50-16·25], p=0·0094), and increased D-dimer (>2 mg/L; OR 4·41 [1·06-18·30], p=0·041). Thrombotic and haemorrhagic events were common complications in patients who died (19 [35%] of 55). Sepsis-induced coagulopathy and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation scores (assessed in 12 patients who survived and eight patients who died) increased over time in patients who died. The onset of sepsis-induced coagulopathy was typically before overt disseminated intravascular coagulation. INTERPRETATION: Rapid blood tests, including platelet count, prothrombin time, D-dimer, and neutrophil to lymphocyte ratio can help clinicians to assess severity and prognosis of patients with COVID-19. The sepsis-induced coagulopathy scoring system can be used for early assessment and management of patients with critical disease. FUNDING: National Key Research and Development Program of China.