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The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics., This Review summarizes the latest evidence indicating that platelet and endothelial dysfunction are essential components of COVID-19 pathology, describes the potential mechanisms underlying the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19, and highlights the roles of coagulopathy, thrombocytopathy and endotheliopathy in COVID-19 pathogenesis., Key points Venous thromboembolism, arterial thrombosis and thrombotic microangiopathy substantially contribute to increased morbidity and mortality in patients with COVID-19.A complex interaction between coagulopathy, thrombocytopathy and endotheliopathy contributes to COVID-19-associated thromboinflammation.Coagulopathy, thrombocytopathy and endotheliopathy are characteristic features associated with cardiovascular risk factors such as diabetes mellitus, obesity and ageing.The combination of cardiovascular risk factors and infection with SARS-CoV-2 leads to exacerbated thrombosis and increased mortality.Age has an important role in COVID-19 pathogenesis; young patients without a predisposition to coagulopathy, thrombocytopathy and endotheliopathy can have a distinct multisystem inflammatory syndrome that includes a Kawasaki disease-like syndrome in very young individuals.Combination therapies targeting inflammation, coagulopathy, thrombocytopathy and endotheliopathy are likely to be more successful than a single agent in tackling the COVID-19-associated thrombotic complications.

The capabilities of digital microscopy for detection of blood plasma platelet aggregation in vitro were demonstrated experimentally using the inducer adenosine diphosphate (ADP) as an example. It was found that digital microscopy permitted not only detection of platelet aggregates, but also determining their distribution over geometric sizes and estimating their average values. The dependence of platelet aggregate parameters on the ratio of volumes of interacting inducer-plasma components was analyzed. This was tested for plasma samples with normal or increased content of platelets, for thrombocytopenia, as well as for samples with the decreased aggregability (thrombocytopathy). The experiments showed that digital microscopy has a high level of sensitivity: it permits detection of aggregates consisting of only a few platelets. On the other hand, the method has a large dynamic range: it is able to detect both small aggregates (consisting of a few platelets) and those including hundreds of cells.

Erblich bedingte Thrombozytopenien sind eine heterogene Gruppe seltener Erkrankungen mit niedrigen Thrombozytenzahlen. Das klinische Spektrum reicht von schweren syndromalen Formen mit Multiorganbeteiligung und schweren Blutungen bis hin zu leichten, nur zufallig diagnostizierten Thrombozytopenien. Zwar konnten bei den meisten Erkrankungen Defekte in Genen beschrieben werden, die fur Membranglykoproteine, fur Proteine des Zytoskeletts und intrazellularer Signalwege oder fur Transkriptionsfaktoren kodieren. Trotzdem sind die zugrunde liegenden Pathomechanismen haufig noch unbekannt. Diese Zusammenfassung beschreibt pathophysiologische, klinische und diagnostische Aspekte erblich bedingter Thrombozytopenien.

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by early platelet destruction mediated by antiplatelet autoantibodies. Platelet membrane glycoproteins (GP), especially GPIIb-IIIa and GPIb-IX, contain major autoantigenic determinants in chronic ITP. Recent advances in the localization of autoantigens as well as in the detection of GP-specific antibodies have improved our understanding of the pathophysiology of the disease. The N-terminal globular head of GPIIb-IIIa, particularly the beta-propeller domain in GPIIb, seems to play an important role as a hot spot for autoantigenic epitopes in chronic ITP.

Experimental hyperammonemia in rats was accompanied by hemostatic disorders manifesting in coagulopathy (activation of the intrinsic pathway of blood coagulation) and suppression of platelet function. Ceruloplasmin in a total dose of 60 mg/kg effectively normalized coagulation hemostasis and functional activity of platelets by improving secretory processes in platelets and increasing aggregation rate.

Trace elements play an essential role in the activation and regulation of metabolic processes. By using the flameless graphite furnace-AAS, accurate results can be obtained. In order to verify blood cells as more representative than plasma to reflect the whole body content of trace elements at uremic state, two patient groups, one with preterminal renal failure (n=40) and the second with chronic renal failure undergoing hemodialysis (n=20) were examined. The concentration levels of zinc, copper and aluminium were measured in different matrices, i.e. whole blood, plasma and corpuscular blood components. The analytical technique is eligible to isolate mono- and polymorphnuclear leucocytes for the determination of intracellular contents. In agreement with other reports, zinc and copper were decreased and aluminium was increased in the plasma of both patient groups. Different results could be found for intracellular contents with mean zinc concentration of erythrocytes, thrombocytes and leucocytes between mean and higher levels, though staying within normal values. Copper was decreased in erythrocytes and increased in thrombocytes, but not detectable in leucocytes. The results of this study point out the differences between the plasmatic and intracellular alteration of trace element contents in uremic patients. However, the concentration levels of all cellular compartments show high standard deviation, which shows the necessity of measuring additional matrices, e.g. plasma. Uremic symptoms relate to the disorders of the trace element homeostasis. Regarding the increased fragility of erythrocytes with shortened life duration, decreased copper contents could play an essential role. Increased aluminium concentration levels might also be one of the interfering factors in the uremic thrombocytopathy. Yet the measurement of the plasma content is inevitable to diagnose and reflect the whole body content of trace elements at uremic state. By keeping analysis control, important information about progression and influence of therapy can be obtained.

This work was supported by grants-in-aid from the Japan Society for the Promotion of Science, Mitsubishi Pharma Research Foundation, and National Hospital Organization Research Fund.

Though it has been generally accepted that uremic serum contains substances which impair platelet function and inhibit erythropoiesis, the mechanism of uremic thrombocytopathy and bleeding tendency is still not clearly understood. By measuring the nuclear DNA content of the megakaryocytes of 20 patients with end-stage renal failure, we demonstrated that ploidy levels correlate with parameters of uremia. High creatinine and BUN levels as well as low hemoglobin or creatinine clearance values correlate with low average ploidy of megakaryocytes. In explaining this phenomenon, uremic inhibition of DNA replication seems to be more important than dialysis or the type of renal disease. As megakaryocytes of higher ploidy are thought to produce more reactive platelets than megakaryocytes of lower DNA content, this could be another reason for uremic thrombocytopathy and bleeding tendency.

ADENOSINE triphosphate (ATP) is found in large amounts in blood platelets1 and disappears rapidly during clotting2 while ADP increases; this nucleotide is able to aggregate platelets3–6. ATP and AMP act as inhibitors in this reaction7,8.