Viral infection is found in approximately 30

Convalescent plasma was proposed for passive immunization against COVID-19; but so far there are conflicting results and still open questions. However, besides antibodies, other plasma proteins may be good candidates for further research and application. Thromboinflammation frequently complicates severe COVID-19, and classical anticoagulants like heparins seem to have limited effect. The natural protease inhibitors antithrombin III (ATIII), α1-antitrypsin (α1-AT) and α2-macroglobulin (α2-M), which are found decreased in severe COVD-19, play a crucial role in prothrombotic and inflammatory pathways. While ATIII and α1-AT are licensed as commercially prepared therapeutic concentrates, there is no preparation of α2-M available. The diagnostic, prognostic, and even therapeutic potential of plasma protease inhibitors should be further explored.

The authors of a systematic review and meta-analysis conclude that the benefit of convalescent plasma (CP) in the treatment of COVID-19 is limited. Among other systematic reviews, only one found an indication of benefit of CP. However, a meta-analysis needs a focused and meaningful clinical question and should include studies which are designed to test a reasonable hypothesis. Clinical trials to support the licensing of medicines should aim to define as exactly as possible the investigational drug and target disease. In the case of COVID-19, trial details (e.g., duration, stage and severity of disease, and antibody content and dose of CP) are quite heterogeneous. The so far available evidence suggests that the hypothesis should be sharpened as to treat COVID -19 patients at risk for developing severe disease as early enough with a sufficiently high dose of specific antibodies. It has been demonstrated that such an approach is feasible, and the lack of an independent reproduction by further trials with a really comparable design can probably not be compensated by compiling all available, heterogenous trials, even with the best methodology of a systematic review and meta-analysis. Though the COVID-19 pandemic appears to be fading, we should not neglect the search for effective prevention and treatments, given the still high death toll of COVID-19. Monoclonal antibodies were found effective in the early phase of the pandemic; however, due to new variants of SARS-COV2 undermining their efficacy they are no longer recommended by the current NIH guidelines. CP can provide a spectrum of polyclonal antibodies in close timely and regional connection to the particular prevalent virus variant. It would be extremely valuable to obtain a solid scientific foundation for the principle of target specific and temporarily adapted passive immunization, which could be a fast and flexible instrument also in future outbreaks of novel pathogens.

The COVID-19 pandemic so far caused millions of deaths, and the therapeutic options for high-risk patients are far from being satisfactory. Active immunization by vaccines against SARS-CoV-2 spike protein provides good protection from a severe course of COVID-19. It has been explored in numerous clinical trials, whether also passive immunization by transfusion of convalescent plasma could positively influence the course of COVID-19. Large randomized clinical trials failed to demonstrate a benefit for patients with advanced disease. However, the antibody dose and timing of transfusion might have contributed to this negative result. Randomized clinical trials are necessary to make evidence-based progress in the development of therapeutic options, and this holds true also for “natural” concepts. However, even highquality trials are just a tool to test predefined hypotheses. Arguments are presented that convalescent plasma should be further evaluated in clinical trials as proactive, quasi “prophylactic” treatment by giving a sufficient amount of CCP early enough (before massive virus replication). A solid scientific foundation for the principle of target specific and temporarily adapted passive immunization would be very important even beyond COVID-19 as fast and flexible instrument also in future outbreaks of novel pathogens.

The complex COVID‐19‐associated coagulopathy appears to impair prognosis. Recently, we presented the hypothesis that children are to some extent protected by higher α2‐macroglobulin (α2‐M) levels from severe COVID‐19. In addition to endothelial cells, thrombin, and platelets, neutrophil granulocytes also appear to play an important role. Neutrophils extrude extracellular nets, which are histone‐ and protease‐coated web‐like DNA structures; activate coagulation and platelets; and release radicals and proteases such as elastase. The unique phylogenetically ancient and “versatile” inhibitor α2‐M contributes particularly during childhood to the antithrombin activity of plasma, binds a broad spectrum of proteases, and interacts with other mediators of inflammation such as cytokines. It is suggested that the scope of basic research and clinical studies would include the potential role of α2‐M in COVID‐19.

This report contains the updated consensus recommendations for optimal hemophilia care produced in 2019 by three Working Groups (WG) on behalf of the European Directorate for Quality of Medicines and Healthcare in the frame of the Kreuth V Initiative. WG1 recommended access to prophylaxis for all patients, the achievement of plasma factor trough levels of at least 3-5% when extended half-life factor VIII (FVIII) and FIX products are used, a personalized treatment regimen, and a choice of chromogenic assays for treatment monitoring. It was also emphasized that innovative therapies should be supervised by hemophilia comprehensive care centers. WG2 recommended mandatory collection of postmarketing data to assure the long-term safety and efficacy of new hemophilia therapies, the establishment of national patient registries including the core data recommended by the European Medicines Agency and the International Society on Thrombosis and Haemostasis, with adequate support under public control, and greater collaboration to facilitate a comprehensive data evaluation throughout Europe. WG3 discussed methodological aspects of hemophilia care in the context of access decisions, particularly for innovative therapies, and recommended that clinical studies should be designed to provide the quality of evidence needed by regulatory authorities, HTA bodies and healthcare providers. The dialogue between all stakeholders in hemophilia care and patient organizations should be fostered to implement these recommendations.

We are overwhelmed by scientific publications on clinical observations, virology and epidemiology of SARS-CoV-2 infections. There is a growing body of evidence that hypercoagulability complicates COVID-19, probably contributing to poor prognosis.

We are overwhelmed by scientific publications on clinical observations, virology and epidemiology of SARS-CoV-2 infections. There is a growing body of evidence that hypercoagulability complicates COVID-19, probably contributing to poor prognosis.

We are overwhelmed by scientific publications on clinical observations, virology and epidemiology of SARS-CoV-2 infections. There is a growing body of evidence that hypercoagulability complicates COVID-19, probably contributing to poor prognosis.

Response to 'Inaccurate conclusions by Tang and colleagues'We appreciate the opportunity to respond to the letter from Dr Greenstein.It's true that most of the heparin users just received a prophylaxis dose in our study, due to lack of evidence of arterial or venous thromboembolism (VTE), and typical signs of disseminated intravascular coagulation (DIC) in the majority of the patients; in addition, some of them were also too unstable to transport for imaging examinations.Therapeutic doses of heparin had been used in patients with definite thrombosis but were not specifically mentioned in our paper.According to a recent report about VTE prophylaxis in the management of COVID-19, 1 40% of the patients were considered at high risk of VTE on the basis of the Padua Prediction Score 2 in a Chinese cohort with COVID-19; however, only 7% of all patients received anticoagulant drugs during hospitalization.In a previous Chinese multicenter study, 3 36.6% of medical patients and 53.4% of surgical patients had a high risk of VTE during hospitalization, and only 6.0% and 11.8% of them, respectively, received an appropriate prophylactic.We have to say that routine thromboprophylaxis has not been routinely practiced in China.Even so, our study has highlighted the importance of appropriate anticoagulant treatment for COVID-19 patients with coagulopathy.Close monitoring of coagulation markers and early intervention are critical.Further prospective studies are required to elucidate whether higher doses of anticoagulants will provide more benefits in COVID-19 patients with coagulopathy.

Background: Platelet concentrates play an important role in transfusion medicine. Their short lifespan and lack of robustness require efforts to ensure adequate product quality. In this study, we compared the in vitro quality of the main concentrate types, pooled platelet concentrate (PPC) from whole blood donations, and platelet concentrate from single-donor apheresis (APC). Methods: Twenty PPCs and 20 APCs prepared in plasma were analyzed on days 2, 4, and 7 of storage. Variables related to metabolism, degranulation, platelet aggregation, P-selectin expression, and annexin V binding were analyzed. Morphology was assessed by transmission electron microscopy of ultrathin sections. A microfluidic device was applied to test the effects of shear stress on platelet function. Results: The metabolic parameters indicated stable storage conditions throughout the 7-day period. The resting discoid form was the prevailing morphology on days 2 and 4 in the PPCs and APCs. Chemokine release and receptor shedding of soluble P-selectin and soluble CD40L equally increased in PPCs and APCs. Aggregation responses to ADP and collagen were heterogeneous, with marked losses in collagen responsiveness on day 4 in individual concentrates. Baseline expression of P-selectin in PPCs and APCs was low, and inducibility of P-selectin was well preserved until day 4. Under shear stress, equal adhesiveness and stability were found with platelets from PPCs and APCs. Conclusions: Platelets from PPCs and APCs showed similar in vitro function and stability parameters. However, platelet concentrates presented a high variability and individual concentrates an impaired functional capability. Identifying the factors contributing to this would help increase product reliability.