COVID-19 vaccine-associated immune thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a new syndrome.

Very rare cases of thrombosis associated with thrombocytopenia have occurred following the vaccination with AstraZeneca COVID-19 vaccine. The aim of this concise review is to summarize the current knowledge on the epidemiologic and pathogenic mechanisms of this syndrome named vaccine-associated immune thrombosis and thrombocytopenia (VITT). A practical patient management section will also be dealt with using information available from national and international scientific societies as well as expert panels. A literature search on the VITT syndrome was carried out in PubMed using appropriate MeSH headings. Overall, 40 VITT cases have been reported. Continuous pharmacovigilance monitoring is needed to collect more data on the real incidence and the pathogenesis of VITT syndrome. Such information will also help us to optimize the management this rare but often clinically severe thrombotic condition associated with COVID-19 vaccination.

The Three Pillars of COVID-19 Convalescent Plasma Therapy.

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly around the world in the last year causing the coronavirus disease 2019 (COVID-19), which still is a severe threat for public health. The therapeutic management of COVID-19 is challenging as, up until now, no specific and efficient pharmacological therapy has been validated. Translating the experience from previous viral epidemics, passive immunotherapy by means of plasma from individuals recovered from COVID-19 has been intensively investigated since the beginning of the pandemic. In this narrative review, we critically analyze the three factors, named "pillars", that play a key role in determining the clinical effectiveness of this biologic therapy: the convalescent plasma, the disease (COVID-19), and the patients.

Hemostatic therapy as a management strategy for acquired hemophilia: what does the future hold?

Introduction: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies that bind and inactivate factor VIII (FVIII), predisposing to a potentially life-threatening bleeding.Areas covered: The main epidemiological, clinical, laboratory and therapeutic features of AHA are critically discussed. In particular, we focus on the hemostatic management of AHA patients analyzing the currently available treatment options and showing the latest data on the innovative hemostatic agents still under investigation. Authors searched the Medline and PubMed electronic databases for publication on AHA in the last twenty years.Expert opinion: While a rapid recognition of suspected cases of AHA is essential to make a correct diagnosis and appropriately and timely treat the hemorrhagic manifestations, the multidisciplinary approach to this challenging, rare and life-threatening bleeding disorder is of equal importance to improve patients' outcome. Although promising, the safety and efficacy of the clinical use of emicizumab in AHA needs to be validated by trials including an adequate number of patients, before registering the drug also for this indication.

Potential mechanisms of action of convalescent plasma in COVID-19.

The COVID-19 pandemic will be remembered as one of the worst catastrophic events in human history. Unfortunately, no universally recognized effective therapeutic agents are currently available for the treatment of severe SARS-CoV-2 infection. In this context, the use of convalescent plasma from recovered COVID-19 patients has gained increasing interest thanks to the initially positive clinical reports. A number of mechanisms of action have been proposed for convalescent plasma, including direct neutralization and suppression of viremia, anti-inflammatory and immunomodulation effects and mitigation of the COVID-19-associated hypercoagulable state. These immune and non-immune mechanisms will be critically discussed in this narrative review.

Convalescent Plasma for the Treatment of Severe COVID-19.

The COVID-19 pandemic in 2020 is one of the worst catastrophic events in human history. Several non-specific antiviral drugs have been tried to defeat the SARS-CoV-2, with mixed results. Convalescent plasma from patients who have recovered from COVID-19 is one of the specific biologic therapies being considered to treat SARS-CoV-2 infection. Preliminary studies have shown that convalescent plasma, containing antibodies able to neutralize SARS-CoV-2, is promising in blocking viral replication and improving patients' clinical symptoms. The results of several ongoing randomized controlled trials are, however, keenly awaited to definitively elucidate the safety and efficacy of this blood component in COVID-19. In this narrative review, we summarize the current evidence from the literature on the treatment of severe COVID-19 with convalescent plasma. A concise overview of the hypothesized mechanisms of action is also presented.

The use of whole blood in traumatic bleeding: a systematic review.

Hemostatic resuscitation is currently considered a standard of care for the management of life-threatening hemorrhage, but in some critical settings the access to high quantities of blood components is problematic. Whole blood (WB) transfusion has been proposed as an alternative modality for hemostatic resuscitation of traumatic major bleeding. To assess the efficacy and safety of WB in trauma-associated massive bleeding, we performed a systematic review of the literature. We selected studies comparing WB transfusions to transfusion of blood components (COMP) in massive trauma bleeding; both randomized clinical trial (RCT) and observational studies were considered. The outcomes were mortality (30-day/in-hospital and 24-h mortality) and adverse events/transfusion reactions. The effect sizes were crude odds ratio (OR), adjusted OR and hazard ratio (HR). The methodological quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs, and the ROBIN-1 tool for observational studies. The overall quality of the available evidence was assessed with the GRADE system. One RCT (2 reports) and 6 cohort studies were included (3642 adult patients; 675 receiving WB, 2967 receiving COMP). Three studies were conducted in military setting, and 4 in civilian setting. In the overall analysis, 30-day/in-hospital and 24-h mortality did not differ significantly between groups (very low quality of the evidence due to high risk of bias, imprecision and inconsistency). After adjustment for baseline covariates in three cohort studies, the OR for mortality was significantly lower in WB recipients compared to COMP (OR 0.22; 95% CIs 0.10/0.45) (moderate grade of evidence). Adverse events and transfusion reactions were overlooked and not consistently reported. The available evidence does not allow to draw definite conclusions on the short-term and long-term efficacy and safety of WB transfusion compared to COMP transfusion. Further well designed research is needed.

A retrospective study assessing the characteristics of COVID-19 convalescent plasma donors and donations.

BACKGROUND: Although many trials are currently investigating the safety and efficacy of convalescent plasma (CP) in critically ill COVID-19 patients, there is a paucity of ongoing and published studies evaluating the CP donors' side. This retrospective study reports the first Italian experience on CP donors' selection and donations. METHODS: Patients aged 18-68 years who had recovered from COVID-19 at least 2 weeks previously were recruited between March 18 and June 30, 2020 in a study protocol at the Italian hospitals of Pavia and Mantova. RESULTS: During the study period, 494 of 512 donors recruited were judged eligible and underwent 504 plasmapheresis procedures. Eighty-five percent (437/512) of the CP donors were males. The average time between symptom recovery and CP donation was 36.6 (±20.0) days. Four hundred and eighty-eight plasmapheresis procedures (96.8%) were concluded and each unit was divided into two subunits (total 976) with an average volume of 316.2 (±22.7) mL. Ninety-three percent (460/494) of CP donors at the time of plasma donation had a neutralizing IgG titer ≥1:80. Plasmapheresis-related adverse reactions occurred in 2.6% (13/504) of cases; all the reactions were mild and none required therapeutic intervention. Donors' age and COVID-19 severity were positively associated with greater antibody responses. CONCLUSION: This study demonstrates the feasibility and safety of a pilot CP program conducted in Italy. The identification of factors (ie, age and severity of COVID-19) positively associated with higher neutralizing antibody titers at the time of donation may help to optimize the selection of CP donors.

COVID-19-associated coagulopathy.

Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recently recognized as a systemic disorder inducing a prothrombotic state. The molecular mechanisms underlying the hypercoagulable state seen in patients with COVID-19 is still incompletely understood, although it presumably involves the close link between inflammatory and hemostatic systems. The laboratory coagulation monitoring of severely ill COVID-19 patients is mandatory to identify those patients at increased thrombotic risk and to modulate thromboprophylaxis accordingly. In this review, we summarize the current understanding on the pathogenesis, epidemiology, clinical and laboratory features and management of coagulopathy associated with COVID-19.

Advances in managing rare acquired bleeding disorders.

INTRODUCTION: Rare acquired bleeding disorders include a wide spectrum of coagulopathies characterized by spontaneous or post-trauma and post-surgery hemorrhages in patients without a previous personal or family history of bleeding. AREAS COVERED: This review, based on a Medline/PubMed search during the last 20 years, will focus mainly on rare acquired bleeding disorders caused by autoantibodies against coagulation factors, including autoantibodies against factor VIII (acquired hemophilia A), von Willebrand factor (acquired von Willebrand syndrome) and other coagulation factors (factors V, X, XI, and XIII). The pathogenic, laboratory, and clinical features of these rare hemorrhagic conditions will be discussed, with particular attention to their management. EXPERT OPINION: The treatment of rare acquired bleeding disorders includes the control of bleeding and the elimination of the autoantibody and of the underlying disease, when present. As the bleeding clinical phenotype is often severe, the management of affected patients is particularly challenging. Thus, while an early diagnosis of the acquired coagulopathy is essential to start the most appropriate treatment and to improve patients' outcomes, the support of specialized centers is equally important to provide a correct management of such complicated cases.

Investigational drugs to treat hemophilia.

Introduction: Hemophilia A and B are congenital bleeding disorders. The current standard management of patients with severe hemophilia is prophylaxis which is given intravenously two or three times weekly; however, this is associated with a significant burden on the quality of life of the patient. The main attempts to improve the management of hemophilia is hence through the development of a new generation of products with properties facilitating prophylaxis and/or a better control of bleeding.Areas covered: This review describes the preclinical and phase 1/2 studies investigating the innovative products for the management of hemophilia patients with or without coagulation factor inhibitors.Expert opinion: Numerous innovative therapeutics, including factor concentrates and non-clotting factor-based therapies with extended half-life, are under clinical investigation. Among replacement therapies for hemophilia A, the results from phase 1/2 studies indicate that the most interesting products are those bioengineered using XTEN fusion technology. The anti-tissue factor pathway inhibitor antibody concizumab is the most innovative and interesting agent among non-clotting factor products. If the results of ongoing trials confirm the preliminary positive results, these promising agents will provide further improvements in the management and quality of life of patients with hemophilia.

Rare congenital bleeding disorders.

The rare congenital bleeding disorders are a heterogeneous group of diseases which include deficiencies of fibrinogen, prothrombin and factors V, V + VIII, VII, X, XI and XIII. They are usually transmitted as autosomal recessive disorders, and the prevalence of the severe forms ranges from one case in 500,000 for factor VII up to one in 2,000,000 for factor XIII in the general population. Patients with rare congenital bleeding disorders may have a broad spectrum of clinical symptoms, ranging from mucocutaneous bleeding to life-threatening haemorrhages, such as those occurring in the central nervous system. The treatment of these disorders is based principally on the replacement of the deficient factor using, when available, specific plasma-derived or recombinant products. The aim of this narrative review is to summarise current knowledge about these rare bleeding conditions.

An early start of West Nile virus seasonal transmission: the added value of One Heath surveillance in detecting early circulation and triggering timely response in Italy, June to July 2018.

In Italy, the 2018 West Nile virus transmission season started early with a high number of cases reported. One-Health surveillance, within the Italian West Nile national preparedness and response plan, detected viral circulation 9 days before symptom-onset of the first confirmed human case; triggering timely implementation of blood and transplant safety measures. This is an example of how functional coordination allows health authorities to use early warning triggers from surveillance systems to implement preventive measures.

Inhibitors in Patients with Congenital Bleeding Disorders Other Than Hemophilia.

The most worrying complication of replacement therapy for severe hemophilia A and B is currently the occurrence of inhibitory alloantibodies against infused factor VIII and factor IX, respectively. Inhibitors compromise the management of hemorrhage in affected patients, with a considerable increase in complications, disability, and costs. While these alloantibodies have been extensively studied in the past years in hemophilia A and B, those occurring in patients with other inherited bleeding disorders are less well characterized and still poorly understood, mostly due to the rarity of these hemorrhagic conditions. This narrative review will deal with inhibitors arising in patients with inherited bleeding disorders other than "classical" hemophilia, focusing in particular on those developing in patients with congenital deficiency of coagulation factor V, factor VII, factor XI, and factor XIII.

Acquired hemophilia A: a review of recent data and new therapeutic options.

OBJECTIVES: Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function. METHODS: We performed a narrative review focusing on the diagnostic aspects of AHA and on the current treatment strategies with particular regard to new data and therapeutic developments. RESULTS: The management of this severe hemorrhagic disorder is based on the control of bleeding with the use of bypassing agents and on the utilization of a variety of immunosuppressant agents with the goal of eliminating the autoantibody permanently. CONCLUSION: The optimal management of AHA should be multidisciplinary and requires a close collaboration between physicians from various specialties.

The Role of ABO Blood Type in Thrombosis Scoring Systems.

In addition to their major role in transfusion medicine, there is increasing evidence that ABO blood group antigens (complex carbohydrate molecules widely expressed on the surface of red blood cells and several other cell types) are implicated in the development of a wide array of pathologic conditions. In particular, intense research has been dedicated over the last 50 years to the study of the association between non-O blood type and the risk of developing cardiovascular disorders. Several pathways have been hypothesized to explain this relationship, the most reasonable implying the influence of the ABO blood group on circulating plasma levels of von Willebrand factor, factor VIII, and several inflammatory cytokines. This narrative review summarizes the current knowledge on the role of ABO antigens in both venous and arterial thromboses, focusing on their association with clinical scoring systems evaluating thrombotic risk.