Anti‐platelet factor 4 immunothrombotic syndromes

Anti‐platelet factor 4 immunothrombotic syndromes comprise a group of disorders that include heparin‐induced thrombocytopenia and vaccine‐induced immune thrombocytopenia and thrombosis. These are highly prothrombotic, immunological disorders characterised by specific clinical and pathological criteria which include thrombocytopenia and thrombosis. While they are predominantly triggered by heparin and the adenoviral vector vaccines, respectively, other provoking factors have been described, as well as spontaneous forms. The unexplained co‐occurrence of thrombocytopenia with thrombosis should raise suspicion and prompt testing. This nutshell review discusses the pathophysiology, presenting features and diagnostic criteria for these conditions

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia:Who, When, and How?

Although the majority of patients with acute myeloid leukemia (AML) treated with intensive chemotherapy achieve a complete remission (CR), many are destined to relapse if treated with intensive chemotherapy alone. Allogeneic stem cell transplant (allo-SCT) represents a pivotally important treatment strategy in fit adults with AML because of its augmented anti-leukemic activity consequent upon dose intensification and the genesis of a potent graft-versus-leukemia effect. Increased donor availability coupled with the advent of reduced intensity conditioning (RIC) regimens has dramatically increased transplant access and consequently allo-SCT is now a key component of the treatment algorithm in both patients with AML in first CR (CR1) and advanced disease. Although transplant related mortality has fallen steadily over recent decades there has been no real progress in reducing the risk of disease relapse which remains the major cause of transplant failure and represents a major area of unmet need. A number of therapeutic approaches with the potential to reduce disease relapse, including advances in induction chemotherapy, the development of novel conditioning regimens and the emergence of the concept of post-transplant maintenance, are currently under development. Furthermore, the use of genetics and measurable residual disease technology in disease assessment has improved the identification of patients who are likely to benefit from an allo-SCT which now represents an increasingly personalized therapy. Future progress in optimizing transplant outcome will be dependent on the successful delivery by the international transplant community of randomized prospective clinical trials which permit examination of current and future transplant therapies with the same degree of rigor as is routinely adopted for non-transplant therapies.</p

Trivalent nanobody-based ligands mediate powerful activation of GPVI, CLEC-2 and PEAR1 in human platelets whereas FcγRIIA requires a tetravalent ligand

Background: Clustering of the glycoprotein receptors GPVI, CLEC-2, FcγRIIA and PEAR1 leads to powerful activation of platelets through phosphorylation of tyrosine in their cytosolic tails and initiation of downstream signalling cascades. GPVI, CLEC-2 and FcγRIIA signal through YxxL motifs that activate Syk. PEAR1 signals through a YxxM motif that activates phosphoinositide 3-kinase (PI3K). Current ligands for these receptors have an undefined valency and show significant batch variation and, for some, uncertain specificity. Objectives: We have raised nanobodies against each of these receptors and multimerised them to identify the minimum number of epitopes to achieve robust activation of human platelets. Methods: Divalent and trivalent nanobodies were generated using a flexible glycine-serine linker. Tetravalent nanobodies utilise a mouse Fc domain (IgG2a, which does not bind to FcγRIIA) to dimerise the divalent nanobody. Ligand affinity measurements were determined by surface plasmon resonance. Platelet aggregation, ATP secretion and protein phosphorylation were analysed using standardised methods. Results: Multimerisation of the nanobodies led to a stepwise increase in affinity with divalent and higher-order nanobody oligomers having sub-nanomolar affinity. The trivalent nanobodies to GPVI, CLEC-2 and PEAR1 stimulated powerful and robust platelet aggregation, secretion and protein phosphorylation at low nanomolar concentrations. A tetravalent nanobody was required to activate FcγRIIA with the concentration-response relationship showing a greater variability and reduced sensitivity compared to the other nanobody-based ligands, despite a sub-nanomolar binding affinity. Conclusions: The multivalent nanobodies represent a series of standardised, potent agonists for platelet glycoprotein receptors. They have applications as research tools and in clinical assays

Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial

AbstractDisease relapse is the major causes of treatment failure after allogeneic stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). As well as demonstrating significant clinical activity in AML, azacitidine (AZA) upregulates putative tumor antigens, inducing a CD8+ T cell response with the potential to augment a graft-versus-leukemia effect. We, therefore, studied the feasibility and clinical sequelae of the administration of AZA during the first year after transplantation in 51 patients with AML undergoing allogeneic SCT. Fourteen patients did not commence AZA either because of transplantation complications or withdrawal of consent. Thirty-seven patients commenced AZA at a median of 54 days (range, 40 to 194 days) after transplantation, which was well tolerated in the majority of patients. Thirty-one patients completed 3 or more cycles of AZA. Sixteen patients relapsed at a median time of 8 months after transplantation. No patient developed extensive chronic graft-versus-host disease. The induction of a post-transplantation CD8+ T cell response to 1 or more tumor-specific peptides was studied in 28 patients. Induction of a CD8+ T cell response was associated with a reduced risk of disease relapse (hazard ratio [HR], .30; 95% confidence interval [CI], .10 to .85; P = .02) and improved relapse-free survival (HR, .29; 95% CI, .10 to .83; P = .02) taking into account death as a competing risk. In conclusion, AZA is well tolerated after transplantation and appears to have the capacity to reduce the relapse risk in patients who demonstrate a CD8+ T cell response to tumor antigens. These observations require confirmation in a prospective clinical trial

The joint influence of area income, income inequality, and immigrant density on adverse birth outcomes: a population-based study

<p>Abstract</p> <p>Background</p> <p>The association between area characteristics and birth outcomes is modified by race. Whether such associations vary according to social class indicators beyond race has not been assessed.</p> <p>Methods</p> <p>This study evaluated effect modification by maternal birthplace and education of the relationship between neighbourhood characteristics and birth outcomes of newborns from 1999–2003 in the province of Québec, Canada (N = 353,120 births). Areas (N = 143) were defined as administrative local health service delivery districts. Multi-level logistic regression was used to model the association between three area characteristics (median household income, immigrant density and income inequality) and the two outcomes preterm birth (PTB) and small-for-gestational age (SGA) birth. Effect modification by social class indicators was evaluated in analyses stratified according to maternal birthplace and education.</p> <p>Results</p> <p>Relative to the lowest tertile, high median household income was associated with SGA birth among Canadian-born mothers (odds ratio (OR) 1.13, 95% confidence interval (CI) 1.06, 1.20) and mothers with high school education or less (OR 1.13, 95% CI 1.02, 1.24). Associations between median household income and PTB were weaker. Relative to the highest tertile, low immigrant density was associated with a lower odds of PTB among foreign-born mothers (OR 0.79, 95% CI 0.63, 1.00) but a higher odds of PTB among Canadian-born mothers (OR 1.14, 95% CI 1.07, 1.21). Associations with income inequality were weak or absent.</p> <p>Conclusion</p> <p>The association between area factors and birth outcomes is modified by maternal birthplace and education. Studies have found that race interacts in a similar manner. Public health policies focussed on perinatal health must consider the interaction between individual and area characteristics.</p

Blood coagulation and beyond:Position paper from the Fourth Maastricht Consensus Conference on Thrombosis

The 4th Maastricht Consensus Conference on Thrombosis (MCCT), included the following themes: Theme 1: The coagulome as a critical driver of cardiovascular disease Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infections associated-coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies This theme included state of the art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: how to utilize ex vivo models? Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularised organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation (ECMO) associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management Plenary presentations addressed controversial areas, ie thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies and clinically tested factor XI(a) inhibitors,both possibly with reduced bleeding risk. Finally, Covid-19 associated coagulopathy is revisited.</p

Interpersonal violence: an important risk factor for disease and injury in South Africa

<p>Abstract</p> <p>Background</p> <p>Burden of disease estimates for South Africa have highlighted the particularly high rates of injuries related to interpersonal violence compared with other regions of the world, but these figures tell only part of the story. In addition to direct physical injury, violence survivors are at an increased risk of a wide range of psychological and behavioral problems. This study aimed to comprehensively quantify the excess disease burden attributable to exposure to interpersonal violence as a risk factor for disease and injury in South Africa.</p> <p>Methods</p> <p>The World Health Organization framework of interpersonal violence was adapted. Physical injury mortality and disability were categorically attributed to interpersonal violence. In addition, exposure to child sexual abuse and intimate partner violence, subcategories of interpersonal violence, were treated as risk factors for disease and injury using counterfactual estimation and comparative risk assessment methods. Adjustments were made to account for the combined exposure state of having experienced both child sexual abuse and intimate partner violence.</p> <p>Results</p> <p>Of the 17 risk factors included in the South African Comparative Risk Assessment study, interpersonal violence was the second leading cause of healthy years of life lost, after unsafe sex, accounting for 1.7 million disability-adjusted life years (DALYs) or 10.5% of all DALYs (95% uncertainty interval: 8.5%-12.5%) in 2000. In women, intimate partner violence accounted for 50% and child sexual abuse for 32% of the total attributable DALYs.</p> <p>Conclusions</p> <p>The implications of our findings are that estimates that include only the direct injury burden seriously underrepresent the full health impact of interpersonal violence. Violence is an important direct and indirect cause of health loss and should be recognized as a priority health problem as well as a human rights and social issue. This study highlights the difficulties in measuring the disease burden from interpersonal violence as a risk factor and the need to improve the epidemiological data on the prevalence and risks for the different forms of interpersonal violence to complete the picture. Given the extent of the burden, it is essential that innovative research be supported to identify social policy and other interventions that address both the individual and societal aspects of violence.</p

Blood coagulation and beyond: Position paper from the Fourth Maastricht Consensus Conference on Thrombosis

The 4th Maastricht Consensus Conference on Thrombosis (MCCT), included the following themes: Theme 1: The coagulome as a critical driver of cardiovascular disease Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infections associated-coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies This theme included state of the art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: how to utilize ex vivo models? Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularised organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation (ECMO) associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management Plenary presentations addressed controversial areas, ie thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies and clinically tested factor XI(a) inhibitors,both possibly with reduced bleeding risk. Finally, Covid-19 associated coagulopathy is revisited