New Developments in Diagnosis and Management of Acquired Hemophilia and Acquired von Willebrand Syndrome

Acquired hemophilia A and acquired von Willebrand syndrome are rare, but life-threatening bleeding disorders that require prompt diagnosis and treatment by hematologists. Acquired hemophilia A is defined as an acquired severe bleeding tendency caused by autoantibody formation against coagulation factor VIII. Acquired von Willebrand syndrome is characterized by a new onset bleeding tendency caused by a reduced concentration and/or function of von Willebrand factor. These disorders are associated with a variety of underlying disorders, including various hematological malignancies, for example, plasma cell disorders, lymphoproliferative disorders, monoclonal gammopathy of undetermined significance, and myeloproliferative neoplasms. It is of utmost important to recognize these acquired bleeding disorders in these patients who are at risk for severe bleeding, and to perform additional diagnostic hemostasis laboratory evaluation. This will enable immediate diagnosis of the acquired bleeding disorder and management of both the bleeding episodes and the causative underlying disorder. In recent years, several new etiological factors for acquired hemophilia A, such as treatment with immune checkpoint inhibitors or DPP-4 inhibitors and SARS-CoV2 infection, and for acquired von Willebrand syndrome, for example, left ventricular assist devices, have been identified and also new treatment options have become available. In this concise review, the most recent data on etiology, diagnosis, and treatment of acquired bleeding disorders are presented and discussed

Construction and functional analysis of hybrid interleukin-6 variants Characterization of the role of the C-terminus for species specificity

AbstractWe have constructed several hybrid human interleukin-6 (IL-6) variants in which the carboxyl-terminus, which includes a receptor binding site of IL-6 has been replaced with the C-terminus of various proteins homologous to human IL-6, IL-6 hybrids with the C-terminus of human growth hormone and human granulocyte-colony stimulating factor maintain part of the biological activity of human IL-6. Replacing the C-terminus of human IL-6 with the C-terminus of mouse and rat IL-6 resulted in a normal or increased activity on a mouse cell line; however, this gave a low (to 200-fold less) activity on a human cell line compared to wild-type human IL-6. We therefore conclude that the C-terminus of IL-6 plays in important role in the species specificity of IL-6

A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis

The aim of this study was to assess the cause of enhanced fibrinolysis in cirrhosis by studying the balance between profibrinolytic and antifibrinolytic proteins in 24 patients with mild or severe cirrhosis. Antigen levels of both tissue-type plasminogen activator and plasminogen-activator inhibitor 1 were increased in mild and severe cirrhosis. Activity levels showed a very wide variability, but median activity levels of both proteins were normal. In most patients, the increase in tissue-type plasminogen activator was counterbalanced by the increased levels of plasminogen-activator inhibitor 1, but in a subgroup of patients the change in balance resulted in extremely high tissue-type plasminogen-activator levels. The specific activity of both proteins (activity/ antigen quotient) was reduced in either mild or severe cirrhosis. This finding indicates either that more enzyme-inhibitor complexes circulate in the blood of patients with cirrhosis than in normal individuals or that dysfunctional molecules circulate. Plasminogen and α2-antiplasmin antigen and activity levels were decreased in both mild and severe cirrhosis. The binding of α2-antiplasmin to fibrin was decreased in severe cirrhosis, making fibrin clots more susceptible to lysis. Clot lysis experiments were performed to see if equal decreases in plasminogen and α2-antiplasmin levels, as found in cirrhosis, result in a change in the rate of fibrinolysis. It was found that the proportionate decreases led to enhancement of fibrinolysis, indicating that the inhibitor depletion is more important than the proenzyme depletion. The authors conclude that enhanced fibrinolysis frequently found in cirrhosis may be attributed to an increased tissuetype plasminogen-activator activity relative to plasminogen-activator-inhibitor activity and decreased levels of α2-antiplasmin, resulting in a reduced binding of α2-antiplasmin to fibrin.</p

A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis

The aim of this study was to assess the cause of enhanced fibrinolysis in cirrhosis by studying the balance between profibrinolytic and antifibrinolytic proteins in 24 patients with mild or severe cirrhosis. Antigen levels of both tissue-type plasminogen activator and plasminogen-activator inhibitor 1 were increased in mild and severe cirrhosis. Activity levels showed a very wide variability, but median activity levels of both proteins were normal. In most patients, the increase in tissue-type plasminogen activator was counterbalanced by the increased levels of plasminogen-activator inhibitor 1, but in a subgroup of patients the change in balance resulted in extremely high tissue-type plasminogen-activator levels. The specific activity of both proteins (activity/ antigen quotient) was reduced in either mild or severe cirrhosis. This finding indicates either that more enzyme-inhibitor complexes circulate in the blood of patients with cirrhosis than in normal individuals or that dysfunctional molecules circulate. Plasminogen and α2-antiplasmin antigen and activity levels were decreased in both mild and severe cirrhosis. The binding of α2-antiplasmin to fibrin was decreased in severe cirrhosis, making fibrin clots more susceptible to lysis. Clot lysis experiments were performed to see if equal decreases in plasminogen and α2-antiplasmin levels, as found in cirrhosis, result in a change in the rate of fibrinolysis. It was found that the proportionate decreases led to enhancement of fibrinolysis, indicating that the inhibitor depletion is more important than the proenzyme depletion. The authors conclude that enhanced fibrinolysis frequently found in cirrhosis may be attributed to an increased tissuetype plasminogen-activator activity relative to plasminogen-activator-inhibitor activity and decreased levels of α2-antiplasmin, resulting in a reduced binding of α2-antiplasmin to fibrin.</p

Prognostic markers in young patients with premature coronary heart disease

AbstractObjectivesTo evaluate the survival and prognostic implications of cardiovascular, inflammatory and prothrombotic risk factors in young patients with premature coronary heart disease (CHD).MethodsFollow-up data were obtained from 353 young patients with a first cardiac event (men ≤45 years and women ≤55 years). Baseline characteristics on traditional risk factors were collected at the time of the first event, and plasma levels of C-reactive protein (CRP), von Willebrand Factor (VWF), and fibrinogen were measured one to three months after the first event to exclude an acute phase response. We performed age and sex adjusted Cox regression analyses to assess the relationship between these factors and recurrent events with three different endpoints: all cause mortality, recurrent cardiac event (myocardial infarction or revascularisation procedure), and any recurrent event (cardiac event, cerebrovascular event or all cause mortality).ResultsDuring a total follow-up time of 1483 person years (mean 4.2 years), 11 patients died (3%), 42 patients had a recurrent cardiac event (12%), and 53 patients had any recurrent event (15%). CRP was associated with an increased risk of any recurrent event (HR 1.28[95% CI = 1.02–1.59] per unit increase in lnCRP). Also, both CRP (5.00[1.04–24.04]) and fibrinogen (5.04[1.05–24.23]) were associated with all cause mortality when levels were above the 50th percentile.ConclusionsFifteen percent of young patients with a first cardiac event have a recurrent event or die within a median follow-up of 4.2 years. In these young patients we have shown that, independently of cardiovascular risk factors, high CRP levels contribute to the risk of recurrent events, including all cause mortality, and high fibrinogen levels are associated with all cause mortality

Effect of etranacogene dezaparvovec on quality of life for severe and moderately severe haemophilia B participants:Results from the phase III HOPE-B trial 2 years after gene therapy

Introduction:For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%. Aim: Assess how EDZ affects HRQoL in HOPE-B trial participants. Methods: HRQoL was evaluated using generic and disease-specific patient reported outcomes (PROs) including the EQ-5D-5L and the Hem-A-QoL questionnaires. Mean domain and total scores were compared 6 months pre- and the first 2 years post-EDZ administration using repeated measures linear mixed models. The percentage of participants with minimal clinically important improvements in HRQoL was also evaluated. Results: Two years post-EDZ, there were nominally significant increases in the least squares (LS) mean score for the EQ-5D-5L Index Value (.04; p =.0129), reflecting better HRQoL. Nominally significant decreases in the LS mean scores, reflecting better HRQoL, were also found for the Hem-A-QoL total score (−6.0; p &lt;.0001) and the Treatment (−13.94; p &lt;.0001), Feelings (−9.01; p &lt;.0001), Future (−6.45; p =.0004) and Work/School (−5.21; p =.0098) domains. The percentage of participants with ≥15-point improvement ranged from 45.83% (95% CI: 31.37%, 60.83%) for Treatment to 13.89% (95% CI: 4.67%, 29.50%) for Family Planning. Results were similar for Year 1. Conclusion:In conclusion, gene therapy with EDZ improved HRQoL in the first and second years in several Hem-A-QoL domains, including Treatment, Feelings, Work/School and Future domains, whereas improvement in other aspects of HRQoL were not demonstrated.</p

The transcription factor GATA6 is essential for branching morphogenesis and epithelial cell differentiation during fetal pulmonary development

Recent loss-of-function studies in mice show that the transcription factor GATA6 is important for visceral endoderm differentiation. It is also expressed in early bronchial epithelium and the observation that this tissue does not receive any contribution from Gata6 double mutant embryonic stem (ES) cells in chimeric mice suggests that GATA6 may play a crucial role in lung development. The aim of this study was to determine the role of GATA6 in fetal pulmonary development. We show that Gata6 mRNA is expressed predominantly in the developing pulmonary endoderm and epithelium, but at E15.5 also in the pulmonary mesenchyme. Blocking or depleting GATA6 function results in diminished branching morphogenesis both in vitro and in vivo. TTF1 expression is unaltered in chimeric lungs whereas SPC and CC10 expression are attenuated in abnormally branched areas of chimeric lungs. Chimeras generated in a ROSA26 background show that endodermal cells in these abnormally branched areas are derived from Gata6 mutant ES cells, implicating that the defect is intrinsic to the endoderm. Taken together, these data demonstrate that GATA6 is not essential for endoderm specification, but is required for normal branching morphogenesis and late epithelial cell differentiation