Distinct Mechanisms of IgM Antibody-Mediated Acquired von Willebrand Syndrome and Successful Treatment with Recombinant von Willebrand Factor in One Patient

Acquired von Willebrand Syndrome (AVWS) is a rare coagulation disorder which can be associated with IgM paraproteinaemia. Recently, recombinant von Willebrand factor (rVWF) has become available for the treatment of bleedings in patients with inherited von Willebrand disease, but experience in patients with AVWS is limited. We report on 2 patients with AVWS with underlying IgM paraproteinaemia with distinct underlying pathomechanisms. In 1 patient, the paraprotein built unspecific complexes with von Willebrand factor (VWF). In the other patient, we were able to detect an IgM antibody against VWF. Bleeding in this patient was successfully treated with rVWF. To our knowledge, this is the first report about the successful use of rVWF in a patient with AVWS with the detection of a VWF-specific antibody

Platelet lipidomics indicates enhanced thrombocyte activation in patients with antiphospholipid syndrome in vivo

Background Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies in patients with thromboembolic/thromboinflammatory events and/or obstetric complications. Objectives The aim of this study was to examine whether there are alterations in the platelet lipidome of APS patients in comparison with patients affected by thromboembolism without APS (control) and healthy volunteers. Methods We applied quantitative mass spectrometry-based lipidomics to investigate the platelet lipidome of isolated resting and thrombin-stimulated platelets as well as platelet release in patients with APS, controls, and healthy volunteers. Results Lipidomic data revealed an increase in lysophospholipids (LPLs) in platelets from APS patients, specifically in lysophosphatidylcholine and lysophosphatidylethanolamine species. As LPLs are cleavage products generated by phospholipase A (PLA) from the corresponding phospholipid precursor, LPL/phospholipid ratios may be employed as surrogates for PLA1 and PLA2 activities. The surrogate ratios for PLA2, which participates in the release of arachidonic acid during platelet activation, were significantly increased in APS in both resting platelets and upon thrombin-induced activation for phosphatidylcholine and phosphatidylethanolamine. The phosphatidylcholine-PLA2 surrogate ratio was found to correlate with serum levels of anti–β2-glycoprotein I and anticardiolipin immunoglobulin G. Finally, receiver operator characteristic analysis demonstrated excellent discrimination of patients with APS from controls and healthy volunteers. Conclusion These findings provide substantial evidence that platelet activation is enhanced in APS in vivo, involving the activation of PLA2

Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic malignancies

Chimeric antigen receptor (CAR-) T cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that is thus far considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR-T cell therapy between 01/2020 and 05/2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet, DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose dependent manner (r = -0.44, p = 0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, p < 0.001). We thus hypothesize that fibrinogen synthesis in CRS is upregulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR-T cell therapy and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS

Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic malignancies

Chimeric antigen receptor (CAR) T-cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that has up to now been considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated the incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR T-cell therapy between January 2020 and May 2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose-dependent manner (r = -0.44, P=0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, P<0.001). We thus hypothesize that fibrinogen synthesis in CRS is up-regulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR T-cell therapy, and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS

Distinct Mechanisms of IgM Antibody-Mediated Acquired von Willebrand Syndrome and Successful Treatment with Recombinant von Willebrand Factor in One Patient

Acquired von Willebrand Syndrome (AVWS) is a rare coagulation disorder which can be associated with IgM paraproteinaemia. Recently, recombinant von Willebrand factor (rVWF) has become available for the treatment of bleedings in patients with inherited von Willebrand disease, but experience in patients with AVWS is limited. We report on 2 patients with AVWS with underlying IgM paraproteinaemia with distinct underlying pathomechanisms. In 1 patient, the paraprotein built unspecific complexes with von Willebrand factor (VWF). In the other patient, we were able to detect an IgM antibody against VWF. Bleeding in this patient was successfully treated with rVWF. To our knowledge, this is the first report about the successful use of rVWF in a patient with AVWS with the detection of a VWF-specific antibody. </jats:p

Comorbidity and adverse events in acquired hemophilia A: data from the GTH-AHA-EMI study

Background: Persons with acquired hemophilia A are often older and suffer from comorbidity or frailty. Little is known about the impact on clinically relevant outcomes of acquired hemophilia A. Objectives: To assess the relevance of age, physical performance status, comorbidity, and concomitant medication on the risk of bleeding and other outcomes. Methods: Post hoc analysis of data from the GTH-AHA-EMI study that used emicizumab for bleed protection and withheld immunosuppressive treatment during the early phase of management. Primary endpoint was the rate of clinically relevant new bleeding (CRNB) during the first 12 weeks of emicizumab prophylaxis. Results: Forty-seven patients were enrolled. Median age was 76 years; performance status (World Health Organization performance status [WHO-PS]) was 3 or worse in 41%; Charlson comorbidity index (CCI) was 5 or higher in 63%; antithrombotic drugs were reported in 34%. Rate of CRNB during 12 weeks of emicizumab prophylaxis was similar across subgroups of age, sex, WHO-PS, CCI, baseline factor VIII activity, and inhibitor titer. Patients with CRNB during the study had more severe anemia already at baseline. However, persistent severe anemia in week 4 was not related to risk of bleeding beyond this time. CRNB was associated with injury from falling in 7 of 14 patients. Adverse events grade 3 or higher were not related to baseline CCI or age but were more frequent in patients with poor WHO-PS. Conclusion: Emicizumab provided bleed protection regardless of age and comorbidity. Clinical baseline characteristics did not predict breakthrough bleeding under emicizumab. Poor WHO-PS at baseline was associated with severe adverse events during the study