Acquired bleeding disorders.

Acquired bleeding disorders can develop in previously healthy people irrespective of age or gender but are particularly common in patients with certain underlying conditions. Here, we review recent advances in the management of acquired haemophilia A (AHA), acquired von Willebrand syndrome (AVWS), and patients with hemostatic abnormalities due to chronic liver disease (CLD). Patients with AHA can now benefit from prophylaxis with emicizumab, a therapeutic antibody that mimics the function of activated coagulation factor VIII. The treatment of AVWS remains challenging in many situations and requires careful consideration of the underlying condition. Haemostatic abnormalities in CLD are often compensated by proportional reduction in pro and anti-haemostatic factors resulting in sustained or even increased thrombin generation. Consequently, bleeding in CLD is rarely caused by haemostatic failure and infusion of plasma or coagulation factor concentrates may not be effective.

Rates of venous thromboembolism and use of thromboprophylaxis after major orthopedic surgery in patients with congenital hemophilia A or B: a systematic review.

BACKGROUND: Venous thromboembolism (VTE) is a well-recognized complication after total joint replacement (TJR). Persons with hemophilia A or B are considered at low postoperative VTE risk due to their coagulation factor deficiencies, and administering pharmacologic thromboprophylaxis is often considered contraindicated. However, using factor replacement therapy could increase the postoperative VTE risk. OBJECTIVES: To analyze best available evidences of VTE rates in persons with hemophilia A or B undergoing lower limb TJR and the use of postoperative pharmacologic thromboprophylaxis. METHODS: We systematically screened 4 online biomedical databases to identify studies reporting VTE rates in patients with hemophilia after TJR. Case reports and case series with less than 10 patients were excluded. RESULTS: Twenty-six observational studies were included in this systematic review, reporting 1181 TJRs in patients with hemophilia A or B. Eight studies had VTE rates as the primary outcome. Five studies reported screen-detected VTE, while 21 reported symptomatic VTE events. Overall, 17 VTE events were reported (1.4%; 95% CI, 0.9%-2.3%), including 10 (6.6%) after 151 surgeries with postoperative VTE screening and 7 (0.7%) after 1080 surgeries without postoperative screening. Thromboprophylaxis protocols were specified in 21 studies; postoperative thromboprophylaxis was used in 15 (1.3%) surgeries. This information was not available for 29.0% of the analyzed population. CONCLUSION: Despite the low thromboprophylaxis use in patients with hemophilia, rates of symptomatic VTE after TJR appeared to be low. We also highlighted the need to better report the thrombotic outcome in persons with hemophilia to face the ongoing changes in the hemophilia landscape.

Immunotherapy of acquired hemophilia A.

Acquired hemophilia A (AHA) is an autoimmune disorder characterized by the formation of autoantibodies that neutralize the function of coagulation factor VIII. Immunosuppressive therapy (IST) with glucocorticoids, cyclophosphamide, rituximab, or combinations thereof is the standard of care to suppress autoantibody formation and induce remission of AHA. About 80% of patients achieve remission over the course of a few weeks to several months. However, patients with AHA are often elderly and frail and have adverse events from IST. Therefore, guidelines suggest an individualized approach using caution in elderly and frail patients. Prophylaxis with emicizumab may reduce the need for early and aggressive IST in the future.

Emicizumab for the Treatment of Acquired Hemophilia A: Consensus Recommendations from the GTH-AHA Working Group.

BACKGROUND: Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Standard treatment consists of bleeding control with bypassing agents and immunosuppressive therapy. Emicizumab is a bispecific antibody that mimics the function of activated FVIII irrespective of the presence of neutralizing antibodies. Recently, the GTH-AHA-EMI study demonstrated that emicizumab prevents bleeds and allows to postpone immunosuppression, which may influence future treatment strategies. AIM: To provide clinical practice recommendations on the use of emicizumab in AHA. METHODS: A Delphi procedure was conducted among 33 experts from 16 German and Austrian hemophilia care centers. Statements were scored on a scale of 1 to 9, and agreement was defined as a score of ≥7. Consensus was defined as ≥75% agreement among participants, and strong consensus as ≥95% agreement. RESULTS: Strong consensus was reached that emicizumab is effective for bleed prophylaxis and should be considered from the time of diagnosis (100% consensus). A fast-loading regimen of 6 mg/kg on day 1 and 3 mg/kg on day 2 should be used if rapid bleeding prophylaxis is required (94%). Maintenance doses of 1.5 mg/kg once weekly should be given (91%). Immunosuppression should be offered to patients on emicizumab if they are eligible based on physical status (97%). Emicizumab should be discontinued when remission of AHA is achieved (97%). CONCLUSION: These GTH consensus recommendations provide guidance to physicians on the use of emicizumab in AHA and follow the results of clinical trials that have shown emicizumab is effective in preventing bleeding in AHA.

Emicizumab prophylaxis in patients with acquired haemophilia A (GTH-AHA-EMI): an open-label, single-arm, multicentre, phase 2 study.

BACKGROUND: Acquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis. METHODS: We report final results of an open-label, single-arm, phase 2 clinical trial. Adult patients with acquired haemophilia A from 16 haemophilia treatment centres in Germany and Austria were eligible if they had not previously received immunosuppression. Patients received emicizumab subcutaneously (6 and 3 mg/kg on days 1 and 2, 1·5 mg/kg weekly until week 12), but no immunosuppression. Follow-up was until week 24. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. Emicizumab was considered effective if the mean bleeding rate was significantly below 0·15 bleeds per patient-week, the rate observed in a previous study of patients with acquired haemophilia A treated with bypassing agents and immunosuppression but no emicizumab. The study is registered with clinicaltrials.gov, NCT04188639 and is complete. FINDINGS: Of 49 patients screened from March 25, 2021, to June 10, 2022, 47 were enrolled (23 women, 24 men). Median age was 76 years (IQR 66-80), 46 (98%) of 47 patients were White, median factor VIII activity was 1·4 IU/dL (0·3-5·6), and median inhibitor concentration was 11·4 Bethesda units per mL (3·9-42·7). Mean breakthrough bleeding rate was 0·04 bleeds per patient-week (upper 97·5% CI 0·06). 33 (70%) of 47 patients had no bleeding events, seven patients (15%) had one bleed, six patients (13%) had two bleeds, and one patient (2%) had three bleeds. Adverse events of grade 3 or worse included COVID-19 (n=2), acute kidney injury (n=2), and stroke (n=1). Four of 47 patients died, including two deaths related to bleeding, one from COVID-19, and one from cardiac arrest (none were judged as related to emicizumab). INTERPRETATION: This study suggests that emicizumab prophylaxis prevents bleeding in patients with acquired haemophilia A and that immunosuppressive therapy can be deferred while patients are receiving this treatment. The low number of thromboembolic events, severe infections, and fatalities observed in this study are promising. FUNDING: This study was supported by funding from Hoffman-La Roche.

The monosialoganglioside GM1a protects against complement attack.

The complement system is a part of the innate immune system in the fluid phase and efficiently eliminates pathogens. However, its activation requires tight regulation on the host cell surface in order not to compromise cellular viability. Previously, we showed that loss of placental cell surface sialylation in mice in vivo leads to a maternal complement attack at the fetal-maternal interface, ultimately resulting in loss of pregnancy. To gain insight into the regulatory function of sialylation in complement activation, we here generated trophoblast stem cells (TSC) devoid of sialylation, which also revealed complement sensitivity and cell death in vitro. Glycolipid-analysis by multiplexed capillary gel electrophoresis coupled to laser-induced fluorescence detection (xCGE-LIF) allowed us to identify the monosialoganglioside GM1a as a key element of cell surface complement regulation. Exogenously administered GM1a integrated into the plasma membrane of trophoblasts, substantially increased binding of complement factor H (FH) and was sufficient to protect the cells from complement attack and cell death. GM1a treatment also rescued human endothelial cells and erythrocytes from complement attack in a concentration dependent manner. Furthermore, GM1a significantly reduced complement mediated hemolysis of erythrocytes from a patient with Paroxysmal nocturnal hemoglobinuria (PNH). This study demonstrates the complement regulatory potential of exogenously administered gangliosides and paves the way for sialoglycotherapeutics as a novel substance class for membrane-targeted complement regulators.

von Willebrand factor modulates immune complexes and the recall response against factor VIII in a murine hemophilia A model.

Achieving tolerance toward factor VIII (FVIII) remains an important goal of hemophilia treatment. Up to 40% of patients with severe hemophilia A (HA) develop neutralizing antibodies against FVIII, and the only proven treatment to achieve tolerance is infusion of FVIII over prolonged periods in the context of immune tolerance induction. Here, we addressed the role of von Willebrand factor (VWF) as a modulator of anti-FVIII antibody effector functions and the FVIII-specific recall response in an HA mouse model. Analytical ultracentrifugation was used to demonstrate formation of FVIII-containing immune complexes (FVIII-ICs). VWF did not fully prevent FVIII-IC formation but was rather incorporated into larger macromolecular complexes. VWF prevented binding of FVIII-ICs to complement C1q, most efficiently when it was preincubated with FVIII before the addition of antibodies. It also prevented binding to immobilized Fc-γ receptor and to bone marrow-derived dendritic cells. An in vitro model of the anti-FVIII recall response demonstrated that addition of VWF to FVIII abolished the proliferation of FVIII-specific antibody-secreting cells. After adoptive transfer of sensitized splenocytes into immunocompetent HA mice, the FVIII recall response was diminished by VWF. In summary, these data indicate that VWF modulates the formation and effector functions of FVIII-ICs and attenuates the secondary immune response to FVIII in HA mice.

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance.

Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are <20 IU/dL, but specific recommendations in patients with very low levels according to the different clinical situations are lacking and mainly based on the anecdotal series. For PWH with baseline clotting factor levels >20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH.

Prophylaxis with recombinant von Willebrand factor in patients with type 3 von Willebrand disease: Results of a post hoc analysis from a phase 3 trial.

OBJECTIVES: To describe efficacy/safety of recombinant von Willebrand factor (rVWF) prophylaxis in patients with type 3 von Willebrand disease (VWD). METHODS: This post hoc analysis of a phase 3 open-label trial provides a more detailed analysis of adults with type 3 VWD, categorized based on prior treatment at screening: "Prior On-Demand (OD)" (OD VWF; ≥3 documented spontaneous bleeding events [BEs] requiring VWF in previous 12 months) or "Switch" (plasma-derived [pd] VWF prophylaxis for ≥12 months). Annualized bleeding rates (ABRs) were evaluated during 12 months of rVWF prophylaxis versus historical data from medical records. RESULTS: In the Prior OD group (n = 10), mean spontaneous ABR (sABR) for treated BEs was reduced by 91.6% (ratio, 0.08; 95% CI, 0.02-0.45) versus mean historical sABR. In the Switch group (n = 8), mean sABR for treated BEs was reduced by 47% (ratio, 0.53; 95% CI, 0.08-3.62). One non-serious adverse event (AE) was considered possibly related to rVWF. No treatment-related, fatal, or life-threatening serious AEs were reported, and no patient developed VWF inhibitors. CONCLUSIONS: rVWF prophylaxis reduced sABR in type 3 VWD patients previously treated with OD VWF therapy, and maintained a similar level of hemostatic control in those switching from pdVWF prophylaxis to rVWF prophylaxis.

von Willebrand factor neutralizing and non-neutralizing alloantibodies in 213 subjects with type 3 von Willebrand disease enrolled in 3WINTERS-IPS.

BACKGROUND: Type 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived products containing VWF or recombinant VWF rarely cause the development of alloantibodies against VWF that may be accompanied by anaphylactic reactions. OBJECTIVE: The objective of this study was to assess the prevalence of anti-VWF alloantibodies in subjects with type 3 VWD enrolled in the 3WINTERS-IPS. METHODS: An indirect in-house enzyme-linked immunosorbent assay has been used to test all the alloantibodies against VWF. Neutralizing antibodies (inhibitors) have been tested with a Bethesda-based method by using a VWF collagen binding (VWF:CB) assay. Samples positive for anti-VWF antibodies were further tested with Bethesda-based methods by using the semiautomated gain-of-function glycoprotein-Ib binding (VWF:GPIbM) and a VWF antigen (VWF:Ag) enzyme-linked immunosorbent assay. RESULTS: In total, 18 of the 213 (8.4%) subjects tested positive for anti-VWF antibodies and 13 of 213 (6%) had VWF:CB inhibitors. These 13 were among the 18 with anti-VWF antibodies. Of the 5 without VWF:CB inhibitors, 3 had non-neutralizing antibodies, 1 only inhibitor against VWF:GPIbM, and one could not be tested further. Ten of the 13 subjects with VWF:CB inhibitors also had VWF:GPIbM inhibitors, 6 of whom also had VWF:Ag inhibitors. Subjects with inhibitors were homozygous for VWF null alleles (11/14), homozygous for a missense variant (1/14), or partially characterized (2/14). CONCLUSIONS: Anti-VWF antibodies were found in 8.4% of subjects with type 3 VWD, whereas neutralizing VWF inhibitors were found in 6%, mainly in subjects homozygous for VWF null alleles. Because inhibitors may be directed toward different VWF epitopes, their detection is dependent on the assay used.

[Gene therapy of Hemophilia: Recommendations from the German, Austrian, and Swiss Society for Thrombosis and Haemostasis Research (GTH)]. / Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH).

Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centers according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as a primary source of data for pharmacovigilance, postmarketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization.

[Use of Thrombopoetin-Receptor-Agonists (TPO-RA) in patients with liver cirrhosis before invasive procedures]. / Einsatz von Thrombopoetin-Rezeptor-Agonisten (TPO-RA) vor invasiven Eingriffen bei Patienten mit Leberzirrhose.

Advanced chronic liver disease is accompanied with relevant changes in the corpuscular and plasmatic coagulation system. Due to thrombocytopenia that is regularly observed in these patients, platelet transfusions are often performed prior invasive procedures to prevent possible bleeding complications. However, platelet transfusions are associated with clinically significant adverse events and economically relevant health care costs. Thus, avoiding unnecessary platelet transfusions remains pivotal in daily clinical practice. The first step is to carefully check if increasing platelet counts prior to a planned invasive procedure is really necessary. Nowadays, two well-tolerated thrombopoetin-receptor agonists (TPO-RAs), Avatrombopaq and Lusutrombopaq, to treat thrombocytopenia preemptively before an invasive procedure in patients with liver cirrhosis are available. This review provides a guide for clinician when to increase platelet counts prior an invasive procedure in patients with liver cirrhosis and helps to identify situations in which the use of TPO-RA may be reasonable.

Targets of autoantibodies in acquired hemophilia A are not restricted to factor VIII: data from the GTH-AH 01/2010 study.

The root cause of autoantibody formation against factor VIII (FVIII) in acquired hemophilia A (AHA) remains unclear. We aimed to assess whether AHA is exclusively associated with autoantibodies toward FVIII or whether patients also produce increased levels of autoantibodies against other targets. A case-control study was performed enrolling patients with AHA and age-matched controls. Human epithelial cell (HEp-2) immunofluorescence was applied to screen for antinuclear (ANA) and anticytoplasmic autoantibodies. Screening for autoantibodies against extractable nuclear antigens was performed by enzyme immunoassay detecting SS-A/Ro, SS-B/La, U1RNP, Scl-70, Jo-1, centromere B, Sm, double-stranded DNA, and α-fodrin (AF). Patients with AHA were more often positive for ANA than control patients (64% vs 30%; odds ratio [OR] 4.02, 1.98-8.18) and had higher ANA titers detected than controls. Cytoplasmic autoantibodies and anti-AF immunoglobulin A autoantibodies were also more frequent in patients with AHA compared with controls. Autoantibodies against any target other than FVIII were found in 78% of patients with AHA compared with 46% of controls (OR 4.16, 1.98-8.39). Results were similar preforming sensitivity analyses (excluding either subjects with autoimmune disorders, cancer, pregnancy, or immunosuppressive medication at baseline) and in multivariable binary logistic regression. To exclude that autoantibody staining was merely a result of cross-reactivity of anti-FVIII autoantibodies, we tested a mix of 7 well-characterized monoclonal anti-FVIII antibodies. These antibodies did not stain HEp-2 cells used for ANA detection. In conclusion, a diverse pattern of autoantibodies is associated with AHA, suggesting that a more general breakdown of immune tolerance might be involved in its pathology.

Microembolic signal monitoring in patients with HeartMate 3 and HeartWare left ventricular assist devices: Association with antithrombotic treatment and cerebrovascular events.

BACKGROUND: In patients with left ventricular assist devices (LVADs), ischemic and hemorrhagic stroke are dreaded complications. Predictive markers for these events are lacking. This study aimed to investigate the prevalence and predictive value of microembolic signals (MES) for stroke, detected by Transcranial Doppler sonography (TCD) in patients with HeartMate 3 (HM 3) or HeartWare (HW). METHODS: A thirty-minute bilateral TCD monitoring of the middle cerebral artery (MCA) was performed in 62 outpatients with LVAD (HM 3 N = 31, HW N = 31) and 31 healthy controls. Prevalence and quantity of MES were investigated regarding clinical and laboratory parameters. Cerebrovascular events (CVE) were recorded on follow-up at 90 and 180 days. RESULTS: MES were detected in six patients with HM 3, three patients with HW, and three controls. Within the LVAD groups, patients on monotherapy with vitamin-K-antagonist (VKA) without antiplatelet therapy were at risk for a higher count of MES (negative binomial regression: VKA: 1; VKA + ASA: Exp(B) = 0.005, 95%CI 0.001-0.044; VKA + clopidogrel: Exp(B) = 0.012, 95%CI 0.002-0.056). There was no association between the presence of MES and CVE or death on follow-up (p > 0.05). CONCLUSION: For the first time, the prevalence of MES was prospectively investigated in a notable outpatient cohort of patients with HM 3 and HW. Despite optimized properties of the latest LVAD, MES remain detectable depending on antithrombotic therapy. No association between MES and CVE could be detected.

Impact of different factor VIII inhibitor kinetic profiles on the inhibitor titer quantification using the modified Nijmegen-Bethesda assay.

Background: Coagulation factor VIII (FVIII) inhibitor titer quantification is vital for optimizing care in people with hemophilia A. Objectives: This study analyzed the impact of the different kinetic profiles of four FVIII monoclonal antibodies on inhibitor titer quantification using the modified Nijmegen-Bethesda assay. Methods: Concentration-related and time-related profiles of FVIII antibodies (4A4, BO2C11, 2-54, ESH-8) were evaluated in vitro. FVIII residual activity was measured using a one-stage clotting assay and chromogenic substrate assay. Profiles of the FVIII antibodies were compared with the theoretical kinetic model: the ideal log (residual activity)-linear (inhibitor concentration) relationship. Different theoretical kinetic model-dependent and -independent criteria to calculate FVIII inhibitor titer were compared. Results: Factor VIII monoclonal antibodies had different concentration-related and time-related profiles, ideal for comparative analysis using the modified Nijmegen-Bethesda assay. The kinetic profile of 4A4 was similar to the theoretical kinetic model, while BO2C11 showed a steeper curve, and 2-54 and ESH-8 a flatter curve, than the model. In the modified Nijmegen-Bethesda assay, conversion of measured FVIII residual activities for different inhibitor dilutions into FVIII inhibitor titer is based on the theoretical kinetic model. Therefore, titer calculations for FVIII inhibitors that deviate from the model are prone to underestimation or overestimation. Calculating a theoretical dilution at 50% FVIII residual activity by sigmoidal regression reflecting different kinetic inhibition profiles can provide a more accurate titer result. Conclusion: Kinetic profiles of FVIII antibodies can deviate from the theoretical kinetic model in the modified Nijmegen-Bethesda assay, leading to differences in FVIII inhibitor titer quantification.

Gene Therapy for Hemophilia-Opportunities and Risks.

BACKGROUND: AAV (adeno-associated virus)-based gene therapy is a new treatment for hemophilia and has recently received approval for the treatment of severe hemophilia A. It does not suffer from the limitations of the current standard treatment (regular prophylactic intravenous injections of the missing clotting factor; subcutaneous injection of a bispecific antibody in hemophilia A) and can, it is hoped, raise the concentration of the missing clotting factor over the long term. AAV-based gene therapy can only be performed once, however, because of the generation of antibodies to AAV. METHODS: This review is based on publications retrieved by a selective search in the MEDLINE/PubMed database employing the relevant key words, supplemented by expert opinions and the recommendations of the relevant medical societies. RESULTS: Data from non-randomized phase 1 to phase 3 trials reveal an adequate expression of factors VIII and IX in patients with mostly severe hemophilia A or B. Even though they were no longer receiving prophylactic treatment, most patients experienced a considerable reduction, by 53% to 96%, in the number of bleedings compared to previous therapy. Persistently elevated factor levels have been described for up to six years in hemophilia A and up to eight years in hemophilia B. The most common side effect of gene therapy is an inflammatory response with elevated alanine aminotransferase levels (17% to 89%, depending on the study), which may be associated with a reduced clotting factor level and requires treatment with transient immunosuppression. CONCLUSION: Gene therapy for hemophilia holds out the prospect of freedom from hemorrhage without the need for regular treatment with drugs. The various steps that need to be carried out in gene therapy should be coordinated in a graded and partly overlapping integrated care model (a so-called hub-and-spoke model). Electronic platforms should be used for data acquisition and transmission.

Long-Term Outcomes after Vaccine-Induced Thrombotic Thrombocytopenia.

Vaccine-induced thrombotic thrombocytopenia (VITT), or thrombosis with thrombocytopenia syndrome (TTS), is a rare but serious complication of adenovirus-based vaccines against severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Observation of long-term outcomes is important to guide treatment of affected patients. This single-center consecutive cohort study included all patients diagnosed based on (1) vaccination 4 to 21 days before symptom onset, (2) signs or symptoms of venous or arterial thrombosis, (3) thrombocytopenia < 150/nL, (4) positive anti-platelet factor 4 (PF4) antibody, and (5) elevated D-Dimer > 4 times the upper limit of normal. Nine patients were enrolled. Acute management consisted of parenteral anticoagulants, corticosteroids, intravenous immunoglobulin (IVIG), and/or eculizumab. Eculizumab was successfully used in two patients with recurrent thromboembolic events after IVIG. Direct oral anticoagulants were given after hospital discharge. Median follow-up duration was 300 days (range 153 to 380). All patients survived the acute phase of the disease and were discharged from hospital. One patient died from long-term neurological sequelae of cerebral venous sinus thrombosis 335 days after diagnosis. Eight out of nine patients were alive at last follow-up, and seven had fully recovered. Anti-PF4 antibodies remained detectable for at least 12 weeks after diagnosis, and D-Dimer remained elevated in some patients despite oral anticoagulation. No recurrent thromboembolic events, other signs of VITT relapse, or bleeding complications occurred after discharge. In conclusion, VITT appears to be a highly prothrombotic condition. IVIG is not always successful, and eculizumab may be considered a rescue agent. Long-term management with direct oral anticoagulants appears to be safe and effective.

Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination.

OBJECTIVE: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. METHODS: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. RESULTS: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). CONCLUSIONS: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573.

Safety of intramuscular COVID-19 vaccination in patients with haemophilia.

BACKGROUND: Guidelines recommend that patients with haemophilia should preferably receive vaccination subcutaneously. COVID-19 and other vaccines, however, are only licenced for intramuscular application. AIMS: To assess the safety of intramuscular COVID-19 vaccination in patients living with haemophilia. METHODS: Part A of this prospective observational study enrolled consecutive patients with haemophilia A (HA) and B (HB) of all ages and severities and assessed injection site bleeding and other complications within 30 days of vaccination. Part B enrolled patients providing informed consent for detailed data collection including medication and prophylaxis around the time of vaccination. Logistic regression was performed to assess potential risk factors for bleeding. RESULTS: Four hundred and sixty-one patients were enrolled into part A. The primary endpoint injection site bleeding occurred in seven patients (1.5%, 95% confidence interval .7-3.1%). Comprehensive analysis of 214 patients (404 vaccinations, part B) revealed that 97% of patients with severe haemophilia had prophylaxis before vaccination, either as part of their routine prophylaxis or using additional doses. 56% and 30% of patients with moderate and mild haemophilia, respectively, received prophylaxis before vaccination. Among the seven bleeds recorded, three occurred when intramuscular vaccination was done without prophylaxis (odds ratio 12). CONCLUSIONS: This is the first prospective study reporting on the safety of intramuscular vaccination in haemophilia. The rate of injection site bleeding was low in mild haemophilia, and in moderate and severe haemophilia if patients received factor prophylaxis.