Paul Knoebl

Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

Demographic and clinical data in acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2)

Summary.  Background:  Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA.

Immunosuppression for acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2)

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

Safety and pharmacokinetics of anti‐TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial

Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia.

Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura.

quency counts and percentages. Continuous variables were summarized using one or more of the following: mean, standard deviation, median, minimum, and maximum, 75th and 90th percentile, ignoring missing data when applicable. Age at survey, age at start of chronic transfusion therapy, average weight, average pretransfusion Hb and %HbS, average transfusion volume, duration of transfusion therapy and predominant transfusion type were summarized with each patient contributing equally. Weight, pretransfusion Hb and %HbS, transfusion volume, and days late were also summarized with each transfusion contributing equally. The probability of pretransfusion %HbS less than 30% was modeled using generalized estimating equations to account for the lack of independence induced by multiple transfusions per subject. The models were used to generate estimates of the odds ratio (OR) and 95% confidence intervals. Results were considered statistically significant if the confidence interval excluded one.

Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry.

Please cite this paper as: Tengborn L, Baudo F, Huth‐Kühne A, Knoebl P, Lévesque H, Marco P, Pellegrini F, Nemes L, Collins P on behalf of the EACH2 registry contributors. Pregnancy‐associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry. BJOG 2012;119:1529–1537.

Blood coagulation disorders in septic patients.

ZusammenfassungAbwehrsystem und Blutgerinnung sind eng verknüpfte und interagierende Systeme, die für die Integrität eines Organismus von entscheidender Bedeutung sind. Komplexe Mechanismen regulieren die Intensität einer Antwort auf eindringende Pathogene oder andere potentiell gefährliche Situationen. Normalerweise ist so eine Reaktion zeitlich limitiert und auf den Ort der Verletzung beschränkt. Manchmal jedoch erfolgt die systemische Antwort überschießend und unangepasst und führt zur Schädigung des Organismus anstatt zur Heilung. Abhängig vom genetischen Repertoire des Organismus, von seiner derzeitigen Immunkompetenz und der Art des Auslösers verursacht die systemische Antwort das klinische Bild einer Sepsis (in ihren verschiedenen Stadien). Die septische Organfunktionsstörung wird dabei von einer generalisierten Fibrinablagerung in der Mikrozirkulation verursacht, die aus überschießender Gerinnungsaktivierung, insuffizienten Antikoagulantien und gehemmter Fibrinolyse entsteht. Dieser Artikel beschreibt die zugrundeliegenden pathophysiologischen Mechanismen und stellt www.SepDIC.eu vor, eine Internetplattform zur Sepsis und der damit assoziierten Koagulopathie.SummaryHost defense and blood coagulation are tightly connected and interacting systems, necessary for the integrity of an organism. Complex mechanisms regulate the intensity of a host response to invading pathogens or other potentially dangerous situations. Under regular conditions, this response is limited in time and located to the site of injury. Sometimes, however, systemic host response is overwhelming and disproportional and causes damage, not cure. Dependent on the genetical predisposition of the host, its current immunocompetence, or the type of injury, the reaction leads to the clinical picture of the different degrees of sepsis. Septic organ dysfunction is caused by intravascular fibrin deposition as a result of coagulation activation, anticoagulant breakdown, and shut down of fibrinolysis. This article describes the major pathophysiologic reactions in these situations and presents www.SepDIC.eu, an online tool on sepsis and associated coagulopathy.

Respiratory failure after stem cell transplantation : Improved outcome with non-invasive ventilation

We retrospectively analyzed the efficacy of non-invasive ventilation in 35 patients with acute hypoxemic respiratory failure after autologous or allogeneic stem cell transplantation (SCT). Non-invasive ventilation was delivered by a standard face mask or helmet. Decisions to intubate were made according to standard criteria. Between 1993 and 2003, 836 patients underwent an autologous or allogeneic bone marrow or SCT. Eighty-two patients developed respiratory failure. Of these, 47 patients were initially intubated and mechanically ventilated. None of these patients survived. Thirty-five patients initially underwent non-invasive ventilation at the bone marrow transplant unit. Seven of these patients survived and were discharged from the hospital (20%). Eleven of the 35 (31%) patients improved within the first 4 h of non-invasive ventilation with respect to oxygenation and were regarded as responders. Seven of these patients survived to hospital discharge (64%), while all non-responders died (P<0.001). In all survivors, the partial pressure of arterial oxygen (PaO2) improved after the initiation of non-invasive ventilation. In non-survivors, PaO2 improved in only 4 of 28 patients (17%) (P<0.0001). Non-invasive ventilation in patients with acute respiratory failure after SCT could improve prognosis in a carefully selected group of patients.

Evaluation of in vivo antineoplastic effects of rapamycin in patients with chemotherapy-refractory AML.

BACKGROUND The mammalian target of rapamycin (mTOR) has recently been identified as a potential target in acute myeloid leukemia (AML). METHODS We treated 5 patients with chemotherapy-refractory AML with the mTOR-inhibitor rapamycin at 2mg per os daily for 14 days, with dose adjustment allowed to reach a target serum rapamycin concentration of 10-20 ng/mL. Four of five patients received additional hydroxyurea at constant dose during treatment with rapamycin. RESULTS Two patients achieved a leukocyte response, in one of them, a prolonged response was seen. In the other patients, blast counts remained stable or increased during rapamycin therapy. We did not observe severe hematologic or non-hematologic side effects of rapamycin. CONCLUSION Rapamycin at 2mg per day acts mildly cytoreductive in a subgroup of patients with refractory AML. Higher doses and drug combinations may be required to obtain long lasting anti-leukemic effects in these patients.

Acquired hemophilia A: Updated review of evidence and treatment guidance

Acquired hemophilia A (AHA) is a rare disease resulting from autoantibodies (inhibitors) against endogenous factor VIII (FVIII) that leads to bleeding, which is often spontaneous and severe. AHA tends to occur in elderly patients with comorbidities and is associated with high mortality risk from underlying comorbidities, bleeding, or treatment complications. Treatment, which consists of hemostatic management and eradication of the inhibitors, can be challenging to manage.