A phase 1b/2 clinical study of marstacimab, targeting human tissue factor pathway inhibitor, in haemophilia.

A phase 1b/2, three-month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300-mg loading dose with subsequent 150-mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment-emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n = 16 (61.5%); haemophilia A with inhibitor, n = 7 (26.9%); haemophilia B, n = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on-demand control group (p < 0.0001) and versus pretreatment ABR (p < 0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose-related manner, with steady-state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment-related changes for all PD biomarkers indicated effective targeting of TFPI. (Clinicaltrials.gov identifier, NCT02974855).

Principles of care for acquired hemophilia.

OBJECTIVE: To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management. METHOD: These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists. RESULTS: The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long-term follow-up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research. CONCLUSION: The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non-specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management.

Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management.

Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU/mL and is characterised by traumatic bleeds. Major issues associated with mild haemophilia are that it may not present for many years after birth, and that awareness, even within families, may be low. Methodological problems exist in diagnosis, such as inconsistencies in results obtained from different assays used to measure factor levels in mild haemophilia. Advances in genetic testing provide insight into diagnosis as well as the likelihood of inhibitor development, which is not uncommon in patients with mild or moderate haemophilia and can increase morbidity. The management of patients with mild haemophilia is a challenge. This review includes suggestions around formulating treatment plans for these patients, encompassing the full spectrum from clinical care of the newly diagnosed neonate to that of the ageing patient with multiple comorbidities. Management strategies consider not only the vast differences in these patients' needs, but also risks of inhibitor development and approaches to optimally engage patients.

Beyond stopping the bleed: short-term episodic prophylaxis with recombinant activated factor FVII in haemophilia patients with inhibitors.

Preventing haemarthroses and arthropathy is a major challenge in patients with haemophilia and inhibitors, as treatment options are limited. One potential strategy is short-term episodic prophylaxis, which extends bypassing agent therapy beyond the resolution of bleeding to include the post-bleed inflammatory phase. At the 13th Zürich Haemophilia Forum, an expert panel reviewed the rationale behind this strategy, explored its current use with recombinant activated factor VII (rFVIIa) and considered treatment monitoring and optimisation. Two protocols are currently used for short-term episodic prophylaxis, both of which stipulate on-demand rFVIIa until resolution of bleeding, followed by daily dosing for ≥3 days to prevent re-bleeds. Short-term episodic prophylaxis should be individualised to optimise outcomes, perhaps through early treatment initiation or by combining rFVIIa with other treatments (e.g. factor VIII, tranexamic acid). Encouraging treatment compliance can also improve outcomes. Additionally, there is a need to develop objective clinical outcome measures, biomarkers and imaging protocols that can monitor treatment outcomes and joint disease in patients with inhibitors. A proactive approach incorporating a systematic package of care is needed. Currently, short-term episodic prophylaxis with rFVIIa may be an alternative treatment option to on-demand treatment for patients with inhibitors.

Pain and pain management in haemophilia.

Joint pain is common in haemophilia and may be acute or chronic. Effective pain management in haemophilia is essential to reduce the burden that pain imposes on patients. However, the choice of appropriate pain-relieving measures is challenging, as there is a complex interplay of factors affecting pain perception. This can manifest as differences in patients' experiences and response to pain, which require an individualized approach to pain management. Prophylaxis with factor replacement reduces the likelihood of bleeds and bleed-related pain, whereas on-demand therapy ensures rapid bleed resolution and pain relief. Although use of replacement or bypassing therapy is often the first intervention for pain, additional pain relief strategies may be required. There is an array of analgesic options, but consideration should be paid to the adverse effects of each class. Nevertheless, a combination of medications that act at different points in the pain pathway may be beneficial. Nonpharmacological measures may also help patients and include active coping strategies; rest, ice, compression, and elevation; complementary therapies; and physiotherapy. Joint aspiration may also reduce acute joint pain, and joint steroid injections may alleviate chronic pain. In the longer term, increasing use of prophylaxis or performing surgery may be necessary to reduce the burden of pain caused by the degenerative effects of repeated bleeds. Whichever treatment option is chosen, it is important to monitor pain and adjust patient management accordingly. Beyond specific pain management approaches, ongoing collaboration between multidisciplinary teams, which should include physiotherapists and pain specialists, may improve outcomes for patients.

Beyond patient benefit: clinical development in hemophilia.

Historically in hemophilia, outcome measures have not been collected systematically. Hence, there are insufficient clearly defined, evidence-based measures that can be applied consistently across hemophilia trials. This review focuses on some key challenges to evaluating patient outcomes and performing trials identified by experts at the Fourth and Fifth Zurich Haemophilia Forums. As procedures appear inconsistent across Europe, guidelines require modification to be more appropriate and/or realistically achievable. The outcome measures utilized, and the timing of their collection, should also be standardized, and more objective measures used where feasible. Implementation of outcome measures could be refined through greater understanding of patient heterogeneity, and tailored to differentiate between hemophilia- and aging-related disease effects. Furthermore, robust outcome measures that can also inform health-economic decisions are increasingly needed. Lastly, as patient recruitment poses a challenge, the panel proposed a call for action to motivate physicians and patients to participate in clinical trials.

Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice.

For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zürich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤ 5 yr of inhibitor detection) when inhibitor titers are <10 Bethesda units (BU) and should be stopped when successful tolerance is achieved. For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel considered that patients with a high bleeding frequency should be offered additional prophylaxis with a bypassing agent. For patients with hemophilia B, there may be a benefit of genetic testing to indicate the risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these patients. For high-titer inhibitor (≥ 5 BU) hemophilia B patients, the panel advised that bypassing agents could be offered on demand in addition to ITI. Within future ITI regimens, there may be a role for additional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI therapy that offer durable and sustained effects and reduced rates of complications.

Treatment of multiple relapsing non-melanoma skin cancers in a patient with severe hemophilia A.

Although non-melanoma skin cancers are the most predominant malignancies in the Caucasian population and hemophilia A is one of the most frequent hereditary bleeding disorders, medical literature data about the management of non-melanoma skin cancers in patients with hemophilia are surprisingly scarce. In this case report we describe the treatment of a patient with multiple recurrent non-melanoma skin cancers and severe hemophilia A. The management of such patients could be very challenging, with possible significant bleeding complications, and requires a multidisciplinary approach.

Hypercoagulability in Cushing's syndrome: the role of specific haemostatic and fibrinolytic markers.

OBJECTIVE: Hypercoagulability is a commonly described complication in patients with Cushing's syndrome. Recent clinical studies have indicated various abnormalities of coagulation and fibrinolysis parameters which may be related to that phenomenon. The aim of this study was to investigate the mechanisms underlying the hypercoagulable state in patients with Cushing's syndrome. RESEARCH METHODS AND PROCEDURES: A wide range of serum markers involved in the processes of blood coagulation and fibrinolysis was measured in a group of 33 patients with Cushing's syndrome and 31 healthy controls. No participant was taking medication which could influence the result or had known diseases, except hypertension and diabetes, which could affect blood coagulation or fibrinolysis parameters. RESULTS: Patients with Cushing's syndrome had higher levels of clotting factors II (P = 0.003), V (P < 0.001), VIII (P < 0.001), IX (P < 0.001), XI (P < 0.001) and XII (P = 0.019), protein C (P < 0.001), protein S (P < 0.001), C1-inhibitor (P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) (P = 0.004). The activity of fibrinolytic markers, plasminogen (P < 0.001), antithrombin (P < 0.001) and antithrombin antigen (P = 0.001) was also increased in the patient group. CONCLUSION: The study has demonstrated hypercoagulability in patients with Cushing's syndrome manifest as increased prothrombotic activity and compensatory activation of the fibrinolytic system. We propose the introduction of thromboprophylaxis in the preoperative and early postoperative periods, combined with a close follow-up in order to prevent possible thromboembolic events in patients with Cushing's syndrome.