Eman Hassan

This chapter provides a comprehensive overview of direct oral anticoagulants (DOACs), focusing on their mechanisms of action, clinical utility, and practical considerations in anticoagulation management. DOACs have revolutionised anticoagulation by selectively targeting thrombin and activated factor X (FXa), offering improved safety, predictable pharmacokinetics, and reduced need for monitoring. The chapter covers their indications, contraindications, dosing, perioperative management, reversal, and use in special populations, including those with renal or hepatic impairment, cancer-associated thrombosis, and extreme body weights. It provides clinicians with practical guidance for the effective application of DOACs in various clinical settings.

Introduction: Secondary and idiopathic polycythaemia is far more common than polycythaemia vera. Whilst venesection for polycythaemia vera has a robust evidence base, the data supporting this treatment for secondary and/or idiopathic polycythaemia are limited to small single‐arm studies showing transient improvement in symptoms or physiologic endpoints. As a result the British Society for Haematology Guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis suggests considering venesection in patients with hypoxic lung disease with Hct > 0.56 or to a target Hct < 0.55 in those with idiopathic polycythaemia. We hypothesised that this paucity of evidence results in widespread variation in management of secondary polycythaemia. Methods: To assess attitudes and practice in the treatment of secondary and idiopathic polycythaemia we designed an international clinician survey to evaluate current practice and define the point of clinical equipoise at which clinicians would be content to enter patients into a randomised venesection study. This survey was distributed using the wide‐reaching HaemSTAR research network. Results: A total of 123 clinicians responded, of which 90 were experienced senior clinicians. 62% reported not routinely offering regular venesection whereas 38% of respondents did. Those considering venesection rose to ∼2/3 of respondents in specific circumstances such as polycythaemia‐related symptoms, previous arterial or unprovoked venous thrombosis. Respondents were more likely to offer venesection to patients with idiopathic‐ compared to androgen‐ or hypoxia‐driven polycythaemia. Of those who would venesect, most would use a threshold Hct ≥ 0.55, with a target Hct < 0.55 but there was significant variability. Conclusions: Our survey showed considerable variability in venesection practice for patients with secondary or idiopathic polycythaemia, probably reflecting the paucity of the evidence base. There was widespread support for a trial of venesection vs observation in secondary polycythaemia and this survey has helped to define the threshold Hct at which clinical equipoise exists.

BACKGROUND: Sickle cell disease (SCD) is a challenging genetic disorder characterized by hemolytic anemia, vaso-occlusive crises (VOC), and progressive organ damage. Despite its severity, effective treatments are limited. The recent withdrawal of promising therapies, such as the anti–P-selectin antibody Crizanlizumab and the hemoglobin polymerization inhibitor Voxelotor, highlights the urgent need for innovative approaches to alleviate VOC and thromboinflammation. METHODS: In this study, we used advanced techniques, including intravital microscopy, laser speckle contrast imaging, and histological analysis, to examine the role of platelets and neutrophils in thrombo-inflammation, VOC, and blood perfusion in the lung, kidney, liver, and spleen. RESULTS: In the Berkeley SCD model, hemin-induced VOC and impairment in pulmonary blood perfusion were independent of red cell congestion and fibrin deposition. Hypoperfusion was driven by adhesion of neutrophils and platelets in the microcirculation and exacerbated by pulmonary emboli. Hemin-induced cell adhesion and hypoperfusion were also observed in the renal microcirculation, whereas it was absent in the liver and spleen of SCD mice, suggesting that organ-specific mechanisms drive hypoperfusion and VOC. To explore therapeutic options, we investigated the potential of Syk (spleen tyrosine kinase) inhibition in improving blood perfusion and reducing thrombo-inflammation. Syk is constitutively phosphorylated in the neutrophils and platelets of SCD mice. Selective Syk inhibition, using BI-1002494, reduced cellular adhesion in the pulmonary and renal microvasculature, effectively restoring blood perfusion and reducing thrombo-inflammation. Low-dose Syk inhibitor was effective in reducing neutrophil adhesion and improving blood perfusion without inducing bleeding. On the contrary, increasing the dose exacerbated hemin-induced bleeding in the lungs due to the complete abolishment of platelet adhesion in the pulmonary microcirculation. CONCLUSIONS: These findings underscore the critical role of Syk in vascular thrombo-inflammation and hypoperfusion in SCD, suggesting that Syk inhibition is a promising strategy to reduce VOC, improve renal and pulmonary perfusion, and reduce organ damage.

Summary: Vaccine‐induced immune thrombocytopenia and thrombosis (VITT) is one of several anti‐platelet factor 4 (anti‐PF4)‐associated immune thrombocytopenia and thrombosis (PITT) syndromes. As well as following adenoviral vector vaccines, VITT has recently been described following acute adenovirus infection. We describe a patient with PITT following acute cytomegalovirus infection. The antibody clonotype and PF4 epitopes were distinct from those identified in VITT, and they were detectable as a paraprotein. PITT should be considered in all patients with thrombocytopenia and thrombosis, even without preceding vaccination or heparin, but who otherwise meet the VITT criteria defined by the British Society of Haematology Expert Panel.

Emicizumab has revolutionised haemophilia A treatment landscape and significantly reduced treatment burden, particularly in the paediatric population. We conducted a retrospective study, focused on infants aged ≤18 months with severe haemophilia A. The study included 16 patients, with a median age of 8.2 months and median treatment duration of 61.6 weeks. Before commencing emicizumab, six patients were minimally treated with ≤5 exposure days while 10 were previously untreated patients. Notably, all patients had no inhibitors at baseline, and none developed new inhibitors during the study period. Emicizumab was well tolerated, with no observed side effects or major bleeding events.