Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a rare hereditary multisystem vascular disorder causing visceral arteriovenous malformations and mucocutaneous bleeding. Chronic gastrointestinal bleeding and epistaxis often produce profound anaemia refractory to conventional treatment. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, may be effective in treatment of bleeding in HHT. METHODS: All HHT patients treated with systemic bevacizumab for chronic bleeding were selected for retrospective analysis. Data collected included demographics, baseline HHT characteristics, epistaxis grade, surgical interventions, bevacizumab dosing, adverse events, haemoglobin, red cell transfusions, intravenous iron infusions, and other anaemia and/or bleeding-directed therapies. RESULTS: Thirteen HHT patients were treated with bevacizumab for a median of 13.9 (range 4.9-30.1) months. Compared with pretreatment values, bevacizumab treatment increased the mean haemoglobin by 4.0 g dL-1 (95% CI, 2.6-5.3 g dL-1 ) [mean (95% CI) haemoglobin 8.5 (7.8, 9.9) g dL-1 vs. 12.5 (11.2, 13.7) g dL-1 , P < 0.001)], reduced red cell units transfused by 92% [median of 6 (range 0-59) units vs. 0 (range 0-15) units, P = 0.004] and reduced quantity of iron infused by 73% [mean (95% CI) 462 (257, 668) mg month-1 vs. 126 (75, 178) mg month-1 , P = 0.002]. Epistaxis control was achieved in 85% with bevacizumab versus 0% before treatment (P < 0.001). No patient required nasal or GI procedures during the maintenance period. Two patients (15%) developed grade 3 hypertension requiring medical management. CONCLUSION: Systemic bevacizumab was highly effective to treat chronic bleeding in HHT. Further study is needed to confirm the magnitude of benefit and further define optimal dosing, treatment duration and long-term safety.

Perioperative thrombocytopenia: evidence, evaluation, and emerging therapies.

Thrombocytopenia is a common perioperative clinical problem. While global haemostasis is influenced by many patient- and procedure-related factors, the contribution of thrombocytopenia to bleeding risk is difficult to predict, as platelet count does not linearly correlate with likelihood of bleeding. Thus, the widely used definition of thrombocytopenia and grading of its severity have limited clinical utility. We present a summary and analysis of the current recommendations for invasive procedures in thrombocytopenic patients, although the platelet count at which any given procedure may safely proceed is unknown. The benefits and risks of preoperative platelet transfusions should be assessed on a patient-by-patient basis, and alternatives to platelet transfusion should be considered. In non-emergent surgeries or in postoperative thrombocytopenic patients, haematology consultation should be considered to guide diagnostics and management. We present a pragmatic approach to the evaluation of perioperative thrombocytopenia.

Emapalumab for the treatment of hemophagocytic lymphohistiocytosis.

Emapalumab-Igsz (Gamifant) is a human monoclonal antibody directed against interferon-γ (IFN-γ), and the first Food and Drug Administration (FDA)-approved therapy for primary hemophagocytic lymphohistiocytosis (HLH). HLH is a disorder characterized by hypercytokinemia in the setting of unbridled immune activation, and emapalumab represents the first therapeutic developed to address the underlying pathophysiology of HLH. Emapalumab is approved for treatment of primary HLH that is refractory, recurrent, progressing or intolerant to current HLH treatments in both adult and pediatric patients. FDA approval was based on the results of a phase II/III clinical trial evaluating the safety and efficacy of emapalumab in 34 pediatric patients with primary HLH, 27 of whom were refractory to current therapies. Additional studies of emapalumab are currently ongoing in adults and other pediatric populations. Here, we will review the pharmacology, safety and efficacy of emapalumab for the treatment of HLH.

Cancer and thrombosis: new insights to an old problem.

Venous thromboembolism (VTE) is a common complication in patients with cancer and portends a poor prognosis. Our understanding of the underlying pathophysiology of VTE in cancer has advanced since Trousseau first described hypercoagulability in patients with malignancy and Virchow described his famous triad of thrombosis formation. Malignancy itself induces a thrombophilic state by increasing the risk of venous stasis, endothelial injury and an imbalance of pro and anti-thrombotic factors leading to a hypercoaguable state. Additional insults to this thrombotic balance are introduced by patient-specific, treatment related and tumor-specific factors. The importance of understanding the factors associated with increased thrombosis in cancer is paramount in order to adequately identify patients who will benefit from thromboprophylaxis.

Avatrombopag maleate for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease.

Avatrombopag maleate (Doptelet; Dova Pharmaceuticals) is an oral, small-molecule second-generation thrombopoietin (TPO) receptor agonist under development for the treatment of thrombocytopenia. Recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease on the basis of the results of two phase III trials, it is currently under investigation for treatment of immune thrombocytopenia (two randomized trials demonstrating efficacy have already been completed), chemotherapy-induced thrombocytopenia and perioperative thrombocytopenia in patients undergoing major surgical procedures. This review will evaluate the preclinical pharmacology, pharmacokinetics, clinical studies, safety, indications and drug interactions of avatrombopag, with a focus on its use for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease.