Expert review of hematology
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Acute hemorrhage is a global healthcare issue, and remains the leading preventable cause of death in trauma. Acute severe hemorrhage can be related to traumatic, peripartum, gastrointestinal, and procedural causes. Hemostatic defects occur early in patients requiring massive transfusion. Early recognition and treatment of hemorrhage and hemostatic defects are required to save lives and to achieve optimal patient outcomes. ⋯ Patients with acute hemorrhage requiring massive transfusion commonly develop coagulopathy due to specific hemostatic defects, and accurate diagnosis and prompt correction are required for definitive hemorrhage control. Damage control resuscitation and massive transfusion protocols are optimal initial treatment strategies, followed by goal-directed individualized resuscitation using real-time coagulation monitoring. Distinct phenotypes exist in trauma-induced coagulopathy, including 'Bleeding' or 'Thrombotic' phenotypes, and hyperfibrinolysis vs. fibrinolysis shutdown. The trauma 'lethal triad' (hypothermia, coagulopathy, acidosis) has been updated to the 'lethal diamond' (including hypocalcemia). A number of controversies in optimal management exist, including whole blood vs. component therapy, use of factor concentrates vs. blood products, optimal use of tranexamic acid, and prehospital plasma and tranexamic acid administration.
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COVID-19 has similarities to the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, as severe patients and non-survivors have frequently shown abnormal coagulation profiles. Immune-mediated pathology is a key player in this disease; hence, the role of the complement system needs assessment. The complement system and the coagulation cascade share an intricate network, where multiple mediators maintain a balance between both pathways. Coagulopathy in COVID-19, showing mixed features of complement-mediated and consumption coagulopathy, creates a dilemma in diagnosis and management. ⋯ A tailored anticoagulant regimen, including intensification of standard prophylactic regimens with low-molecular-weight heparin is advisable for COVID-19 patients. Atypical manifestations and varying D-dimer levels seen in different populations bring forth the futility of uniform recommendations for anticoagulant therapy. Further, direct thrombin inhibitors and platelet inhibitors in a patient-specific manner should also be considered.
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Introduction: Waldenström Macroglobulinaemia (WM) is a heterogeneous, incurable condition which often relapses after chemoimmunotherapy. Novel therapies such as Bruton tyrosine-kinase (BTK) inhibitors have shown to be efficacious in treating WM but with an established, significant toxicity profile seen in the first-generation inhibitor Ibrutinib. Zanubrutinib is a selective, potent BTK inhibitor with the potential to reduce toxicity and improve efficacy. ⋯ Expert opinion: Zanubrutinib induces deeper responses and have greater activity in MYD88WT and CXCR4WHIM WM. Zanubrutinib also has a favorable toxicity profile when compared to Ibrutinib. This may potentially translate to lower discontinuation rates, improved quality of life and ultimately longer progression-free survival in patients with WM.
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Blinatumomab, first in a class of bispecific T-cell engagers, revolutionized treatment paradigm of B-cell precursor relapsed/refractory or minimal residual disease positive acute lymphoblastic leukemia (ALL) in adults and children, inducing deep remissions in a proportion of patients. However, significant numbers of patients do not respond or eventually relapse. Strategies for improvement of treatment outcomes are required. ⋯ Better understanding the mechanisms of response and resistance to blinatumomab might help us to identify the group of patients benefiting most from treatment and to spare potentially toxic subsequent treatment strategies. Data emerging from ongoing clinical trials might change the treatment landscape of ALL and beyond. Early use of blinatumomab in frontline protocols with more advantageous treatment sequences and in combination with other targeted therapies might reduce the failure rates. Exponentially increasing number of novel treatment options and their possible combinations might complicate treatment decision-making without data from randomized trials.
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Review
An evaluation of zanubrutinib, a BTK inhibitor, for the treatment of chronic lymphocytic leukemia.
Recent years have seen a tremendous increase in the availability of therapeutic options for the management of patients with chronic lymphocytic leukemia (CLL). Notable among those are Bruton's tyrosine kinase (BTK) and b-cell lymphoma-2 (bcl-2) inhibitors. ⋯ Two BTK inhibitors are currently Food and Drug Administration (FDA) approved for use in CLL, and multiple additional agents are in development. Zanubrutinib is currently approved for the treatment of patients with relapsed mantle cell lymphoma and has demonstrated an impressive safety and efficacy profile. The choice of a specific BTK inhibitor for clinical use is dependent on its efficacy and relative toxicity profile. In addition, drug interactions also influence this decision. Zanubrutinib therefore provides an exciting option to utilize a specific BTK inhibitor with potentially limited toxicities. Additional comparative studies are currently underway to establish its advantage over currently available BTK inhibitors. Combination strategies are also being pursued to increase the depth and durability of remissions.