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1.
Effect of Therapeutically Related Drugs on Coagulation-Anticoagulation Balance in Acute Promyelocytic Leukemia.
Xiao, M, Zhou, P, Sun, K
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2022;:10760296221080166
Abstract
Acute promyelocytic leukemia (APL) usually presents with a series of coagulation-anticoagulation disturbance. Early administration of All-trans retinoic acid (ATRA) can reduce the risk of bleeding, but the potential for thrombosis needs to be addressed in some cases. The role of arsenic agent in correcting coagulation disorder remains to be studied, but oral arsenic agent shows potential advantages in coagulation recovery compared with intravenous agent, and chemotherapy can aggravate the progress of coagulation disease. In addition to early application of ATRA, avoiding invasive procedures and transfusion support can reduce the risk of bleeding. Whether the administration of heparin, thrombomodulin, recombinant factor VIIa or antifibrinolytics reduces the risk of bleeding and thrombosis associated with APL remains to be further explored, and their routine use outside of clinical trials is not recommended. This article reviews the effects of related drugs on coagulation-anticoagulation balance in APL patients.
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2.
Antithrombotic strategies in elderly patients with acute coronary syndrome.
Dillinger, JG, Laine, M, Bouajila, S, Paganelli, F, Henry, P, Bonello, L
Archives of cardiovascular diseases. 2021;(3):232-245
Abstract
Elderly patients represent a growing proportion of the acute coronary syndrome population in Western countries. However, their frequent atypical symptoms at presentation often lead to delays in management and to misdiagnosis. Furthermore, their prognosis is poorer than that of younger patients because of physiological changes in platelet function, haemostasis and fibrinolysis, but also a higher proportion of comorbidities and frailty, both of which increase the risk of recurrent thrombotic and bleeding events. This complex situation, with ischaemic and haemorrhagic risk factors often being intertwined, may lead to confusion about the required treatment strategy, sometimes resulting in inadequate management or even to therapeutic nihilism. It is therefore critical to provide a comprehensive overview of our understanding of the pathophysiological processes underlying acute coronary syndrome in elderly patients, and to summarise the results from the latest clinical trials to help decision making for these high-risk patients.
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3.
A review of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery.
Milling, TJ, Ziebell, CM
Trends in cardiovascular medicine. 2020;(2):86-90
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Abstract
Oral anticoagulants, old and new, are effective therapies for prevention and treatment of venous thromboembolism and reduction of stroke risk in patients with atrial fibrillation. However, blocking elements of the clotting cascade carries an inherent risk of bleeding. Also, anticoagulated patients sometimes require urgent surgery or invasive procedures. This has led to the emergence of a body of scientific literature on the reversal of anticoagulation in these two settings. Traditionally, vitamin K antagonists (VKAs), which indirectly inactivate clotting factors II, VII, IX and X (and natural anticoagulant proteins C and S), had been the mainstay of oral anticoagulation for half a century. Only a few years ago, the US Food and Drug Administration (FDA) approved a specific VKA reversal agent, 4-Factor Prothrombin Complex Concentrate (4F-PCC). The last decade has seen the rise of non-Vitamin K oral anticoagulants (NOACs), which target specific factors, i.e. Factors IIa and Xa. Investigators have rapidly developed reversal agents for these agents as well, idarucizumab for the Factor IIa inhibitor dabigatran (Pradaxa) and andexanet alfa for the entire class of Factor Xa inhibitors (FXaIs), currently four drugs: rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) and betrixaban (Bevyxxa). Clinicians still use off-label PCC for reversing FXaIs in some settings, and a universal reversal agent, ciraparantag, remains in development. This review summarizes the safety and efficacy of these reversal agents in the setting of anticoagulant-associated major bleeding and the need for urgent surgery.
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4.
The rebirth of the contact pathway: a new therapeutic target.
Srivastava, P, Gailani, D
Current opinion in hematology. 2020;(5):311-319
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Abstract
PURPOSE OF REVIEW Anticoagulation with vitamin-K antagonists or direct oral anticoagulants is associated with a significant risk of bleeding. There is a major effort underway to develop antithrombotic drugs that have a smaller impact on hemostasis. The plasma contact proteins factor XI (FXI) and factor XII (FXII) have drawn considerable interest because they contribute to thrombosis but have limited roles in hemostasis. Here, we discuss results of preclinical and clinical trials supporting the hypothesis that the contact system contributes to thromboembolic disease. RECENT FINDINGS Numerous compounds targeting FXI or FXII have shown antithrombotic properties in preclinical studies. In phase 2 studies, drugs-targeting FXI or its protease form FXIa compared favorably with standard care for venous thrombosis prophylaxis in patients undergoing knee replacement. While less work has been done with FXII inhibitors, they may be particularly useful for limiting thrombosis in situations where blood comes into contact with artificial surfaces of medical devices. SUMMARY Inhibitors of contact activation, and particularly of FXI, are showing promise for prevention of thromboembolic disease. Larger studies are required to establish their efficacy, and to establish that they are safer than current therapy from a bleeding standpoint.
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Female Sex as a Thromboembolic Risk Factor in the Era of Nonvitamin K Antagonist Oral Anticoagulants.
Gallù, M, Marrone, G, Legramante, JM, De Lorenzo, A, Di Daniele, N, Noce, A
Cardiovascular therapeutics. 2020;:1743927
Abstract
Sex-specific differences have been definitively demonstrated in cardiovascular (CV) diseases. These differences can also impact on the effects of CV therapies. Female sex is recognized as an independent predictor of thromboembolic risk, particularly in older patients. Most of strokes are due to atrial fibrillation (AF). Women affected by AF have higher stroke risk compared to men. The introduction of novel oral anticoagulants (NOACs) for long-term anticoagulation completely changed the anticoagulant therapeutic approach and follow-up of patients affected by nonvalvular atrial fibrillation (NVAF). CHA2DS2-VASc stroke risk scoring in use in the current international guidelines attributes 1 point to "female sex". Besides, no anticoagulation is indicated for AF female patients without other risk factors. Interestingly, NOACs seem to normalize the differences between males and females both in terms of safety and efficacy, whereas residual higher stroke risk and systemic embolism persist in AF women treated with vitamin K antagonist anticoagulants VKA with optimal time in therapeutic range. Based on the CHA2DS2-VASc score, NOACs represent the preferred choice in NVAF patients. Moreover, complete evaluation of apparently lower risk factor along with concomitant clinical conditions in AF patients appears mandatory, particularly for female patients, in order to achieve the most appropriate anticoagulant treatment, either in male or in female patients. The present review was performed to review sex differences in AF-related thromboembolic risk reported in the literature and possibly highlight current knowledge gaps in prevention and management that need further research.
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6.
Coagulopathy reversal in intracerebral haemorrhage.
Sweidan, AJ, Singh, NK, Conovaloff, JL, Bower, M, Groysman, LI, Shafie, M, Yu, W
Stroke and vascular neurology. 2020;(1):29-33
Abstract
As intracerebral hemorrahge becomes more frequent as a result of an aging population with greater comorbidities, rapid identification and reversal of precipitators becomes increasingly paramount. The aformentioned population will ever more likely be on some form of anticoagulant therapy. Understanding the mechanisms of these agents and means by which to reverse them early on is critical in managing the acute intracerebral hemorrhage.
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Role of rivaroxaban in the management of atrial fibrillation: insights from clinical practice.
Vimalesvaran, K, Dockrill, SJ, Gorog, DA
Vascular health and risk management. 2018;:13-21
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it leads to significant morbidity and mortality, predominantly from ischemic stroke. Vitamin K antagonists, mainly warfarin, have been used for decades to prevent ischemic stroke in AF, but their use is limited due to interactions with food and other drugs, as well as the requirement for regular monitoring of the international normalized ratio. Rivaroxaban, a direct factor Xa inhibitor and the most commonly used non-vitamin K oral anticoagulant, avoids many of these challenges and is being prescribed with increasing frequency for stroke prevention in non-valvular AF. Randomized controlled trial (RCT) data from the ROCKET-AF(Rivaroxaban once daily oral direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) trial have shown rivaroxaban to be non-inferior to warfarin in preventing ischemic stroke and systemic embolism and to have comparable overall bleeding rates. Applicability of the RCT data to real-world practice can sometimes be limited by complex clinical scenarios or multiple comorbidities not adequately represented in the trials. Available real-world evidence in non-valvular AF patients with comorbidities - including renal impairment, acute coronary syndrome, diabetes mellitus, malignancy, or old age - supports the use of rivaroxaban as safe and effective in preventing ischemic stroke in these subgroups, though with some important considerations required to reduce bleeding risk. Patient perspectives on rivaroxaban use are also considered. Real-world evidence indicates superior rates of drug adherence with rivaroxaban when compared with vitamin K antagonists and with alternative non-vitamin K oral anticoagulants - perhaps, in part, due to its once-daily dosing regimen. Furthermore, self-reported quality of life scores are highest among patients compliant with rivaroxaban therapy. The generally high levels of patient satisfaction with rivaroxaban therapy contribute to overall favorable clinical outcomes.
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Hereditary angioedema: the plasma contact system out of control.
De Maat, S, Hofman, ZLM, Maas, C
Journal of thrombosis and haemostasis : JTH. 2018;(9):1674-1685
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The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1-INH) deficiency. C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1-INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.
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9.
Use of direct oral anticoagulants in antiphospholipid syndrome.
Cohen, H, Efthymiou, M, Isenberg, DA
Journal of thrombosis and haemostasis : JTH. 2018;(6):1028-1039
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Abstract
The direct oral anticoagulants (DOACs) are therapeutic alternatives to warfarin and other vitamin K antagonists (VKAs), and constitute the standard of care for many indications. VKAs constitute the conventional therapy for the treatment and secondary thromboprophylaxis of thrombotic antiphospholipid syndrome (APS), but are often problematic, owing to the variable sensitivity of thromboplastins to lupus anticoagulant. Thus, the International Normalized Ratio may not accurately reflect anticoagulation intensity, or be clinically effective. Definition of the current role of DOACs in the treatment of APS is based on limited clinical trial data and information from other sources, including manufacturers' data, case series or cohort studies, and expert consensus. The Rivaroxaban in Antiphospholipid Syndrome (RAPS) randomized controlled trial (RCT), which had a laboratory surrogate primary outcome measure, suggests that rivaroxaban has the potential to be an effective and convenient alternative to warfarin in thrombotic APS patients with a single venous thromboembolism event requiring standard-intensity anticoagulation. However, further studies, in particular to provide better long-term efficacy and safety data, are needed before it can be widely recommended. APS patients are clinically heterogeneous, with the risk of recurrent thrombosis and the intensity of anticoagulation being influenced by their clinical phenotype and risk profile. DOAC trials involving homogeneous thrombotic APS populations, with the antiphospholipid antibody status well defined, will help to optimize the appropriate treatment in APS patient subgroups. Ongoing and emerging DOAC RCTs should provide further information to guide the use of DOACs in APS patients. Optimal identification of APS patients is a key step in working towards improved therapeutic strategies in these individuals.
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10.
State of play and future direction with NOACs: An expert consensus.
Cohen, AT, Lip, GY, De Caterina, R, Heidbuchel, H, Zamorano, JL, Agnelli, G, Verheugt, F, Camm, AJ
Vascular pharmacology. 2018;:9-21
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Abstract
Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice.