Approaches to prevent bleeding associated with anticoagulants: current status and recent developments

Abstract

Anticoagulants are widely used for the prophylaxis and treatment of cardiovascular disorders and to prevent blood clotting during surgeries. However, the major limitation associated with anticoagulant therapy is bleeding; all the current anticoagulants do have a bleeding risk. The propensity to bleed is much higher among the elderly population and patients with renal insufficiency. Therefore, there is an utmost and urgent clinical need for a highly efficient, nontoxic antidote with excellent anticoagulant reversal activity. This will significantly improve the safety of anticoagulation therapy. This review summarizes the current options and approaches to reverse anticoagulation activity of clinically used anticoagulants. We start with an introduction to thrombosis and then summarize the details of current clinically available anticoagulants and their mechanisms of action and limitations. This is followed by current practices in anticoagulant neutralization including the details of the only clinically approved unfractionated heparin antidote, protamine; recent advances in the development of antidotes against heparin-based drugs; and direct oral anticoagulants (DOACs).

Chemical and pharmacological aspects of neutralization of heparins from different animal sources by protamine

“…Most of the research on protamine neutralization of UFHs is based on clinical cases of patients undergoing procedures involving heparinization or in vitro and ex vivo assessments of their anticoagulant activities after the neutralization reactions . It has already been demonstrated that the anticoagulant activity of HPI is neutralized more effectively than that of HBI ; however, the chemical aspects leading to these different neutralization profiles have not been clearly elucidated so far.…”

Novel reversal agents and laboratory evaluation for direct-acting oral anticoagulants (DOAC): An update

“…NOACs are no longer “novel” but their reversal agents definitely are. DOAC reversal agents at a glance [Table 3][17181920212223242526272829] and a summary of 16 human in vivo clinical trials involving specific and non-specific DOAC reversal agents[3031323334353637383940414243444546] [Table 4] are presented here for ready referral.…”

“…Early administration of activated charcoal can hamper absorption of DOACs from the gutand can be followed by charcoal filtration. [26] Haemodialysis is partially successful in removing Dabigatrin from the circulation, but is ineffective for anti-Factor Xa DOACs whereas therapeutic plasma exchange maybe employed for urgent rivaroxaban reversal. [2627] Intermittent haemodialysis reduced dabigatran concentrations by 52%-77% but a rebound reaching 87% within 120 minutes post dialysis was observed in a case series of five patients[28] Recombinant activated factor VII can also be empirically used.…”

Engineered protein cages for selective heparin encapsulation

“…5 This has initiated diverse attempts to develop safer heparin antidotes, such as cationic polymers and small molecules, which all largely rely on the electrostatic binding with heparin. [6][7][8][9][10][11][12] Although efficient binding can be achieved, cationic platforms often lack specificity to heparin and usually exhibit high cytotoxicity. Furthermore, the complexes formed with heparin are often large and ill-defined aggregates.…”