Unlike Heparins Newer Oral Anticoagulants Do Not Interact with HIT Antibodies and Maybe Useful in the Longterm Anticoagulant Management of Heparin Compromised Patients

Heparin and low molecular weight heparins such as enoxaparin and dlateparin are widely used in the management of thrombosis and cardiovascular disorders. However these anticoagulants are capable of producing the generation of HIT antibodies and their use is not recommended in patients with previous history of HIT. More recently several new oral anticoagulants have been approved around the world. These include the oral anti-Xa agents namely, Apixaban (Bristol-Myers Squibb), Rivaroxaban(Bayer Healthcare) and anti-IIa agents, dabigatran (Boehringer-Ingelheim). All of these represent synthetic low molecular weight compounds. Apixaban and Rivaroxaban are active agents where as Dabigatran requires endogenous activation. The purpose of this investigation was to determine the relative effects of the newer anticoagulants and enoxaparin on HIT antibody mediated platelet aggregation and other interactions with platelets.

Rivaroxaban was obtained in powdered form from Bayer Healthcare (Wuppertal, Germany) Apixaban and Dabigatran were of synthetic origin. Enoxaparin was obtained from Sanofi-Aventis (paris, France). All drugs were dissolved in appropriate solutions and a working solution of 100 ug/ml was prepared in buffered saline. Pooled HIT sera was prepared by pooling clinically symptomatic HIT patients with high titers of anti-heparin platelet factor 4 antibodies.

Whole blood samples drawn from normal healthy volunteers were supplemented with each of these agents at a graded concentration of 0–100 ug/ml for 60 minutes to determine the relative release of platelet factor 4. To test the interaction of HIT antibody with each of these agents 50 ul of PRP samples were mixed with 150 ul HIT positive heat inactivated sera/plasma or plasmapheresis fliud (collected from symptomatic HIT patients). Graded amounts of each of these new anticoagulants at 0.1, 1.0 and 10 ug/ml were added to test the platelet aggregation response at a period of 60 minutes.

In contrast to enoxaparin which produced an increase in the platelet factor 4 release upon 60 minute incubation 25.6+3.1 ng/ml), none of the new oral anticoagulants produced an increase in the PF4 <15.0 ng/ml. Enoxaparin also produced a strong HIT antibody mediated response, whereas none of these newer oral agents produced any aggregation responses.

These studies demonstrate that –enoxaparin the newer oral anticoagulant drugs do not interact with HIT antibody to mediate plarelet aggregation responses. Moreover, these newer agents do not promote platelet factor 4 release. Thus, these agents can be used in the long term anticoagulant management of heparin compromised patients.

No relevant conflicts of interest to declare.