Non-Warfarin Oral Anticoagulants in Heparin-Induced Thrombocytopenia

Introduction: Heparin-Induced Thrombocytopenia (HIT) is an antibody-mediated reaction where exposure to heparin products (unfractionated and, less commonly, low molecular weight heparins) leads to a paradoxical prothrombotic state. Current treatment guidelines recommend immediate cessation of all heparin products and initiation of a non-heparin anticoagulant. This is typically accomplished with argatroban and then transitioning to a vitamin K antagonist once platelets have recovered. An attractive alternative is the use of the non-warfarin oral anticoagulants (NOACs) in the treatment of HIT, namely the direct Xa inhibitors apixaban and rivaroxaban which have already proven safe and effective for the treatment of venous thromboembolism.

Methods: We designed a retrospective analysis of all patients at the University of Virginia with a positive serotonin release assay (for a definitive diagnosis of HIT) that were treated with either apixaban or rivaroxaban since September 2011.  Results from heparin induced platelet antibody testing were also recorded. Patients were reviewed for recurrent thrombi, severe bleeding or other complications that led to changes in their management. 

Results: Eleven patients were identified based on the inclusion criteria. All patients had a positive serotonin release assay despite 4/11 (36%) testing negative for heparin induced platelet antibody. All patients received intravenous argatroban or bivalirudin at the time of diagnosis and were transitioned to an oral anticoagulant at time of hospital discharge.  9/11 (81%) were treated with apixaban and 2/11 (19%) were treated with rivaroxaban.  Zero patients developed recurrent thrombi (summarized in Table 1). One patient in each group developed major bleeding leading to discontinuation of anticoagulation.  Of these, both had additional risk factors for bleeding prior to initiation of anticoagulation (one with concurrent clopidogrel use after coronary artery bypass grafting and prior bleeding from gastric varices; the other with previously diagnosed metastatic squamous cell lung cancer). Of the remaining 9 patients, safe and effective anticoagulation with a NOAC was noted for up to18 months without adverse effects.

Conclusion: Apixaban and rivaroxaban, along with all forms of anticoagulation, should be used with caution in patients with risk factors for severe bleeding.  These medications, however, showed to be a safe and effective first line outpatient regimen for patients with HIT. Further prospective studies are needed before their use should be accepted as standard of care.  

Table 1. Patients with Heparin-Induced Thrombocytopenia Treated with Non-Warfarin Oral Anticoagulant

Patient	Heparin Induced Platelet Antibody (%)	Serotonin Release Assay (%)	Anticoagulant	Length of Therapy (in months)	Bleeding Complications	Thrombotic Complications	Current Plan
1	-	+ (93)	Apixaban	8	No	No	Continue
2	+ (110)	+ (100)	Apixaban	2*	No	No	Continue
3	+ (81)	+ (53)	Apixaban	13	No	No	Continue
4	-	+ (91)	Apixaban	9	No	No	Continue
5	+ (108)	+ (100)	Apixaban	16	No	No	Continue
6	-	+ (92)	Apixaban	6	No	No	Continue
7	+ (126)	+ (100)	Apixaban	2†	Gastrointestinal	No	Off since bleed
8	-	+ (30)	Rivaroxaban	1‡	Hemoptysis	No	Off since bleed
9	+ (107)	+ ( 77)	Apixaban	10	No	No	Continue
10	+ (89)	+ (44)	Apixaban	6	No	No	Continue
11	+ (106)	+ (67)	Rivaroxaban	18	No	No	Continue

*No evidence of thrombosis at diagnosis, only thrombocytopenia

†severe bleeding from known gastric varices; also on clopidogrel for CAD

‡moderate hemoptysis secondary to known squamous cell lung cancer