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Clinical Dilemmas: Case of Heparin Allergy In a Neurointerventional Procedure

Shobana Rajan, MD; Gargi Banerjee, MD; Rafi Avitsian, MD
Cleveland Clinic Department of General Anesthesia

INTRODUCTION
Neurointerventional procedures mandate use of anticoagulants and manipulation and control of bleeding and clotting within a precariously narrow range. Recently there has been a prolific market of coagulants and anticoagulants which seem to be still expanding as is our sophistication and expertise of facing such challenges. We recently encountered a patient with allergy to Heparin, one of our most valuable and routinely used anticoagulants.

CASE MANAGEMENT
An elderly 62-year-old female with past medical history of smoking was scheduled for a Pipeline Embolization of RICA (right internal carotid artery aneurysm). She initially presented with headache and dizziness and an MRA with unruptured cerebral aneurysm. Her past medical history included a documented episode of Heparin induced thrombocytopenia wherein her platelet count had dropped to 54 on administration of heparin during a previous hospitalization.

Since heparin administration seemed hazardous in this patient, we were considering alternative anti-coagulants. Since bivaluridin seemed the next logical choice, we decided to choose it. Our next concern was drug dosing and activated clotting time monitoring. Bivalirudin has been studied extensively by cardiologists performing percutaneous coronary interventions and its use over heparin in those cases has been greatly encouraged due to the shorter half-life, the more predictable ACT values and the reduced incidence of peri procedural ischemic complications when compared to heparin.1 Yet, this data failed to reassure us since not many studies reported the use of bivalirudin in neuro-interventional procedures.

Target ACT values remains a matter of debate (it was required to be in the range of 170-200 during our procedure). Current data suggest ACT values to be more predictable with bivalirudin, but presently there is no consensus regarding the optimal dosing of the drug in neuro-interventional procedures. Another major obstacle was the lack of reversibility of bivalirudin. An infusion of bivalirudin at 1.5 mg/kg/hr was started and adjusted to maintain a target ACT of 170-200. Despite the short half-life of bivaluridin (25 minutes), we could at any moment find ourselves in a situation where very rapid reversal of anticoagulation could be paramount. To our relief, we did not encounter any hemorrhagic complications throughout the procedure and the post-op period remained uneventful. Platelet counts were unaltered by the use of bivalirudin.

DISCUSSION
Heparin-induced thrombocytopenia (HIT) is not an uncommon adverse reaction. Up to 8% of patients receiving heparin are at risk of developing HIT antibodies,2 but only 1–5% on heparin will progress to develop HIT with thrombocytopenia3 and subsequently one-third of them may suffer from arterial and/or venous thrombosis.4 It is believed to be the most common cause of drug-induced thrombocytopenia. A HIT diagnosis, particularly HIT 2, which is characterized with more than 50% reduction in platelet count on heparin administration and HITT (heparin induced thrombocytopenia thrombosis) which are both more severe than HIT 1, preclude the use of heparin.

We were thus faced with a number of clinical questions:

  1. What anticoagulant to use in place of heparin?
  2. How to monitor the anticoagulation? Is ACT effective or do we need to do some other testing?
  3. What dosage should we use?
  4. How do we reverse in a situation of emergency?

Other important questions are:

  1. Was the patient’s episode of thrombocytopenia heparin induced?
  2. Has it been documented by PF4(platelet factor) antibodies?
  3. Should we postpone the case to get PF4 antibodies done? There was no record of a PF4 antibody in this patient on chart review. Even if we did do a PF4 antibody at this point, is it safe to give heparin in a patient about to undergo coiling? After considering all the above questions, we decided to go with heparin alternatives and get the case done.

Our choices were non-heparin alternatives which included the direct thrombin inhibitors: Lepirudin, Argatroban, Bivalirudin, Danaparoid and Fondaparinux. Lepirudin, a recombinant form of hirudin derived from leech saliva, has a long half-life and irreversible binding. Argatroban, a synthetic direct thrombin inhibitor also binds irreversibly and has a long half-life. Fondaparinux, a pentasaccharide anticoagulant, despite its structural similarity to heparin and its negative charge does not usually promote antibody binding to PF4; however, the risk of de novo HIT or exacerbating HIT when the antibodies are already present is not zero. These alternatives to Heparin as a choice of drug in HIT have therefore fallen out of favor. Bivalirudin, on the other hand, offers promise by virtue of its short half-life of 25 minutes versus 90 minutes in the case of Heparin. We thus decided to use Bivalirudin during the stent placement.

The use of this alternative to heparin in cases of HIT for neurovascular procedures is still encumbered by a number of clinical dilemmas. At present, we do not have a safe protocol for the use of this drug. Drug dosing and monitoring cannot simply be extrapolated from the studies conducted with percutaneous coronary interventions since the demands of anticoagulation in neurovascular surgery are different and more exacting. The need for strict control of ACT within a narrow range demands a more tailored regime. Lastly, and most disturbing, is the lack of reversibility and immediate termination of action which poses a great threat to our control of coagulation parameters with a desired range. Bivalirudin, despite these shortcomings, is the only suitable anticoagulant alternative to Heparin in a patient with HIT. This lacuna in our armamentarium calls for definite guidelines for the use of Bivalirudin and in future, novel drugs with reversibility of anticoagulation.

References:

  1. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. The New England Journal of Medicine. 1995; 333:764–9.
  2. Warkentin T E, Levine M N, Hirsh J. et al Heparin‐induced thrombocytopenia in patients treated with low‐molecular‐weight heparin or unfractionated heparin. N Engl J Med 19953321330–1335. 
  3. Kelton JG: Heparin‐induced thrombocytopenia: an overview Blood Rev. 2002; 16:77–80.
  4. Nand S, Wong W, Yuen B. et al Heparin‐induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol 19975612–16.

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