Heparin Induced Thrombocytopenia (HIT-Type 2) by: Tom Pizzoferrato, PharmD

Heparin-Induced Thrombocytopenia Learning Objectives Understand the etiology and pathogenesis of Heparin-Induced Thrombocytopenia Be able to differentiate the two types of HIT; Type I and Type II. Recognize the signs and symptoms of Heparin-Induced Thrombocytopenia and institute appropriate treatment Gain the knowledge and skills necessary to assist physicians and nurses in starting Argatroban for a patient suspected for having HIT Type 2 Effectively monitor a patient on the IV Argatroban Protocol to achieve optimal outcomes Assist providers in transitioning to warfarin

Many OTHER Causes of Thrombocytopenia Pseudothrombocytopenia- plt. clumping Decreased Platelet (plt) Production - viral infections, HIV, congenital or acquired bone marrow aplasia or hypoplasia - Etoh toxicity - B12/ Folate deficiency * Increased Plt. Destruction - ITP - Drugs- heparin, quinine, quinidine, and valproic acid - DIC, Sepsis- common in ICU patients - TTP - HELLP syndrome (hemolytic anemia, elevated liver function tests, and low platelet count) in pregnant women - Mono, CMV Dilutional –Common w Blood products, IVF’s Spenic Sequestration

Types of HIT Type 1 HIT – common form of thrombocytopenia - no clinical consequence - slight fall in platelet count within the first two days after heparin (plt. >100,000) - returns to normal with continued heparin administration - nonimmune Type 2 HIT = heparin associated thrombocytopenia - less common - serious consequences- thrombosis and white clot ( arterial) - large fall in platelet count within 1-7 days after heparin (Plt < 100,000) - platelets rise in 6-8 days after all heparin/lmwh is dc’d - immune-mediated with Antibodies vs Plt-F4

HIT –Type 2 Antibody-mediated, adverse effect of heparin •Affects 1-4% of patients receiving heparin for at least 7 days –Higher rate for UFH –Lower for LMWH •Strong association with venous and arterial thrombosis (30-75% risk in untreated patients)

HIT- type 2 Clinical features Thrombocytopenia occurring after 5-7 days of heparin therapy, can occur sooner on re-exposure Platelet count nadir is between 20,000 and 150,000/ul, median 50,000/ul Bleeding is rare

Mechanisms of Type 2 HIT Heparin-PF4 complex binds to activated platelet surface and forms heparin-PF4-AB complex on the platelet surface [32,42]. The Fc portion of this bound IgG further activates other platelets and leads to more platelet activation with further release of PF4 Activated PLT-Hep-PF4-AB complex undergoes aggregation and are removed prematurely from the circulation leading to thrombocytopenia (HIT) Generation of procoagulant platelet-derived microparticles, frequently resulting in thrombin generation and thrombosis (HITT) The AB complex also activates microvascular endothelial cells, resulting in release of IL-6- von Willebrand factor can injure endothelium which promotes thrombosis [

missing data, onset after day 10, or fall <1 day, T Score System 2 points 1 point 0 point Thrombo- cytopenia Plt Ct fall > 50% and plt nadir > 20K Plt Ct fall 30-50% or nadir 10-19K Plt ct fall < 30% or nadir <10K Timing of Plt Ct Fall Onset between days 5-10 or < 1 day if prior hep exposure w/in 30 days Consistent w/ fall between days 5-10, but missing data, onset after day 10, or fall <1 day, hep exposure 30-100 days ago Plt ct fall < 4 days without recent exposure Thrombo-sis, of other sequelae New thrombosis, skin necrosis, acute systemic reaction, post IV UFH bolus Progressive or recurrent thrombosis, non necrotizing skin lesions, suspected clots, not proven None OTher causes for Thrombo-cytopenia T Score: Probability None apparent 6-8 pts- HIT Likely Possible 4-5- HIT Possible Definite 0-3- HIT Unlikely

Possible sequela from HIT (Heparin/LMWH Exposure) These may be indication of Developing HIT Type 2 Erythematous Plaques Heparin-Induced Skin Necrosis Venous Gangrene (extremities) Warkentin TE. Heparin Induced Thrombocytopenia, 2nd Ed. Marcel Dekker, Inc; New York 2001

HIT should be considered a clinico-pathologic syndrome HIT – Diagnosis HIT should be considered a clinico-pathologic syndrome •Diagnosis requires both a compatible clinical history and demonstration of HIT antibody seroconversion •Demonstration of a heparin dependent platelet antibody alone is insufficient * Use T score to help screen * The HIT tests should NOT be used for screening of asymptomatic patients prior to or during heparin exposure -Warkentin, 2005

Heparin Antibody Assays Platelet Aggregation- not useful 14C-Serotonin Release Assay (SRA) For confirmation Heparin-Induced Platelet Agglutination (HIPA) Heparin/PF4 ELISA- Initial screen

Test Advantages Disadvantages SRA=Serotonin Release Assay “ Gold Std.” For confirmation Sensitivity: high Specificity: high Rare false +’s Technically demanding, Not readily available- sent out- 4-7 days turnover Platelet Aggregation Plt-F 4 Ab Sensitivity: low Specificity: ? Technique-dependent Immunoassay=(ELISA) for Initial screen w T Score probability/clinical presentation Technically easy Faster turnaround time Specificity: low (false+ common for Faster turnaround time some PIFA® Rapid turnaround time Sensitivity: poor Specificity: poor not “quantifiable”

HIT The incidence of HIT is likely to increase as an aging patient population develops diseases and undergoes more complex procedures requiring heparin anticoagulation. Early recognition, thorough risk assessment and platelet count monitoring, and appropriate treatment of HIT are critical in reducing morbidity and mortality. The essence of appropriate treatment is: - Immediate discontinuation of all sources of heparin,(IV, subq, Heparin coated catheters & flushes and LMWH’s) and warfarin. - Initiation of alternative anticoagulant (even if no clinical thrombosis) - Do not delay treatment pending confirmation by laboratory tests.

Treatment Goals Based on Pathophysiology and Clinical Studies Interrupt the immune response - Discontinue heparin & flushes, LMWH Inhibit thrombin generation - Treat active thrombosis Prevent new thrombosis Minimize complications of HIT - Thromboses, limb amputation, death

Half-life in healthy subjects 39-51 min 1.3 hours 25 minutes Argatroban Lepirudin Bivalirudin Half-life in healthy subjects 39-51 min 1.3 hours 25 minutes Elimination Hepatic Renal 80% Enzymatic 20% Renal Monitoring needed aPTT, ACT aPTT Thrombin binding Reversible Irreversible Partially reversible Antidote Adapted from Chen JL. Heart Dis.2001;3:189-198. None Warkentin, TE, GreinacherA. Heparin-Induced Thrombocytopenia. 3rd ed. Revised and Expanded. 2004;:339-479.

Direct Thrombin Inhibitors: FDA Indications and Usage Argatroban - Preferred -Indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with HIT Type 2 - Indicated as an anticoagulant in patients with or at risk for HIT undergoing PCI – bivalirudin is used @ JDH *Lepirudin- not made, supplies to be exhausted in mid2013 - Indicated for anticoagulation in patients with HIT and associated thromboembolic disease to prevent further thromboembolic complications Bivalirudin - Indicated as an anticoagulant in patients undergoing percutaneoustransluminalcoronary angioplasty (PTCA)

Argatroban Indication: Treatment of Heparin Induced thrombocytopenia Dosing: Infusion Concentration 250 mg/ 250 mls NS= 1mg/1 ml= 1000 mcg/ml No initial bolus dose required. Criteria for Use: - Patient at intermediate to high risk for HIT Have MD’s follow existing protocol If you receive a request to vary from protocol 1st. Discuss w provider that the Hem/Onc team has agreed to protocol and no literature demonstrates that varying the Goal PTT is of benefit. If still an issue then 2. Call Clinical Coordinator to have discussion w provider

IV Argatroban- High Expense ( > $1,000/day) High Alert Med) Argatroban Initial dose: 2 mcg/kg/min for HIT Titrate to maintain aPTT 1.5-3 x pt’s baseline or 1.5-3 x mean of lab control range (27 sec). = Goal aPTT 40-70 secs Draw a PTT 2 hours after initiation of infusion x 2 and 2 hours after each dose change x 2 then follow the titrating chart below: Lab result Infusion Rate Change Next aPTT Ptt (sec) mcg/kg/min < 30 sec increase CI rate by 1 in 2 hr 30-40 sec increase CI rate by 0.5 in 2 hr 40-70 sec same rate in 2-4 hrs, if in range aPTT in am 71-90 sec decrease CI rate by 0.5 in 2 hrs > 90 sec decrease CI rate by 1 in 2 hrs Notes: Patients usually reach goal PTT between 1- 1.5 mcg/kg/min Max dose is 10 mcg/kg/min. No initial dose adjustment with renal impairment, in absence of factors requiring dose reduction as listed HIT. Hepatic elimination. Not renally cleared.

Warfarin Overlap with Argatroban Argatroban will significantly elevate PT/INR values. Follow warfarin dosing guideline below when determining adjustment of warfarin dosing. 1. Initiate warfarin only when the platelet count has substantially recovered to > 100,000 cells/mm 3 or greater. 2. Obtain a baseline PT/INR prior to starting the warfarin. Do not give a loading dose of warfarin 3. Initiate warfarin dose at a low, maintenance dose ( maximum of 5 mg unless patients was stable on prior doses > 5mg. 4. Adjust warfarin dose for approximate goal of INR 4-5 during the first 5 days of concomitant argatroban and warfarin therapy. 5. After 5 days of concomitant argatroban and warfarin therapy, decrease argatroban rate to 2 mcg/kg/min (if > 2 mcg/kg/min) and check INR: A. If INR ≥ 4, Discontinue argatroban and recheck INR in 6 hrs. a. If INR is 2-3 , restart argatroban at 2 mcg/kg/min (or original rate if <2 mcg/kg/min) and keep patient on same warfarin dose. Repeat process daily until INR off argatroban remains 2-3 for 2 consecutive days. Then discontinue argatroban b. If INR >3, restart argatroban and reduce warfarin dose. Repeat process daily until INR is within range for 2 consecutive days. Then discontinue argatroban. c. If INR <2, increase argatroban to original therapeutic rate and increase warfarin dose and repeat above process the next day

Argatroban Protocol B. If INR < 4, Return argatroban infusion to original therapeutic rate and increase warfarin dose. Check INR daily for 2 days. a. If after 2 days INR has not increased, increase warfarin dose and repeat process. b. If INR has increased but still < 4, repeat process at same warfarin dose until INR ≥ 4, then follow as in a above c. If new INR ≥ 4, follow as in a above MD/LIP Responsibility: Order labs: Baseline: PT, PTT, CBC with platelet count, Stool for blood, urinalysis Platelet count, Hematocrit q 2-3 days Nursing Responsibility: Requires RN/LPN verification double check on MAR. Infusion via Guardrails on Alaris Volumetric Infusion Pump Order f/u PTT’s and Monitor PTT Monitor bleeding symptoms, Pharmacist responsibilities: - Upon initial Order validation provide Argatroban written protocol for RN, Review w them - Assure DC of all heparin/lmwh sources - Double calc’s, monitor supplies and dispensing to minimize waste - Monitor daily & document in Siemans notes, PUP Com. sheet, shift report - Warfarin dose validation - Monitor for compliance with transition to warfarin - to references for transition to warfarin. Adjust dose for approximate goal of INR 4-5 during the first 5 days of concomitant argatroban and warfarin therapy.

ACCP Guidelines: HIT Do not use Vitamin K antagonists (\warfarin) until after the platelet count is > 150,000/ul And only during overlap with alternative anticoagulation Start VKA at lower dose (5-6 mg) Alternative anticoagulants should not be dc’d until platelet count has reached a stable plateau and with at least the last 2 days of INR within target therapeutic range

The End Proceed to Post Test