HIT: Heparin-induced Thrombocytopenia

West Coast University, School of Pharmacy Spring 2024 ¡ ¡ ¡ ¡ Jessica Louie, PharmD, APh, BCCCP Associate Professor, Pharmacy Practice West Coast University, School of Pharmacy Spring 2024 Describe the epidemiology and incidence of heparin-induced thrombocytopenia (HIT) Identify the criteria for diagnosis of HIT Differentiate advantages and disadvantages of pharmacologic treatment options for HIT Select an appropriate treatment plan for a patient who develops HIT consistent with clinical presentation and current practice guidelines 1 2 Recommended: § DiPiro et al. (2023) Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw-Hill. eChapter 125: Drug Induced Hematologic Disorders. Guidelines: ¡ Cuker A, Gowthami M, et al. American Society of Hematology 2018 guidelines for the management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Advances;2(22):33603392. ¡ Linkins L, Dans A, et al. Treatment and Prevention of heparininduced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th edition: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2):495s-530s. Epidemiology/Incidence Objective: Describe the epidemiology and incidence of HIT 3 Jessica Louie, PharmD, APh, BCCCP 4 1 West Coast University, School of Pharmacy Spring 2024 HIT = heparin-induced thrombocytopenia ¡ Heparin: any type of heparin at any dose and any route of administration (IV, SQ) ¡ Heparin exposure in US annually ® 12+ million patients ¡ 1% or ~120,000 develop HIT ¡ HIT is frequently misdiagnosed § Heparin products often used for prevention or treatment of thrombus (clot) in surgeries, acute coronary syndromes (MI), atrial fibrillation (Afib), dialysis, etc. § Unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) ¡ ¯ Platelets Thrombocytopenia: abnormally low amount of platelets § Platelets: help blood to clot ¡ Potentially life-threatening acquired hypercoagulability syndrome, with or without thrombotic complications 5 u Bovine > Porcine heparin 3 UFH > LMWH r¡ Platelet Factor 4 (PF4) z Surgical > Medical pts § Basic protein § Stored in platelet alpha-granules a Female > § Expressed on surface during activation Male HIT 2 ¡ Heparin s Exposure to heparin products for >5 days § Negative charge § High affinity for PF4 7 Jessica Louie, PharmD, APh, BCCCP 6 j 8 2 West Coast University, School of Pharmacy Spring 2024 9 ¡ Citation: Chapter e121 Drug-Induced Hematologic Disorders, DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. Pharmacotherapy: A Pathophysiologic Approach, 11e; 2020. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577§ionid=235639814 Accessed: January 26, 2022 Copyright © 2022 McGraw-Hill Education. All rights reserved 10 Thrombotic events: 30x > control population! Venous • Predominate 4x > arterial thrombosis in surgical patients • DVT/PE • Adrenal hemorrhagic necrosis (adrenal vein thrombosis) ¡ ¡ Arterial • Predominates in patients with cardiovascular disease • MI • Stroke (thrombotic) • Limb artery occlusion requiring amputation Diagnosis Objective: Identify the criteria for diagnosis of HIT Necrotizing skin lesions at heparin injection sites Mortality rate: 8-20% 11 Jessica Louie, PharmD, APh, BCCCP 12 3 West Coast University, School of Pharmacy Spring 2024 common Amore Type I b Type II Frequency 10-20% 1-3% Timing of onset 1-4 days 5-10 days Nadir platelet count 100,000/uL >20,000/uL Median 60,000/uL Heparin (re) Exposure Typical HIT Rapid-onset HIT (hours-days) Antibody mediated No Yes Thromboembolic sequelae None 30-80% Hemorrhagic sequelae None Rare Management Observe CONTINUE heparin STOP heparin Start non-heparin alternative to prevent thrombosis Day 1 Mean day 9 (4-14 days) Day 4 Delayed HIT (9-40 days) Day 14 Day 30 13 14 g It 2 points Thrombocytopenia • >50% ¯ plt count & nadir >20 with no surgery w/in prior 3 days Thrombosis 3 whereat happen oTher causes Category 0 points • <30% ¯ plt count • Nadir <10 • 5-10 days • £1 day if exposed to heparin w/in past 5-30 days • Onset unclear • >10 days or <1 day if exposed to heparin 31100 days ago • £ 4 days w/o heparin exposure in last 100 days • New thrombosis • Skin necrosis at IV site • Anaphylactic rxn after IV heparin bolus • Adrenal hemorrhage • Progressive or recurrent thrombosis • Erythematous skin lesions • Suspected thrombosis not proven • Thrombosis suspected • No other cause evident • Possible other cause evident • Probable other cause is present countppets Timing (of plt fall or thrombosis) 1 point • 30-50% ¯ plt count • >50% ¯ plt count WITH surgery w/in prior 3 days • Nadir 10-19 Link: http://www.qxmd.com/calculate-online/hematology/hit-heparin-induced-thrombocytopenia-probability Jessica Louie, PharmD, APh, BCCCP Immunoassays • Detect circulating PF4/heparin antibodies, irrespective of their capacity to activate cells Functional assays High Score 6-8 points; Intermediate Score 4-5 points; Low Score £3 points 15 Principles • Detect antibodies that activate cells in a heparindependent manner Examples Advantages Disadvantages • Polyspecific ELISA • IgG-specific ELISA • High sensitivity • Simple to perform • Widely available • Limited specificity • Serotonin release assay (SRA) • Heparin-induced platelet activation (HIPA) • High sensitivity • High specificity • Technically difficult • Limited availability s I I 16 4 West Coast University, School of Pharmacy ¡ Spring 2024 Functional Use of Assays § GOLD STANDARD = SRA & HIPA Clinical Assessment (4Ts Score) ▪ Not available at all centers due to technical difficulty and cost (heparin-induced thrombocytopenia Abs phantasmELISA PF4) + § ▪ Most centers use these ▪ Primary drawback = over-diagnosis potential Laboratory Evaluation + Clinical Condition ▪ Detecting antibodies that are NOT pathologic sew Adapted from Review 2013 and Pouplard et al. Nellen et al. 17 Thrombocytopenia in patient receiving heparin product ¡ 4T Score or HEP Score High clinical suspicion (4T: 6-8) D/C Heparin Start alternative therapy ELISA (-): HIT Unlikely D/C Heparin Start alternative therapy ELISA (+): HIT likely. Confirm with SRA (4T: £3) Order ELISA w/reflex to SRA ELISA (-): HIT Unlikely (ELISA) Low clinical suspicion C. ELISA with reflux to SRA D. None of the above Continue heparin ELISA (+): HIT possible. Confirm with SRA Ifit.snEiFioadisgntinouseaue heminprojects Jessica Louie, PharmD, APh, BCCCP What is the optimal test to order for our patient KL? A. SRA, unfractionated heparin B. Heparin-induced thrombocytopenia Abs PF4 Intermediate (4T: 4-5) Order ELISA w/reflex to SRA 18 19 20 5 West Coast University, School of Pharmacy ¡ Spring 2024 A patient with Type I HIT can continue on heparin. A. True B. False Management Objective: Differentiate advantages and disadvantages of pharmacologic treatment options for HIT 22 21 Fyi Characteristic ¡ WHY treat? clotting § Minimize complications of HIT including thrombosis, x¡ HOW does treatment work? morbidity and mortality Ed § Interrupt immune response ▪ Immediately discontinue heparin use AND § Inhibits thrombin effects ▪ Stabilize hypercoagulable state ▪ Treat active thrombosis ▪ Prevent new thrombosis Argatroban Lepirudin Bivalirudin Fondaparinux Target Thrombin Thrombin Thrombin Factor Xa Half-life 40-50 min 80 min 25 min 17-20 hours Elimination Hepatobiliary Renal Enzymatic (80%) Renal (20%) Renal FDA approved for HIT Treatment/PCI Treatment PCI/Cardiac surgery No Route IV IV/SQ IV SQ Monitoring aPTT or ACT aPTT or ECT (high doses) aPTT or ACT/ECT (high doses) Anti-Xa level Effect on INR +++ + ++ 0 Immunologic features None 40-60% lepirudin Ab Potentially cross-reactive with anti-lepirudin Ab May produce heparin anti-PF4 antibodies Antidote available No No No No Crosses placenta Unclear Unclear Unclear Yes (Category B) Dialyzable 20% High-flux 25% 20% 23 24 notable inus Jessica Louie, PharmD, APh, BCCCP 6 West Coast University, School of Pharmacy Spring 2024 Agyjjostcommoninongeporin agoeetolioor Advantages Product Labeling ¡ Dosing: § 2 mcg/kg/min 2 § No initial bolus 3 § Hepatic adjustment: 0.5 mcg/kg/min ▪ May need to start lower than this rate in clinical practice n § Adjust to achieve aPTTs 1.5-3x baseline value Disadvantages • FDA approved for all forms of HIT • No antidote or reversal agent (not only PCI) • Effects INR, making transition to • Hepatically cleared; can be used warfarin more difficult in renal dysfunction • IV only • Longer half-life compared to bivalirudin (80 min vs. 25 min) • No immunologic effects • Premix vial reducing compounding time ▪ Check 2 hours after initiation and then q4-6 hours until therapeutic then q24 hours* 25 26 quiffs I Od gongtosedinptwiserenally Advantages Product Labeling (Angiomax®) ¡ Dosing: • Inhibits both circulating and clotbound thrombin • Short-acting • Half-life: 25 minutes • Normal coagulation w/in 60 minutes of discontinuation • Possibly less expensive than argatroban § Bolus 0.75 mg/kg immediately before PCI § Additional bolus 0.3 mg/kg if ACT <225 seconds 5 minutes after bolus dose § Infusion 1.75 mg/kg/hour during procedure & up T Disadvantages • No antidote or reversal agent • Cross-reactivity to anti-lepirudin antibodies • Effects INR, making transition to warfarin more difficult • Not FDA-approved for HIT in absence of PCI • Renally cleared to 4 hours post-procedure if needed § After 4 hours, may continue infusion at 0.2 mg/kg/hour up to 20 hours 27 Jessica Louie, PharmD, APh, BCCCP 28 7 West Coast University, School of Pharmacy havesaggy reraldysatiy use it Spring 2024 aint Product Labeling (Arixtra®) ¡ Dosing: Advantages • Does not cause HIT • Induces formation of antibodies reactive to heparin-PF4 at comparable rate to LMWH • However, fondaparinuxinduced antibodies do not promote HIT • Prefilled syringes that can be used in outpatient setting • No effect on INR; makes transition to warfarin easier § NOT FDA approved for HIT § DVT prophylaxis: 2.5 mg SQ once daily § DVT/PE treatment or acute thrombosis: ▪ <50 kg: 5 mg SQ once daily ▪ 50-100 kg: 7.5 mg SQ once daily ▪ >100 kg: 10 mg SQ once daily § Renal adjustment ▪ CrCl 30-50 mL/min: 50% reduction in dose ▪ CrCl <30 mL/min: contraindicated § Monitoring ▪ Thromboprophylaxis: 3 hours post dose; anti-Xa 0.4-0.5 mg/L ▪ Therapeutic: 3 hours post dose; anti-Xa 1.2 mg/L Disadvantages • No antidote or reversal agent • Does not inhibit circulating thrombin • Long half-life (17-20 hours) • Contraindicated if CrCl <30 mL/min 29 ¡ Consider transition to vitamin-K antagonist (i.e. warfarin) for long-term anticoagulation 30 ¡ DOAC – dabigatran, rivaroxaban, apixaban suggests treatment with these agents are reasonable compared to warfarin ¡ The same contraindications to their use for VTE apply to these HIT patients § HIT-related thrombosis is considered a reversible provoking risk factor § Treat for a minimum of 3 months for HIT-related thrombosis § Treat for a minimum of 4 weeks for HIT without thrombosis 31 Jessica Louie, PharmD, APh, BCCCP 32 8 West Coast University, School of Pharmacy ¡ Spring 2024 Transitioning to Warfarin from Argatroban Start warfarin & continue argatroban Start warfarin & continue bivalirudin Day 4 of warfarin, if INR >4 hold argatroban for 6 hours O Discontinue argatroban if: aPTT at baseline + INR at goal Check aPTT & INR at end of 6-hour period Resume argatroban + consider increasing warfarin if: aPTT at baseline + INR < goal I Hold argatroban + recheck aPTT & INR in 4-6 hours if: aPTT is > baseline ¡ Day 4 of warfarin, if INR >4 hold bivalirudin for 6 hours Discontinue bivalirudin if: INR at goal Check aPTT & INR at end of 6-hour period Resume bivalirudin + consider increasing warfarin if: INR < goal 33 HIT antibody days Can you give a patient who had confirmed HIT 1-year ago heparin again? A. Yes B. No Can theoretically give heparin again for <4 days 35 Jessica Louie, PharmD, APh, BCCCP 34 ¡ § Transient, Median time to disappearance is 50-80 ¡ Transitioning to Warfarin from Bivalirudin ¡ 36 9 West Coast University, School of Pharmacy ¡ ¡ ¡ ¡ ¡ Spring 2024 HIT is a potentially life-threatening acquired hypercoagulability syndrome, with or without thrombotic complications HIT with thrombosis is rare but early recognition is key to diagnosis 4T scores can assist with assessing HIT likelihood Immunoassay (ELISA) and functional assays (SRA) are used to confirm diagnosis Argatroban, Bivalirudin, and Fondaparinux are management options in the US Lee G, Arepally G. Heparin-induced thrombocytopenia. American society of hematology 2013; 668-74. Jang IK, Hursting M. When heparins promote thrombosis: review of heparin-induced thrombocytopenia. Circulation 2005;111:2671-2683. 3. Levy J, Hursting M. Heparin-induced thrombocytopenia, a prothrombotic disease. Hematology/Oncology clinics of North America 2007;21(1):65-88. 4. Warkentin TE, Sheppard JA, et al. Gender imbalance and risk factor interactions in heparininduced thrombocytopenia. Blood. 2006;108(9):2937. 5. Warkentin TE, Eikelboom JW. Who is (still) getting HIT? Chest. 2007;131(6):1620. 6. Stein PD, Hull RD, et al. Incidence of thrombocytopenia in hospitalized patients with venous thromboembolism. Am J Med. 2009;122(10):919. 7. Lubenow N, Hinz P, et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood. 2010;115(9):1797. 8. Arepally G, Ortel T. Heparin-induced thrombocytopenia. New England Journal of Medicine 2006;355(8):809-817. 9. Links L, Dans A, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012;141(2):495s-530s. 10. Brieger DB, Mak KH et al. Heparin-induced thrombocytopenia. J American college of cardiology 1998; 31:1449. 1. 2. 37 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Thank you for your attention Lo G, Juhl D, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparininduced thrombocytopenia in two clinical setting. Journal of thrombosis and haemostasis 2006;4(4):759-65. Cuker G, Arepally M, et al. The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. Journal of thrombosis and haemostasis 2010;8(2):2642-50. Li X, Hunt L, et al. Drug-induced thrombocytopenia: an updated systematic review. Ann Intern Med 2005;142(6):474-5. Cuker A. Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: an integrated approach. Seminars in thrombosis and hemostasis 2013. DOI 10.1055/s-0033-1363461. Warkentin T, Greinacher A, et al. Treatment and prevention of heparin-induced thrombocytopenia: American college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133(6):340s-380s. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc. Accessed January 13, 2014. Argatroban [package insert]. Princeton, NJ: Sandoz Pharmaceuticals Inc; 2012. Angiomax [package insert]. Parsippany, NJ: The Medicines Company; 2013. Bivalirudin and Argatroban Physician Orders. Charleson, South Carolina. Revised March 2008. Bivalirudin Continuous Infusion Orders. Seattle, Washington. Revised December 2009. Arixtra [package insert]. France: GlaxoSmithKline, 2011. ANY QUESTIONS??? 39 Jessica Louie, PharmD, APh, BCCCP 38 Jessica Louie, PharmD, APh, BCCCP jLouie@westcoastuniversity.edu 40 10