Heparin Induced Thrombocytopenia

Simultaneous bleeding and clotting risks from an immune-mediated drug reaction

Melissa Whitehouse PharmD Candidate 8/9/2013

Patient case

Patient case
History of present illness
YS is a 64 yo white male 6/18/2013: Acute pain and weakness in left lower extremity. Thought to be critical limb ischemia and transferred to IMC on heparin. Acute left lower extremity ischemia 6/18/13 Attempted femoral thromboembolectomy 6/18/13 Above knee amputation 6/25/13 Active HepC with high viral load Liver mass

Patient case
Past medical history
PUD with ulcer perforation in 2011 MI requiring CABG left ventricular thrombus
Warrants lifelong anticoagulation Developed GI bleed and discontinued warfarin

Diabetes mellitus type two Hypertension Hyperlipidemia Chronic back pain d/t degenerative spine disease

Social history
Heavy drinker: multiple glasses of hard alcohol daily Active smoker

Patient case

Labs
94 kg SCr: normal to low CrCl: 117 ml/min Hepatitis C Ab: + Viral load: 4.8x106 Creatinine kinase: 9000 range

Date 7/1 7/2 7/3 7/4 7/5 7/6 7/8 7/9 7/10 7/11 7/12 7/13

Platelet Count 346 332 313 322 297 285 183 107 120 131 161 194

Date 6/18 6/20 6/21 6/23 6/27 7/9 7/10

Alb
3.34.8

ALT
1261

AST
1650

3.3 2.3 2.3 2.7 3.3 2.9 3.1

138 168 151 82 71 104 101

520 740 464 105 84 93 82

Patient case

Heparin induced thrombocytopenia (HIT) diagnosed on 7/9/13 Bilateral upper limb DVTs 7/4/13

Learning outcomes
Name the patient populations at higher risk for developing HIT Describe the pathophysiology and structures involved in the immune response to heparin Identify and utilize the tests used to diagnose HIT Choose an appropriate HIT treatment based on patientspecific factors

HIT Pathophysiology
HIT is an adverse immunemediated drug reaction that is associated with a high risk of venous and arterial thrombosis. CHEST 9th edition HIT guidelines

http://bloodjournal.hematologylibrary.org/content/117/7/2083/F1.large.jpg

HIT risks and epidemiology

Duration and type of heparin Women Surgical > medical patients
Postop patients Heparin ppx Heparin tx Heparin flush LMWH ppx/tx Cardiac surgery Incidence (%) 15 15 0.11 0.11 13 Medical patients Cancer patients Heparin ppx/tx LMWH ppx/tx ICU patients Heparin flush Obstetrics patients Incidence (%) 1 0.11 0.6 0.4 <0.1 <0.1
Linkins LA, et al. Chest 2012; 141:e495S

Clinical presentation of HIT Thrombocytopenia

Platelet count < 150 x 109

Venous thrombosis Venous limb gangrene Necrotizing skin lesions at injection site
Linkins LA, et al. Chest 2012; 141:e495S

Clinical presentation of HIT Adrenal hemorrhagic necrosis Acute systemic reaction with 30 minutes of bolus Petechiae or other bleeding

Diagnosis
The 4Ts score (see handout)
Poor sensitivity High specificity

Enzymelinked immunosorbent assay (ELISA)

Tests for antibodies reactive against PF4 Very sensitive Moderate specificity Done if moderate or high 4Ts score

Seratonin release assay (SRA)

Detect only antibodies capable of activating platelets Specific and sensitive Done only if positive ELISA
Linkins LA, et al. Chest 2012; 141:e495S Lo GK, et al.J Thromb Haemost. 2006;4(4):759

Case presentation revisited

Lets calculate the 4T score for YS:
346107= 239 239/346= .69 69% decrease = 2 points Platelet fall after day 10 = 1 point Confirmed new thrombosis (upper DVT)= 2 points No alternative= 2 points = 7 high probability

Case presentation revisited

ELISA:
OD > 1.0, strong evidence positive for HIT antibody

http://www.uptodate.com/contents/image?imageKey=HEME%2F70437&topicKey=HEME%2F1369&rank=1%7E1 50&source=see_link&search=heparin+induced+thrombocytopenia&utdPopup=true

Management of HIT

Management of HIT
For patients with HIT complicated by thrombosis (HITT):
Discontinue all heparin products Recommend the use of nonheparin anticoagulants over use of low molecular weight heparin (LMWH) or initiation/continue VKA
Argatroban, lepirudin or danaparoid over others

Start VKA only after platelets > 150 and at max dose of 5 mg daily with minimum 5 days overlap and INR therapeutic
INR affected by some agents

Safety of platelet transfusions not defined

Linkins LA, et al. Chest 2012; 141:e495S

Management of HIT
Lepirudin Argatroban Danaparoid Bivalirudin Fondaparinux Target T 1/2 Elimination Approved? Route Monitoring INR effect Cross reactive? Reversal? No No Thrombin 80 min Renal Treatment IV, SQ aPTT + Thrombin 4050 min Hepatic
Treatment /PCI

Xa 24 hours Renal Treatment IV, SQ Anti Xa level

Thrombin 25 min Enzymatic (80%) Renal (20%) PCI/surgery IV aPTT ++

Xa 1720 hours Renal No SC AntiXa level

IV aPTT +++

5% cross reactive No No

May cause HIT No

Linkins LA, et al. Chest 2012; 141:e495S

ManagementofHIT
Whatpatientspecificdetailsaffectour decisiononanticoagulant?
Liverfunction! Notcoveredintheguidelines:
Drugavailability Cost Monitoringparameters

Whichonewouldyoupick?

ManagementofHIT
Lepirudin Argatroban Danaparoid Bivalirudin Fondaparinux Target T1/2 Elimination Approved? Route Monitoring INReffect Cross reactive? Reversal? No No Thrombin 80min Renal Treatment IV,SQ aPTT + Thrombin 4050min Hepatic
Treatment/PCI

Xa 24 hours Renal Treatment IV,SQ Anti Xa level

Thrombin 25min Enzymatic (80%) Renal(20%) PCI/surgery IV aPTT ++

Xa 1720hours Renal No SC AntiXa level

IV aPTT +++

5%cross reactive No No

MaycauseHIT No

Patientcase
Bridgetherapyto warfarin
IfINRis>3,hold bivalirudin and checkagain
Date INR Warfarin Bridging Dose Therapy 5mg 5mg 5mg 2.5mg 2.5mg 5mg 5mg 2.5mg 5mg 5mg Bivalirudin gtt Bivalirudingtt Bivalirudingtt Bivalirudin gtt hold Bivalirudin D/CBivalirudin 7/12/13 1.7 7/13/13 1.7 7/14/13 2.0 7/15/13 2.7 4.0on 7/16/13 2.2off 7/17/13 2.1 7/18/13 2.3 7/19/13 2.8 7/20/13 2.6 7/21/13 2.6

Patientcase
Initiationofwarfarin
Rememberyoumustwaituntilplatelets returntonormal.Didthey?
Yes,warfarinstarted7/12afterCBCshowed normalplatelets

Whateffectsdidthebivalirudin have ontheINR?

Patientcase
Warfarinteaching
Recall:patientstoppedwarfarinafterGIbleedand INRof11 Patientreportsheavyalcoholuse Patientissmokerof30+years Lowhealthliteracy Nowunderstandslifelongnecessityforwarfarin

WhatbecameofYS?
YSwasdischargedon8/2toaskillednursing facilitywithhopesofreturninghome,still adjustingtolifewithAKAandnewHepC diagnosis

Insummary
HITisanimmunemediateddrugreaction Theincreasedriskforclotsismorecommon thanthebleedingrisk Anticoagulationtherapyshouldbechosen basedonpatientspecificfactorsfromnon heparinanticoagulants

Questions?

References
Linkins LA,Dans AL,Moores LK,etal.Treatmentandpreventionofheparininduced thrombocytopenia:AntithromboticTherapyandPreventionofThrombosis,9thed: AmericanCollegeofChestPhysiciansEvidenceBasedClinicalPracticeGuidelines.Chest 2012Feb;141(2Suppl):e495S530S WarkentinTE,LevineMN,HirshJ,etal.Heparininducedthrombocytopeniainpatients treatedwithlowmolecularweight heparinorunfractionatedheparin.N Engl J Med .1995;332(20):1330 1335. Warkentin TE,SheppardJA,Sigouin CS,Kohlmann T,Eichler P,Greinacher A.Gender imbalanceandriskfactorinteractionsinheparininducedthrombocytopenia.Blood .2006;108(9):2937 2941. LoGK,Juhl D,Warkentin TE,Sigouin CS,Eichler P,Greinacher A.Evaluationofpretest clinicalscore(4T's)forthediagnosisofheparininducedthrombocytopeniaintwo clinicalsettings. JThromb Haemost.2006;4(4):759 Brieger DB,etal.Heparininducedthrombocytopenia.JAmColl Cardiol 1998;31:1449 59 KiserTH,FishDN.Evaluation ofbivalirudin treatmentforheparininduced thrombocytopeniaincriticallyillpatientswithhepaticand/orrenaldysfunction. Pharmacotherapy. 2006Apr;26(4):45260.