heparin-induced thrombocytopenia (hit): pathophysiology, clinical implications, therapy, and cases...

Heparin-Induced ThrombocytopeniaHeparin-Induced Thrombocytopenia(HIT): Pathophysiology, Clinical (HIT): Pathophysiology, Clinical Implications, Therapy, and CasesImplications, Therapy, and Cases

Jerrold H Levy, MDJerrold H Levy, MDEmory University School of MedicineEmory University School of Medicine

Atlanta, GeorgiaAtlanta, Georgia

ARG266R0

HITHIT Immune-mediated allergic reaction to heparin/platelet Immune-mediated allergic reaction to heparin/platelet

factor 4 complexfactor 4 complex

Thrombocytopenia Thrombocytopenia – Platelet count <150,000 thrombocytes/mcL or a 30% to 50% Platelet count <150,000 thrombocytes/mcL or a 30% to 50%

drop from baseline during heparin exposuredrop from baseline during heparin exposure– Onset 5 to 14 days after initiating heparin but can be earlier or Onset 5 to 14 days after initiating heparin but can be earlier or

laterlater

With or without thrombotic complications at With or without thrombotic complications at presentationpresentation

Diagnosis is clinicalDiagnosis is clinical

Any type of heparin or route of administration can Any type of heparin or route of administration can lead to HITlead to HIT

Kelton. Kelton. Semin Hematol.Semin Hematol. 1999;36(suppl 1):17-21; Matthai. 1999;36(suppl 1):17-21; Matthai. Semin Thromb HemostSemin Thromb Hemost. . 1999;25(suppl 1):57-60; Rice et al. 1999;25(suppl 1):57-60; Rice et al. Ann Intern MedAnn Intern Med. 2002;136(3):210-215. Greinacher et al. . 2002;136(3):210-215. Greinacher et al. Thrombosis ResearchThrombosis Research. 2005 In Press.. 2005 In Press.

Incidence of HITIncidence of HIT

HIT occurs in up to 5% of patients HIT occurs in up to 5% of patients receiving unfractionated heparin receiving unfractionated heparin (UFH) (UFH)

Up to 1% incidence with low molecular Up to 1% incidence with low molecular weight heparin (LMWH)weight heparin (LMWH)

Gruel et al. Gruel et al. Br J HaematolBr J Haematol. 2003;121;786-792;. 2003;121;786-792; Warkentin. Warkentin. J Crit IllnessJ Crit Illness. 2005:20(1):6-13.. 2005:20(1):6-13.

Consequences of HITConsequences of HIT

Thrombotic complicationsThrombotic complications– Amputation: ~20%Amputation: ~20%

– Death: ~30% to 50%Death: ~30% to 50%

If left untreated, the overall risk of If left untreated, the overall risk of thrombosis is 38% to 76% in HIT patients thrombosis is 38% to 76% in HIT patients based on 3 studies (n=425)based on 3 studies (n=425)

Based on increased morbidity and mortality, Based on increased morbidity and mortality, heparin cessation alone is inadequateheparin cessation alone is inadequate

Hirsh et al. Hirsh et al. Arch Intern MedArch Intern Med. 2004;164:361-369;. 2004;164:361-369; Warkentin. Warkentin. Semin HematolSemin Hematol. 1998;35. 1998;35(suppl 5):9-16.(suppl 5):9-16.

Heparin-Induced Skin NecrosisHeparin-Induced Skin Necrosis

Warkentin. Warkentin. Br J HaematolBr J Haematol. 1996;92:494-497.. 1996;92:494-497.

Skin Manifestations of HITSkin Manifestations of HIT

Erythematous Plaques

Warkentin TE. Heparin Induced Thrombocytopenia, 2nd Ed. Marcel Dekker, Inc; New York 2001.

Venous GangreneVenous Gangrene

Warkentin, Elavathil, Hayward et al. Ann Intern Med. 1997;127:804-812.

Warkentin and Kelton. Warkentin and Kelton. Am J Med.Am J Med. 1996;101:502-507. 1996;101:502-507.

Days after isolated HIT recognized Days after isolated HIT recognized

Cumulative Frequency of ThrombosisCumulative Frequency of Thrombosis

52.8%52.8%

00 44 66 1010 1212 1414 161688 1818 2222 2626 2828 303024242020

Cu

mu

lati

ve f

req

ue

ncy

of

Cu

mu

lati

ve f

req

ue

ncy

of

thro

mb

os

is (

%)

thro

mb

os

is (

%)

2200

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

N=62

Consequences of HIT Consequences of HIT

38% to 52% of HIT patients managed by 38% to 52% of HIT patients managed by heparin cessation alone developed heparin cessation alone developed thrombotic complications, including DVT, thrombotic complications, including DVT, PE, stroke, or MI within 1 monthPE, stroke, or MI within 1 month

Since thrombotic events have been observed Since thrombotic events have been observed even after cessation of heparin exposure, even after cessation of heparin exposure, early recognition and initiation of appropriate early recognition and initiation of appropriate therapy are essential steps in managementtherapy are essential steps in management

Levine et al. Levine et al. Ann Emer MedAnn Emer Med. 2004;44:511-515. 2004;44:511-515. . Adapted from Parker. Adapted from Parker. J Crit Ill. J Crit Ill. 2005’20(3):64-71.2005’20(3):64-71.

Consequences of HIT Consequences of HIT

Mortality rate of 22% to 28% has been Mortality rate of 22% to 28% has been reported in patients with HIT associated with reported in patients with HIT associated with thrombosis not treated with alternative thrombosis not treated with alternative anticoagulation.anticoagulation.

Levine et al. Levine et al. Ann Emer Med. Ann Emer Med. 2004;44:511-515.2004;44:511-515.

HIT Patients Presenting with ThrombosisHIT Patients Presenting with Thrombosis Deep venous thrombosis (50%)Deep venous thrombosis (50%)

Pulmonary embolism (25%) Pulmonary embolism (25%)

Skin lesions at injection site (10% to 20%)Skin lesions at injection site (10% to 20%)

Acute limb ischemia (5% to 10%)Acute limb ischemia (5% to 10%)

Warfarin-associated venous limb gangrene Warfarin-associated venous limb gangrene (5% to 10%)(5% to 10%)

Acute thrombotic stroke or myocardial infarction Acute thrombotic stroke or myocardial infarction (3% to 5%)(3% to 5%)

Acute systemic reactions following IV bolus Acute systemic reactions following IV bolus (~25%)(~25%)

Warkentin. Warkentin. Thromb HaemostThromb Haemost. 1999;82:439-447; . 1999;82:439-447; Warkentin. Warkentin. J Crit IllnessJ Crit Illness. 2005;20(1):6-13.. 2005;20(1):6-13.

PF-4 binds to surface ofPF-4 binds to surface ofplatelet following activationplatelet following activation

PathophysiologyPathophysiology

Complexes of heparin (GAG)Complexes of heparin (GAG)and PF-4 molecules formand PF-4 molecules form

IgG binds to the PF-4/IgG binds to the PF-4/heparin complexheparin complex

IgG/PF-4/heparin complex activatesIgG/PF-4/heparin complex activatesvia the Fc receptorvia the Fc receptor

Fc stimulation leads to the generation of Fc stimulation leads to the generation of procoagulant-rich microparticlesprocoagulant-rich microparticles

alpha granulealpha granule PF-4/heparinPF-4/heparincomplexcomplex

IgGIgG

Fc receptorFc receptormicroparticlesmicroparticles

PlateletPlatelet

Courtesy of Dr John G. Kelton, McMaster UniversityCourtesy of Dr John G. Kelton, McMaster University .. Hirsh et al. Hirsh et al. Arch Intern MedArch Intern Med. 2004;164:361-369. 2004;164:361-369..

Clinical Diagnosis of HITClinical Diagnosis of HIT

Timing of thrombocytopeniaTiming of thrombocytopenia– 5 to 14 days after initiation of heparin, except in 5 to 14 days after initiation of heparin, except in

patients with recent heparin exposure patients with recent heparin exposure

– Earlier onset of thrombocytopenia with heparin Earlier onset of thrombocytopenia with heparin

re-exposurere-exposure

– Onset may be delayed and may can occur weeks to Onset may be delayed and may can occur weeks to months after heparin discontinuationmonths after heparin discontinuation

Degree of thrombocytopeniaDegree of thrombocytopenia– Decrease from baseline of 30% to 50%Decrease from baseline of 30% to 50%

– 10% to 15% of HIT patients will have platelet count WNL10% to 15% of HIT patients will have platelet count WNL

Other causes of thrombocytopenia excludedOther causes of thrombocytopenia excludedRice et al. Rice et al. Ann Intern MedAnn Intern Med. 2002:136(3):210-215;. 2002:136(3):210-215; Warkentin. Warkentin. Thromb Haemost.Thromb Haemost. 1999;82:439-447; 1999;82:439-447; Warkentin. Warkentin. Semin HematolSemin Hematol. 1998;35(suppl 5):9-16.. 1998;35(suppl 5):9-16.

Temporal Patterns of Thrombocytopenia in HIT

Day 1 Day 5 Day 14 Day 30

Delayed-Onset HIT

(9-40+ days)

Rapid-onset HIT

(hours-days)

Typical-Onset HITMean day 9(5-14 days)

Heparin (re) Exposure

THROMBOCYTOPENIA (± THROMBOSIS)

Warkentin TE et al. Warkentin TE et al. ChestChest. 2004;126(3 suppl):311S-337S. . 2004;126(3 suppl):311S-337S. Rice et al. Ann Intern Med. 2002;136(3):210-215. Warkentin et al. Ann Intern Med. 2001;135:502-506. Warkentin et al. NEJM. 2001;344(17):1286-92. DeEugenio DL, et al. Pharmacotherapy. 2005;25:615-619. Courtesy of Dr Ahjad AlMahameed, Cleveland Clinic, OH

Distribution of Platelet Count in HITDistribution of Platelet Count in HIT

Warkentin. Warkentin. Semin Hematol.Semin Hematol. 1998;35(suppl 5):9-16. 1998;35(suppl 5):9-16.

Nu

mb

er

of

pati

en

ts w

ith

HIT

Nu

mb

er

of

pati

en

ts w

ith

HIT

Platelet count nadir Platelet count nadir 10 1099/L/L

4040

3030

2020

1010

0033 55 1010 3030 100100 100010002020 50501515 7070 200200300300 500500

No HIT-associatedNo HIT-associatedthrombosisthrombosis

HIT-associatedHIT-associatedthrombosisthrombosis

Median platelet count nadir=59 Median platelet count nadir=59 10 1099/L/L

n=142

Differential Diagnosis of ThrombocytopeniaDifferential Diagnosis of ThrombocytopeniaClinical Setting Clinical Setting – – OutpatientOutpatient

PregnancyPregnancy

Myelodysplastic syndromeMyelodysplastic syndrome

HypersplenismHypersplenism

Antiphospholipid syndromeAntiphospholipid syndrome

Immune thrombocytopenia purpura (ITP)Immune thrombocytopenia purpura (ITP)

Aird AC, Mark EJ. Aird AC, Mark EJ. N Engl J Med.N Engl J Med. 2002;346:1562-1570. 2002;346:1562-1570.

Differential Diagnosis of Differential Diagnosis of ThrombocytopeniaThrombocytopenia

Clinical Setting Clinical Setting – – InpatientsInpatients Drug InducedDrug Induced

SepsisSepsis

Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC)(DIC)

Dilutional thrombocytopeniaDilutional thrombocytopenia

Posttransfusion purpuraPosttransfusion purpura

Aird AC, Mark EJ.Aird AC, Mark EJ. N Engl J MedN Engl J Med. 2002;346:1562-1570.. 2002;346:1562-1570.

Differential Diagnosis of Differential Diagnosis of ThrombocytopeniaThrombocytopenia

Clinical Setting Clinical Setting – – Cardiac InpatientsCardiac Inpatients

HITHIT

Use of platelet GP IIb/IIIa-receptor Use of platelet GP IIb/IIIa-receptor antagonists antagonists

Use of adenosine diphosphate-Use of adenosine diphosphate-receptor antagonistsreceptor antagonists

Coronary-artery bypass graftingCoronary-artery bypass grafting

Use of intra-aortic ballon pumpUse of intra-aortic ballon pumpAird AC, Mark EJ. Aird AC, Mark EJ. N Engl J MedN Engl J Med. 2002;346:1562-1570.. 2002;346:1562-1570.

SRASRA Sensitivity: high Sensitivity: high Technically demandingTechnically demandingSpecificity: highSpecificity: high (radioisotopes) (radioisotopes) (false (false positives rare) positives rare) Not readily availableNot readily available

Platelet (HIPA)Platelet (HIPA) Specificity: high Specificity: high Sensitivity: lowSensitivity: low aggregationaggregation Technique-dependentTechnique-dependent

ImmunoassayImmunoassay Sensitivity: high Sensitivity: high Specificity: low (falseSpecificity: low (false (ELISA)(ELISA) Technically easy Technically easy positives common for positives common for

Rapid turnaround time Rapid turnaround time some populations)some populations)

PIFAPIFA®® Sensitivity: highSensitivity: high Limited clinical historyLimited clinical history Specificity: highSpecificity: high Positive & NegativePositive & Negative Technically easyTechnically easy controls not providedcontrols not provided Rapid Rapid

turnaround timeturnaround time with assaywith assay

TestTest AdvantagesAdvantages Disadvantages DisadvantagesLaboratory Testing for HITLaboratory Testing for HIT

HIT Requires a Clinical HIT Requires a Clinical DiagnosisDiagnosis SRA=serotonin-release assay; ELISA=enzyme-linked immunosorbent assay.SRA=serotonin-release assay; ELISA=enzyme-linked immunosorbent assay.

Fabris et al. Fabris et al. Arch Pathol Lab Med.Arch Pathol Lab Med. 2000;124:1657-1666; Kelton. 2000;124:1657-1666; Kelton. Semin Hematol.Semin Hematol. 1999;36(suppl 1):17-21. 1999;36(suppl 1):17-21. PIFAPIFA®® Heparin/Platelet Factor 4 Rapid Assay [package insert]. Thorofare, NJ: Akers Biosciences, Inc.; 2005. Heparin/Platelet Factor 4 Rapid Assay [package insert]. Thorofare, NJ: Akers Biosciences, Inc.; 2005.

Diagnosis and Management Diagnosis and Management Decisions for HITDecisions for HIT

Current or recent heparin exposure with Current or recent heparin exposure with thrombocytopeniathrombocytopenia

Presence of thrombosis or other Presence of thrombosis or other characteristic sequelaecharacteristic sequelae

If HIT is suspected, discontinue all forms If HIT is suspected, discontinue all forms of heparin IMMEDIATELY: Initiate of heparin IMMEDIATELY: Initiate alternative anticoagulant,alternative anticoagulant, as indicatedas indicated

Hirsh et al. Hirsh et al. Arch Intern MedArch Intern Med. 2004;164:361-369;. 2004;164:361-369; Warkentin. Warkentin. Thromb Haemost.Thromb Haemost. 1999;82:439- 1999;82:439-447; Warkentin. 447; Warkentin. Semin HematolSemin Hematol. 1998;35(suppl 5):9-16.. 1998;35(suppl 5):9-16.

Prophylaxis and Treatment of HIT:Prophylaxis and Treatment of HIT:Patient Risk FactorsPatient Risk Factors

HIT with/without thrombosis should be suspected HIT with/without thrombosis should be suspected in patients with a 30% to 50% drop in platelets andin patients with a 30% to 50% drop in platelets and– Heparin use Heparin use

– History of HITHistory of HIT

– Recent exposure to heparin Recent exposure to heparin

– Surgery Surgery Venous thrombosis: more common in orthopedic surgeryVenous thrombosis: more common in orthopedic surgery Arterial thrombosis: more common in cardiac proceduresArterial thrombosis: more common in cardiac procedures

Boshkov et al. Boshkov et al. Br J Haematol.Br J Haematol. 1993;84:322-328; Hirsh et al. 1993;84:322-328; Hirsh et al. Arch Intern MedArch Intern Med. 2004;164:361-. 2004;164:361-369;369; Spencer. Spencer. J Thromb ThrombolysisJ Thromb Thrombolysis. 2000;10(suppl 1):21-25; Warkentin and Kelton. . 2000;10(suppl 1):21-25; Warkentin and Kelton. Am J Am J MedMed. 1996;101:502-507; Warkentin et al. . 1996;101:502-507; Warkentin et al. N Engl J Med.N Engl J Med. 1995;332:1330-1335. 1995;332:1330-1335.

Treatment Goals Based on Pathophysiology Treatment Goals Based on Pathophysiology and Clinical Studiesand Clinical Studies

Interrupt the immune responseInterrupt the immune response– Discontinue heparinDiscontinue heparin

Inhibit thrombin generationInhibit thrombin generation– Treat active thrombosisTreat active thrombosis

– Prevent new thrombosisPrevent new thrombosis

Minimize complications of HITMinimize complications of HIT– Thromboses, limb amputation, deathThromboses, limb amputation, death

Mechanisms of Thrombin InhibitionMechanisms of Thrombin Inhibition

Saito H. Disorders of Hemostasis. 3rd ed. 1996;2:23-52.

Direct Thrombin Inhibitors: Direct Thrombin Inhibitors: Mechanism of ActionMechanism of Action

Directly inhibit procoagulant and prothrombotic Directly inhibit procoagulant and prothrombotic actions of thrombinactions of thrombin

Do not require a cofactor to inhibit thrombinDo not require a cofactor to inhibit thrombin

Active against both free and clot-bound Active against both free and clot-bound thrombinthrombin

Do not interact with or produce heparin-Do not interact with or produce heparin-dependent antibodiesdependent antibodies

AngiomaxAngiomax®® (bivalirudin) for Injection [package insert]. The Medicines Company; 2004; (bivalirudin) for Injection [package insert]. The Medicines Company; 2004; Argatroban Injection [package insert]. GlaxoSmithKline; 2005; Chen. Argatroban Injection [package insert]. GlaxoSmithKline; 2005; Chen. Heart Dis.Heart Dis. 2001;3:189- 2001;3:189-198; Refludan198; Refludan®® [lepirudin (rDNA) for injection] [lepirudin (rDNA) for injection] [package insert]. Berlex Laboratories; 2004.[package insert]. Berlex Laboratories; 2004.

Potential Benefits of Potential Benefits of Direct Thrombin InhibitorsDirect Thrombin Inhibitors

Predictable anticoagulant responsePredictable anticoagulant response

Inhibition of clot-bound and circulating Inhibition of clot-bound and circulating thrombin thrombin

Direct binding to thrombin (no cofactor Direct binding to thrombin (no cofactor required) required)

Lack of heparin/PF4 antibody formationLack of heparin/PF4 antibody formation

Weitz JI, Buller HR. Weitz JI, Buller HR. CirculationCirculation. 2002;105:1004-1011.. 2002;105:1004-1011.

Direct Thrombin InhibitorsDirect Thrombin Inhibitors

Synthetic Synthetic LL-arginine -arginine derivativederivative

Recombinant Recombinant hirudinhirudin

Semisynthetic Semisynthetic hiruloghirulog

Half-life in healthy Half-life in healthy subjectssubjects 39-51 min39-51 min 1.3 hours1.3 hours 25 minutes25 minutes

EliminationElimination HepaticHepatic Renal Renal 80% Enzymatic80% Enzymatic20% Renal20% Renal

Monitoring neededMonitoring needed aPTT, ACTaPTT, ACT aPTTaPTT aPTT, ACTaPTT, ACT

Thrombin bindingThrombin binding ReversibleReversible Irreversible Irreversible PartiallyPartiallyreversiblereversible

AntidoteAntidote None None NoneNone NoneNone

aPTT = activated partial thromboplastin time; ACT = activated clotting time.Adapted from Chen JL. Heart Dis. 2001;3:189-198. Warkentin, TE, Greinacher A. Heparin-Induced Thrombocytopenia. 3rd ed. Revised and Expanded. 2004;:339-479.Warkentin TE, Greinacher A. Chest 2004;126:311s–337s.

Argatroban Lepirudin Bivalirudin

Direct Thrombin Inhibitors: Direct Thrombin Inhibitors: FDA Indications and UsageFDA Indications and Usage

ArgatrobanArgatroban– Indicated as an anticoagulant for prophylaxis or treatment of Indicated as an anticoagulant for prophylaxis or treatment of

thrombosis in patients with HITthrombosis in patients with HIT

– Indicated as an anticoagulant in patients with or Indicated as an anticoagulant in patients with or at risk for HIT undergoing PCIat risk for HIT undergoing PCI

LepirudinLepirudin– Indicated for anticoagulation in patients with HIT and Indicated for anticoagulation in patients with HIT and

associated thromboembolic disease to prevent further associated thromboembolic disease to prevent further thromboembolic complications thromboembolic complications

Bivalirudin*Bivalirudin*– Indicated as an anticoagulant in patients undergoing Indicated as an anticoagulant in patients undergoing

percutaneous transluminal coronary angioplasty (PTCA)percutaneous transluminal coronary angioplasty (PTCA)

*Recently approved for with or at risk HIT patients undergoing PCI. (Dec. 2005)*Recently approved for with or at risk HIT patients undergoing PCI. (Dec. 2005)

AngiomaxAngiomax®® (bivalirudin) for injection [package insert]. Parsippany, NJ: The Medicines Company; 2005; (bivalirudin) for injection [package insert]. Parsippany, NJ: The Medicines Company; 2005; Argatroban Injection [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005; RefludanArgatroban Injection [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005; Refludan®® [lepirudin (rDNA) for Injection] [package insert]. Montvale, NJ: Berlex Laboratories, Inc.; 2004.[lepirudin (rDNA) for Injection] [package insert]. Montvale, NJ: Berlex Laboratories, Inc.; 2004.

The Seventh ACCP Conference on The Seventh ACCP Conference on Antithrombotic and Thrombolytic Antithrombotic and Thrombolytic

Therapy: Evidence-Based GuidelinesTherapy: Evidence-Based Guidelines

CHEST: HIT RecommendationsCHEST: HIT Recommendations

Warkentin TE, Greinacher A, Warkentin TE, Greinacher A, ChestChest 2004;126:311s–337s. 2004;126:311s–337s.

ACCP Guidelines: ACCP Guidelines: Strongly Suspected or Confirmed HITStrongly Suspected or Confirmed HIT

ACCP recommends use of an alternative nonheparin anticoagulant in therapeutic doses over further UFH, LMWH, or no anticoagulation

Grade 1C: Intermediate recommendationGrade 1C: Intermediate recommendation Danaparoid (Grade 1B)Danaparoid (Grade 1B) Lepirudin (Grade 1C+)Lepirudin (Grade 1C+) Argatroban (Grade 1C)Argatroban (Grade 1C)

Grade 2C: Very weak recommendationGrade 2C: Very weak recommendation

▪ ▪ Bivalirudin (Grade 2C)Bivalirudin (Grade 2C)

Warkentin TE et al. Warkentin TE et al. Chest.Chest. 2004;126(3 suppl):311S-337S. 2004;126(3 suppl):311S-337S.

ACCP Guidelines: Strongly Suspected or ACCP Guidelines: Strongly Suspected or Confirmed HITConfirmed HIT

Grade 1C: Intermediate recommendationGrade 1C: Intermediate recommendation

Routine ultrasonography of lower limb Routine ultrasonography of lower limb veins should be performed to evaluate veins should be performed to evaluate thrombosisthrombosis


Grade 1C+ : Do not useGrade 1C+ : Do not useACCP recommends strongly ACCP recommends strongly AGAINSTAGAINST use of vitamin K antagonists use of vitamin K antagonists

CoumadinCoumadin® ® until after platelet count has recovered (100,000-until after platelet count has recovered (100,000-150,000/mcL)150,000/mcL)

Vitamin K antagonists should be administered only during Vitamin K antagonists should be administered only during overlap with alternative anticoagulationoverlap with alternative anticoagulation

Begin with low, maintenance doses (maximum 5 mg warfarin; Begin with low, maintenance doses (maximum 5 mg warfarin; 6 mg phenprocoumon)6 mg phenprocoumon)

Alternative anticoagulants should not be Alternative anticoagulants should not be STOPPED STOPPED until platelet until platelet count has reached a stable plateau and with at least the last 2 count has reached a stable plateau and with at least the last 2 days of INR within target therapeutic rangedays of INR within target therapeutic range

ACCP Guidelines: HITACCP Guidelines: HIT

CoumadinCoumadin®® (Warfarin Sodium for Injection, USP) [package insert]. Princeton, NJ: Bristol-Myers (Warfarin Sodium for Injection, USP) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2005. Squibb Company; 2005. Warkentin TE et al. Warkentin TE et al. Chest.Chest. 2004;126(3 suppl):311S-337S. 2004;126(3 suppl):311S-337S.


Grade 2C: Very weak recommendationGrade 2C: Very weak recommendation

ACCP recommends for patients receiving ACCP recommends for patients receiving vitamin K antagonist therapy at the time vitamin K antagonist therapy at the time of diagnosis, reversal of vitamin K of diagnosis, reversal of vitamin K antagonism by use of oral or IV vitamin Kantagonism by use of oral or IV vitamin K


ACCP Guidelines: Acute or Previous HIT in ACCP Guidelines: Acute or Previous HIT in Patients Who Require Catheterization or PCIPatients Who Require Catheterization or PCI

Grade 1C: Intermediate Grade 1C: Intermediate recommendationrecommendation

ArgatrobanArgatroban Bivalirudin Bivalirudin Lepirudin Lepirudin


Grade 1C+: Do not useGrade 1C+: Do not use

ACCP recommends strongly ACCP recommends strongly AGAINSTAGAINST use use of lowof low––molecular-weight heparins in HIT molecular-weight heparins in HIT patientspatients

Grade 2C: Do not useGrade 2C: Do not use

ACCP recommends ACCP recommends AGAINSTAGAINST prophylactic prophylactic platelet transfusions for patients who do platelet transfusions for patients who do not have active bleedingnot have active bleeding



2004 ACCP Summary of Recommendations for HIT2004 ACCP Summary of Recommendations for HIT

DanaparoidDanaparoid 1B1B 1B1B

ArgatrobanArgatroban 1C1C 1C1C

LepirudinLepirudin 1C+1C+ 1C+1C+

BivalirudinBivalirudin 2C2C 2C2C


Prophylaxis Prophylaxis thrombosis in thrombosis in

HITHIT

TreatmentTreatment thrombosis in thrombosis in

HITHIT

2004 ACCP Summary of Recommendations 2004 ACCP Summary of Recommendations for HITfor HIT

Acute HITAcute HIT

LMWHLMWH Do not use 1C+Do not use 1C+

VKAVKA Do not use 1CDo not use 1C

Platelet transfusionPlatelet transfusion Do not use 2CDo not use 2C


LMWH = low–molecular-weight heparin; VKA = vitamin K antagonists.

HIT CASE STUDIESHIT CASE STUDIES

HIT CASE STUDY - Patient #1HIT CASE STUDY - Patient #1

45 yo F Stage IB Endometrial Carcinoma45 yo F Stage IB Endometrial Carcinoma

TAH, BSO, LND TAH, BSO, LND

Received prophylactic post op IV heparin x 4 daysReceived prophylactic post op IV heparin x 4 days

Post-op Day 6 - chest pain and SOB, collapsed, cyanoticPost-op Day 6 - chest pain and SOB, collapsed, cyanotic

VQ scan (+) for PE & 5mm thrombosis @ tip of CVCVQ scan (+) for PE & 5mm thrombosis @ tip of CVC

IV Heparin re-initiated + urokinase given for thrombolysis IV Heparin re-initiated + urokinase given for thrombolysis with initial improvement in signs and symptomswith initial improvement in signs and symptoms

Post-op Day 9 - sudden PLT drop 238,000 to 39,000mcLPost-op Day 9 - sudden PLT drop 238,000 to 39,000mcL

HIT suspected, heparin d/c'dHIT suspected, heparin d/c'd

Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia. Obstet Gynecol. 2001;98:952-954.

HIT CASE STUDY - Patient #1 HIT CASE STUDY - Patient #1 (cont'd)(cont'd)

POD 10, CVC thrombus larger. Underwent successful POD 10, CVC thrombus larger. Underwent successful thrombectomythrombectomy

Argatroban was administered intra- and postoperativelyArgatroban was administered intra- and postoperatively

PLT post-op Day 1 - 104,000/mcL PLT post-op Day 1 - 104,000/mcL

Oral warfarin and ASA initiatedOral warfarin and ASA initiated

PLT post-op Day 4 - 236,000/mcL PLT post-op Day 4 - 236,000/mcL

Patient was discharged home without further complications Patient was discharged home without further complications on hospital Day 32on hospital Day 32

Case based on an actual patient. Individual results may vary.Case based on an actual patient. Individual results may vary.

Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia. Obstet Gynecol. 2000;98:952-954.

HIT DIAGNOSIS - Patient #1HIT DIAGNOSIS - Patient #1Potential CausesPotential Causes

Drug therapyDrug therapy– anesthesia, pain meds, anesthesia, pain meds,

heparin, urokinaseheparin, urokinase

Patient FactorsPatient Factors– obese, carcinomaobese, carcinoma

EventsEvents– surgerysurgery

Timing of PLT dropTiming of PLT drop– re-exposure of heparinre-exposure of heparin

– day 3day 3

Degree of PLT fallDegree of PLT fall– 238,000 to 39,000mcL238,000 to 39,000mcL

Concurrent eventsConcurrent events– CVC thrombosisCVC thrombosis

– PEPE

Lab findingsLab findings– elevated IgG antibody by elevated IgG antibody by

immunoassayimmunoassay

Aida H, Aoki Y, Ohki I, & Tanaka K. (2001). Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia. Obstet Gynecol. 2001;98:952-954.


60 yo female underwent repair of aortic aneurysm with 60 yo female underwent repair of aortic aneurysm with aortic valve replacement. aortic valve replacement.

She received LMWH 30mg SQ bid from POD 1 through 6 She received LMWH 30mg SQ bid from POD 1 through 6 followed by warfarin therapy upon D/Cfollowed by warfarin therapy upon D/C

POD 4 she experienced transient amnesia that was POD 4 she experienced transient amnesia that was attributed to medicationsattributed to medications

Re-presented to ED 33 days later after initial heparin Re-presented to ED 33 days later after initial heparin exposure with proximal-thigh DVT despite a INR of 4.2 exposure with proximal-thigh DVT despite a INR of 4.2

Patient admitted and IV heparin initiated in EDPatient admitted and IV heparin initiated in ED

Rice L, Attisha WK, Drexler, AD, Francis JL. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med. 2002;136(3):210-215.


Immediately after receiving IV heparin bolus, she developed Immediately after receiving IV heparin bolus, she developed dyspnea, tachycardia & hypotension which required intubation dyspnea, tachycardia & hypotension which required intubation and mechanical ventilationand mechanical ventilation

An inferior vena cava filter was placed for suspected PEAn inferior vena cava filter was placed for suspected PE

PLT count was 420,000/mcL on readmission, but dropped to PLT count was 420,000/mcL on readmission, but dropped to 47,000/mcL after the heparin bolus47,000/mcL after the heparin bolus

VQ scan low probability for PE VQ scan low probability for PE

ELISA (+) for heparin antibodiesELISA (+) for heparin antibodies

Started on danaparoid* Started on danaparoid*

Patient D/C without further sequelae, PLT’s 343,000/mcLPatient D/C without further sequelae, PLT’s 343,000/mcL

Case based on an actual patient. Individual results may vary.Case based on an actual patient. Individual results may vary.*No longer available in the US.


HIT DIAGNOSIS - Patient #2HIT DIAGNOSIS - Patient #2 Onset of HITOnset of HIT

– HIT has been documented HIT has been documented to occur up to 40 days after to occur up to 40 days after heparin discontinuationheparin discontinuation

– Patient presented to the ED Patient presented to the ED with a DVT 33 days after with a DVT 33 days after initial exposureinitial exposure

Thrombotic complicationsThrombotic complications– venous vs arterial venous vs arterial

– Suspect transient amnesia Suspect transient amnesia during first hospitalization during first hospitalization was related to HITwas related to HIT

– New onset DVTNew onset DVT

Degree of PLT fallDegree of PLT fall– 10% to15% of patients with 10% to15% of patients with

HIT, PLT nadir is above HIT, PLT nadir is above 150,000/mcL 150,000/mcL

– Upon heparin re-exposure, Upon heparin re-exposure,

dramatic drop in PLT count dramatic drop in PLT count

420,000/mcL to 47,000/mcL 420,000/mcL to 47,000/mcL after bolusafter bolus

Delayed-onset HIT should be a Delayed-onset HIT should be a primary diagnostic primary diagnostic consideration whenever a consideration whenever a recently hospitalized patient recently hospitalized patient presents with presents with thromboembolismthromboembolism



63 yo F w/ metastatic Ovarian Carcinoma63 yo F w/ metastatic Ovarian Carcinoma

Presented to clinic c/o (R) arm swellingPresented to clinic c/o (R) arm swelling

Hickman catheter placement 2 1/2 weeks prior to Hickman catheter placement 2 1/2 weeks prior to chemochemo

Received Cisplatin, Taxol, CTX Received Cisplatin, Taxol, CTX

Daily heparin saline flushes for 3 wksDaily heparin saline flushes for 3 wks

Day 10 after chemo PLT drop 329,000 to 73,000/mcLDay 10 after chemo PLT drop 329,000 to 73,000/mcL

At clinic visit, day 18, PLT continued to fall to At clinic visit, day 18, PLT continued to fall to 20,000/mcL with R subclavian vein thrombosis 20,000/mcL with R subclavian vein thrombosis documenteddocumented

Kadidal VV, Mayo DJ, Horne MK. Heparin-induced thrombocytopenia (HIT) due to heparin flushes: a report of three cases. J Int Med. 1999;246:325-329.


PLT transfusion givenPLT transfusion given

IV heparin initiatedIV heparin initiated

Due to failure of PLT to rise, HIT was suspectedDue to failure of PLT to rise, HIT was suspected

Heparin was d/c'dHeparin was d/c'd

Danaparoid* was initiatedDanaparoid* was initiated

Pre-heparin ELISA and SRA assays were (+)Pre-heparin ELISA and SRA assays were (+)

PLT count rose >100,000mcL within 3 days while on PLT count rose >100,000mcL within 3 days while on danaparoid*danaparoid*


*No longer available in the US.



DrugsDrugs– chemotherapy, chemotherapy,

heparin flush, IV heparin flush, IV heparin, platelet heparin, platelet transfusiontransfusion

Patient factorsPatient factors– cancer, Hickman linecancer, Hickman line

Timing of PLT fallTiming of PLT fall– initial fall suspected to be chemo initial fall suspected to be chemo

nadir Day 10 nadir Day 10

– continuation of fall Day 18continuation of fall Day 18

Delayed onset HIT??Delayed onset HIT??

Degree of PLT fallDegree of PLT fall– 329,000 to 73,000 to 20,000/mcL329,000 to 73,000 to 20,000/mcL

– lack of response to transfusion lack of response to transfusion and IV heparinand IV heparin

Development of ThrombosisDevelopment of Thrombosis– subclavian vein thrombosissubclavian vein thrombosis

Laboratory findingsLaboratory findings– (+) ELISA and SRA(+) ELISA and SRA



75 yo male had infected knee prosthesis removed75 yo male had infected knee prosthesis removed

Received LMWH 30 mg SQ BID POD 1-9Received LMWH 30 mg SQ BID POD 1-9

Discharge Day 9Discharge Day 9

Readmitted Day 12 with swollen, dusky left arm, the Readmitted Day 12 with swollen, dusky left arm, the site of subclavian cathetersite of subclavian catheter

Venography showed subclavian thrombosisVenography showed subclavian thrombosis

Day 12 Platelet count 145,000/mcLDay 12 Platelet count 145,000/mcL

Initiated LMWH 80 mg SQ BIDInitiated LMWH 80 mg SQ BID

Day 13 platelet count 85,000/mcLDay 13 platelet count 85,000/mcL



Arm worsened with impending gangreneArm worsened with impending gangrene

Day 15 hematology consultDay 15 hematology consult

Due to failure of PLT to rise, HIT was suspectedDue to failure of PLT to rise, HIT was suspected

Tissue plasminogen activator given Tissue plasminogen activator given

Hirudin was initiatedHirudin was initiated

Arm improved dramatically within 2 daysArm improved dramatically within 2 days

Result of ELISA was (+)Result of ELISA was (+)

Discharged on warfarin with PLT 240,000/mcLDischarged on warfarin with PLT 240,000/mcL




DrugsDrugs– Low molecular weight Low molecular weight

heparin, anesthesia, heparin, anesthesia, pain medspain meds

Patient factorsPatient factors– orthopedic patient, orthopedic patient,

subclavian cathetersubclavian catheter

Timing of PLT fallTiming of PLT fall– initial documented fall day 12initial documented fall day 12

Typical onset HITTypical onset HIT

Degree of PLT fallDegree of PLT fall– 145,000 to 85,000/mcL145,000 to 85,000/mcL

– Question platelet count on Question platelet count on initiation of enoxaparin and prior initiation of enoxaparin and prior to dischargeto discharge

Development ThrombosisDevelopment Thrombosis– subclavian vein thrombosissubclavian vein thrombosis

Laboratory findingsLaboratory findings– (+) ELISA (+) ELISA



67 y/o male had undergone coronary artery bypass surgery 67 y/o male had undergone coronary artery bypass surgery

POD 7 presented to ED with sudden onset of confusionPOD 7 presented to ED with sudden onset of confusion

CT scan revealed no intracranial hemorrhageCT scan revealed no intracranial hemorrhage

Diagnosed with left-sided cerebrovascular accidentDiagnosed with left-sided cerebrovascular accident

Intravenous heparin initiated in ED for possible Intravenous heparin initiated in ED for possible thromboembolic strokethromboembolic stroke

POD 7 PLT 233,000/mcLPOD 7 PLT 233,000/mcL

POD 9 PLT 84,000/mcLPOD 9 PLT 84,000/mcL

Heparin d/c’d due to suspicion of HITHeparin d/c’d due to suspicion of HIT

HIT antibody testing (+)HIT antibody testing (+)

Levine et al. Levine et al. Annals of Emergency MedicineAnnals of Emergency Medicine. 2004;44:511-515.. 2004;44:511-515.


Neurologic status deterioratedNeurologic status deteriorated

Repeat CT scan showed large area of ischemia w/o bleedingRepeat CT scan showed large area of ischemia w/o bleeding

IV Argatroban initiated but d/c’d after 2 hoursIV Argatroban initiated but d/c’d after 2 hours

Concerns of possible intracranial bleedingConcerns of possible intracranial bleeding

Serial CT scans revealed no bleedingSerial CT scans revealed no bleeding

No further anticoagulant administeredNo further anticoagulant administered

During next 3 days patient remained unresponsive, developed During next 3 days patient remained unresponsive, developed multiple bilateral cerebral infarcts with clinical deteriorationmultiple bilateral cerebral infarcts with clinical deterioration

Withdrawal of life support and patient expiredWithdrawal of life support and patient expired




DrugsDrugs– Anesthesia, cardiac Anesthesia, cardiac

medsmeds

Patient factorsPatient factors

- cardiac surgery patient- cardiac surgery patient

Timing of PLT fallTiming of PLT fall– initial documented fall day 9initial documented fall day 9

Typical onset HITTypical onset HIT

Degree of PLT fallDegree of PLT fall– 233,000/mcL to 84,000/mcL233,000/mcL to 84,000/mcL

– Question platelet count post Question platelet count post cardiac surgery and prior to cardiac surgery and prior to dischargedischarge

Development ThrombosisDevelopment Thrombosis– ? Thromboembolic stroke? Thromboembolic stroke

Laboratory findingsLaboratory findings– (+) antibody test (+) antibody test


Management of HITManagement of HIT

Identify HIT early with diligent PLT Identify HIT early with diligent PLT monitoringmonitoring

D/C all heparin sourcesD/C all heparin sources– IV, SC, flushes, coated linesIV, SC, flushes, coated lines

Avoid platelet transfusionsAvoid platelet transfusions– Exception: major bleedingException: major bleeding

Initiate alternative anticoagulation as Initiate alternative anticoagulation as indicatedindicated

Warkentin, TE. Arch Pathol Lab Med. 2000;126:1415-1423.

Nursing & Pharmacy RoleNursing & Pharmacy Role

Key to limiting early morbidity and mortality Key to limiting early morbidity and mortality from HIT is from HIT is – Rapid recognition of signs & symptomsRapid recognition of signs & symptoms

– Early identification with diligent PLT monitoringEarly identification with diligent PLT monitoring

– Avoid platelet transfusions except in major bleedingAvoid platelet transfusions except in major bleeding

– Immediate cessation of all heparin sourcesImmediate cessation of all heparin sources

– Initiation of alternate therapyInitiation of alternate therapy

Nurses & pharmacists play a vital role in the Nurses & pharmacists play a vital role in the early recognition of HIT by monitoring vigilantly early recognition of HIT by monitoring vigilantly for drops in platelet counts & new thrombotic for drops in platelet counts & new thrombotic events while patients are on heparinevents while patients are on heparin

Miller, P. AORN. 2003; 78(1): 79-89. Warkentin, TE. Arch Pathol Lab Med. 2000;126:1415-1423.

For adjusted- and full-dose therapy, perform platelet For adjusted- and full-dose therapy, perform platelet counts pre-treatment and at least on alternate dayscounts pre-treatment and at least on alternate days

– Begin on day 4 for heparin-naïve patients Begin on day 4 for heparin-naïve patients

– Begin on day 1 for patents with prior heparin Begin on day 1 for patents with prior heparin

exposureexposure

For high-risk patients:

– Obtain baseline – Monitor regularly – Monitor frequently

Monitor Platelet CountsMonitor Platelet Counts

College of American Pathologists Consensus Arch Pathol Lab Med 1998;122:782–798.

Summary of HIT Summary of HIT HIT is a life- and limb-threatening medical HIT is a life- and limb-threatening medical

emergencyemergency

HIT is a relatively common and often under-HIT is a relatively common and often under-recognized devastating complication of heparin recognized devastating complication of heparin therapytherapy

However the consequences of HIT are largely However the consequences of HIT are largely preventable with early recognition and proper preventable with early recognition and proper treatment treatment

Awareness of the clinical presentation of HIT and Awareness of the clinical presentation of HIT and the ability to distinguish it from other causes of the ability to distinguish it from other causes of platelet count reduction are keys to avoiding platelet count reduction are keys to avoiding serious sequelaeserious sequelae

Greinacher et al. Thrombosis Research. Thrombosis Research. 2005 In Press. Warkentin. J Crit Ill. J Crit Ill. 2005 ;20(1):6-13.

Summary of HIT Summary of HIT Diagnosis of HIT is based upon clinical suspicionDiagnosis of HIT is based upon clinical suspicion

Treatment of HIT should not be delayed while Treatment of HIT should not be delayed while awaiting laboratory confirmationawaiting laboratory confirmation

Untreated patients with HIT are at a high risk Untreated patients with HIT are at a high risk of having thromboembolic complicationsof having thromboembolic complications

Management of HITManagement of HIT– Discontinue all types of heparinDiscontinue all types of heparin

– Assess risk of thrombosisAssess risk of thrombosis

– Initiate alternative anticoagulant therapy, as indicatedInitiate alternative anticoagulant therapy, as indicated

Greinacher et al. Thrombosis Research. Thrombosis Research. 2005 In Press. Warkentin. J Crit Ill. J Crit Ill. 2005;20(1):6-13.

heparin-induced thrombocytopenia (hit): pathophysiology, clinical implications, therapy, and cases...

Documents

heparin antibodiesstarted

heparin bolusvq

mcl patient

hit case study patient

heparin dcdaida h

hit diagnosis patient

actual patient

initial heparin exposure