heparin induce thrombocytopenia

Heparin induce thrombocytopenia

Presented by the American Society ofHematology, adapted in part from the:American College of ChestPhysicians Evidence-BasedClinical Practice Guidelineon Antithrombotic andThrombolytic Therapy(8th Edition).

DEFENITION

• Nonimmune heparin-associated thrombocytopenia

– Previously called HIT type I

• Immune HIT – Previously called HIT type II

Shantsila E,Chest 2009,135:6

Variables Immune HIT (Previously Type II HIT)

Nonimmune Heparin-Associated

Thrombocytopenia (Previously Type I HIT)

Frequency 2–3% 10–30%Reduction in platelet

count Moderate or severe Mild

Time from initiation of heparin therapy

> 5 d (may be less after recent heparin

exposure)<5 d

HIT antibodies Present AbsentRisk of thrombosis High Low

Management

Heparin therapy discontinuation; administration of

alternative anticoagulants

Observation

Epidemiology

• Drug Dependent Characteristics

• Patient Characteristics

ASH State of Art symposium 2009

• DRUG DEPENDENT CHARACTERISTICS

• Chain length: – UFH> LMWH>Fondaparinux

• Source:– Bovine> Porcine

• Dose /Duration – Possibly increased(Heparin duration >4 days)


The frequency of HIT among patients exposed toheparin is highly variable, and is influenced by theheparin preparation (bovine UFH porcine UFH low-molecular-weight heparin [LMWH]),type of heparin-exposed patient population (postsurgery medical pregnancy), duration of heparin exposure patient sex (female male).Thus, whether to perform platelet count monitoring,and the intensity of such monitoring, depends on theseconsiderations, particularly heparin and patient typeand the duration of heparin use

• PATIENT CHARACTERISTICS

• High Risk: 3-5%– Surgical( Postsurgical > medical > obstetric)

• Intermediate Risk: 0.8-3%– General medical

• Low Risk: <0.1%– Obstetrics, general pediatrics, chronic

hemodialysisASH State of Art symposium 2009

PF-4 binds to surface ofplatelet following activation

Pathophysiology

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

IgG binds to the PF-4/heparin complex

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

Fc stimulation leads to the generation of procoagulant-rich microparticles

alpha granule PF-4/heparincomplex

IgG

Fc receptormicroparticles

Platelet

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

PF-4 binds to surface ofplatelet following activation

Pathophysiology

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

IgG binds to the PF-4/heparin complex

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

Fc stimulation leads to the generation of procoagulant-rich microparticles

alpha granule PF-4/heparincomplex

IgG

Fc receptormicroparticles

Platelet

Arch Intern Med. 2004;164:361-369.

HIT - a vicious cycle of platelet activation and coagulation

PF4/Heparin/HIT-IgG

Platelet Activation

Coagulation

Platelet Activation

Release PF4

Monocyte Activation

Coagulation

Endothelial Cell Injury

Thrombosis Embolism

Morbidity&

Death

Platelet Activation

Release PF4

/HIT-IgGPF4 /HIT-IgG

Iceberg model of HIT

Thrombocytopenia Positivewashedplatelet activationassay

PositivePF4 antigenassay

ThrombosisHIT

syndrome

Numbers of Patients

Warkentin TE. Br J Haematol 2003,121:535

Clinical presentation

• Classic Presentation:– 5-10 days after exposure– Isolated thrombocytopenia or with thrombosis

• Delayed HIT: – Days to weeks after exposure– Often with thrombocytopenia and thrombosis

• Rapid/Acute Onset:– Within 24 hour


Day 1 Day 5 Day 14Day 30

Delayed-onset HIT

(14–30 days)

Rapid-onset HIT

(hours–days)

Typical HITMean Day 9(5–14 days)

Heparin (re) Exposure

THROMBOCYTOPENIA (± THROMBOSIS)

HIT Temporal Variants

Consequences of HIT

• If left untreated, risk of thrombosis persists even after

platelet counts have returned to normal

• Approximately 5-10% increased risk per day

immediately following discontinuation of heparin


Clinical Consequences of HIT

Features of the history and physical examination that support a diagnosis of HIT

Unusual Clinical Events Suspicious for HIT

• Adrenal hemorrhagic infarction (caused by adrenal

vein thrombosis)

• Warfarin-induced venous limb gangrene

• Fever, chills, flushing, or transient amnesia beginning

5 to 30 minutes after an IV heparin bolus

• Heparin-induced skin lesions associated with HIT

antibodies, even in the absence of thrombocytopania

Venous Gangrene

Warkentin. Ann Intern Med. 1997;127:804-812.

Skin Manifestations of HIT

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

Skin necrosis

Diagnostic specificity can befurther increased by use of a sensitive washed plateletactivation assay; a positive platelet activation assay ismuch more specific for clinical HIT than a positiveplatelet factor 4 (PF4)-dependent immunoassay

Diagnosis

The 4Ts: A clinical probability scoring model

High probability: 6-8 points; intermediate probability: 4-5 points,low probability: ≤3points.

Functional Assays

• Exploits the ability of HIT antibodies to activate normal

platelets– Platelet aggregation assay (PAA)– Serotonin release assay (SRA)

– Heparin induced platelet activation (HIPA)

• Use of washed donor platelets increase sensitivity and

specificity to >90% for SRA and HIPA

Serologic Assays

• Antibodies against heparin/PF4 complexes antigen of are

measured by colorimetric absorbance– PF4/heparin ELISA– Gel-particle assay

High sensitivity , Lower specificity for clinically significant HIT Detects IgA and IgM

Functional assays analyzewhether the combination of heparin and the patient’s plasma can inducenormal platelets to aggregate or to secrete serotonin; these assays have veryhigh specificity but relatively low sensitivity.

Immunologic assays test thepatient’s plasma for antibodies that bind to the heparin-PF4 complex; theyhave very high sensitivity but lack specificity. Consequently, a negative immunologic assay is useful in excluding this diagnosis, and a positive functional assayis very useful in confirming the diagnosis of HIT.

Thrombocytopenia in a patient on UFH/LMWH

High or intermediate clinical suspicion of HIT

Discontinue heparin or LMWH; initiate alternative anticoagulant therapy

Results of immunoassay

Low clinical suspicion of HIT

Heparin or LMWH therapy maybe continued

N Eng J Med 2006;355:809-17

Immunoassay

Pos /High Suspicious

HIT Confirmed

Pos /Intermediate

Suspicious

Functional Assay

Positive

HIT Likely

Negative

HIT Indetermi

nate

Neg /High Suspicious

HIT Indetermin

ate

Neg/Intermediate

Suspicious

Other DXRestart Heparin

N Eng J Med 2006;355:809-17

Objectives of Treatment for HIT

Management of HIT

• Stop heparin (UFH/LMWH), even in patients without

thrombosis

• Initiate alternative non-heparin anticoagulant because of

high risk of symptomatic thrombosis

• Test for HIT antibodies

• Duplex ultrasonography for lower-limb DVT

2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia ASH

Management of HIT

• Do not start a vitamin K antagonist (VKA) - if started prior to

diagnosis it should be reversed by vitamin K

• Do not use low-molecular-weight heparin (LMWH)

• Do not give platelet transfusions unless needed to manage

serious hemorrhage


Transitioning to warfarin

• Warfarin should not be initiated until platelet count

is ≥ 150 x 109/L

• Initial warfarin dose should be ≤ 5 mg/day. Larger

loading doses should be avoided.

• • A parenteral non-heparin anticoagulant should be

overlapped with warfarin for ≥ 5 days and until INR

has reached intended target .


Duration of anticoagulation

• For patients with HITT:– anticoagulate for a defined course (typically 3-6 months

• For patients with HIT without thrombosis– the optimal duration of anticoagulation is unknown.

Because there is an elevated risk of thrombosis extending at least 30 days after the diagnosis of HIT, anticoagulation for at least one month should be considered.


Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction caused byplatelet-activating immunoglobulin G (IgG) antibodies that recognize complexes ofplatelet factor 4 (PF4) bound to heparin. HIT is highly prothrombotic: at least 50% ofaffected patients develop thrombosis involving veins, arteries, or even the microcirculation.

summery

Because the diagnosis is based on both clinical and serologic grounds, clinicians should consider HIT a clinicopathologic syndrome. Thus, neither thrombocytopenia

or thrombosis without the presence ofheparin-dependent antibodies, nor the

isolated presenceof antibodies without thrombocytopenia, thrombosis,or other clinical sequelae, meet the criteria for

HIT.

Rather, clinicians make a diagnosis of HIT whenany of the following events occurs in association withthe presence of “HIT antibodies” detected by in vitro assays:

(1)an otherwise unexplained platelet count

(2)venous orarterial thrombosis (most often, deep venous thrombosis [DVT] pulmonary embolism limb artery thrombosis, thrombotic stroke, myocardial infarction,

adrenal hemorrhagic necrosis (3) skin lesions at heparin injectionsites; (4) acute systemic (anaphylactoid) reactions(eg, fever/chills, tachycardia, hypertension, dyspnea,cardiopulmonary arrest) that occur after IV heparin bolus administration.

Steps to Prevent HIT

• Porcine heparin preferred over bovine heparin• LMWH preferred over unfractionated heparin• Oral anticoagulation should be started as early as possible to reduce the

duration of heparin exposure• Intravenous adapters should not be flush with heparin• Monitoring serial plate counts for developing thrombocytopenia

Serial platelet counts in patients receiving heparin: Check platelets at baseline, 24 hours, and then every other day for first 14 days

heparin induce thrombocytopenia

Documents

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weight heparin lmwh

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frequency of hit

immune hit

increasedheparin duration