Heparin induce thrombocytopenia
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Transcript of Heparin induce thrombocytopenia
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Heparin induce thrombocytopenia
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Presented by the American Society ofHematology, adapted in part from the:American College of ChestPhysicians Evidence-BasedClinical Practice Guidelineon Antithrombotic andThrombolytic Therapy(8th Edition).
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DEFENITION
• Nonimmune heparin-associated thrombocytopenia
– Previously called HIT type I
• Immune HIT – Previously called HIT type II
Shantsila E,Chest 2009,135:6
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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
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Epidemiology
• Drug Dependent Characteristics
• Patient Characteristics
ASH State of Art symposium 2009
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• DRUG DEPENDENT CHARACTERISTICS
• Chain length: – UFH> LMWH>Fondaparinux
• Source:– Bovine> Porcine
• Dose /Duration – Possibly increased(Heparin duration >4 days)
ASH State of Art symposium 2009
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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
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• 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
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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.
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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.
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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.
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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.
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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.
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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
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Iceberg model of HIT
Thrombocytopenia Positivewashedplatelet activationassay
PositivePF4 antigenassay
ThrombosisHIT
syndrome
Numbers of Patients
Warkentin TE. Br J Haematol 2003,121:535
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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
ASH State of Art symposium 2009
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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
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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
ASH State of Art symposium 2009
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Clinical Consequences of HIT
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Features of the history and physical examination that support a diagnosis of HIT
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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
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Venous Gangrene
Warkentin. Ann Intern Med. 1997;127:804-812.
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Skin Manifestations of HIT
Warkentin. Br J Haematol. 1996;92:494-497
Skin necrosis
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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
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The 4Ts: A clinical probability scoring model
High probability: 6-8 points; intermediate probability: 4-5 points,low probability: ≤3points.
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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
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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
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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.
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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
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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
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Objectives of Treatment for HIT
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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
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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
2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia ASH
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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 .
2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia ASH
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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.
2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia ASH
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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
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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.
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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:
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(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.
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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
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