David C. Sane, MD
September 25, 2015
Heparin Induced Thrombocytopenia
No Conflicts
I will mention several off label treatments for HIT
• Detail the mechanisms of heparin-induced thombocytopenia
• Review forms of heparin exposure and clinical characteristics associated with HIT
• Consider diagnostic and treatment options for managing HIT patients
Objectives
Heparin-Induced Thrombocytopenia (HIT): Broad Overview
Heparin-Induced Thrombocytopenia (HIT): Broad Overview
• Heparin Utilization :More than 1 trillion units of heparin are used each year in the United States; 1/3 of hospitalized exposed
• HIT Prevalence: up to 5% of heparin-treated patients• Consequences: ~50% of untreated HIT patients are at
risk for developing life- or limb-threatening thromboembolic complications within 30 days
• Management: immediate cessation of heparin; use alternative anticoagulant
Unfractionated Heparin use in Acute Coronary Syndromes
66% of STEMIs
42% of NSTEMIs
NCDR-ACTION registry-GWTG survey
360 hospitals, 2007-2009
JACCI: 2010; 3: 1166-1177
Prevalence of anti-PF4/heparin in Cardiac Patients
• 15.3% after PCI/stenting
• 13-20% pre-CABG; ~ 50% post-CABG
• 10.6% NSTE-ACS patients not undergoing early revascularization
Gremmel et al Clin Res Cardiol 2012; Williams et al Circulation. 2003;107:2307-2312.Bennett-Guerrero J Thorac Cardiovasc Surg 2005 Dec;130(6):1567-72.
Heparin-Induced Thrombocytopenia (HIT): Older Terminology
Heparin-Induced Thrombocytopenia (HIT): Older Terminology
HIT Type I HIT Type II• Transient, mild, non–
immune mediated
• Early onset (<4 d of heparin treatment)
• Reversible, asymptomatic (?)
• Not transient, severe, immune mediated
• Typically 4 to 14 d after start of heparin
– Can occur within 12 h with recent exposure
• Associated with thromboembolic complications; also known as HIT-T or HAT
HIT ParadoxesHIT Paradoxes
• Anticoagulant-induced thrombosis• Clotting disorder, not bleeding disorder
(Petechiae or hemorrhage considered evidence against HIT)
• Absolute thrombocytopenia not required• Platelet transfusions can increase thrombosis risk• Simply stopping heparin may not prevent thrombosis• Warfarin contraindicated as acute monotherapy• Reversal of anticoagulant effect in the setting of
thrombosis (ie., vitamin K for warfarin)
Formation of PF4-heparin complexes
IgG antibody
Formation of immune complexes(PF4-heparin-IgG)
EC injury
PF4 release
Plateletactivation*
Microparticlerelease
Fc receptor(FcRIIa)
Platelet
ECs in vessel wall
Heparin-likemolecules
Blood vessel
PF4 Heparin
Pathophysiology
Cells can be activated by PF4 bound to endogenous heparin-like molecules on their surfaces
• Platelets
• Endothelial Cells
• Monocytes
• PMNs
thus disease can progress even when heparin is stopped
Platelets
The Nature of Heparin ExposureThe Nature of Heparin Exposure
HIT can occur with any exposure to heparin• Type of heparin: UFH > LMWH (5-10 fold lower)• Bovine lung UFH > Porcine gut UFH• Dose and duration: high dose > low dose • Dose and duration of current exposure: long-term
> short-term• Route of administration: IV > SC, flushes,
catheters, heparin-coated devices (0.5%)
Clinical Factors• Age : rare < 40 years old
• Surgical (3X)> Medical > Hemodialysis (<1%) > Obstetric (<0.1%)
• Sex (female > Male) OR: 2.37
• Major trauma > Minor trauma
• Cardiopulmonary Bypass: 50% seroconversion by day 5; 2-3% incidence of HIT
Cuker and Cines Blood 2012 119; 2209-2218
Temporal Aspects and Severity of Thrombocytopenia
HIT: Temporal AspectsHIT: Temporal Aspects
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 21 40
DaysDays
Heparin exposure
Rapid-onset HIT(recent heparin exposure)
Delayed-onset HITDelayed-onset HIT( ~ 9 days after heparin is stopped)( ~ 9 days after heparin is stopped)
Typical-onset HITTypical-onset HIT(within 4 to 14 days)(within 4 to 14 days)
DIC
“Spontaneous HIT”- no prior heparin exposure
J Thromb Haemostas 2008; 6:1598-1600; J Thromb Haemostas 2009; 7:499-501;Am J Clin Pathol 2010; 134:774-780;Blood 2011;117:1370-1378; Blood 2011; 118:1395-1401
• Emerging cases of clearly documented HIT without any prior heparin exposure
• Antibodies that react to bacteria and cross react to heparin may be the culprit
?
Another Reason for Regular Dental Hygiene?
Severity of TCP in HIT: Platelet Counts in Laboratory-Confirmed
HIT May Be “Normal”
Warkentin TE. Semin Hematol. 1998;35(4):9-16.
No HIT-associated thromboses
HIT-associated thromboses
HIT-associated thromboses occurred in patients with platelet counts >150,000/mm3
Platelet Count Nadir (X1,000/mmPlatelet Count Nadir (X1,000/mm33))
Number of Number of Patients Patients With HITWith HIT
5 10 20 30 50 70 100 200 300150 500 10000
10
20
30
40
Median ~ 60KSeldom< 20K in absenceof concomitant
DIC
Heparin-Induced Thrombocytopenia:
Relative
H.I.R.T. ?
Differential Diagnosis ofThrombocytopenia in ICU Setting
Differential Diagnosis ofThrombocytopenia in ICU Setting
• Other thrombotic thrombocytopenias- Antiphospolipid antibody syndrome Malignancy associated microangiopathy TTP
• Drugs - antibiotics, H2 blockers, GP IIb/IIIa• Mechanical, eg, CABG (median 40% decline at 72 hours), intra-
arterial balloon pump, VADs• Severe infection/sepsis, DIC• Dilutional• Miscellaneous, eg, pseudothrombocytopenia (abciximab),
posttransfusion purpura
Common - 50% of all patients admitted to ICUs
Thrombocytopenia in the CCU: HIT vs GP IIb/IIIa
Thrombocytopenia in the CCU: HIT vs GP IIb/IIIa
• Timing of onset of thrombocytopenia• GP IIb/IIIa antagonist: rapid (2-31 hrs)• Typical onset HIT: 4-14 days• Rapid onset HIT: rapid (2-18 hrs)
• Severity of thrombocytopenia• GP IIb/IIIa antagonists are more likely to cause
severe thrombocytopenia (<20,000/mm3)
• Bleeding vs thrombosis
Platelet Time Course Post CABG
Day 4-5
Secondary drop after day 4-5
Persistent decline after day 4-5
BaselineCount
Anti-PF4/H: 50%HIT: 2-3%
Diagnosis
ASH Education Program 2003; 497-519
Diagnosis: Clinical Suspicion of HIT(the 4 T’s)
Laboratory Tests for HIT
“False positives”Poor-Moderate(75-86%)
High (near 100%)*
Antigen/ELISA
SRA Technically difficult;Radioactivity
HighModerate-High
Functional
WeaknessesSpecificitySensitivityAssay
HIPA Moderate- Moderate- Results vary High High Considerable
“The 5th T”: Tests
Methods to Increase the Specificity of Diagnosis while Maintaining
Sensitivity
• Perform a Clinical assessment (4T’s ≥ 4)
• Note the OD value of the ELISA (OD > 1.0)
• Use the IgG Specific ELISAs
• Is the OD reduced > 50% by adding heparin?
• Is the SRA positive (> 50% serotonin release)
Optical Density in ELISA• ELISA results reported
as measurement of optical density (OD)
• OD directly related to avidity of antibody
• Higher OD values have been shown to correlate strongly with risk of thrombosis • Up to 6x risk with OD
>1.0
Iceberg Model of HIT: Clinical HIT is “above the water line”
Warkentin TE Hematology 2011; 143-149
ELISAELISA
TCPTCP
ELISA
Special Circumstances
• Looks like HIT but ELISA negative• Rare case of antibodies to heparin/IL-8 or
heparin/NP-2• More common scenario?
anti-heparin/protamine
• ELISA positive but SRA negative• Thrombocytopenia - Consider APS (± SLE)• Not thrombocytopenia- Clinical
Consequences of non-platelet activating antibodies ?
mitral valve leaflets
with thrombotic vegetation
APS
focal, nodular,
symmetric thickening
of the mitral valve
leaflet tips
mitral regurgitation
ELISA Positive, SRA negative
-Emerging data suggest that anti-PF4/heparinantibodies increase risk of adverse outcomes including thrombosis even if these are non-platelet activating (absence of thrombocytopenia)
Formation of PF4-heparin complexes
IgG antibody
Formation of immune complexes(PF4-heparin-IgG)
EC injury
PF4 release
Plateletactivation*
Microparticlerelease
Fc receptor(FcRIIa)
Platelet
ECs in vessel wall
Heparin-likemolecules
Blood vessel
PF4 Heparin
Pathophysiology
The Iceberg Appears to be Rising Growing Evidence for Clinical Consequences of
ELISA positivity without Thrombocytopenia
So, should we test and treat more patients ? Probably not …Most Current Experts are now concerned about HIT Over-diagnosis
• Exposure of patients without HIT to
expensive anticoagulants
• Higher bleeding risks of these alternatives anticoagulants
• But… a False Negative Assay (eg. HIPA) could lead to treating a HIT patient with UFH
Integrating Clinical Probabilitywith Test Results
Clinical Manifestations and Treatment
Heparin-Induced Thrombocytopenia :Clinical Sequelae in Absence of DTI
Heparin-Induced Thrombocytopenia :Clinical Sequelae in Absence of DTI
Sequelae 30-day Incidence
New thromboses ~50%
(arterial or venous)
Amputation ~21%
Death ~30%
Warkentin TE, Kelton JG. Am J Med. ; King DJ, Kelton JG. Ann Intern Med.
Thrombosis in HIT
• Predominantly venous thrombosis (4:1) DVT PE Venous gangrene of fingers, toes MI Limb ischemia/amputation*
* Cyanosis and ischemic gangrene can occur despite preserved proximal pulses Due to diffuse microvascular disease
Atypical Manifestations of HIT• Heparin resistance• Acute Systemic Reaction (fever, chills, dyspnea,
chest pain)• Painful red plaques, skin necrosis at injection
sites• Warfarin-induced skin necrosis or limb gangrene• Adrenal venous thrombosis/ hemorrhagic
infarction• Neurological- transient global amnesia
Monitor Platelet Count + Monitor Platelet Count + Maintain Clinical Suspicion (4Ts)Maintain Clinical Suspicion (4Ts)
HIT: First Steps
Stop all forms of heparin immediatelyStop all forms of heparin immediately
Strongly consider anticoagulation with DTIStrongly consider anticoagulation with DTIDO NOT DELAY TREATMENT – Clinical DxDO NOT DELAY TREATMENT – Clinical Dx
1. Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia.
Perform confirmatory tests;Perform confirmatory tests;Assess Lower Limbs for DVTAssess Lower Limbs for DVT
If HIT > 1% monitor Q2-3 days
Days 4-14 or until heparin is
stoppedACCP, 2C
Lepirudin (Refludan®)
Indication: HIT with TECDose: Bolus of 0.2 mg/kg**, then 0.10 mg/kg/hr to keep aPTT 1.5-2.5 X controlReduce dose with renal insufficiency Half-life: 1.7 hoursAntibodies form in ~ 50%; increase plasma level (Anaphylaxis in ~ 0.2% after re-exposure). Monitoring: aPTT or ECTAntidote: None
Bayer Health Care discontinued Refludan injection on May 31, 2012. This was a business decision and not due to safety concerns.
Not availableIn USA
Not FDA ApprovedFor HIT
Not FDA ApprovedFor HIT
Fondaparinux for treatment of HIT
Warkentin TE Hematology 2011; 143-149.
AnticoagulantsNot to Be Used in Acute HIT
• Warfarin• Not acceptable as monotherapy• Increases risk for venous limb gangrene and
skin necrosis (suppression of protein C/S)• Co-therapy may limit achieving full
anticoagulation with DTI
• LMWH• Crossreactivity (~100%) with heparin
antibodies
Warfarin and HIT
• If warfarin has already been started when a patient is diagnosed with HIT, vitamin K should be administered (Grade 2C).
Transitioning to Warfarin
Special Considerations for Argatroban Warfarin
How long to anticoagulate for “Isolated HIT” (TCP without TEC) ?
Cardiac Cath and PCI(ACCP recommendations)
Cardiac and Vascular Surgery(ACCP recommendations)
Dabigatran (Pradaxa®)
Rivaroxaban(Xarelto®)
Apixaban(Eliquis®)
EdoxabanSavaysa®)
NVAF FDA Approved
FDA Approved
FDA Approved
FDA Approved
VTE treatment
FDA Approved
FDA Approved
FDA Approved
Applied for approval
VTE prevention, Ortho surgery
Not Approved
FDA Approved
FDA Approved
Not Approved
ACS Not approved
Approval Denied
APPRAISE-2 stopped early
Not Approved
HIT Not Approved
Not Approved
Not Approved
Not Approved
NOAC Indications
Questions and Discussion
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