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