Heparin-Induced Thrombocytopenia

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Heparin-Induced Thrombocytopenia

• Neil A. Lachant, MD
• Chief, Section of Hematology
• Director, Thrombosis Program
• Associate Director, Hematologic Malignancy
  Program
• Cooper Cancer Institute
• Professor of Medicine
• UMDNJ Robert Wood Johnson Medical School

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Aventis (lovenox) GlaxoSmithKline (arixtra,
argatroban)
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Why Care About HIT?

• Moderate thrombocytopenia
• No bleeding

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Why Care About HIT?

• Moderate thrombocytopenia
• No bleeding
• Devastating thrombosis
• Highest thrombotic risk of any known
  hypercoaguable state
• 6 per day awaiting therapy on HAT studies
• 18 - 52 thrombosis if identified patients not
  anticoagulated

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• Need to identify HIT patients before
  devastating thrombotic events occur!

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Risk of HIT

• High (gt1)
• full dose UFH
• post-op receiving UFH prophylaxis
• Intermediate (0.1 1)
• medical patients receiving UFH prophylaxis
• post-op receiving LMWH
• Low (lt0.1)
• Medical or pregnant patients receiving LMWH

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Natural History Of HIT

• After discontinuation of heparin
• platelets rise in days (4-5) to weeks
• antibody detectable for months
• HIT may present in 3 time periods

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Typical Onset HIT

• 5 - 15 days after beginning heparin exposure
• day heparin started day 0
• ? 65 of all HIT

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Rapid Onset HIT

• Minutes to day(s) after heparin started
• Recent heparin exposure (lt100 days)
• Cath ? CABG
• Abrupt onset of platelet activation due to
  residual circulating HIT antibodies
• not anamnestic response
• ? 25 - 30 of all HIT

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Delayed Onset HIT

• Recent uncomplicated heparin exposure
• especially cardiac or orthopedic surgery
• often additional remote heparin exposure
• Presents as thrombosis
• 12 (5-40) days after heparin discontinued
• after discharge from hospital
• platelets often normal
• diagnosis often missed
• ? 5 of all HIT
• likely underdiagnosed

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Clinical Picture Of HITT

• Venousarterial thrombi 41
• Low risk
• dialysis, children, pregnancy, cancer
• Bleeding uncommon

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Clinical Sequelae in HIT

• Sequelae Incidence
• New thrombosis 30 to 50
• 41 incidence ratio venous to arterial
• Amputation 20
• associated with arterial thrombosis
• Death 30
• associated with arterial thrombosis

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Venous Thromboembolic Consequences of HIT

• DVT
• Pulmonary embolism
• Cerebral sinus thrombosis
• Limb gangrene
• Skin necrosis at injection sites
• Adrenal hemorrhage

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Arterial Thromboembolic Consequences of HIT

• Extremities
• aortic-iliofemoral
• upper
• CVA
• MI

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Arterial Thromboembolic Consequences of HIT

• Unusual
• spinal
• renal
• mesenteric

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Acute Systemic Reaction Caused By IV Heparin Bolus

• The following can occur in patients sensitized to
  heparin within 5-30 minutes
• fever, chills
• tachycardia, hypertension
• flushing, headache
• chest pain, dyspnea
• nausea, vomiting, diarrhea
• transient global amnesia
• sudden anaphylactoid death

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Pathophysiology Of HIT-II

• Activated platelets express PF4
• Heparin binds PF4 causing a steric change in PF4
• chain length and sulphation critical determinants
• IgG binds to the heparin-PF4 complex
• does not bind heparin or PF4 alone
• IgG binds FCR?II
• 1000-2000 per platelet
• FCR?II activates platelets
• Activated platelets release thrombogenic
  microparticles
• No association of HITT with common thrombophilias

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Iceberg Model of HIT
Thrombosis 0.020.5 Thrombocytopenia
3 Platelet activating antibody 2-20 Antibody
formation 350
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Iceberg Model of HIT
Thrombosis 0.020.5 Thrombocytopenia
3 Platelet activating antibody 2-20 Antibody
formation 350
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The Diagnosis of HIT

• The diagnosis of HIT is clinicopathologic
• clinical setting
• laboratory testing

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When Should You Consider HIT?

• During/soon after heparin exposure
• and

• When a patient...
• experiences a drop in platelet count
• develops thrombosis

Heparin exposure may be through any preparation
(including LMWH), at any dose, and by any route
(including flushes and coated lines)
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Distribution of Platelet Count
Warkentin. Semin Hematol 35(4)9-16, 1998.
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Clinical Criteria For HIT(HIT until proven
otherwise)

• 1. Current use of heparin or heparin exposure
  within 40 d
• 2. At least 1 of the following
• a. Platelets lt 100,000/ul
• b. Platelets lt 50 of baseline or lt 50 of
  maximum level if reactive thrombocytosis present
• c. Platelets lt baseline 5 days after open heart
  surgery
• d. New arterial or venous thrombotic event
• e. Inflammation or necrosis at heparin injection
  sites
• f. Acute allergic or anaphylactic reaction to
  heparin bolus

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• Consider HIT in any patient who has recently been
  hospitalized, been in rehab, etc. who
• 1. Develops any thromboembolic or ischemic
  event, or
• 2. Develops otherwise unexplained
  thrombocytopenia

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Differential Diagnosis Of HIT

• Sick patients, often postoperative with multiple
  complications
• Differential diagnosis
• pseudothrombocytopenia
• bacteremia/sepsis
• pulmonary emboli with DIC
• drug-induced thrombocytopenia
• DIC
• bleeding/hematoma
• IABP, LVAD destruction
• cholesterol emboli
• post-transfusion thrombocytopenia
• APLS

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Drug-Induced Thrombocytopenia

• Platelets on the Web
• http//w3.ouhsc.edu/platelets/index.html
• google platelets on the web
• Updated through October 2008

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Pretest Probability
(gt 80)
(lt5)
Warkentin Curr Hematol Rep 2148, 2003
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Pretest Probability
(gt 80)
(lt5)
Warkentin Curr Hematol Rep 2148, 2003 Circ
110454, 2004
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Pretest Probability
(gt 80)
(lt5)
Warkentin Curr Hematol Rep 2148, 2003 Circ
110454, 2004
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Laboratory Evaluation Of Suspected HIT-II

• Retrospective confirmation of diagnosis
• dont wait for testing result
• act on clinical suspicion
• No gold standard

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Laboratory Evaluation Of Suspected HIT

• Immunologic
• best for screening
• Biologic
• best used as confirmatory test

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Laboratory Evaluation Of Suspected HITELISA

• Immunologic
• ELISA
• rapid
• can do large numbers of tests
• may be too sensitive (IgG, IgM, IgA)
• only measures Ig and heparin-PF4 complexes
• need OD reading
• does not correlate well with SRA

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ELISA Positivity After Heparin Exposure(Remember
the icebergs!)

• Positive ELISA after heparin exposure without
  thrombocytopenia or clinical evidence of HIT
• 45 cardiac surgery
• 20 peripheral vascular surgery
• 17 PCI
• 10 - 15 general medical patients
• 3 - 4 dialysis

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Discordance Between The Two Commercially
Available ELISA Assays
Test A
28 discordance
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Laboratory Evaluation Of Suspected HITBiologic
Assays

• Biologic assays
• seratonin release (SRA)
• ? best predictive value
• reference labs
• flow cytometry
• undergoing evaluation

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Seratonin Release Assay

• All home brew methods
• no commercial kits
• not FDA approved
• no performance standards
• Require fresh platelets
• reactive donor platelets vary from day to day
• Interobserver variability between labs
• Persnickety lab directors

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The Bottom Line

• The diagnosis of HIT is clinicopathologic
• clinical setting
• laboratory testing

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The Bottom Line

• Low clinical suspicion and negative testing makes
  diagnosis of HIT unlikely
• High clinical suspicion and positive testing
  confirms diagnosis of HIT
• Otherwise
• balance clinical gestalt vs lab testing
• err on side of treating with DTI if no
  contraindication

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Every Case of HIT is a DISASTERWaiting to Happen

• (If not a disaster already)
• Larry Rice, MD

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Treatment Goals Based on Pathophysiology and
Clinical Manifestations of HIT

• Interrupt the immune response
• discontinue heparin
• Inhibit thrombin generation
• treat active thrombosis
• prevent new thrombosis

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Simplified Coagulation Cascade
Fondaparinux
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Simplified Coagulation Cascade
Fondaparinux
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Simplified Coagulation Cascade
Fondaparinux
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Initial Management Of HIT

• Discontinue heparin
• Remove heparin coated catheters
• Anticoagulate dialysis/pheresis catheters with 4
  citrate or tPA
• Do not initiate LMWH
• Do not initiate coumadin
• Avoid platelet transfusions
• Assess need for immediate anticoagulation
• versus emergent intervention

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Venous Limb Gangrene
Warkentin et al. Ann Intern Med 1997127804812.
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Therapy Of HIT(T)

• Initiate direct thrombin inhibitor
• Initiate low dose coumadin day 3-5 when platelets
  gt150,000/ul
• D/C DTI when INR therapeutic
• Minimum 5 day overlap with DTI
• Continue therapy until antibody negative

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Direct Thrombin InhibitorsPharmacologic and
Clinical Parameters
Argatroban
Lepirudin
Bivalirudin
Composition Synthetic L-arginine derivative Recombinant hirudin Semisynthetic hirulog
Half-life in healthy subjects 40-50 min 1.3-3 hrs 25-40 min
Elimination Hepatic Renal Renal
Monitoring needed aPTT, ACT aPTT aPTT, ACT
Thrombin-binding Reversible Irreversible Partially Reversible
Clot-bound thrombin Inhibition Inhibition Inhibition
Based on in vitro data. aPTTactivated partial
thromboplastin time ACTactivated clotting
time. Adapted from Chen. Heart Dis.
20003189-198.
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Hirudin

• Dose depends upon hirudin type
• Lepirudin (Refludan)
• package insert
• DVT/PE
• if aPTT and renal function normal
• 0.4 mg/kg iv bolus (15-20 s)
• 0.15mg/kg/hr iv constant infusion
• new recommendation
• no bolus
• 0.10 mg/kg/hr iv constant infusion

Chest, June 2008
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HirudinRenal Dose Adjusment
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Hirudin

• Monitor
• aPTT
• goal 1.5 - 2.5 x midnormal control
• check 4 hr after each dose change

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Development of Anti-Hirudin Antibodies in HAT-1
and HAT-2

• 40 develop IgG antibodies
• No effect on clinical outcome
• Delayed renal excretion
• increased anticoagulant effect after 1 week
• monitor PTT daily
• Rare anaphylactic reactions to re-exposure
• Re-exposure to lepirudin not recommended

Chest, June 2008
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Argatroban Dosing for Prophylaxis and Treatment
of HIT/HITTS
Dose Adjustment
Patient Condition
Initial Dose
HIT/HITTS
Titrate until steady-state aPTT is 1.5-3.0
times baseline value
2 mcg/kg/min
HIT/HITTS with renal impairment
HIT/HITTS with hepatic impairment
0.5 mcg/kg/min
As a result of an approximate 4-fold decrease in
Argatroban clearance relative to those with
normal hepatic function. Not to exceed a dose of
10 mcg/kg/min or aPTT of 100 seconds. Argatroban
Injection prescribing information.
GlaxoSmithKline 2003.
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Initial Dose Reduction

• 0.5 1.2 mcg/kg/min
• CHF
• Multiorgan failure
• Severe anasarca
• Open heart

Chest, June 2008
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Argatroban

• Monitor
• aPTT
• goal 1.5 - 2.5 x patients baseline
• check 2 hr after each dose change
• check 4-6 hr after each dose change if impaired
  hepatic function

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Conversion to Oral Anticoagulant Therapy

• All DTIs, especially Argatroban, increase
  prothrombin time (PT) and INR
• Important to remember when converting to warfarin
  therapy
• Co-administration of Argatroban and warfarin
  produces a combined effect on the laboratory
  measurement of the INR
• Concurrent therapy with Argatroban and warfarin
  has no further reduction in vitamin K?dependent
  factor Xa activity
• An INR of 4 on cotherapy does not have the same
  bleeding risk as an INR of 4 on warfarin
  monotherapy

Sheth et al. Thromb Haemost. 200185435-440.
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Transitioning from Argatroban to Warfarin

• Retrospective analysis of 165 HIT patients who
  received Argatroban and transitioned to warfarin
  (overlap for median of 4 days)
• Median aPTTs and INRs respectively
• aPTT INR
• monotherapy 59.8 (38.8-82.9) 3.2 (1.7-7.0)
• cotherapy 68.6 (44.5-104) 5.3 (2.4-16.0)
• Major Bleeding
• occurred in 1 patient prior to transition
  postoperatively
• no patients during or after cotherapy
• In this clinical trial, INRs gt 5 commonly
  occurred in HIT patients during Argatroban
  monotherpay and cotherapy with warfarin, but
  these were not associated with an increase in
  major bleeding

Hursting M, Lewis B, Macfarlane D. Transitioning
from Argatroban to Warfarin Therapy in Patients
with Heparin-induced Thrombocytopenia. Clinical
Applied Thrombosis/Hemostasis. In Press 2004.
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Guidelines for Conversion to Oral Anticoagulant
Therapy
Initiate warfarin therapy using the expected
daily dose of warfarin while maintaining
argatroban infusion. A loading dose of
warfarin should not be used
Measure INR daily
If INR is gt4.0, stop argatroban infusion
If INR is ?4.0,continue concomitant therapy
Repeat INR 46 hours later
If INR is below the therapeutic range for
warfarin alone, resume argatroban therapy
If INR is within therapeutic range on warfarin
alone, continue warfarin monotherapy
For argatroban infusion at ?2 µg/kg/min, the
INR on monotherapy may be estimated from the INR
on cotherapy (see prescribing information). If
the dose of argatroban is gt2 ?g/kg/min,
temporarily reduce to a dose of 2 ?g/kg/min 46
hours prior to measuring the INR.  
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2008 ACCP Guidelines for Conversion to Oral
Anticoagulant Therapy

• Continue DTI infusion
• Monitor chromogenic factor X assay
• Continue argatroban until factor X lt 45

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Monitoring And Prevention Of HIT

• Avoid unnecessary heparin
• e.g., flushes, coated catheters

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Monitoring and Prevention of HIT

• High Risk (gt1)
• full dose UFH
• post-op receiving UFH prophylaxis
• Intermediate Risk (0.1 1)
• medical patients receiving UFH prophylaxis
• post-op receiving LMWH
• Low Risk (lt0.1)
• Medical or pregnant patients receiving LMWH

• Daily CBC
• Q 2-3 days between days 4 and 14
• No monitoring

Consultative Hemostasis and Thrombosis, 2007
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