HeparinHeparin--Induced Thrombocytopenia Induced Thrombocytopenia -- HITHIT

John R. Bartholomew, MD, FACCSection Head Vascular Medicine

Departments of Cardiovascular Medicine and Hematology/OncologyCleveland Clinic

“It don’t come easy”

HeparinHeparin

The standard of care for the management

of venous and arterial disorders

for 75 years!

Arterial Embolism Occurring During Arterial Embolism Occurring During Systemic Heparin TherapySystemic Heparin Therapy

Weismann and Tobin. Arch Surg.1958;76:219-227

6 of 10 died 6 of 10 died

Cerebral and mesenteric embolus

410Bilateral femoral artery occlusion10

Renal, Mesenteric Embolus439Popliteal Artery Thrombus9

Cerebral and renal Embolus537√Femoral Artery Embolism8

Femoral, Iliac Embolus7912Femoral Artery Thrombosis7

Popliteal, Iliac Embolus3111Pulmonary Infarct6

Acute MI, Cerebral Embolus6613Thrombophlebitis5

Femoral Embolus5811Femoral Endarterectomy4

Femoral/Popliteal Embolus2711Femoral Endarterectomy3

Femoral/Popliteal Embolus2310Thrombophlebitis2

Femoral Embolus6515√Thrombophlebitis1

ComplicationsLWCTDay Rx

Indication for UFHCase #

3 of 10 had a cerebral embolus3 of 10 had a cerebral embolus

HeparinHeparin--induced Thrombocytopeniainduced Thrombocytopenia

• A common iatrogenic “adverse reaction” to UFH or LMWH

• Affects: - 1% to 5% of patients exposed to UFH- <1% of patients exposed to LMWH- case reports with Fondaparinux exposure

• Antibody formation in as many as 8% (LMWH) to 40% (UFH)

J Vasc Surg 2003; 38: 1316-1322

8th EditionEvidence-Based Clinical Practice GuidelinesAmerican College of Chest PhysiciansHeparin-Induced Thrombocytopenia:Treatment and Prevention of pages 340S-380S

Is HIT Important?Is HIT Important?

Definition of HITDefinition of HIT

• An otherwise unexplained platelet count fall- develops 5 -14 days after UFH/LMWH exposure- thrombocytopenia defined as < 150,000 mm3

- or a 30 to 50% drop in platelets from baseline• With or without thrombosis (arterial or venous)• Platelet recovery once UFH or LMWH stopped

Temporal Patterns of HITTemporal Patterns of HIT

Heparin exposureHeparin exposure

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 21 40DaysDays

RapidRapid--onset HIT (with aonset HIT (with arecent heparin exposure)recent heparin exposure)

Typical-onset HIT (within 5 to 14 days)2/3 of all HIT cases

Delayed-onset HIT(average of 9 days after heparin

stopped)

Hours to

days

RapidRapid--Onset HITOnset HIT

Warkentin et al. NEJM. 2001;344:1286-1292.

243 HIT Patients

• 30% developed thrombocytopenia under 4 days (median time 10.5 hours)

• All patients received heparin w/in past 100 days (most w/in 30 days)

• Represents 25 to 30% of all HIT cases

NEJM 2001 344:1286-1292

DelayedDelayed--Onset HITOnset HIT

Recent UFH exposure uncomplicated

• Patient discharged home off UFH

• Readmitted

- 9 to 40 days later

- new thrombosis

± thrombocytopenia

• High titers of platelet-activating antibodies

• Represents 3%-5% of all HIT cases

Who Develops HIT?Who Develops HIT?InfluenceFactor

Proportional platelet count fall (>50%) is more sensitive than absolute count of <150,000 mm3

Definition of thrombocytopenia

Female > maleSex

>1 week of UFH or LMWH more likely Duration of treatment

Post surgery > medical > obstetrical(orthopedic, cardiovascular highest risk)

Patient Population

Bovine lung > porcine intestinal UFHUFH > LMWH

Type of Heparin

Warkentin. Br J Haematol. 2003;121:535-555.

Following exposure to UFH or LMWH during treatment for arterial orvenous disorders, prophylaxis of VTE, surgical or interventional procedures, during dialysis, in TPN solutions, heparin flushes, heparin-coated catheters

Complications of HITComplications of HIT

Deep vein thrombosisPulmonary embolism

Cerebral vein thrombosisAdrenal vein thrombosis

Venous Thrombosis Arterial Thrombosis

Acute limb ischemiaThrombotic stroke

Myocardial infarctionAortic thrombus

Renal artery thrombosisVascular graft occlusion

4 of 5 thrombotic events are venous!

Venous ThrombosisVenous Thrombosis

PE in 25% of HIT Patients

Arterial ThrombosisArterial Thrombosis

Acute limb ischemia more likely than MI or Stroke

Unusual Complications of HITUnusual Complications of HIT

• Skin lesions at heparin injection sites• Adrenal hemorrhagic infarction• Disseminated intravascular coagulation • Acute systemic reactions following IV bolus• Warfarin-associated venous limb gangrene

and/or Warfarin-associated skin necrosis

..

Adrenal hemorrhagic infarction

DICSkin necrosis at injection site

Venous limb gangrene

PFPF--4 binds to surface of4 binds to surface ofplatelet following activationplatelet following activation

PathophysiologyPathophysiology

Complexes of heparin (GAG)Complexes of heparin (GAG)and PFand PF--4 molecules form4 molecules form

IgG binds to the PFIgG binds to the PF--4/4/heparin complexheparin complex

IgG/PFIgG/PF--4/heparin complex activates4/heparin complex activatesvia the Fc receptorvia the Fc receptor

Fc stimulation leads to the generation of Fc stimulation leads to the generation of procoagulantprocoagulant--rich microparticlesrich microparticles

alpha granulealpha granule PFPF--4/heparin4/heparincomplexcomplex

IgGIgG

Fc receptorFc receptormicroparticlesmicroparticles

PlateletPlatelet

Courtesy of Dr John G. Kelton, McMaster University

PathophysiologyPathophysiology

Fc stimulation leads to the generation of procoagulant-rich microparticles

microparticles

heparan suflate

activated endothelium

activated plts Antibody binding to PF4 on endotheliumleading to activation/injury

Enhanced monocyte expression and release

of tissue factor with antibody binding

tissue factor

Courtesy of Dr John G. Kelton, McMaster University

HIT is a clinicopathologic syndrome

How do we diagnose HIT?

Estimating Pretest Probability of HIT: Four TEstimating Pretest Probability of HIT: Four T’’ss

Definite other cause is present

Possible other cause is evident

No other cause for platelet count fall is

evident

oTher causes of thrombocytopenia

not evident

NoneProgressive or recurrent thrombosis:

erythematous skin lesions; suspected thrombosis not yet

proven

New thrombosis; skin necrosis; post heparin bolus acute systemic

reaction

Thrombosis or other sequelae

(skin lesions)

Platelet count falls too early (without recent heparin exposure)

Consistent with immunization but not

clear, or onset of thrombocytopenia after

day 10

Clear onset between 5-10 days; or less than 1 day if heparin exposure

w/in past 100 days

Timing of platelet count fall or other

sequelae

Fall <30% or platelet nadir: <10,000

30-50% fall or platelet nadir: 10,000 -19,000

>50% fall or platelet nadir: 20,000 -100,000

Thrombocytopenia

Points: 0,1, 2 for each of 4 categories: Maximum possible score = 8

2 1 0

Pretest probability score: 6-8 = high, 4-5 = intermediate, 0-3 = lowBr J Haem 2003 121: 535-55

Laboratory Testing for HITLaboratory Testing for HIT

Activation assays (Functional antibodies)Activation assays Activation assays (Functional antibodies)(Functional antibodies)

Antigen assays(all antibodies)

Antigen assaysAntigen assays(all antibodies)(all antibodies)

Serotonin Release AssaySerotonin Release AssaySerotonin Release Assay

Platelet Aggregation AssayPlatelet Aggregation AssayPlatelet Aggregation Assay

Enzyme-Linked Immunoassay

(ELISA) forHeparin-PF4

EnzymeEnzyme--Linked Linked Immunoassay Immunoassay

(ELISA) for(ELISA) forHeparinHeparin--PF4PF4

Less sensitive, Less sensitive, more specificmore specific

More sensitive,More sensitive,less specificless specific

HITHIT-- What is the Risk of Thrombosis?What is the Risk of Thrombosis?

Antiphospholipid syndrome

Factor V Leiden

Protein S

Protein C

Antithrombin

HIT

Hypercoagulable State

5.4

6.6

10.9

14.4

24.1

36.9

Odds Ratio

Can J Cardiol 1995;11 (Suppl C):29C-34C

HeparinHeparin--Induced Thrombocytopenia:Induced Thrombocytopenia:Clinical Consequences if Unrecognized Clinical Consequences if Unrecognized

and/or Untreatedand/or Untreated

20-30%Death

10-20%Amputation

30-50%New Thromboses (Arterial or Venous)

Warkentin, Greinacher. Heparin-Induced Thrombocytopenia. 4th ed. 2007

Optimizing Treatment of HITOptimizing Treatment of HIT

Interrupt the immune response- DISCONTINUE heparin or LMWH immediately

- DO NOT wait for laboratory confirmation

Inhibit thrombin generation- INITIATE an alternative anticoagulant

- treat active thrombosis- prevent new thrombosis

Minimize complications- limb amputation, DVT/PE or death

Direct Thrombin InhibitorsDirect Thrombin Inhibitors

NONONOCross- reactivity with HIT antibodies

IVIV, SCIVMethod of administration

aPTTaPTTaPTTMonitoring

Proteolytic +20% Renal

RenalHepaticElimination

25 minutes1.3 hours40 - 50 minutesHalf-life in healthy subjects

Bivalirudin* semi

synthetic hirulog

Lepirudin: recombinant

hirudin

Argatroban: L-arginine derivative

Composition

*Only FDA approved for HIT in patients undergoing PCI

Guidelines for Oral Anticoagulants: HITGuidelines for Oral Anticoagulants: HIT

• Avoid warfarin until platelet count has recovered (preferably to > 150,000mm3)

• Minimum 5 day overlap with DTI (or alternative non-heparin anticoagulant)

• Begin low doses of warfarin (5 mg maximum)• Do not stop DTI until INR is = 2 for at least 2

consecutive days (minimum 5 day overlap)

Chest 2008; 133: 340S-380S (8th ACCP Guidelines)

Srinivasan et al. Arch Intern Med 2004; 164: 66-70

Venous Limb Gangrene and Skin Venous Limb Gangrene and Skin Necrosis in HITNecrosis in HIT

Treatment Principles of HITTreatment Principles of HIT

DO investigate for lower limb DVT with

ultrasound

DON’T give platelet transfusions unless bleeding develops

DO start an alternative non-

heparin anticoagulant

DO test for HIT antibodies

DON’T give Warfarin until the platelet count

recovers

DON’T place an IVC filter unless absolutely

necessary

DO stop Heparin or LMWH immediately!DO give vitamin K if Warfarin has already been started when

HIT is first recognized

TWO DIAGNOSTICS

THREE DON’TS

TWO DO’S

CHEST 2008; 126:340S -380S

How is the Neurology patient

affected?

Arterial Embolism Occurring During Arterial Embolism Occurring During Systemic Heparin TherapySystemic Heparin Therapy

Weismann and Tobin. Arch Surg.1958;76:219-227

Cerebral and mesenteric embolus

410Bilateral femoral artery occlusion10

Renal, Mesenteric Embolus439Popliteal Artery Thrombus9

Cerebral and renal Embolus537√Femoral Artery Embolism8

Femoral, Iliac Embolus7912Femoral Artery Thrombosis7

Popliteal, Iliac Embolus3111Pulmonary Infarct6

Acute MI, Cerebral Embolus6613Thrombophlebitis5

Femoral Embolus5811Femoral Endarterectomy4

Femoral/Popliteal Embolus2711Femoral Endarterectomy3

Femoral/Popliteal Embolus2310Thrombophlebitis2

Femoral Embolus6515√Thrombophlebitis1

ComplicationsLWCTDay Rx

Indication for UFHCase #

3 of 10 had a cerebral embolus3 of 10 had a cerebral embolus

Neurologic Complications of HITNeurologic Complications of HIT

• Cerebral ischemia• Cerebral venous

sinus thrombosis• Transient amnestic

confusional states• Recurrent stroke• Recurrent TIA’s• Spinal ischemia

HeparinHeparin--induced thrombocytopenia in patients induced thrombocytopenia in patients with cerebrovascular ischemic diseasewith cerebrovascular ischemic disease

• Prospective study of 137 patients treated with heparin for cerebral infarction, RIND, TIA

• 21 (15.3%) = 40% decline in their platelet count– 5 suffered extension of cerebral infarction– 3 of 5 died

• Recommended that a platelet count be performed before UFH therapy and at least every 3rd day in patients with acute ischemic strokes.

• Heparin should be discontinued if the platelet count drops by 30 to 35% of pretreament values

Neurology 1984; 34: 736-740

HeparinHeparin--Induced Thrombocytopenia and Induced Thrombocytopenia and Thrombosis in Ischemic StrokeThrombosis in Ischemic Stroke

• 2527 carotid endarterectomies• 19 occlusions occurred in 18 patients• 6 of 18 had a “heparin-induced

coagulation disorder”• “Although heparin is a useful

anticoagulant, it may precipitate occlusion of vessels after an endarterectomy procedure”

Mayo Clin Proc 1988; 63: 353-361

HeparinHeparin--Induced Induced ThrombocytopeniaThrombocytopenia

• 29 individuals with stroke due to heparin therapy

• Onset between 0.5 -14 days• Platelet count was between 7,000 – 84,000• 7 deaths• Infarcts observed in carotid and basilar

territories and 3 cases of superior sagittal sinus

Stroke 1989:20:1449-1459

Neurologic complications in immuneNeurologic complications in immune--mediated mediated heparinheparin--induced thrombocytopeniainduced thrombocytopenia

• Retrospective study of 120 patients with HIT• 11/120 (9.2%) had neurological complications

- 7 ischemic cerebrovascular events- 3 cerebral vein thrombosis- 1 transient confusional state

• Mortality was greater in patients with neurologic complications from HIT (55%) than non neurologic patients (11%)

• Predicted 1 in 1,000 patients receiving UFH will have neurologic complications due to HIT

Neurology 2000; 54: 1240-1245

HeparinHeparin--induced thrombocytopenia in induced thrombocytopenia in neurologic disease treated with heparinneurologic disease treated with heparin

• Prospective study of 200 neurologic patients receiving UFH

• 5 (2.5%) fulfilled criteria for HIT• 4/5 (2%) had HIT-associated thromboses• Prevalence heparin antibodies (41/200) (20.5%) • Increased awareness of HIT is mandatory • In cases of HIT-associated neurologic

complications - neurologists will always consider other etiologic conditions before they think of HIT

Neurology 2004: 62:657-659

HeparinHeparin--Induced Thrombocytopenia: A Serious Induced Thrombocytopenia: A Serious Complication of Heparin Therapy for Acute StrokeComplication of Heparin Therapy for Acute Stroke

• 392 of 1,078 consecutive patients with acute ischemic stroke receiving IV UFH

• 10 (0.5%) developed/suspected HIT)• 3 patients developed further thrombosis• 2 patients died • Clinical severity and outcomes were unfavorable

when compared to other acute patients• Monitoring for HIT should be part of the medical

management of stroke to avoid further complications

Cerebrovascular Disease 2008; 26: 641-649

Stroke in patients with HIT and the effect of Stroke in patients with HIT and the effect of argatroban therapyargatroban therapy

• 960 patients with HIT (largest population of HIT patients evaluated for acute stroke)

- 767 treated with argatroban- 193 historical controls

• 30 (3.1%) HIT patients had stroke- 20 (2.6%) argatroban group- 10 (5.2%) control group

• 9 strokes present at entry• 24 new strokes occurred during follow-up• 4 patients had more than one stroke

Critical Care Medicine 2004; 32:976-980

Stroke in patients with HIT and the effect of Stroke in patients with HIT and the effect of argatroban therapyargatroban therapy

• Stroke common in HIT- 3.1% of HIT patients overall and a significant predictor of death

• More often in females• Argatroban therapy vs. historical control -

significantly reduced the likelihood of new stroke and stroke-associated mortality

Critical Care Medicine 2004; 32:976-980

HIT Myths and MisconceptionsHIT Myths and Misconceptions

I can just transfuse platelets11

I can just start warfarin10

I can switch to LMWH9

I can just stop heparin8

I can wait for the lab tests to start treatment7

This can’t be HIT the patient is no longer on heparin6

This can’t be HIT (its too late) 5

This can’t be HIT (its too early following exposure)4

This can’t be HIT (the platelets are too high)3

This can’t be HIT (the platelets are too low)2

HIT is rare, I do not have to worry about it1

Arch Intern Med 2004; 1961-1964

“HIT - it don’t come easy”