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Heparin Induced

Thrombocytopenia2009

Robert D. McBane II

Division of Cardiology

Gonda Vascular CenterMayo Clinic Rochester

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Disclosure Information

Heparin Induced ThrombocytopeniaRobert McBane, MD

None

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Resources

Treatment and Prevention of Heparin-Induced

Thrombocytopenia: Evidence-Based Clinical Practice

Guidelines American College of Chest Physicians

http://www.chestjournal.org/cgi/reprint/133/6_suppl/340S

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Objectives

Background Recognition

Diagnosis Management

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Prothrombotic nature of HIT:

Comparison with other thrombophilia

Thrombophilia Odds ratio for thrombosis

HIT 36.9

Factor V Leiden 6.6

Protein C deficiency 14.4 Protein S deficiency 10.9

AT deficiency 24.1

Dysfibrinogenemia 11.3

Lupus anticoagulant 5.4

Warkentin:1995,2

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Pathophysiology of H.I.T.

GAG

Endothelium

PF4

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GAG

Endothelium

PF4

Heparin PF4:Heparin

Complexes

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HIT antibodies

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Platelet

FC

Receptor

a

granule

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Case 1

76 year old male

3 month history of progressive chest pain

3 day history of angina at rest Admitted to Cardiology service

No prior medical assessment

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Case 1

0

100

150

200

250

300

PlateletC

ount(x109/L)

50

1 2 3 4 5 6 7 8 9 10 11

Heparin

Days

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Case 1

The next most appropriate step in this patients

management would be:

1. Stop all heparin products

2. Obtain Heparin-platelet factor 4 ELISA

3. Begin direct thrombin inhibitor

4. No change in anticoagulants is necessary

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Case 1

The next most appropriate step in this patients

management would be:

1. Stop all heparin products

2. Obtain Heparin-platelet factor 4 ELISA

3. Begin direct thrombin inhibitor

4. No change in anticoagulants is necessary

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Heparin-Induced Thrombocytopenia

Type I: Non-immune

t ~1-4 days

Platelets 100-150,000

Recovery despite heparin

Not symptomatic

Platelet agglutination

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HIT Terminology

Isolated HIT: Type II, Immune thrombocytopeniaAsymptomatic

Onset ~ 514 days

Thrombocytopenia persists until heparin stopped

HITT: HIT thrombosis

Arterial or venous thromboembolismnew / progressiv

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H.I.T.: Clinical SpectrumVenous Thrombosis

Arterial Thrombosis

Miscellaneous

DVTPE

Phlegmasia Dolens

Cerebral Sinus Thrombosis

50%25%

5%

Rare

Acute Limb Ischemia

Stroke

MI

Mesenteric Ischemia

10%

5%

5%

Rare

Adrenal Hemorrhage

Heparin Skin Necrosis

Rare

Rare

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Case 2

62 y/o woman Right ovarian mass

Preoperative workup:

Severe mitral valve stenosis MVR: metallic prosthesis

Chronic warfarin

One month later admitted for TAH-BSO

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Case 2

Admitted to Gynecology service for

transitioning warfarin to UFH

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Case 3

0

100

150

200

250

300

PlateletC

ount(x109/L

)

50

1 2 3 4 5 6 7 8 9 10 11

Heparin

Days

Lepirudin > warfarin

Thrombotic

Stroke

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HIT Terminology

Rapid Onset HIT (2530%) Occurs < 24 hours after exposure

History of prior heparin exposure within past 100 days

Results from circulating HIT antibodies Notamnestic response

Check baseline CBC and repeat within 24 hours if priorheparin exposure (within 100 days)

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Case 3

74 yr Male

3/21 Right Total Knee Arthroplasty

(DVT prophylaxis: Unfractionate Heparin, SCDs, Teds)

3/23 Physical therapy initiated

3/28 Uneventful hospital discharge

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Case 3

4/3 Develops cough and slight dyspnea

4/4 Notes right leg swelling

US Extensive DVT

CTA Multiple PE

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Case 3

Management options in the ED include:

1. Initiate outpatient LMW-heparin

2. Admit for inpatient Unfractionated heparin

3. Admit for argatroban therapy

4. Obtain Heparin PF 4 antibodies

5. Need more clinical information

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Case 3

Management options in the ED include:

1. Initiate outpatient LMW-heparin

2. Admit for inpatient Unfractionated heparin

3. Admit for argatroban therapy

4. Obtain Heparin PF 4 antibodies

5. Need more clinical information

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Case 3

Laboratory Assessment: CBC: Hgb 11.0

WBC 8.1

Platelet 132

Creatinine: 1.2

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Case 3

0

150

225

300

375

425

PlateletCount(x109/L

)

75

1 2 3 4 5 6 7 8 9 10 11

Days

HIT T i l

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HIT Terminology

Delayed Onset HIT (3-5%) Occurs several days after heparin discontinued

Always obtain platelet count prior to starting heparin

Review history for heparin exposure (past 100 days)and recent platelet data

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Objectives



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Immune H.I.T. Type II

Is thereThrombocytopenia > 50% fall

Nadir 20-100

Timing 5-10 days

< 1day (prior heparin)

Thrombosis New eventSkin necrosis

Other causes None

Look for

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Heparin PF4 ELISA

Sensitivity > 90%

Specificity ~ 50%

Relatively easily performed

False negative: heparin therapy

Obj i

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Objectives



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Case 5

75 year old woman

Admitted with community acquired pneumonia

Received subcutaneous UFH prophylaxis

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Case 5

0

100

150

200

250

300

PlateletCount(x109/L

)

50

1 2 3 4 5 6 7 8 9 10 11

Heparin

Days

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Case 5

1. Start enoxaparin now

2. Start argatroban now

3. Start argatroban and warfarin now

4. Search for thrombosis and if present start lepirudin

The heparin PF-4 ELISA was strongly positive,consistent with the diagnosis of isolated HIT. After

stopping all heparin, which of the following is the most

acceptable next step?

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Case 5

1. Start enoxaparin now

2. Start argatroban now

3. Start argatroban and warfarin now

4. Search for thrombosis and if present start lepirudin

The heparin PF-4 ELISA was strongly positive,consistent with the diagnosis of isolated HIT. After

stopping all heparin, which of the following is the most

acceptable next step?

Natural History of H I T

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0

20

40

60

80

100

Natural History of H.I.T.

CumulativeThrombotic

Eve

ntRate

2 6 10 14 18 22 26 30Days after Diagnosis of H.I.T.

52.8%

Am J Med 96;10

HIT Treatment

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HIT Treatment

Argatroban

Hepatic excretion

Lepirudin

Renal excretionWarfarin

Do not start until platelet count >100

Do not load (max dose 5 mg) Overlap with DTI for 5 days

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Case 6

1. Proceed with CABG now using argatroban

2. Proceed with CABG now using bivalirudin

3. Proceed with CABG now using lepirudin

4. Postpone for 3 months and repeat ELISA

5. Repeat ELISA now

74 year old male with recent outside diagnosis of HIT.

He is transferred to your cardiovascular service with

progressive angina. Coronary angiography discloses

severe three vessel disease with EF 35%. Which of the

following is the most acceptable next step?

C

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Case 6

1. Proceed with CABG now using argatroban

2. Proceed with CABG now using bivalirudin

3. Proceed with CABG now using lepirudin

4. Postpone for 3 months and repeat ELISA

5. Repeat ELISA now

74 year old male with recent outside diagnosis of HIT.

He is transferred to your cardiovascular service with

progressive angina. Coronary angiography discloses

severe three vessel disease with EF 35%. Which of the

following is the most acceptable next step?

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HIT and Cardiopulmonary Bypass

HIT antibodies

Weak or undetected by 100 days

Not regenerated with brief re-exposure Restrict heparin to CPB use onlysafe*

*Nuttall et al. Anesth Analg. 2003 Feb;96(2):344-50

Patients With Prior HIT Undergoing

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Patients With PriorHIT Undergoing

Cardiac or Vascular Surgery

HIT ELISA antibody negative

UFH is preferred over a non-heparin anticoagula

(Grade 1B).

CHEST 2008; 133:340S380S

Patients With PriorHIT Undergoing

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at e ts t o U de go g


ELISA positive but platelet activation assay negativ

UFH is preferred over a non-heparin anticoagula

(Grade 2C).

Preoperative and postoperative anticoagulation, indicated, should be given with a non-heparin

anticoagulant.

CHEST 2008; 133:340S380S

Patients WithAcuteHIT Undergoing

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g g


ELISA positive :

Delay surgery (if possible) until HIT has resolved

and antibodies are negative [Grade 1B]

Bivalirudin [Grade 1B]

Lepirudin [Grade 2C]

CHEST 2008; 133:340S380S

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Bivalirudin (Angiomax)

Direct thrombin inhibitor

Short T: 25 min

Proteolytic inactivation

minor renal excretion (20%)

ACT monitored

Several Studies

EVOLUTION-OFF EVOLUTION-ON

J Thorac Cardiovasc Surg 2006; 131:686

J Thorac Cardiovasc Surg 2006; 131:533

Bivalirudin during cardiopulmonary bypass in

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a ud du g ca d opu o a y bypass

patients with HIT: CHOOSE-ON trial

Open-label,multicenter

49 patients

On pump

Ann Thorac Surg 2007; 83:572

Primary endpoints (day 7/discharge)Death 1 (2.0%)

Q-wave MI 0 (0.0%)

Revascularization 1 (2.0%)

Stroke 1 (2.0%)

Intra op blood loss 575524 m

24 hr blood loss 998595 m

Transfusion

RBC 4.75.3 U

Plts 6.58.8 U

FFP 5.85.5 U

Off-Pump Coronary Artery Bypass With Bivalirudin

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p y y yp

for patients with HIT: CHOOSE-OFF trial

Open-label,multicenter

51 patients

Off pump

Ann Thorac Surg. 2007;84:836

Primary endpoints (day 7/discharge)Death 0

Q-wave MI 3 (6%)

Revascularization 0

Stroke 1 (2.0%)

Intra op blood loss 404420 ml

24 hr blood loss 936525 ml

Transfusion

RBC 5.63.8 U

Plts 8.67.2 UFFP 6.04.7 U

Heparin Induced Thrombocytopenia

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p y p

AfterCardiac Surgery

When to think of HIT post CPB:

Platelet count falls by >50%

New thrombotic event Especially between days 5 and 14

Perform pre-test probability assessment

[Grade 1C]

CHEST 2008; 133:340S380S

Conclusion

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Immune mediated

Common

Clinically importantthrombosis riskAwarenessmonitor platelet count

Conclusion

HIT 2009 Final

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