The HITS Keep Coming

Marc J. Kahn, MD, MBA, FACPPeterman-Prosser Professor

Tulane University School of MedicineNew Orleans, LA

Clinical Case

You are asked to see a 43 year old women following bilateral elbow fractures with new onset thrombocytopenia. The patient suffered a fall in a dog park and sustained bilateral radial and ulnar fractures requiring open reduction. She has a history of antiphospholipid antibody syndrome and is maintained on warfarin. Her platelet count fell from 290K to 50 K over five days. She is asymptomatic.

Definitions

• Lupus anticoagulant: prolongation of a clotting time (aPTT, DRVVT)

• Antiphospholipid Antibody: antibodies to cardiolipin, phospholipid, or b2GP1

• APLA Syndrome: thrombosis with APLA

Lupus Anticoag Anti cardiolipin AB

Anti b2GP1

Anti phospholipid AB

Antiphospholipid Antibody Syndrome

• High rate of arterial and venous thrombosis– 32% DVT– 9% PE– 13% CVA– 8% fetal loss

• 5-15% warfarin failure in preventing recurrence

Ann Rheum Dis. 2011

Management of APLAS

• INR 2.0 to 3.0• INR 3.0 to 4.0 is NOT better*• Indefinite anticoagulation

*J Thromb Haemost. 2005;3:848-53.

Thrombocytopenia and APLAb

• Estimated that up to 25% patients with thrombocytopenia may have APLAb

• Nearly 25% patients with APLAb have thrombocytopenia

Our Patient’s Platelets

2-Nov

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DDx of Thrombocytopenia

• Drug induced• Heparin Induced• Sepsis/DIC• TTP• Catastrophic APLA syndrome• Not routine APLA due to sudden drop

Copyright © 2011 American Society of Hematology. Copyright restrictions may apply.

John Lazarchick, ASH Image Bank 2011; 2011-1376

Peripheral smear

Ruled out diagnosis

• TTP• DIC/Sepsis• Catastrophic APLAS

Heparin Induced Thrombocytopenia

• Occurs 5 or more days after heparin therapy• Can occur faster in patients with prior

exposure (Warkentin NEJM 2001;344:1286)• estimated to occur in up to 3% patients

treated with unfractionated heparin• 24-fold increased relative risk of thrombosis

Representative Case of Typical-Onset Heparin-Induced Thrombocytopenia, Followed by a Rapid-Onset Episode.

Warkentin TE, Kelton JG. N Engl J Med 2001;344:1286-1292.

HITT pathophysiology

P

PF4 + heparin

IgG

Platelet activation, aggregation and clearance

Aster RH. N Engl J Med 1995;332:1374-1376.

Platelet factor 4 (PF4)

• Expressed in megakaryocytes• stored in platelet a-granules• highest heparin affinity of any platelet basic

protein derived compound• physiologic function remains unknown

– ? Role in thrombosis– ? Role in platelet recovery after radiation

• chemokine class of molecule

4 T’s

• Thrombocytopenia (>50% fall)• Timing (5 to 10 days after heparin)• Thrombosis (new)• Thrombocytopenia from other causes• Very HIGH negative predictive value

J Thromb Haemost 2006;4:759

HIT workup

• ELISA for heparin/platelet factor 4 antibodies– Sensitivity = >90%– Specificity = 24-90%

• Functional serotonin release assay– Sensitivity > 90%– Specificity>90%

14C-serotonin release assay

+ 14C-serotonin + pt. serum + heparin

DPM

[heparin]0.1 0.2

Management of HIT

• Need for anticoagulation• AVOID WARFARIN as initial therapy• Argatroban• Lepirudin• Bivalirudin (off-label)• Fondaparinux (off-label)

Warfarin and HITT

• Associated with venous limb gangrene– Warkentin, et al. Ann Int Med 1997;127:804.

Factor Half-life (hrs)

II 72

VII 8

IX 24

X 39

Protein C 14

Protein S 42

Argatroban

• Small molecule direct thrombin inhibitor• Licensed by FDA for HIT in 2000• IV infusion• Follow aPTT• Also increases PT• Metabolized by the liver

Lepirudin (Refludan®)

• Direct thrombin inhibitor• Recombinant hirudin from medicinal leech• IV infusion• Follow aPTT• Cleared by the kidney

Bivalirudin (Angiomax®)

• Direct thrombin inhibitor• Synthetic congener of naturally occurring

leech anticoagulant• IV infusion• Cleared by kidney• Follow aPTT• Not FDA approved for treatment of HIT

Fondaparinux (Arixtra®)

• Synthetic pentasaccharide Xa inhibitor• subQ daily injection• Renal excretion• If monitoring necessary, anti Xa assay• Not FDA approved for treatment of HIT

Low molecular weight heparin

antithrombin Factor Xa

Thrombin

Unfractionated heparin Low mol wt heparin

Low molecular weight heparins

• Less likely to cause HIT than UFH• But, in one study, 62% of HIT cases caused by

dalteparin (Semin Thromb Hemost. 2011;37:653)

• Best avoided in setting of HIT

Thrombosis in hospitalized patients

• HIT• APLA Syndrome• Trauma• Brain injury• Pelvic surgery• Orthopedic surgery• Pregnancy• Cancer

VT Prevention in Medical Patients

• Importance of risk stratification• No difference in outcomes between LMWH

and UFH• Mechanical prophylaxis provided no benefit

with harm in stroke patients

Ann Int Med. 2011;155:602.

Platelet transfusion

• Bleeding very uncommon in HIT• Transfused platelets can cause aggregation

and thrombosis• Platelet transfusions are to be avoided in HIT

unless significant bleeding

Back to the Patient

Heparin-PF4 ELISA NEGATIVESerotonin Release Assay POSITIVEClinically consistent with HITTreated with Fondaparinux

When to start warfarin?

Platelet counts

11-Nov

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Patient

• Warfarin started when platelet count normalized

• Fondaprinux stopped when INR >3.0• Patient D/C from hospital without thrombosis

or bleeding• Returned to work on warfarin

How often do we need to monitor INR?

Warfarin monitoring every 12 weeks is not inferior to monitoring every 4 weeks in patients on stable warfarin doses.

Schulman S, Parpia S, Stewart C, et al. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Ann Intern Med. 2011;155(10):653-9,

12 week monitoring

• Patients stable for 6 months• Otherwise uncomplicated patients

Pearls

• Antiphospholipid antibodies increase risk for arterial and venous thrombosis

• Typical patient with APLAS requires INR 2.0 to 3.0

• Clinical suspicion important in diagnosis HIT• AVOID WARFARIN with acute HIT• HIT requires anticoagulation

Questions