Heparin induced thrombocytopenia

By: Boushra Al Saoor, PharmD intern, Al Maarefa college

20 May 2015

Definition:•Heparin-induced thrombocytopenia (HIT) is a life-

threatening complication of exposure to heparin (ie, unfractionated heparin, low molecular weight [LMW] heparin) that occurs in up to 5 percent of patients exposed, regardless of the dose, schedule, or route of administration.

Types of HIT:HIT type I (HIT I): is a mild, transient drop in platelet count that typically occurs within the first two days of heparin exposure.

The platelet count typically returns to normal with continued heparin administration.

Direct effect of heparin on platelets by non-immune-mediated platelet aggregation.

Not clinically significant.

Types of HIT:•HIT type II (HIT II)  an immune-mediated disorder that

typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications.

In general medical practice, the term HIT refers to type 2 HIT

Mortality/Morbidity

•20-50% risk of developing new thromboembolic events.

•10% of patients require amputations or suffer other major morbidity.

•The mortality rate is approximately 20%.

Pathophysiology(mechanism of HIT):

Courtesy of Laura Ibsen, MD.

RISK FACTORS1. Unfractionated versus LMW heparin

• UH >LMW in surgical patients.

2. Heparin dose:

• Therapeutic doses > prophylactic doses>very high doses.

3. Sex:

• female=2×male taking UH .

4. Surgery 

• Surgical patients >medical patients (possibly due to the vascular trauma of surgery).

Complications:1. Deep venous thrombosis2. Pulmonary embolism3. Myocardial infarction4. Occlusion of limb arteries (possibly resulting in amputation)5. Transient ischemic attack and stroke6. Skin necrosis7. End-organ damage (eg, adrenal, bowel, spleen, gallbladder,

or hepatic infarction; renal failure)8. Bleeding (rare)9. Death

Diagnosis:•Quick presumptive judgment using 4 Ts.

•Definitive diagnosis by clinical features supported by laboratory testing.

HIT suspicion:•It must be suspected when a patient who is receiving

heparin has a decrease in the platelet count, particularly if the fall is over 50% of the baseline count, even if the platelet count nadir remains above 150 x 109/L. 

Evaluation: 4Ts Feature Score

2 points 1 point 0 pointsThrombocytopenia >50% fall 

andplatelet nadir 20-100 × 109/L

30%-50% fall orplatelet nadir 10-19× 109/L

>30% fall orplatelet nadir < 10× 109/L

Timing of platelet count fall Clear onset on day 5-10, or =1 d if heparin exposure within past 30 d

Consistent with day 5-10 fall, but not clear (eg, missing platelet counts); onset after day 10; or fall = 1 day if heparin exposure 30-100 days ago

Platelet count fall =4 d without recent heparin exposure

Thrombosis or other sequelae

New thrombosis (confirmed); skin necrosis; acute systemic reaction after IV UHF bolus

Progressive or recurrent thrombosis; erythematous skin lesions; thrombosis suspected but not proven

None

Other causes of thrombocytopenia

None apparent Possible Definite

www.hematology.org/Practice/Guidelines/11747.aspx (Accessed on January 07, 2014

Evaluation: 4Ts Total scores and corresponding probability of HIT are as follows:0-3: Low probability4-5: Intermediate probability6-8: High probability

Diagnosis, Laboratory tests:The two types of HIT antibody tests are :

1 -Immunoassays [ELISAs], which detect the presence of a HIT antibody in patient serum.

2 -Functional assays, which measure the ability of a HIT antibody from patient serum to activate test platelets.

Management of HIT

Suspected HIT

-ve

+ve HIP AB

Rational for anticoagulant use:

1. The condition for which heparin was administered originally .

2. The risk of thrombosis associated with HIT.40 to 61 % of the thrombotic events occurring more than

24 hours after cessation of heparin.Subsequent 30-day thrombosis risk is 53 %.

 

*Important massage:Use non heparin anticoagulant with HIT regardless of

the dose of heparin used.

One exception: if patient has bleeding or at high risk.

Choice of non-heparin anticoagulant 

 Bivalirudin  Argatroban

Fondaparinux

Danaparoid

Use any of the alternative anticoagulants.

Argatroban –Bivaluridin in reduced dose.

Danaparoid,or fondaparinux at therapeutic doses.

Argatroban or bivalirudin at reduced doses.

General rule of anticoagulant dose and duration:

•Therapeutic dose should be used, with the exception of patients with combined renal and hepatic impairment.

•Anticoagulant should be used for at least 2 to 3 months, and for at least 3 to 6 months if a thrombotic event has occurred.

1 -Bivalirudin  • Bivalirudin is parenteral hirudin analog.• It is a competitive, direct inhibitor of thrombin that inhibits both free and clot-

bound thrombin and thrombin-induced platelet aggregation. • Approved for use in patients who are undergoing PCI and have, or are at risk for

HIT.• Its effect is monitored by the aPTT. • Bivalirudin is hemodialyzable.

The recommended initial dose of bivalirudin for HIT:Normal patient: 0.15 mg/kg /hr.Hepatic dysfunction: of 0.14 mg/kg /hr.Renal or combined hepatic and renal dysfunction : 0.03 to 0.05 mg/kg/hr.Receiving continuous renal replacement therapy: 0.03 to 0.04 mg/kg /hr.

 2 -Argatroban 

• Argatroban is a DTI; it inhibits fibrin formation, platelet aggregation, and activation of coagulation factors V, VIII, XIII, and protein C.

• Metabolized hepaticlly . • Not excreted by kidney(Ideal alternative if patient receiving

dialysis).• Its effect is monitored by the aPTT, and also has dose-dependent

increases in the PT. • Steady-state anticoagulation is reached 1 to 3 hrs after IV

administration.

Argatroban dose:Standard starting dose:Normal hepatic function:2 mcg/kg/min by continuous IV infusion, adjusted to maintain the aPTT at 1.5 to 3 times baseline, not to exceed 100 seconds.Hepatic dysfunction, combined hepatic/renal dysfunction,

heart failure, severe anasarca, or who are post cardiac surgery:

0.5 to 1.2mcg/kg per minute. Check the aPTT at four-hour intervals after drug initiation or dose change.Critically ill patients with multiple organ dysfunction

syndrome and HIT: 0.5 mcg/kg per minute .

3 -Fondaparinox:• A synthetic anticoagulant that works by inhibiting factor Xa.• It provides a highly predictable response.• Bioavailability is 100%, has a rapid onset of action, and a half-life of

14-16 h, allowing for sustained antithrombotic activity over 24-h period.

• It does not affect PT or aPTT, nor does it affect platelet function or aggregation.

• Administered SC.• Patients taking it for prolonged periods should have periodic

monitoring of renal function.• Use full therapeutic dose of fondaparinux ( 5 to 10 mg/day).

4 -Danaparoid:Heparan derivative that consists predominantly of dermatan sulfate and low-sulfated heparan sulfate; it is devoid of heparin. • SC or IV•Monitored by anti-factor Xa activity (four hours after

injection if administered subcutaneously).

The recommended therapeutic dose of danaparoid in HIT:

•Doses are adjusted to achieve anti-factor Xa levels of 0.5 to 0.8 anti-Xa units/mL.

IV) bolus of 2250 units-

IV infusion400 units/hour

IV infusion300 units/hr

IV infusion200 units/hr

4 hrs 4hrs

Warfarin:•For long term oral treatment.

Warfarin should be started in a patient with HIT only when both of the following have been accomplished:1. The patient has been stably anticoagulated with an

alternative anticoagulant.2. The platelet count has increased to at

least 150,000/microL.

Warfarin, cont:•Overlap between warfarin and other anticoagulant for at least

5 days.•Use low starting dose (5mg or less) and adjust dose according

to INR.

Managing complication: Bleeding(rare):•Rare (platelet in HIT >20,000/microL).•Manage by platelet transfusion.

References:•Steven coutre. Clinical presentation and diagnosis of

heparin-induced thrombocytopenia. Up to date. April 2015.•Steven coutre. Management of heparin-induced

thrombocytopenia. Up to date. April 2015.•Sancar Eke,Emmanuel C Besa. Heparin-Induced

Thrombocytopenia. Medscape. Aug 2014

THANK YOU