Anticoagulants and HIT

8/10/2019 Anticoagulants and HIT

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Anticoagulants and HIT


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Heparin-induced thrombocytopenia

Type II or delayed type (HIT): occurs in 0.3-3% of patients exposed to heparin for more than 4

days. It is an immune-mediated disorder It is associated with thrombosis

This is a serious disorder.Type I or early type: occurs in 10-20% of patients within the first 2 days after heparin

initiation It is non-immune disorder due to a direct effect of heparin on

platelet activation. Lesser fall in platelet count that often returns to normal with

continued heparin administration.This type is of no clinical significance.


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Platelets aggregation

Pathophysiology of HIT

IgG

PF4

HeparinHeparin-PF4-IgG

complexHeparin-PF4complex

Fc -RIIAreceptors

Platelet activationand release


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Clinical picture

Onset:

Typical:4-10 days after the initiation of therapy

Unusual:after two weeks

Earlier:as early as 10 hoursHeparin in the previous 3-4 months (persistent

antibodies in 30%)

Delayed:after heparin has been withdrawn

High antibodies titer that exhibit heparin-independentplatelet activation


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Amount & route of heparin administration:

Most:IV or SC prophylactic dose

Occasionally:very small amount e.g.

after exposure to 250 U from a heparin flush after the use of heparin-coated catheters


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Manifestations:

Thrombocytopenia:

Rarely severe (pl count > 20,000/L)

Spontaneous bleeding is unusual

50% subsequent 30-day risk of thrombosis


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Thrombosis:

50% of patients present with a thrombotic event

Most common (80%): venous thrombosis

75% DVT

25% pulmonary embolism

Less common (20%): arterial thrombosis

Stroke

MI

Limb ischemia

Warfarin-induced venous limb gangrene


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Thrombosis:

Skin lesions associated with HIT antibodies, even in theabsence of thrombocytopenia

Cerebral sinus thrombosis: Fever, chills, flushing, ortransient global amnesia beginning 5 to 30 minutesafter an IV heparin bolus

Adrenal hemorrhage (caused by adrenal veinthrombosis)

HIT-associated mortality is high (about 18%)


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Diagnostic testing:

1. The diagnosis is initially made on clinicalgrounds

The assays with the highest sensitivity & specificitymay not be readily available and have a slowturnaround time.

2. The most specific diagnostic tests:

1. Serotonin release assays.2. Heparin-induced platelet aggregation assays.

3. Solid phase immunoassays.


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Prevention

Judicious use of UFH: limiting duration to < 5 days & early warfarin starting

substitution with LMH

Recognize that:

LMH should not be substituted for UFH after HIT develops:Igs once synthesized can cross react with LMH. In addition LMH

may induce heparin-dependent IgG antibody formation

Warfarin should not be given to patients who have HIT untilthe thrombocytopenia resolves

Warfarin -without other anticoagulants- increases the risk ofvenous limb gangrene


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Treatment

Immediate cessation of all exposure to heparins

However, heparin cessation is often not sufficient,since these patients remain at risk for thrombosis.

Give an alternative anticoagulant: Direct thrombin inhibitor

Lepirudin (recombinant hirudin) & Bivalirudin

Argatroban Selective factor X inhibitors

Danaparoid

Fondaparinux


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How a thrombus is formed?

Platelet

TF

VIIa

X Xa

Proth

Th

1. Initiation(Thrombin is generated)


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2. Amplification(Further thrombin is generated)

XIXIa XXa

Th Proth

IXIXa

VVa

VIIIVIIIa

Prothrombinase


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3. Propagation(Fibrin is deposited)

Fibrinogen

Fibrin

Th

THROMBIN is the key enzyme in the clotting cascade

Factor X comes next


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ThrombinAntithrombin

Active site

Reactive center

ThrombinAntithrombin

Anticoagulants targeting thrombin(Thrombin inhibitors)

XaAntithrombin


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a. Indirect thrombin inhibitorsUnfractionated Heparin UFH

Thrombin

Exosite II

Antithrombin

Heparin binding site

The amino

terminus

Heparin

Exosite I


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b. Direct thrombin inhibitors

Thrombin

Exosite I

Exosite II

Bivalent:Hirudin, Lepirudin, BivalirudinUnivalent:Argatroban

& Ximelagatran


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Lepirudin (Refludan)65 amino acids peptide

([Leu1, Thr2]-63-desulfohirudin )

Antihirudin antibodiesin 45% of cases daily monitoring ofAPTT and dose should be reduced accordingly.

Cautious in patients with renal insufficiency


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Bivalrudin (Angiomax)Hemodialyzable hirudin analog; 20 amino acid peptide


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Argatroban (Argatroban)

Lower starting dosage in patients with hepatic dysfunction.


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Ximelagatran (Exanta)


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Anticoagulants targeting active factor X(Selective Factor Xa inhibitors)

Thrombin

Exosite II

Exosite I

Antithrombin

LMH

XaAntithrombin

LMH

Antifactor Xa to antithrombin activity ratio is 3:1

1. Low molecular weight heparins LMH


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Low Molecular Weight HeparinsGenericname

Tradename

Manufacturer

Enoxaparin LovenoxClexane

Rhone

Poulenc Rorer, Collegeville, PAAventis

Dalteparin Fragmin PharmaciaUpjohn, Kalamazoo, MI

Ardeparin Normiflo WyethAyerst, Philadelphia, PA

Tinzaparin Innohep Novo Nordisk, Princeton, NJ

Nadroparin Fraxiparine SanofiWinthrop, New York, NY

Certoparin Sandoparin Sandoz Pharmaceuticals, East Hanover, NJ

Reviparin Clivarin Knoll, Parsippany, NJ

Parnaparin Fluxum Opocrin, Italy


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2. Heparinoid 3. Synthetic heparinpentasaccharides

XaAntithrombin

Fondaparinux

No antithrombin activityAntifactor Xa to antithrombin

activity ratio is 28:1

Danaparoid It is derived from porcine

intestinal mucosa (MWt: 1,000-10,000 daltons):

The inactivation of factor Xa ismediated by ATwhile inactivation of thrombin ismediated by both AT and HC II.


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Danaparoid (Danaparoid)

84% heparin sulfate

12% dermatan sulfate

4% chondroitin sulfate

Although it is not FDA-approved for HIT, there is extensive experience using thisagent in patients with HIT

10 % cross-reactivity between danaparoid and the HIT antibody (in vitro)

Persistence or recurrence of thrombocytopenia without thrombosis in 6.5% of

HIT patients switched to danaparoid


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Fondaparinux (Arixtra)

Blood, 1 January 2005, Vol. 105, No. 1, pp. 139-144.Effect of fondaparinux on platelet activation in the presence of heparin-

dependent antibodies: a blinded comparative multicenter study withunfractionated heparin

Fondaparinux is nonreactive to HIT sera which raises the possibility that thedrug may be used for prophylaxis and treatment of thrombosis in patients

with a history of HIT


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Re-exposure to heparin

Three facts make re-exposure to heparin possible:

1. Disappearance of the antibodies usually occurs 50-85days after cessation of heparin treatment.

2. Secondary immune response should not occur until at

least 3 days after exposure.3. Heparin is rapidly cleared (even if antibodies appeared,

they would not be thrombogenic in the absence ofheparin).

Short-term re-exposure to heparin (e.g. cardiopulmonarybypass) may be safe if:

HIT antibodies are no longer detectable

Heparin is restricted to the operative procedure

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Anticoagulants and HIT