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Anticoagulants and HIT

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.

Pathophysiology of HIT
Heparin

Heparin-PF4
complex

IgG

Heparin-PF4-IgG
complex
Fc -RIIA
receptors

PF4

Platelets aggregation

Platelet activation
and release

Clinical picture
Onset:
Typical: 4-10 days after the initiation of therapy
Unusual: after two weeks
Earlier: as early as 10 hours
Heparin in the previous 3-4 months (persistent
antibodies in 30%)
Delayed: after heparin has been withdrawn
High antibodies titer that exhibit heparin-independent
platelet activation

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

Manifestations:
Thrombocytopenia:
Rarely severe (pl count > 20,000/L)
Spontaneous bleeding is unusual
50% subsequent 30-day risk of thrombosis

Thrombosis:
50% of patients present with a thrombotic event
Most common (80%): venous thrombosis

Less common (20%): arterial thrombosis

75% DVT
25% pulmonary embolism
Stroke
MI
Limb ischemia

Warfarin-induced venous limb gangrene

Thrombosis:

Skin lesions associated with HIT antibodies, even in the


absence of thrombocytopenia

Cerebral sinus thrombosis: Fever, chills, flushing, or


transient global amnesia beginning 5 to 30 minutes
after an IV heparin bolus

Adrenal hemorrhage (caused by adrenal vein


thrombosis)
HIT-associated mortality is high (about 18%)

Diagnostic testing:
The diagnosis is initially made on clinical
grounds
The assays with the highest sensitivity & specificity
may not be readily available and have a slow
turnaround time.
2. The most specific diagnostic tests :
1.

Serotonin release assays.


2. Heparin-induced platelet aggregation assays.
3. Solid phase immunoassays.
1.

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 until


the thrombocytopenia resolves
Warfarin -without other anticoagulants- increases the risk of
venous limb gangrene

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

How a thrombus is formed?


1. Initiation (Thrombin is generated)
Proth

Xa

Th

VIIa
TF
Platelet

2. Amplification

(Further thrombin is generated)

X Xa

XI XIa

Th

IX IXa
V Va
VIII VIIIa

Prothrombinase

Proth

3. Propagation

(Fibrin is deposited)

Fibrinogen
Th
Fibrin

THROMBIN is the key enzyme in the clotting cascade


Factor X comes next

Anticoagulants targeting thrombin


(Thrombin inhibitors)

Antithrombin
Active site

Antithrombin

Reactive center

Thrombin

Thrombin

Antithrombin

Xa

a. Indirect thrombin inhibitors

Unfractionated Heparin UFH


Exosite I

Heparin

Antithrombin
Thrombin

Heparin binding site


The amino
terminus
Exosite II

b. Direct thrombin inhibitors


Bivalent: Hirudin, Lepirudin, Bivalirudin
Univalent: Argatroban & Ximelagatran
Exosite I

Thrombin

Exosite II

Lepirudin (Refludan)
65 amino acids peptide
([Leu1, Thr2]-63-desulfohirudin )

Antihirudin antibodies in 45% of cases daily monitoring of


APTT and dose should be reduced accordingly.
Cautious in patients with renal insufficiency

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

Argatroban (Argatroban)

Lower starting dosage in patients with hepatic dysfunction.

Ximelagatran (Exanta)

Anticoagulants targeting active factor X


(Selective Factor Xa inhibitors)
1. Low molecular weight heparins LMH
LMH

LMH
Exosite I

Antithrombin

Xa

Antithrombin
Thrombin

Exosite II

Antifactor Xa to antithrombin activity ratio is 3:1

Low Molecular Weight Heparins


Generic
name

Manufacturer

Trade
name

Enoxaparin Lovenox
Clexane

RhonePoulenc Rorer, Collegeville, PA


Aventis

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

2. Heparinoid

Danaparoid

It is derived from porcine


intestinal mucosa (MWt: 1,00010,000 daltons):

The inactivation of factor Xa is


mediated by AT
while inactivation of thrombin is
mediated by both AT and HC II.

Antifactor Xa to antithrombin
activity ratio is 28:1

3. Synthetic heparin
pentasaccharides

Fondaparinux

Antithrombin
Xa

No antithrombin activity

Danaparoid (Danaparoid)
84%

heparin sulfate
12% dermatan sulfate
4% chondroitin sulfate

Although it is not FDA-approved for HIT, there is extensive experience using this
agent 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

Fondaparinux (Arixtra)

Blood, 1 January 2005, Vol. 105, No. 1, pp. 139-144.


Effect of fondaparinux on platelet activation in the presence of heparindependent antibodies: a blinded comparative multicenter study with
unfractionated heparin
Fondaparinux is nonreactive to HIT sera which raises the possibility that the
drug may be used for prophylaxis and treatment of thrombosis in patients
with a history of HIT

Re-exposure to heparin
Three facts make re-exposure to heparin possible:
1. Disappearance of the antibodies usually occurs 50-85
days 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 of
heparin).
Short-term re-exposure to heparin (e.g. cardiopulmonary
bypass) may be safe if:
HIT antibodies are no longer detectable
Heparin is restricted to the operative procedure