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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.
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Delayed: after heparin has been withdrawn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
after
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
75% DVT
25% pulmonary embolism
Stroke
MI
Limb ischemia
Thrombosis:
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.
Prevention
Judicious use of UFH:
Recognize that:
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:
Xa
Th
VIIa
TF
Platelet
2. Amplification
X Xa
XI XIa
Th
IX IXa
V Va
VIII VIIIa
Prothrombinase
Proth
3. Propagation
(Fibrin is deposited)
Fibrinogen
Th
Fibrin
Antithrombin
Active site
Antithrombin
Reactive center
Thrombin
Thrombin
Antithrombin
Xa
Heparin
Antithrombin
Thrombin
Thrombin
Exosite II
Lepirudin (Refludan)
65 amino acids peptide
([Leu1, Thr2]-63-desulfohirudin )
Bivalrudin (Angiomax)
Hemodialyzable hirudin analog; 20 amino acid peptide
Argatroban (Argatroban)
Ximelagatran (Exanta)
LMH
Exosite I
Antithrombin
Xa
Antithrombin
Thrombin
Exosite II
Manufacturer
Trade
name
Enoxaparin Lovenox
Clexane
Dalteparin
Fragmin
PharmaciaUpjohn, Kalamazoo, MI
Ardeparin
Normiflo
WyethAyerst, Philadelphia, PA
Tinzaparin
Innohep
Nadroparin
Fraxiparine
Certoparin
Sandoparin
Reviparin
Clivarin
Knoll, Parsippany, NJ
Parnaparin
Fluxum
Opocrin, Italy
2. Heparinoid
Danaparoid
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)
Fondaparinux (Arixtra)
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