(from lecture by Jason Vigue, MD)
 

Clinical Features

• HIT-I (type I)
• nonimmune
• mild decrease in plt count after heparin due to heparin-induced plt aggregation
• plt ct usually not below 100,000
• HIT-II (type II)
• immune-mediated
• profound decrease in plt count to 30,000-50,000 in 7-14 days in first exposures
• In pts with previous exposures, signs may develop in 1-2 days.
• Ab to PF4 (platelet factor 4) complex.

Morbidity

• Thrombotic complications, MI, and skin necrosis.
• A study of 70 pts with HIT for CABG
• w/o anti-plt medication
• 44% thromboembolic complications
• 33% death
• Preop anti-plt meds: no thromboembolic complications or death.

Incidence

• A recent study showed heparin-dependent platelet antibody (HDPA) in 18% of pts screened before cardiac surgery (although only a small fraction probably actually develop HIT)
• HIT
• 1.1% of pts from iv porcine heparin
• 2.9% of pts from iv bovine heparin.
• less with LMWH.
• Thromboses of HAT
• usually arterial and in major vessels of the extremities.
• role in venous thrombosis is less clearly established.
• morbidity and mortality rates for thrombosis: 80% and 30%, respectively.

Pathophysiology

• HIT activates plts before being cleared from the circulation (different than other drug-induced thrombocytopenias)
• Platelet factor 4 (PF4)
• a heparin-binding protein in plasma
• stored in plt alpha-granules, released during plt activation
• A heparin-PF4 complex is the antigenic target for heparin-associated Ab.
• Ab to heparin-PF4 complex binds to plt FcgammaRII receptors, activating plts to release procoagulant micro particles.
• Intravenous gamma globulin and ASA attenuate the thrombocytopenic response to heparin.
• Vascular endothelial injury may contribute to the pathogenesis of  thrombosis
• previously catheterized vessel – higher risk

Diagnosis: Lab Studies

• C-14 – serotonin release assay.
• Serial dilution of pt plasma and radiolabeled (C-14) platelets?
• Serotonin release at therapeutic vs. high levels identifies heparin-assoc Ab.
• Sens and spec rates: 99%
• Gold Standard.
• Plt aggregation studies.
• Donor platelets + patient plasma … look for plt aggregation
• Sens and spec: 81% and 100%, respectively.
• Previously, Most Widely Used
• Enzyme-linked immunosorbent assay (ELISA).
• Detects Ab to the heparin/PF4 complex in plasma.
• “Newest” test
• Sens and spec: 99% and 100%, respectively.
• Rapidly becoming the most common diagnostic test for HIT.

Diagnostic Criteria

• Decreased platelet count during heparin therapy.
• Absence of other causes of thrombocytopenia.
• Resolution of sx after heparin therapy is discontinued.
• Confirm heparin-plt Ab by in vitro testing.

Management Options, Nonsurgical Patient

• discontine heparin immediately, substitute warfarin
• Warfarin requires interim anticoagulation for 3-5 days.
• Use LMWH, danaparoid, or r-hirudin.
• Crossreactivity
• LMWH 20-80%
• danaparoid 10-20%
• r-hirudin <1%.
• Danaparoid
• long half-life
• complicated dosing regimen
• known cross-reactivity.

Management Options, Perioperative

• Delay surgery until the pt’s plasma no longer induces plt aggregation with heparin.
• Although the proaggregatory response may resolve in a few weeks, heparin-induced plt aggregation has been reported months after the initial episode of HIT.
• Plasmapheresis provides symptomatic resolution of HIT within several days, but exposes pts to multiple exchange transfusions and transfusion-transmitted diseases.
• Administer plt inhibitors in addition to heparin.
• ASA and dipyridamole do not inhibit plt aggregation reliably in heparin-assoc Ab. ASA was effective by in vitro testing in only 50% of patients with HIT.Iloprost, a prostanoid inhibitor, effective in cardiac pts receiving heparin, but vasoconstrictors frequently are necessary to counteract the vasodilating effects of iloprost.
• Provide an alternative anticoagulant.
• appears to provide the safest approach to perioperative management
• LMWH, Hirudin

LMWH

• Has a high anti-factor Xa to anti-factor IIa activity ratio, which implies improved antithrombotic potential with fewer bleeding side effects.
• Anti-factor Xa activity can be measured to monitor the effect of LMWH.
• CPB doses of enoxaparin range from 3.8 to 4.5 mg/kg.
• Drawbacks
• Increased cost of administration.
• ACT and aPTT are not useful in titrating the administration of these drugs.
• Inability to measure anti-Xa activity in many hospitals.
• Relative high incidence (~ 27%) of cross-reactivity with HDPA to UFH
• LMWH should be considered only if HDPA are negative for LMWH.

Hirudin

• Source
• Natural hirudin: produced by the leech Hirudo medichalis.
• R-hirudin. Recombinant. From yeast cells.
• Highly specific inhibitor of thrombin: 1 molecule of hirudin binds to 1 molecule of thrombin
• acts independently from AT-III
• doesn’t interact with plts
• short-half life
• no fibrinolytic activity.
• Elimination
• Systemic clearance is proportional to GFR; dose must be adjusted based on renal function.
• 30-60 min with normal renal function.
• Cannot be neutralized or dialyzed.
• Dosing
• for anticoagulation for thrombosis: 0.4 mg/kg bolus, then infusion of 0.15 mg/kg/hr. Dose not increased for wt > 110 kg.
• for CPB: 0.25 mg/kg bolus, 0.2 mg/kg to extracorporeal circuit prime, and bolus doses of 5 mg to maintain plasma [hirudin] >2.5 mug/ml.

Use of LMWH for CEA in HIT pts

• In pts for CEA with HIT, a substitute for unfractionated heparin (UFH) should be used.
• enoxaparin 0.8 to 1.4 mg/kg IV
• Reversing heparin in CEA with protamine sulfate is controversial and its action is unpredictable.

Pts with HIT-II, Renal Impairment for CPB

• In renal impairment, anticoagulation during CPB with ...
• danaparoid sodium or r-hirudin: associated with hemorrhage.
• UFH and prostacyclin (a potent plt aggregation inhibitor): associated with severe hypotension.
• Koster et al. study
• Tirofiban - platelet inhibitor
• a short-acting competive inhibitor of the GP llb-llla receptor
• half-life of 2 h
• 70% biliary elimination
• abciximab (Reopro), which is on the UNC formulary instead, is a non-competitive inhibitor
• ten pts for CPB with renal impairment (CrCl < 50 ml/min and serum [Cr] > 1.5 mg/100 ml)
• Anticoagulation:
• Preop r-hirudin to aPTT of 40-60 s.
• during CPB
• UFH bolus 400 IU/kg
• tirofiban 10mg/kg then 0.15mg/kg/min until 1 h before conclusion of CPB.
• D-dimers measured at 12, 24, and 48 h after surgery as a marker of venous thromboembolism
• Coagulation was monitored by an abciximab-modified-TEG
• Results
• Postop blood loss 110-520 ml. No pt need reexploration.
• No critical increase in D-dimer levels and no signs of intraoperative clot formation in the CPB.
• No evidence of decrease in plt counts or myocardial infarction (by creatinine kinase or troponin levels).
• In HIT-II pts with renal impairment, tirofiban and heparin during CPB is a possible alternative to r-hirudin or prostacyclins