Page 1244 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 90: Bleeding Disorders 851

develop within hours in patients who have had recent prior exposure
TABLE 90-6 Common Drugs Associated With Thrombocytopenia
to heparin. While subcutaneous prophylactic unfractionated heparin
64
Drug Class Specific Drugs and intravenous therapeutic unfractionated heparin are most commonly
Antibiotics Penicillin, methicillin, vancomycin, rifampin, implicated in the disease, HIT may result from any exposure to heparin
ciprofloxacin, trimethoprim/sulfamethoxazole and and heparin-like compounds including intermittent low-dose catheter
sulfonamides, linezolid, rifampin, amphotericin B flushes, low- molecular-weight heparins, and related medications including
fondaparinux. 65-67 The second major feature of HIT is thrombosis. Venous
Analgesics Ibuprofen, diclofenac, naproxen, acetaminophen
clotting including deep venous thrombosis and pulmonary thromboem-
Cinchona alkaloids Quinine, quinidine bolism are the most common manifestations of this clotting risk. However,
Cardiac glycosides and antiarrhythmics Digoxin, procainamide, amiodarone arterial clotting with stroke, myocardial infarction, and limb necrosis also
occur with clinically significant frequency and devastating consequences.
68
Chemotherapeutic and Oxaliplatin, fludarabine, cyclosporine, rituximab, Thrombocytopenia-associated bleeding is rare in HIT.
immunosuppressive agents gold salts, d-penicillamine
The risk of developing HIT depends on both patient-specific factors
Diuretics Chlorothiazide, hydrochlorothiazide as well as the type of heparin exposure. Risk increases with age, female
69
Heparins Unfractionated heparin, low-molecular-weight heparin gender, and postsurgical status. In particular, orthopedic and cardiac
70
Histamine-receptor antagonists Cimetidine, ranitidine surgery patients have higher risk than obstetric and medical patients.
While both LMWH and unfractionated heparin have caused HIT, the risk
Platelet inhibitors Abciximab, eptifibatide, tirofiban is substantially higher with unfractionated heparin at 1% to 5% compared
71
Sedatives and antiseizure agents Carbamazepine, haloperidol, phenytoin, valproic with 0.1% to 1.0%. Given the potentially severe adverse consequences of
acid, diazepam unrecognized HIT, patients groups with more than 1% incidence of HIT,
Data from reference 56, 57, 175. such as cardiac surgery and postoperative patients receiving unfraction-
ated heparin, expert guidelines recommend intermittent platelet count
surveillance and screening every 2 to 3 days while receiving heparin. 72
and bone marrow megakaryocytes, but also may cause significant reduc- The nonspecific findings of thrombocytopenia and thrombosis in
tions in the productive capacity of surviving megakaryocytes. 59 critically ill patients make the clinical diagnosis of HIT particularly
difficult unless the diagnostic and therapeutic approach is based on
Heparin-Induced Thrombocytopenia: Heparins, including unfraction- carefully selected features of the disease. While several scoring systems
ated heparin and, to a lesser degree, low-molecular-weight heparin have been proposed, the 4Ts scoring system may be used to estimate the
(LMWH), are among the most common drugs associated with throm- approximate likelihood of HIT and has been validated in hospitalized
bocytopenia. Heparin-induced thrombocytopenia (HIT) results from populations (Table 90-7). 73-75 The 4Ts system assigns higher likelihood
immune-mediated activation and destruction of platelets. Specifically, to patients with a relative fall in platelet count greater than 50% from
HIT is caused by induction of a specific immune antibody response baseline which clearly occurs between 5 and 10 days after heparin expo-
which results in immunoglobulin binding to FcγIIa receptors on plate- sure, who have severe manifestations of thrombosis, and for whom there
lets and monocytes. 60,61 The specific immune recognition and immuno- are no alternative likely causes. Importantly, profound thrombocytope-
globulin binding site is a complex of heparin attached directly to platelet nia with platelet count nadir ≤20 × 10 /L is less likely to be associated
9
factor 4 (PF4) on the platelet surface. 61-63 A key clinical feature of HIT with HIT than other drug-induced thrombocytopenia.
arises not only from the resulting platelet destruction, but also from the While the diagnosis of HIT would seem to depend on identification
activation of platelets and precipitation of inappropriate thrombosis. of heparin-dependent antiplatelet antibodies, the presence of these anti-
The clinical syndrome of HIT (historically referred to as type 2 HIT) is bodies alone is nonspecific. The clinical specificity of antiplatelet antibodies
characterized by immune-mediated thrombocytopenia and thrombosis. ranges from 74% to 86%, which results in false-positive results and poor
The presence of thrombosis distinguishes HIT from transient, non- positive predictive values in low-risk patients. 70,76 Platelet activation
immune-mediated mild thrombocytopenia (historically referred to as assays which measure platelet serotonin release or platelet aggregation
type 1 HIT), which may occur within the first few days of heparin treat- have higher sensitivity and specificity. Unfortunately, these tests are
ment and is not associated with significant clinical sequelae. often not immediately available. 76
HIT is characterized by mild to moderate thrombocytopenia which Because the consequences of thrombosis and persistent thrombo-
develops over 5 to 10 days after exposure to heparin. HIT may also cytopenia are life threatening, patients with HIT require immediate

TABLE 90-7 4Ts Pretest Scoring System for Heparin-Induced Thrombocytopenia 74
4Ts 2 Points 1 Point 0 Point
Thrombocytopenia Platelet count fall ≥50% and platelet nadir ≥20 Platelet count fall 30%-50% or platelet nadir 10-19 Platelet count fall ≤30% or platelet nadir ≤10
Timing of platelet count fall Clear onset between days 5 and 10 or platelet Fall in platelet counts consistent with onset between Platelet count fall <4 d without recent
fall ≤day in the patient with prior heparin days 5 and 10 but timing is not clear due to missing heparin exposure
exposure within 30 days platelet counts or onset after day 10 of heparin expo-
sure or fall in platelet counts ≤1 d with prior heparin
exposure between 30 and 100 days previously
Thrombosis or other sequelae New thrombosis, skin necrosis, or acute systemic Progressive or recurrent thrombosis or unconfirmed but No thrombosis or thrombosis preceding
reaction after unfractionated heparin exposure clinically suspected thrombosis heparin exposure
Other cause of thrombocytopenia No other causes apparent Possible other causes present Probable other causes present
Sum of 4T Score Clinical Probability of HIT
1, 2, or 3 Low
4, 5 Intermediate
6, 7, or 8 High

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