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2028 Part XII: Hemostasis and Thrombosis Chapter 118: Heparin-induced Thrombocytopenia 2029

HEMORRHAGE IMMUNOASSAYS
In contrast to most other forms of drug-induced immune thrombocytope- These assays detect the presence of circulating anti-PF4–heparin anti-
nia, spontaneous hemorrhage is rare in HIT, even when thrombocytopenia bodies, irrespective of whether they are able to activate platelets and
is severe. In a prospective study, bleeding complications were not increased cause disease. The prototypical immunoassay is the solid-phase enzyme-
in HIT patients compared with nonthrombocytopenic controls. 59 linked immunosorbent assay (ELISA), in which dilute patient serum
is added to microtiter wells coated with complexes of PF4–heparin (or
UNUSUAL CLINICAL MANIFESTATIONS PF4–polyvinylsulfonate). The polyspecific ELISA detects circulating
6
anti-PF4–heparin IgG, IgM, and IgA. At the manufacturer-recommended
Rare sequelae of HIT include anaphylactoid reactions after intravenous cutoff, the sensitivity and specificity of this assay for HIT are 94 to
heparin bolus, transient global amnesia, and skin necrosis at subcutane- 100 percent and 81 to 93 percent, respectively. 22,68–70
ous heparin injection sites. 60,61 Curiously, these phenomena may occur A key limitation of the polyspecific ELISA is its specificity. False-
in the absence of thrombocytopenia. Nonnecrotizing erythematous positive results are common and may result from detection of nonpatho-
injection site lesions are generally caused by delayed type IV hypersen- genic anti-PF4–heparin antibodies or antiphospholipid antibodies against
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sitivity rather than HIT. 62
either PF4 or PF4-bound β -glycoprotein I. Specificity may be improved
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2
by raising the optical density (OD) cutoff. OD is directly associated with
OTHER CAUSES the 4T and HEP scores, the risk of thrombosis, and the likelihood of
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The likelihood of other etiologies of thrombocytopenia must be care- a positive functional assay. In a Canadian study, only one of 37 patient
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fully considered in patients with suspected HIT. Common causes of samples exhibiting a weakly positive OD (0.40 to 0.99) demonstrated
hospital-acquired thrombocytopenia include infection; drugs other heparin-dependent platelet activation compared with 33 out of 37 samples
than heparin; DIC; dilution; and intravascular devices and extracor- with a strongly positive OD (>2.0). In a recent analysis of 1958 patients,
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poreal circuits such as intraaortic balloon pumps, cardiopulmonary increasing the cutoff from a manufacturer-recommended threshold of
bypass, and extracorporeal membrane oxygenation. 63 0.4 to 0.8 OD units increased specificity from 85 percent to 93 percent with
Clinical scoring systems have been developed to permit estima- a slight reduction in sensitivity from 100 percent to 98 percent. 75
tion of the probability of HIT based on the aforementioned features. Several modifications have been made to the PF4–heparin ELISA
The most extensively studied of these systems, the 4T score, classifies with the goal of improving specificity. Because pathogenic antibodies
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the probability of HIT as low, intermediate, or high on the basis of four are primarily of the IgG class, detection systems specific for IgG have
criteria: Thrombocytopenia, Timing, Thrombosis or other sequelae, and been developed. In a pooled analysis of studies comparing the IgG-spe-
the likelihood of other causes of thrombocytopenia (Table 118–2). In a cific and polyspecific ELISA, the former showed greater specificity (93.5
meta-analysis of 13 studies, the negative predictive value of a low proba- percent vs. 89.4 percent) at the cost of reduced sensitivity (95.8 percent
bility 4T score was 99.8 percent (95 percent CI: 97.0 to 100.0). The positive vs. 98.1 percent). Another modification involves the addition of a high
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predictive value of an intermediate and high probability 4T score was 14 heparin confirmatory step, in which reduction of the OD by 50 percent
percent (95 percent CI: 9 to 22) and 64 percent (95 percent CI: 40 to 82), or more with the addition of excess heparin (100 U/mL) is considered
respectively. The 4T score is limited by moderate interobserver agree- to affirm the presence of heparin-dependent antibodies. This method
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ment. An alternative scoring system, the HIT Expert Probability (HEP) improves specificity, but false-positives remain common and false-
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Score, exhibited improved reliability and favorable operating characteris- negatives may also occur, particularly at high OD values. 78,79
tics in a retrospective study, but remains to be prospectively validated. 67 Another limitation of the PF4–heparin ELISA is turnaround time.
Although the analytical turnaround time of the ELISA is only approx-
LABORATORY DIAGNOSIS imately 2 hours, the assay is most cost-effective when multiple samples
are run in batch. Consequently, many laboratories perform the ELISA
In light of the complexity and limited positive predictive value of clinical only once or twice a week, leaving clinicians to make critical initial
diagnosis, clinicians rely heavily on laboratory testing to aid in diag- management decisions without the benefit of laboratory results. This
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nosis. Laboratory assays for HIT fall into two categories: immunoassays drawback of the ELISA has spawned the development of several rapid
and functional assays. immunoassays, which are designed to accommodate single samples and
TABLE 118–2. The 4T Score*
Points Per Category
Clinical Sign 0 1 2
Thrombocytopenia (acute) Very low nadir (<10 × 10 /L) or Low nadir (10–20 × 10 /L) or 30–50% Moderate nadir (20–100 × 10 /L)
9
9
9
<30% fall fall or >50% fall
Timing of first event (throm- ≤4 Days (unless prior heparin Within 5–10 days (but not well docu- Documented occurrence in 5–10
bocytopenia or thrombosis) exposure in last 3 months) mented) or ≤1 day (with exposure in days or ≤1 day with recent prior
last 3 months) exposure
Thrombotic-related event None Progressive, recurrent, or suspected New thrombosis (confirmed) or
(unconfirmed) thrombosis; erythe- skin necrosis or systemic reac-
matous nonnecrotic skin lesions tion after heparin bolus
Thrombocytopenia (other Definite other cause is present Possible other cause is present No other strong explanation for
causes) thrombocytopenia
*Scores of 0–3, 4–5, and 6–8 are classified as low, intermediate, and high probability, respectively. 64

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