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A Hypothesis to Explain the Timing of HIT

There is a possible explanation for these unusual temporal features of HIT: because the HIT antigen(s) is a "cryptic" autoantigen (or neoantigen) comprised of two autologous substances (PF4 and heparin), HIT can be regarded as an autoimmune disorder. Indeed, the target of the immune response appears to be one of at least three dominant conformation-dependent neoepitopes formed on PF4 when it binds to heparin (see Chapters 5-7). There is evidence that transient IgG-mediated autoimmune responses can occur, particularly when the responsible antibodies have a relatively low affinity for the neoepitope (thus having avoided prior clonal deletion as occurs with lymphocytes that have high-affinity binding to autoantigens). In this situation, the antibodies are generated only as long as the autoantigen is present, thus explaining why there is a rapid fall in anti-PF4/H antibodies soon after discontinuation of heparin. The affinity of the HIT antibodies may be substantially enhanced when both Fab "arms" of the IgG molecule can bind to linked epitopes, i.e., two PF4 molecules bound to a single heparin molecule (Newman and Chong, 1999).

This hypothesis could explain several unusual aspects of the timing of HIT, such as: (1) why HIT tends to occur fairly rapidly, beginning as soon as 5 days after starting heparin even in a patient who has never been exposed previously to heparin (autoreactive T-cell or B-cell clones might already be present in small numbers prior to starting heparin); (2) why HIT occurs more often in certain patient populations, such as postoperative patients (cytokine-driven immune responses); and (3) why HIT does not necessarily recur in patients with a previous history of HIT who are subsequently treated with heparin (there is a rapid loss of HIT antibodies following resolution of HIT, and the specific circumstances that favored immune stimulation the first time—e.g., large, stoichiometric concentrations of PF4 and heparin, occurring in an inflammatory milieu—may not be recapitulated during the subsequent heparin exposure).

Implications for Repeat Use of Heparin in a Patient with a History of HIT

The (1) transient nature of the HIT antibody, the (2) apparent minimum of 5 days to regenerate clinically significant HIT antibodies even in a patient who once had HIT, and (3) the observation that HIT antibodies do not necessarily recur, despite heparin rechallenge in a patient with definite prior HIT, all suggest that it may be safe to readminister heparin to such patients. Fortunately, this potentially risky situation is not frequently necessary, as there are several alternative anticoagulants that can be substituted for heparin (see Chapters 12-19).

However, UFH is the unparalleled drug of choice in certain therapeutic settings, particularly heart surgery when using cardiopulmonary bypass, or vascular surgery. Furthermore, there are important disadvantages of newer anticoagulants for these procedures (see Chapter 19). In my opinion, therefore, for patients with a remote history of HIT (>100 days) who require cardiac or vascular surgery, a rational approach is to prove serologically that HIT antibodies are no longer present, and then to give heparin for a brief time to permit the surgery (Olinger et al., 1984; Potzsch et al., 2000; Warkentin and Kelton, 2001a) (see Chapter 19). We have even used this approach successfully in a patient who required heparin for major vascular surgery 1 mo following an episode of HIT, when the HIT antibodies had just become undetectable. After surgery, it seems prudent to avoid postoperative heparin completely and to administer an alternative anticoagulant, such as danaparoid, fondaparinux, lepirudin, or argatroban, as indicated. The actual risk of recurrent HIT beginning 5-10 days later, either following a transient intraoperative heparin exposure or even during prolonged postoperative heparin use, is unknown, but may be low.

For planning a brief reexposure to heparin in a patient who had HIT in the past few weeks or months, a dilemma would arise if the follow-up patient serum now tested negative using a sensitive activation assay (e.g., platelet serotonin release assay), but positive by antigen assay. There is evidence that activation assays are better at detecting clinically significant levels of HIT antibodies (Warkentin et al., 2000, 2005a) (see Chapter 10). Thus, use of heparin in this situation might be a reasonable option, provided that one had confidence in the activation assay performed, the antigen assay result was "weak" (e.g., 0.400-0.750 OD units), there was a strong indication for surgery requiring heparin, and there was limited experience with an alternative anticoagulant. Continued watchful waiting is another option, given the transience of HIT antibodies.

Sensitization by Incidental Heparin Exposure

Sensitizing exposures to heparin can be relatively obscure. For example, incidental use of intraoperative line "flushes" that were not even documented in the medical records has led to HIT antibody formation or acute onset of HIT, with tragic consequences (Brushwood, 1992; Ling and Warkentin, 1998). Greinacher and colleagues (1992) reported a patient who developed recurrent HIT when reex-posed to heparin present in prothrombin complex concentrates. Physicians should suspect possible heparin exposure in a patient whose clinical course suggests HIT, especially if the patient was recently hospitalized or has undergone procedures in which heparin exposure may have occurred.

Delayed Onset of HIT

Rarely, HIT begins several days after discontinuing heparin therapy or persists for several weeks even though heparin administration has been stopped (Castaman et al., 1992; Tahata et al., 1992; Warkentin and Kelton, 2001b; Rice et al., 2002; Warkentin and Bernstein, 2003; Shah and Spencer, 2003; Levine et al., 2004; Smythe et al., 2005; Jackson et al., 2006; Arepally and Ortel, 2006) (Fig. 5). A dramatic case encountered by the author was a female outpatient who presented with transient global amnesia and a platelet count of 40 X 109/L 7 days after receiving two doses of UFH; despite the diagnosis and serologic confirmation of HIT and avoidance of all heparin, this patient's platelet count fell over the next 4 days to 14 X 109/L, along with laboratory evidence for disseminated intravascular coagulation (DIC) (low fibrinogen and elevated fibrin D-dimer levels). This patient's platelet counts gradually recovered to normal over several months, during which time recurrent thrombotic events were managed successfully with an alternative anticoagulant.

The unusual clinical course of these patients could be related to very high titers of platelet-activating IgG antibodies (Warkentin and Kelton, 2001b). Moreover, substantial platelet activation in vitro can be caused by some of these patients' sera even in the absence of added heparin. This finding of substantial heparin-independent platelet activation resembles that described in other patients with drug-induced immune thrombocytopenia, in which prolonged thrombocyto-penia has been reported in association with drug-independent binding of IgG to platelets (Kelton et al., 1981). Given the apparent rarity of these cases, it is perhaps surprising that this syndrome does not occur more frequently, given that HIT—once initiated—resembles somewhat an autoimmune disorder, with IgG

Days after starting heparin

FIGURE 5 Delayed onset of HIT: a 68-yr-old woman who received UFH for heart surgery was noted to have a platelet count of 40 x 109/L on postoperative day 19 and a "rash" of her lower extremities. She presented on day 38 with symptomatic DVT and developed rapid-onset recurrent thrombocytopenia after receiving iv UFH. The patient was successfully treated with D.S. and warfarin. In retrospect, the thrombocytopenia first observed on postoperative day 19 almost certainly was caused by delayed onset of HIT. Abbreviations: D.S., danaparoid sodium; DVT, deep venous thrombosis; iv, intravenous; UFH, unfractionated heparin.

Days after starting heparin

FIGURE 5 Delayed onset of HIT: a 68-yr-old woman who received UFH for heart surgery was noted to have a platelet count of 40 x 109/L on postoperative day 19 and a "rash" of her lower extremities. She presented on day 38 with symptomatic DVT and developed rapid-onset recurrent thrombocytopenia after receiving iv UFH. The patient was successfully treated with D.S. and warfarin. In retrospect, the thrombocytopenia first observed on postoperative day 19 almost certainly was caused by delayed onset of HIT. Abbreviations: D.S., danaparoid sodium; DVT, deep venous thrombosis; iv, intravenous; UFH, unfractionated heparin.

recognizing an autologous protein, PF4. On the other hand, earlier discharge from the hospital and a higher index of suspicion for this syndrome might mean that delayed onset of HIT will become a relatively more common presentation of HIT in the future.

Delayed onset of HIT, however, should not be confused with delayed clinical manifestation of HIT-associated thrombosis. For example, Figure 3 shows a patient who developed typical onset of HIT while receiving postoperative heparin prophylaxis. However, isolated HIT was not clinically recognized, and the patient presented subsequently with a deep vein thrombosis (DVT) and a normal platelet count; when heparin boluses were given, rapid onset of thrombocytopenia occurred. Presumably, subclinical HIT-associated DVT that began during the episode of isolated HIT progressed to symptomatic thrombosis in the absence of anticoagulation. In contrast, patients with delayed onset of HIT develop thrombocytopenia several days after the use of heparin and are thrombocytopenic when they present with thrombosis. Exacerbation of thrombocytopenia occurs if further heparin is given.

The existence of delayed onset of HIT presents a diagnostic dilemma in patients who are no longer receiving heparin but who develop thrombocytopenia 5 or more days after placement of a heparin-coated device, e.g., certain intravascular grafts or stents (Cruz et al., 2003). Such a puzzling situation of delayed onset of thrombocytopenia postvascular surgery prompted investigators to postulate heparin contamination of a graft (the manufacturer insisted otherwise) (Burger et al., 2001). In my view, either delayed onset or a protracted course of thrombocytopenia could reflect the generation and persistence of unusual "autoimmune" HIT antibodies without the need to invoke continuing exposure to heparin.

B. Severity of Thrombocytopenia

Figure 6 shows the platelet count nadirs of patients with laboratory-proved HIT: the median platelet count nadir was approximately 60 X 109/L (Warkentin, 1998a, 2007). This contrasts with "typical" drug-induced immune thrombocytopenic purpura (DITP; e.g., caused by quinine/quinidine, sulfa antibiotics, or vancomycin), for which the median platelet count nadir is 20 x 109/L or less, and patients usually develop bleeding (Pedersen-Bjergaard et al., 1997). The platelet count is 20 x 109/L or fewer in only about 5-10% of patients with HIT (Warkentin, 2003, 2007). But even in this minority of HIT patients with very severe thrombocytopenia, thrombosis, rather than bleeding, predominates. Patients with atypical drug-induced throm-bocytopenic purpura caused by anti-GPIIb/IIIa-blocking drug (e.g., abciximab [ReoPro]) appear to develop severity of thrombocytopenia resembling that of typical DITP (Fig. 6).

Definition of Thrombocytopenia

Figure 6 illustrates that HIT is associated with thrombosis even when the platelet count nadir is more than 150 X 109/L. This suggests that the standard definition

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