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See also Schindewolf M, Kroll H, Ackermann H, Garbaraviciene J, Kaufmann R, Boehncke W-H, Ludwig RJ, Lindhoff-Last E. Heparin-induced non-necrotizing skin lesions: rarely associated with heparin-induced thrombocytopenia. This issue, pp 1486–91.
In recent years, clinical scoring systems have been developed to aid in the diagnosis of immune heparin-induced thrombocytopenia (HIT) [1–3]. One of these, the 4T’s , uses four clinical features: magnitude of Thrombocytopenia, Timing (of thrombocytopenia or thrombosis or other clinical sequelae, in relation to the initiation of a course of heparin), the presence of Thrombosis (or other clinical sequelae), and the presence of oTher potential non-HIT explanations for thrombocytopenia or clinical events observed. In the 4T’s system, the presence of skin lesions at heparin injection sites constitutes one of the potential clinical criteria for HIT: ‘erythematous skin lesions at heparin injection sites’ are scored as ‘1 point’, whereas ‘skin necrosis at injection site’ scores as ‘2 points’. These criteria reflect findings of previous studies of HIT [4,5]. In one study, three patients were identified as having non-necrotizing skin lesions and platelet-activating anti-PF4/heparin antibodies among 332 patients who received unfractionated heparin (UFH) for postorthopedic surgery antithrombotic prophylaxis . Moreover, the presence of skin lesions was strongly associated with formation of the IgG class of anti-PF4/heparin antibodies (OR, ∞ [95% CI, 2.9–∞]; P = 0.001) . However, this patient population (postorthopedic surgery patients receiving UFH) nowadays hardly exists, as agents such as low-molecular-weight heparin (LMWH), fondaparinux, warfarin, and even novel oral antithrombin and anti-Xa agents, are being used.
However, there are two other ways that heparin-induced skin lesions can influence the pretest probability score for HIT. One is through their Timing of onset (i.e. the second T): if skin lesions begin within the characteristic 5–10-day period after initiating a course of subcutaneous heparin, that would score 2 points. Another is through the influence of skin lesions in helping judge whether another non-HIT diagnosis plausibly may be present (the 4th T): 1 point is scored if there is a possible oTher diagnosis, and 0 points are assigned if there is a definite oTher diagnosis to explain the clinical events observed. The question then arises: how should the presence of heparin-induced skin lesions influence this last criterion?
In this issue of the Journal, Schindewolf and colleagues  have performed a prospective study of 87 patients who developed skin lesions at heparin injection sites, identified over 5½ years from the Departments of Internal Medicine and Dermatology at the Goethe University Hospital in Frankfurt/Main. These patients had received most often LMWH (98%), were females (80%), and had received their heparin injections more often in the context of therapeutic- (60%) rather than prophylactic-dose indications (40%). Of note, none of the patients had necrotizing skin lesions. Rather, the lesions had the appearance of infiltrated erythematous plaques, occasionally with emergence of papulovesicles. In seven patients the skin rash was generalized beyond that of injection sites per se. These non-necrotizing skin lesions would therefore score as ‘1 point’ in the Thrombosis (or other sequelae) section of the 4T’s system.
The investigators also performed systematic studies for HIT, including assessment of platelet counts, and two complementary assays for HIT antibodies: a commercially-available heparin-PF4 enzyme-linked immunosorbent assay (ELISA), and a washed platelet assay (the heparin-induced platelet activation [HIPA] assay) that detects antibodies that are capable of activating platelets in a heparin-dependent fashion. Skin biopsies were also performed where appropriate to determine whether patients had a lymphohistiocytic infiltrate without dermal microvascular thrombosis (the hallmark of a so-called delayed-type hypersensitivity [DTH] reaction), or rather the presence of dermal microvascular thrombosis more characteristic of HIT.
The authors identified only one patient who had a profile consistent with HIT, for a HIT frequency of only 1.2% (95% CI, 0–6.4%). This female patient developed erythematous skin lesions beginning 10 days after receiving LMWH (nadroparin) injections for treatment of upper-extremity deep-vein thrombosis. The patient developed a 34% platelet count fall (from 269 to 177 × 109/L, identified at day 15), did not develop any thrombotic manifestations of HIT, and tested strongly positive for HIT antibodies (ELISA, 3.14 optical density units; HIPA test positive). Skin biopsy in this patient revealed features of DTH, without dermal microvascular thrombosis. Before reading this paper by Schindewolf and colleagues, we would have scored such a patient as having 5 points in the 4T’s scoring system: 1 point for Thrombocytopenia, 2 points for Timing (of the erythematous skin lesions), 1 point for heparin-induced skin lesions (Thrombosis or other sequelae of HIT), and 1 point for oTher (due to the possibility of the erythematous skin lesions being due to DTH rather than to HIT). However, after considering this paper, we would score the patient as having only 4 points, because 0 points seems more reasonable for the category ‘oTher’. This is because Schindewolf and colleagues provide strong evidence that DTH in the absence of HIT is the overwhelmingly likely diagnosis when the patient presents with non-necrotizing heparin-induced skin lesions. Note that a score of 4 points (an intermediate score) still leaves HIT to be a possible diagnosis, and indeed the patient’s serologic findings did support that diagnosis. Thus, it seems most likely that the DTH reaction in this patient represents a coinciding complication of the LMWH therapy, rather than part of the HIT syndrome.
This downgrading of the 4th T, ‘oTher’, from 1 to 0 points, for the presence of non-necrotizing skin lesions, is consistent with the authors’ own interpretation of their data. They state in their Discussion: ‘‘Since ‘erythematous non-necrotizing skin lesions’ almost always have another explanation than HIT and are normally due to DTH, we suggest to score these lesions as ‘0’ for the 4th ‘T’ category ‘oTher’, at least when LMWH is the inciting heparin agent’’ . We agree with this interpretation and analysis, and would concur that due to limited data, this change should not be applied to erythematous non-necrotizing skin lesions at injection sites for UFH. As the authors emphasize, this approach does not affect the interpretation of necrotizing skin lesions at heparin injection sites, where a score of 2 points would continue to be assigned for the category ‘Thrombosis (or other sequelae of HIT)’, and a score of 2 points also would be assigned for ‘oTher’, because there are hardly any non-HIT explanations for the presence of necrotizing skin lesions at heparin injection sites. Thus, there is a large difference in score (3 points) depending on whether heparin-induced skin lesions are necrotizing or non-necrotizing in appearance.
This study by Schindewolf and colleagues  adds to the literature  indicating that (non-necrotizing) heparin-induced skin lesions are almost invariably a manifestation of DTH, and not of HIT. Given their suggestion that there ought to be a difference of 3 points between non-necrotizing and necrotizing skin lesions, and given that for both DTH and HIT reactions the Timing criterion would often yield 2 points (i.e. onset between days 5 to 10 after starting heparin), this means that the scores will be 3 and 6, respectively, if there is no accompanying thrombocytopenia. This makes a lot of sense. If a patient only has non-necrotizing skin lesions, they will be classified as low pretest probability for HIT (3 points), unless they develop either a platelet count fall consistent with HIT, or they develop thrombotic manifestation. However, for patients with necrotizing skin lesions (6 points), they already ought to be considered as having a high likelihood scenario for HIT. Indeed, we have observed patients in whom the platelet count begins to fall a few days after the necrotizing skin lesions are already apparent, or who develop other HIT-associated thrombotic events in the absence of any significant platelet count fall , and it seems reasonable to have a high clinical suspicion for HIT as soon as necrotizing skin lesions become apparent.
Since its initial description in 2003 , the 4T’s scoring system has been validated in several studies [3,9–11] and has undergone a number of modifications. Figure 1 shows its current version under prospective study at McMaster University (funded by the Heart & Stroke Foundation of Ontario). Some of the changes to highlight are: (i) platelet declines occurring within 3 days of surgery are scored a maximum of 1 point, even if the platelet count fall exceeds 50%; (ii) for assessing rapid-onset HIT (i.e. platelet count fall within 1 day of reinitiating heparin), an exposure to heparin within the past 5–30 days counts as 2 points, whereas an exposure within the past 31–100 days counts only as 1 point; (iii) adrenal hemorrhage counts as 2 points (because of its strong association with adrenal vein thrombosis secondary to HIT); and (iv) clarity has been added to the sorts of alternative non-HIT diagnoses (‘oTher’) that would lead to scores of 1 or 0 points, including information on helping to judge the probability of a (non-HIT) drug-induced immune thrombocytopenic purpura (‘D-ITP’) being present. Finally, it remains our impression that some clinicians misinterpret the category, ‘Timing’: the beginning of the platelet count fall alleged to be HIT should be used to determine timing, not the point at which the platelet count decline reaches some arbitrary threshold indicating thrombocytopenia (e.g. 50% decline).
Figure 1. Latest version of the 4T’s scoring system (under prospective study at McMaster University). The revision proposed by Schindewolf et al.  is shown in italics.*In some circumstances, it may be appropriate to judge ‘Timing’ based upon clinical sequelae, such as timing of onset of heparin-induced skin lesions. **Usually, ‘oTher’ scores “0 points” if thrombocytopenia is not present. However, it may be appropriate to judge ‘oTher’ based upon clinical sequelae, such as whether heparin-induced skin lesions are necrotizing (2 points, i.e., a non-HIT explanation is unlikely) or non-necrotizing (0 points, i.e., a non-HIT explanation is likely [see text]). DIC, disseminated intravascular coagulation; DTH, delayed-type hypersensitivity; IV, intravenous; LMWH, low-molecular-weight heparin.
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Upon consideration of the new information provided by Schindewolf and colleagues, we would propose two further modifications to Table 1. The first would be to alter the label for ‘Timing’, so it is clear that the onset of ‘Thrombosis (or other clinical events)’, such as skin lesions at heparin injection sites, could be used to influence scoring of the second T, rather than only the timing of thrombocytopenia (as a 2006 version of the 4T’s  might suggest). Schindewolf and colleagues applied the score correctly, but we are concerned that others might have been misled by the labels and arrived at a different score. The second modification would be to list ‘erythematous skin lesions at LMWH injection sites’ under the score = 0 points column for ‘oTher’. As with other diagnostic approaches in medicine, clinical prediction rules must be able to grow as new data emerge.