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(Chest. 2005;127:1857-1861.)
© 2005 American College of Chest Physicians

Heparin-Induced Skin Lesions and Other Unusual Sequelae of the Heparin-Induced Thrombocytopenia Syndrome*

A Nested Cohort Study

Theodore E. Warkentin, MD; Robin S. Roberts, MSc; Jack Hirsh, MD, FCCP and John G. Kelton, MD

* From the Departments of Pathology and Molecular Medicine (Dr. Warkentin), Medicine (Drs. Hirsh and Kelton), and Clinical Epidemiology and Biostatistics (Prof. Roberts), McMaster University, Hamilton, ON, Canada.

Correspondence to: Theodore E. Warkentin, MD, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, General Site, 237 Barton St East, Hamilton, ON, L8L 2X2 Canada; e-mail: twarken{at}mcmaster.ca


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating, heparin-dependent IgG antibodies (HIT-IgG). Although HIT is known to predispose the patient to thrombosis, the relationship between the formation of HIT-IgG and various other unusual clinical sequelae putatively linked with the HIT syndrome, such as heparin-induced skin lesions and acute anaphylactoid reactions following treatment with an IV heparin bolus, is not clear.

Methods: We used data from a clinical trial of postoperative heparin prophylaxis to compare the frequency of one or more predefined unusual clinical sequelae developing in 20 patients who formed platelet-activating HIT-IgG with 80 control patients who did not form HIT-IgG (nested cohort study).

Results: Five of the 20 patients in whom HIT-IgG developed had one or more unusual clinical sequelae, compared with none of 80 control patients (25% vs 0%, respectively; odds ratio, {infty}; 95% confidence interval, 4.3 to {infty}; p < 0.001). The unusual complications included heparin-induced erythematous or necrotic skin lesions (n = 4), an anaphylactoid reaction following IV heparin bolus use (n = 1), and warfarin-associated venous limb ischemia (n = 1). Thrombocytopenia, as it is conventionally defined (ie, platelet count fall to < 150 x 109 cells/L) developed in only one of these five patients.

Conclusions: Certain unusual clinical sequelae, such as heparin-induced skin lesions, are strongly associated with the formation of HIT-IgG and should be considered as manifestations of the HIT syndrome, even in the absence of thrombocytopenia as conventionally defined.

Key Words: anaphylactoid reaction • heparin • IgG • skin lesions • thrombocytopenia


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Heparin-induced thrombocytopenia (HIT) is an Ig-mediated adverse drug reaction characterized by an increased risk for venous and arterial thrombosis.12 There is anecdotal evidence that some patients with HIT can experience other unusual clinical events, including skin lesions at heparin injection sites,345 acute anaphylactoid reactions following IV bolus administration of heparin,567 adrenal hemorrhagic infarction,89 warfarin-associated venous limb ischemia or gangrene,101112 "classic" warfarin-associated (central) skin necrosis,11121314 and transient global amnesia.15 Since thrombocytopenia, as conventionally defined (ie, platelet count fall to < 150 x 109 cells/L), did not develop in some of these patients, the association of these clinical events with the HIT syndrome has been uncertain.34

Previously, we performed a large clinical trial in which patients undergoing elective hip replacement surgery were randomized to receive either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for the treatment of deep-vein thrombosis (DVT) prophylaxis.161718 We performed a systematic serologic investigation for the presence of heparin-dependent IgG antibodies (HIT-IgG) in a large subgroup of these patients and identified 20 patients who formed platelet-activating HIT-IgG that were detectable by both platelet activation assay (ie, platelet serotonin release assay)1920 and platelet factor 4 (PF4)/heparin-enzyme immunoassay.21 We observed a strong association between serologically confirmed HIT and thrombosis in this study.1718 We also found that some patients who form HIT-IgG experience a fall in platelet count of > 50% without developing thrombocytopenia (defined conventionally as a platelet count fall to below < 150 x 109 cells/L).18

We now report our investigation into whether these various unusual sequelae of heparin exposure are associated with the formation of HIT-IgG. We used a nested case-control study design, in which we compared the 20 patients who formed HIT-IgG with 80 randomly selected patients who did not form HIT-IgG. Our study suggests that the spectrum of complications of the HIT syndrome is greater than is widely appreciated, even in the absence of thrombocytopenia as conventionally defined.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical Trial
Analysis was performed using data from a clinical trial of UFH and LMWH1617 that was approved by the institutional review board, and for which all participating patients provided written informed consent. In brief, the clinical trial compared the use of a UFH preparation (Calciparin; Anglo French Drug Company; Montreal, QC, Canada) [7,500 U subcutaneously twice daily] with the LMWH preparation enoxaparin (Lovenox; Rhône-Poulenc Rorer; Montreal, QC, Canada) [30 mg subcutaneously twice daily], both beginning on the first postoperative day.

Assay for Platelet-Activating HIT-IgG
The platelet 14C-serotonin release assay and the PF4/heparin-enzyme immunoassay were used to detect HIT-IgG, as described.192021 For 362 patients, serial plasma samples were available in which at least one of the plasma samples was obtained on postoperative day 7 or later. Plasma samples that gave the following reaction pattern were considered to be strongly positive for platelet-activating HIT-IgG: > 50% release at 0.1 U/mL heparin; < 20% release at 100 U/mL heparin; < 20% release at 0.1 U/mL heparin in the presence of an Fc receptor blocking the monoclonal antibody IV.3; and a positive test result for anti-PF4/heparin antibodies of IgG class (optical density, > 0.45 absorbance units). For all patients who tested positive, HIT-IgG seroconversion was proven by comparative testing with the baseline (preoperative) specimen.

Nested Cohort Study
As 20 of the 362 patients in the subgroup tested positive for HIT-IgG using the criteria defined above, we used a nested case-control (1:4) design, thus designating for detailed chart review 100 patient records, for the 20 patients who tested positive, and 80 randomly selected patients (using a random number table) who tested negative for HIT-IgG with both the platelet activation assay and the anti-PF4/heparin-enzyme immunoassay. All medical and nursing records were reviewed in detail by study personnel who had been blinded to the results of both HIT-IgG assays and platelet counts, using specially prepared data collection sheets that listed the criteria for the following putative sequelae of the HIT syndrome6: (1) heparin-induced skin lesions, defined4 as painful or pruritic inflammatory (erythematous) or necrotic lesions localized to the sites of study drug injections that began on day 5 or later of UFH or LMWH use; (2) acute anaphylactoid reactions beginning within 30 min of IV bolus heparin administration6; (3) warfarin-associated venous limb ischemia or gangrene, defined as acral (distal extremity) ischemia or necrosis despite palpable arterial pulses in a patient receiving warfarin101112; (4) "classic" warfarin-induced (central) skin necrosis, defined as nonacral necrosis of dermal and subcutaneous tissues in a patient receiving warfarin22; (5) adrenal hemorrhagic infarction (compatible clinical picture of abdominal or flank pain and/or hypotension, confirmed by radiologic imaging); (6) transient global amnesia15; and (7) "resistance" to the anticoagulant effect of therapeutic-dose UFH, defined as the requirement for > 35,000 U of heparin per 24 h to maintain a therapeutic activated partial thromboplastin time.23

Statistical Analysis
We compared the proportions of patients who had outcome events between groups by Fisher exact test24 and an associated method by Gart25 for computing confidence intervals around the odds ratio. All quoted p values are two-tailed.


   Results
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Discussion
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Inflammatory skin lesions (n = 3) or necrotic skin lesions (n = 1) at heparin injection sites were more likely to have developed in patients with test results that were positive for HIT-IgG, compared with patients in whom HIT-IgG did not develop (4 of 20 vs 0 of 80 patients, respectively; p < 0.001) [Table 1 ]. These lesions all began on postoperative day 7 or later. The patient in whom necrosis developed at the heparin injection sites had mesenteric artery thrombosis complicating an 81% fall in the platelet count from 401 to 75 x 109 cells/L, but heparin therapy was later restarted as the thrombocytopenia had been attributed to the effects of bowel infarction rather than to HIT (which was not proven serologically until after the patient’s discharge from the hospital). Thrombotic events did not occur in the remaining three patients in whom nonnecrotizing, inflammatory, heparin-induced skin lesions developed.


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  		Table 1.. Relationship Between HIT-IgG Formation and Development of Predefined Unusual Sequelae Putatively Linked to the HIT Syndrome*

 
A severe acute anaphylactoid reaction developed in one patient who tested positive for HIT-IgG on postoperative day 13 that began 10 min after an IV bolus administration of 5,000 U UFH (Fig 1 ). The reaction was characterized by chills and rigors, dyspnea, tachypnea, diaphoresis, headache, flushing, restlessness, and tachycardia, and the platelet count abruptly fell by 58% from 705 to 297 x 109 cells/L. This patient had been noted to have inflammatory (erythematous) skin lesions at the LMWH injection sites 3 days before the UFH bolus was administered, but this had not been recognized as a possible manifestation of the HIT syndrome.



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  		Figure 1.. Clinical course of a patient in whom two unusual sequelae associated with HIT antibodies developed. A 57-year-old man who underwent elective hip replacement surgery received postoperative antithrombotic prophylaxis with LMWH (enoxaparin). Nonnecrotizing, erythematous skin lesions developed at the LMWH injection sites on postoperative day 10. On postoperative day 13, DVT was clinically suspected. As HIT had not been clinically suspected despite the presence of skin lesions at the LMWH injection sites (the platelet count on day 13 was 705 x 109 cells/L), a 5,000 U IV bolus of UFH was administered, followed 10 min later by signs and symptoms of an acute systemic reaction (ie, chills, rigors, dyspnea, tachypnea, diaphoresis, pounding headache, restlessness, flushing, and tachycardia). The platelet count fell by 57.9% from 705 to 297 x 109 cells/L. Heparin therapy was discontinued. Imaging study findings were negative for DVT, and further anticoagulation therapy was not required. The patient tested strongly positive for HIT antibodies (platelet activation assay, 98% serotonin release [normal level, <20%]; PF4/heparin enzyme-immunoassay, 1.508 absorbance units [normal level, < 0.450 U]).

 
Limb ischemia, despite palpable pulses (ie, cyanotic toes and painful forefoot) in the limb affected by venographically proven calf DVT during anticoagulation therapy with warfarin, developed in one patient who had tested positive for platelet-activating HIT-IgG. The clinical manifestations were of sufficient severity to prompt a vascular surgical consultation. The platelet count fell by 58% from 383 to 161 x 109 cells/L in association with this clinical event, which was judged to be a case of warfarin-associated venous limb ischemia (ie, digital and forefoot ischemia associated with warfarin use during the treatment of HIT-associated DVT).

Adrenal hemorrhagic infarction, classic warfarin-induced skin necrosis, or transient global amnesia did not develop in any patients or control patients. Resistance to the anticoagulant effect of IV therapeutic-dose UFH was not more common among patients who formed HIT-IgG, compared with control patients treated with therapeutic-dose UFH.

Thus, 5 of the 20 patients in whom HIT-IgG formed developed six unusual sequelae putatively linked to the HIT syndrome, which was a higher percentage than that in the control population (25% vs 0%, respectively; odds ratio, 4.3 to {infty}; p < 0.001). Thrombocytopenia, as conventionally defined, developed in only one of these five patients, although the platelet count fell by ≥ 50% from the postoperative peak in association with HIT-IgG formation in three of the remaining four patients.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The association between thrombocytopenia and thrombosis in patients who form HIT-IgG has been recognized for > 25 years.26 Subsequently, a number of other unusual clinical events, including heparin-induced skin lesions,3456 acute systemic (anaphylactoid) reactions following IV bolus heparin use,6715 and warfarin-associated peripheral limb or central skin necrosis syndromes,1011121314 among others, have been reported in association with HIT.

In this study, we capitalized on our observation that platelet-activating HIT-IgG developed in 20 of 362 patients participating in a clinical trial comparing UFH and LMWH for postoperative antithrombotic prophylaxis following elective hip replacement surgery. We performed a detailed chart review of these 20 patients, as well as of 80 randomly selected control patients who had tested negative for HIT-IgG. The reviewers were blinded to the HIT-IgG and platelet count results.

Among the 20 patients who tested positive for HIT-IgG, we identified 5 patients in whom one or more unusual clinical sequelae putatively linked to the HIT syndrome had developed. These included four patients in whom heparin-induced skin lesions developed, one patient in whom an acute anaphylactoid reaction developed following administration of an IV heparin bolus, and one patient in whom venous limb ischemia developed during the use of warfarin to treat DVT. Neither these nor any other predefined unusual complications associated with the HIT syndrome developed in any of the 80 control patients. A platelet count fall that reached thrombocytopenic levels, as conventionally defined (platelet count of < 150 x 109 cells/L) developed in only one of the five patients who had tested positive for HIT-IgG. However, a platelet count fall of ≥ 50% developed in four of the five patients in association with HIT-IgG formation. None of these five patients were suspected of having had HIT by the attending physicians when the clinical trial was conducted, suggesting that the infrequent occurrence of thrombocytopenia (as conventionally defined) or the unusual nature of the complicating events obscured the relationship of these clinical features with the HIT syndrome. The importance of recognizing these unusual sequelae as manifestations of the HIT syndrome was illustrated by the patient who evinced erythematous skin lesions at the sites of LMWH injection, and who subsequently received an IV bolus of UFH that resulted in an acute systemic reaction (Fig 1). Although this patient recovered without adverse long-term consequences, fatal cardiopulmonary arrest562728 in association with IV heparin bolus use in the setting of HIT antibodies has developed in other patients. Moreover, in recent years, several nonheparin anticoagulants, such as lepirudin and argatroban have been approved to treat patients who cannot receive UFH or LMWH because of HIT.29 We suggest that unusual, but clinically important, sequelae of the HIT syndrome may be relatively more common than is widely recognized.


   Acknowledgements
 
We thank Luba Klama for assistance with data collection.


   Footnotes
 
Abbreviations: DVT = deep-vein thrombosis; HIT-IgG = heparin-induced thrombocytopenia IgG antibodies; HIT = heparin-induced thrombocytopenia; LMWH = low-molecular-weight heparin; PF4 = platelet factor 4; UFH = unfractionated heparin

This study was supported by Rhone-Poulenc Rorer (now Sanofi-Aventis). The serologic studies described were supported by the Heart and Stroke Foundation of Ontario (grants No. T-4502 [T.E.W], No. T-5207 [T.E.W.], and No. T-4404 [J.G.K]). Neither the clinical trial sponsor nor the funding agency had any role in the analysis or interpretation of the data, or in the decision to submit the manuscript for publication.

The corresponding author had full access to all of the data and had final responsibility for the decision to submit for publication.

Received for publication July 20, 2004. Accepted for publication November 29, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Think of HIT When Thrombosis Follows Heparin.
Chest, September 1, 2006; 130(3): 631 - 632.
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