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Delayed cutaneous hypersensitivity reactions to hirudin. (Case Reports).

* Hirudin is one of the new synthetic antithrombin agents, which is most commonly used in patients with type II heparin-induced thrombocytopenia and in patients with hypersensitivity reactions to unfractionated heparin as well as low-molecular-weight heparins. Hirudin is comparable to heparin as an antithrombotic agent and also has been studied as a primary treatment in patients who experienced acute myocardial infarctions. We describe a patient with a history of type II heparin-induced thrombocytopenia who was placed on intravenous hirudin therapy. After extravasation of the intravenous hirudin site, the patient developed a delayed hypersensitivity reaction that histologically showed an epithelioid granulomatous infiltrate. Although rare reports of hypersensitivity reactions to hirudin have been published, these reactions have not been well characterized and the histopathologic changes have not been described.

(Arch Pathol Lab Med. 2001;125:1585-1587)

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Hirudin and its analogs are new synthetic antithrombin agents that were developed with the use of recombinant DNA techniques. (1) These drugs inhibit thrombin independently of antithrombin III or heparin cofactor II. (1) Hirudin is a 65-amino-acid polypeptide first derived from the saliva of the medicinal leech, Hirudo medicinalis, and is the prototype direct thrombin inhibitor. (1) This low-molecular-weight agent binds with high affinity and specificity to both the catalytic site and fibrinogen-binding exosite of thrombin. (2) With intravenous infusion, hirudin reaches peak levels in 90 to 180 minutes and is excreted predominantly by the kidney with a half-life of approximately 60 minutes. (1) It is a potent inhibitor of both venous and arterial thrombosis. (1)

Hirudin and its analogs are specific for thrombin and have no effect on other serine proteases or coagulation factors. (1) They inhibit free, platelet-bound, and clot-bound thrombin, producing greater antithrombotic effects than heparin at the same level of activated partial thromboplastin time (aPTT). (1) The effect on aPTT is dose dependent, and both plasma levels and aPTT are more stable with much less interpatient and individual variability than is seen with heparin, particularly in preventing arterial thrombosis. (1)

Direct antithrombins, such as hirudin, have emerged as an alternative to the limitations and complications that may occur with heparin therapy. Thrombocytopenia has long been recognized as a possible complication of heparin therapy. (3) There are 2 forms of heparin-induced thrombocytopenia (HIT). (4) Type I HIT is a non-immune-mediated thrombocytopenia secondary to a direct interaction of heparin with platelets, promoting aggregation and removal of platelets by the reticuloendothelial system. (3) Type I HIT is of little clinical importance, occurs during the first days of unfractionated heparin therapy, and occurs in approximately 25% of patients. (3) Type II HIT is immune-mediated and generally occurs after several days of heparin therapy. (4) In general, type II HIT occurs after several days of heparin therapy, but may occur earlier in previously sensitized patients, and is seen in 1% to 3% of patients exposed to heparin. (3) In these patients, antibodies are formed against circulating heparin-platelet factor 4 complexes, which after binding to platelet Fc[gamma] RIIA receptors, lead to platelet activation and clumping. (3) Clinically, this reaction results in thrombosis following thrombocytopenia in greater than one third of patients within 30 days, and 50% or more of these patients eventually undergo amputations and/or die. (4) In patients with type II HIT, platelet counts are usually less than 100 000/m[m.sup.3] or decrease by more than 50%, which rarely occurs in type I HIT. (4) In the limited clinical trial performed, recombinant hirudin proved effective for anticoagulation in type II HIT patients and resulted in resolution of thrombocytopenia in more than 90% of the patients. (4) Hirudin is also used as an alternative antithrombotic agent in patients with hypersensitivity reactions to unfractionated heparin and low-molecular-weight heparins, as well as in patients with known type II HIT, and more recently has been studied as a primary antithrombotic agent in patients after myocardial infarctions.

In phase II studies, the antithrombin agents, including hirudin, showed greater efficacy than heparin in improving angiographic variables in acute coronary syndromes and following coronary angioplasty. Topoi et al (3) showed that a 3- to 5-day infusion of hirudin with aspirin and standard oral antianginal therapy produced greater improvement in average and minimal cross-sectional area, minimal luminal diameter, and percentage diameter stenosis than with heparin, particularly at intermediate infusion doses of 0.1 to 0.2 mg/kg/h. However, phase III clinical studies using high doses of hirudin (0.4-0.6 mg/ kg bolus and 0.15-2.0 mg/kg/h infusion) were terminated early due to unacceptably high rates of intracerebral bleeding and other major hemorrhagic complications. At lower doses (0.1 mg/kg bolus and 0.1 mg/kg/h infusion), the longer term effects of hirudin and heparin were comparable and resulted in no greater risk for bleeding complications with hirudin. (5)

We describe a patient with a past history of type II HIT who was treated with intravenous hirudin after suffering an acute myocardial infarction. The patient experienced infiltration at the site of the intravenous hirudin infusion during his therapy and subsequently developed a cutaneous reaction at this site. Although previous hypersensitivity reactions have been described in association with hirudin, these reactions have not been described histologically, and their significance in terms of repeat therapy is unknown. (6)

REPORT OF A CASE

A 52-year-old white man with a past history of type II HIT suffered an acute myocardial infarction with elevation of his creatine kinase-MB (7346 U/L; normal, 0-203 U/L) and troponin I (308.9 ng/mL; normal, 0.00-2.0 ng/mL) levels. The patient had a past history of development of type II HIT during heparinization with a prior myocardial infarction. The diagnosis of type II HIT was made when the patient's platelet count dropped precipitously approximately 11 days after starting therapy. The platelet count at the time of infarction was 435 000/[micro]L, and 11 days later was 65 000/[micro]L. Confirmatory studies included a positive platelet aggregation test, a positive carbon 14-labeled serotonin release assay, and a positive heparin-platelet' factor 4 enzyme-linked immunosorbent assay.

At the time of admission, the patient was taking 1 baby aspirin per day. The patient was started on hirudin intravenously with a planned 0.1 mg/kg bolus and 0.1 mg/kg/h infusion. During the delivery of the initial bolus, there was vascular damage with extravasation into the surrounding tissue, and the patient continued on therapy for 10 days. The intravenous infusion was restarted at a different site. Over the next 4 weeks, the patient noticed increasing erythema and induration at the site of extravasation, but had no systemic symptoms. The patient's baseline platelet count was 475 000/[micro]L, his aPTT was 28.1 seconds (normal, 23.8-35.5 seconds), and his prothrombin time was 13.2 seconds (normal, 11.9-13.9 seconds). On hirudin therapy his platelet count stabilized around 410 000 to 425 000/[micro]L, his aPTT increased and stabilized at approximately 70 seconds, and his prothrombin time stabilized at approximately 16 seconds with no bleeding problems on hirudin. With discontinuation of hirudin, the patient was started on warfarin (5 mg/d), and his prothrombin time was maintained between 17.5 and 19.0 seconds.

The patient's cutaneous lesion remained relatively unchanged over the next 4 weeks, at which time he presented to the dermatology clinic. The area was biopsied; however, no studies were performed to determine if the patient had developed hirudin-specific antibodies. The patient was given fluocinonide (0.5% cream twice a day) after a diagnosis of granulomatous hypersensitivity reaction was made. During the next 6 weeks, the patient reported gradual decreased erythema and flattening of the cutaneous lesion.

HISTOPATHOLOGIC FINDINGS

The biopsy specimen showed a granulomatous inflammatory infiltrate that extended into the subcutaneous fat (Figure 1). The granulomatous infiltrate was composed of epithelioid histiocytes with mild to moderate lymphoid inflammatory infiltrate (Figure 2). This infiltrate surrounded collagen bundles within the dermis. On routine hematoxylin-eosin stain, there appeared to be variable degrees of calcification of stromal matrix, which corresponded mainly to collagen and occurred throughout the reticular dermis. Calcification corresponding to elastic stromal matrix was limited and seen in the upper reticular dermis. The calcification was more prominent with von Kossa staining and appeared to follow along the collagen bundles in a regular, very distinctive pattern. There was minimal acute inflammatory infiltrate with scattered multinucleated giant cells consistent with Langerhans giant cells and not foreign body giant cells.

[FIGURE 1-2 OMITTED]

Special stains, including Fite, Ziehl-Neelsen, and Gomori methenamine-silver stains, were negative.

COMMENT

With vascular trauma and extravasation of hirudin-containing intravenous solution, there is also extravasation of blood and blood products, including platelets. Although hirudin does inhibit thrombin-induced platelet aggregation by its binding to thrombin, it does not inhibit collagen-induced platelet aggregation. (6) Collagen induces platelet aggregation by direct platelet interaction, resulting in spreading and blebbing of platelets, as well as aggregation. (6) With platelet blebbing, there are high and prolonged increases in [Ca.sup.2+], exposure of both P-selectin and phosphatidylserine on platelets, and increased avidity of platelets in conversion of prothrombin into thrombin. (6) In the absence of hirudin, further thrombin production increases cytosolic [Ca.sup.2+] by accelerating the movement of extracellular [Ca.sup.2+] into the cells, and this action in turn accelerates local [Ca.sup.2+] signaling pathways. However, the thrombin-activated [Ca.sup.2+] influx into cells is inhibited by hirudin. (7) This situation could lead to a local increase in extracellular [Ca.sup.2+] at the site of platelet aggregation on collagen fibers and may explain the resulting deposition of [Ca.sup.2+]. on the collagen fibers.

The delay in onset of the erythema and induration seen in our patient is consistent with a delayed hypersensitivity reaction to hirudin. The features seen within histologic sections from the cutaneous biopsy specimen were those of an epithelioid-type granulomatous reaction with occasional Langerhans giant cells. The lack of a neutrophilic infiltrate and foreign body giant cells would rule against a foreign body. granulomatous reaction. Epithelioid granulomatous reaction patterns have been reported with delayed hypersensitivity reactions to silica, zirconium, palladium, aluminium, and beryllium. However, [Ca.sup.2+] deposition has not been reported to cause epithelioid granulomatous hypersensitivity reactions. The distinctive pattern of calcium deposition on the collagen fibers may have induced sensitization to a novel or unmasked epitope formed by the [Ca.sup.2+] collagen complex. Hypersensitivity granulomatous reactions to nonautologous collagen have been reported previously. (8) In addition, through its thrombin-specific inhibition, hirudin inhibits the proinflammatory effects of thrombin, which lead to release of vasoactive amines from mast cells. (9) Hirudin also has been shown to have a more favorable effect on complement activation and generation of complement C3a than heparin, but does not inhibit the proinflammatory effects of factor Xa. (10)

Although the significance of these reactions in terms of possible future use of hirudin is not known, the present patient did continue hirudin administration without systemic symptoms or additional skin lesions for 10 days. Furthermore, if our speculations as to the development of the cutaneous lesion are correct, intravenous delivery of hirudin would not be expected to replicate the cascade of events that led to the skin lesions without extravasation through a traumatized vessel. This type of delayed hypersensitivity reaction would also not be expected to predispose to anaphylaxis.

References

(1.) Tideman PA. Antithrombins and the importance of good control. Aust N Z J Med. 1999;29:444-450.

(2.) Johnson PH, Sze P, Winant R, et al. Biochemistry and genetic engineering of hirudin. Semin Thromb Hemost. 1989;15:302-315.

(3.) Topol EJ, Fuster V, Harrington RA, et al. Recombinant hirudin for unstable angina pectoris: a multicentre, randomized angiographic trial. Circulation. 1994;89:1557-1566.

(4.) Januzzi JL, Jang I-K. Heparin induced thrombocytopenia: diagnosis and contemporary antithrombin management. J Thromb Thrombolysis. 1999;7:259-264.

(5.) The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) 11b Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med. 1996;335:775-782.

(6.) Kirchmaier CM, Bellinger OK, Schulz B, Breddin HK. Effect of recombinant hirudin on cytosolic Ca2+ concentrations using different platelet stimulators. Haemostasis. 1991;21 (suppl 1):121-126.

(7.) Badimon L, Badimon JJ, Lassila R, Heras M, Chesebro JH, Fuster V. Thrombin regulation of platelet interaction with damaged vessel wall and isolated collagen type I at arterial flow conditions in a porcine model: effects of hirudins, heparin, and calcium chelation. Blood. 1991;78:423-434.

(8.) Garcia-Domingo MI, Alijotas-Reig J, Cistero-Bahima A, Tresserra F, Enrique E. Disseminated and recurrent sarcoid-like granulomatous panniculitis due to bovine collagen injection. J Investig Allergol Clin Immunol. 2000;10:107-109.

(9.) Cirino G, Cicala C, Bucci MR, Sorrintino L, Maraganore JM, Stone SR. Thrombin functions as an inflammatory mediator through activation of its receptor. J Exp Med. 1996;183:821-827.

(10.) Cirino G, Cicala C, Bucci M, et al. Factor Xa as an interface between coagulation and inflammation: molecular mimicry of factor Xa association in vivo. J Clin Invest. 1997;99:2446-2451.

Accepted for publication June 8, 2001.

From the Departments of Dermatology and Pathology, University of Alabama, Birmingham (Drs Smith and Skelton); and the Department of Dermatology, National Naval Medical Center, Bethesda, Md (Dr Rosario-Collazo).

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, the Department of the Navy, or the Department of Defense.

Reprints: COL Kathleen J. Smith, MC, USA, Department of Dermatology and Pathology, University of Alabama, Eye Foundation Hospital, Suite 414, 1720 University Blvd, Birmingham, AL 35294-0009 (e-mail: hskelton@pathuab.edu).
COPYRIGHT 2001 College of American Pathologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2001 Gale, Cengage Learning. All rights reserved.

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Author:Smith, Kathleen J.; Rosario-Collazo, Juan; Skelton, Henry
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Dec 1, 2001
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