Fondaparinux: a suitable alternative in cases of delayed‐type allergy to heparins and semisynthetic heparinoids? A study of 7 cases

Hypersensitivity to unfractionated and low-molecular-weight heparins and semisynthetic heparinoids is increasingly common. 7 female patients between 30 and 74 years with delayed-type allergy to heparins and semisynthetic heparinoids were investigated for (cross)-reactivity to fondaparinux, a new pentasaccharide with selective factor Xa inhibition. All patients showed delayed-type reactions to heparins and some additional cross-reaction to a heparinoid on intracutaneous testing. 6/7 tolerated fondaparinux on intradermal testing as well as on subcutaneous challenge testing. However, the 7th patient developed a characteristic delayed-type reaction to both skin tests with fondaparinux. Fondaparinux is a new synthetic pentasaccharide with a molecular weight of 1.728 Da. In some patients with cross-reactivity between various heparins and semisynthetic heparinoids, lepirudin, a recombinant hirudin, may be a safe and effective alternative. However, combined allergy to hirudin and heparins has been reported. Sometimes, intravenous administration of heparins or heparinoids may be tolerated. However, these patients are at risk of developing a systemic reaction. The pathogenesis of heparin hypersensitivity is not fully understood. Heparins may act as haptens by binding to dermal and/or subcutaneous structural proteins. The chemical structures of heparins and fondaparinux are different concerning their alpha- and beta-configuration and the molecular weight. However, some of their functional groups are nearly identical and therefore similar chemical and pharmacological reactivity is to be expected. Fondaparinux seems to be a valuable alternative in most cases of heparin and hirudin hypersensitivity. The clearly rare cross-reaction between fondaparinux and heparins, now confirmed by us, may be due to differences in the response to haptens.     

Delayed-type hypersensitivity skin reactions due to heparins and heparinoids. Tolerance of recombinant hirudins and of the new synthetic anticoagulant fondaparinux

Eczema-like, infiltrated plaques at subcutaneous heparin-injection sites are well-documented side effects of these anticoagulants. They are due to delayed-type hypersensitivity. In 4 patients, patch, intradermal and subcutaneous tests were performed with a panel of unfractionated heparins (UFHs), low-molecular-weight heparins (LMWHs), heparinoids, recombinant hirudins and a new synthetic pentasaccharide anticoagulant fondaparinux sodium, to find safe alternatives. 3 patients were sensitized to all the UFHs and LMWHs. The LMWH tinzaparin sodium and the heparinoid pentosan polysulfate were found to be a possible substitute in patient no. 1 and 2, respectively. The recombinant hirudins and fondaparinux sodium were tolerated without any side effects in all patients tested. Fondaparinux is a synthetic copy of a pentasaccharide sequence in the heparin molecule. It is the first in a new class of antithrombotic agents. Our study suggests that it is a new safe alternative in patients with eczema-like, infiltrated plaques at subcutaneous heparin-injection sites.     

Delayed-type hypersensitivity to low molecular weight heparins and heparinoids: cross-reactivity does not depend on molecular weight

BACKGROUND: Cross-reactivity is a widespread phenomenon in patients who develop cutaneous delayed-type hypersensitivity (DTH) reactions to low molecular weight heparins (LMWHs). As molecular weight is believed to be a key determinant of sensitization to heparins, the recently developed LMWH bemiparin, with the lowest molecular weight of all LMWHs, appeared to be a significant improvement. OBJECTIVES: To evaluate cross-reactivity between bemiparin and several other LMWHs and heparinoids by means of subcutaneous testing. Methods Test doses of bemiparin and several other LMWHs/heparinoids were given to eight patients with a history of local eczematous reactions after subcutaneous injection of enoxaparin. RESULTS: Seven of eight patients showed cross-reactivity following subcutaneous injection of bemiparin. In addition, nearly all tested substances caused local eczematous reactions in at least some patients, with the exception of fondaparinux, which was well tolerated by all patients. Of all substances tested, bemiparin had the highest cross-reactivity with enoxaparin. Substances with a lower molecular weight did not cross-react less frequently than the others. CONCLUSIONS: No significant correlation was found between the molecular weight of the tested substances and the frequency of DTH reactions. In patients with DTH to enoxaparin, the LMWH bemiparin is not a suitable alternative.     

Placas eritematosas por heparina de bajo peso molecular

—Cutaneous lesions due to low molecular weight heparins (LMWH) are infrequent.We present a case of infiltrated erythematous plaques located at injection sites of subcutaneous sodium enoxaparine and calcium nadroparine. Clinical findings, histological studies and positive epicutaneous and intradermal tests to low molecular weight heparin suggest an allergic reaction to this substance, probably mediated by a type IV hypersensitivity reaction. Cutaneous tests should be performed in order to exclude cross reactions between different types of LMWH. Recombinant hirudin may be an alternative terapeutic agent in these cases.     

Arthus reaction to lepirudin, a new recombinant hirudin, and delayed-type hypersensitivity to several heparins and heparinoids, with tolerance to its intravenous administration

The pathogenesis of allergic reactions to heparin is poorly understood. Clinically, this phenomenon is relevant because of its increasing incidence and the resulting therapeutic challenges due to various cross-reactions between unfractionated and low-molecular weight heparins as well as between heparins and heparinoids. A 44-year-old female patient had developed a delayed-type hypersensitivity to certoparin-sodium. Diagnostic allergy testing revealed various cross-reactions between different heparins as well as an intolerance to heparinoids. After subcutaneous challenge with the recombinant hirudin lepirudin (Refludan) the patient developed a local Arthus reaction at the injection site. In general, recombinant hirudins do not cross-react with high- or low-molecular weight heparins and heparinoids because of a different molecular structure and are therefore an alternative in case of adverse reactions to heparins and heparinoids. Whereas a local Arthus reaction has already been described twice for low-molecular weight heparins, this is to the best of our knowledge the first observation of a superficial leukocytoclastic vasculitis due to s.c. applied lepirudin. Intravenous administration of heparins and heparinoids in case of hypersensitivity to these drugs following topical application risks a generalized eczematous reaction in patients with delayed-type allergy to both groups of substances. In our patient with delayed-type hypersensitivity to heparins and heparinoids and superficial vasculitis due to lepirudin, the intravenous challenge with heparin and a heparinoid was justified as an ultima ratio measure and proved to be the useful therapeutical alternative.     

Haemorrhagic purpura in an elderly man

You are asked to review an 85 year old man with bullous lesions on the torso and limbs (as shown), which developed after treatment with low‐molecular weight heparin (LMWH), unfractionated heparin (UFH), and furosemide. Based on the given history and the clinical and histological images, what is your diagnosis?     

Widespread skin necrosis associated with unfractionated heparin therapy in a patient under chronic coumarin anticoagulation

Coumarins and heparins are commonly used for temporary or long-term anticoagulation. These molecules have potentially devastating side-effects, including widespread skin necrosis. We report the case of an elderly patient under oral anticoagulation with coumarins, who developed widespread necrotic cutaneous lesions upon introduction of intravenous and subcutaneous unfractionated heparin administration for a surgical procedure. Laboratory investigations revealed the presence of circulating antibodies directed against heparin-platelet factor 4. The lesions slowly resolved after withdrawal of heparin, whereas oral coumarin was re-introduced without complications. This case illustrates the rare occurrence of skin necrosis as a result of unfractionated heparin in a patient under chronic coumarin medication. Recognition of this rare complication and appropriate laboratory testing is mandatory for prompt institution of alternative anticoagulant therapies.     

The risk for cross-reactions after a cutaneous delayed-type hypersensitivity reaction to heparin preparations is independent of their molecular weight: a systematic review

Background. Heparins are a widely used class of drugs known to cause delayed‐type hypersensitivity (DTH) reactions. Recent publications indicate that the incidence of these may be higher than previously thought. To date, patient‐related but no drug‐related risk factors for the development of DTH reactions to heparins have been identified, although molecular weight is discussed as a potentially relevant parameter. Objectives. To address this, a systematic review was conducted on the frequency of cross‐reactions after DTH reactions to heparin preparations. Methods. We electronically searched MEDLINE and EMBASE, hand‐searched selected journals and references, and contacted experts for unpublished data. Results. Sixty‐six publications and unpublished data of 14 patients resulted in 198 patients with 1084 tests for cross‐reactivity. The primary causative agents were mostly unfractionated heparin (50%) and low molecular weight heparins (49.5%). Cross‐reactions were more likely after an initial DTH reaction to unfractionated heparin than after an initial DTH reaction to low molecular weight heparin. Our findings also indicate that molecular weight does not correlate with the risk for cross‐reactivity, which is in line with recent observations, indicating that different heparins have to be individually considered. Conclusions. The available data demonstrated the lowest overall risk for cross‐reactions for pentosan polysulfate (36.4%) and fondaparinux (10.4%). In the clinical context, fondaparinux is recommended as the current best alternative when a DTH reaction occurs.     

Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: tolerance of a new recombinant hirudin

BACKGROUND: Eczema-like infiltrated plaques at subcutaneous heparin injection sites are well-documented side effects of these anticoagulants. However, surgical interventions may be problematic if heparin is urgently needed in these patients. OBJECTIVE: The aims of this study were to perform extensive allergy skin testing in 24 patients, including a pregnant woman in whom subcutaneous infiltrated plaques developed after subcutaneous heparin injections, and to find safe therapeutic alternatives for this group of patients. METHODS: Patch, intradermal, and subcutaneous tests were performed with a panel of unfractionated heparins (UFHs), low-molecular-weight heparins (LMWHs), and heparinoids. Since 1997, we have also been performing allergy studies in 8 patients with lepirudin, a new recombinant heparinoid; tolerance of lepirudin was investigated by means of subcutaneous and intravenous injections. The allergy investigations in the pregnant woman were limited to patch tests with heparins and intradermal and subcutaneous tests with pentosanpolysulfate, which are not contraindicated during pregnancy. RESULTS: In our study population 19 of 23 patients were sensitized to all the UFHs and LMWHs tested when intracutaneous and subcutaneous test results were read at up to 96 hours. LMWH was found to be a possible substitute in 4 patients. Five patients were also sensitized to the heparinoid pentosanpolysulfate. Sensitization to the heparinoid danaparoid was observed in 12 of the 13 patients who were tested with this substance. The administration of an intravenous bolus containing a therapeutic dose of lepirudin after negative subcutaneous provocation was tolerated without any side effects in all 8 patients. The pregnant woman was sensitized to LMWH but tolerated subcutaneous pentosanpolysulfate without any side effects. CONCLUSION: Extensive allergy skin testing should be performed to find safe alternatives. With few exceptions, all patients react to both UFHs and LMWHs, as well as to danaparoid. The subcutaneous provocation test is the most reliable diagnostic measure. Intravenous lepirudin, and in some cases subcutaneous pentosanpolysulfate, appears to be a safe alternative in patients with eczema-like infiltrated plaques at subcutaneous heparin-injection sites.     

静脉滴注丙种球蛋白联合低分子肝素联合治疗42例复发性流产临床疗效观察

目的：探讨静脉滴注丙种球蛋白联合低分子肝素对于复发性流产孕妇的临床疗效及安全性。方法：将本院收治的84例抗心磷脂抗体（ACA）阳性的复发性流产患者随机分为实验组和对照组，实验组患者给予静脉滴注丙种球蛋白联合低分子肝素治疗，对照组患者给予黄体酮联合HCG的传统保胎治疗，比较两组患者保胎成功率及不良反应的发生情况。结果：实验组保胎成功率81．0％，对照组保胎成功率31．0％，实验组保胎成功率显著高于对照组（P〈0．05）。两组患者均无严重不良反应发生。结论：对于ACA阳性的复发性流产患者，静脉滴注丙种球蛋白联合低分子肝素疗效显著且安全性高，值得临床推广应用。     

Tolerance to intravenous admiration of heparin and heparinoid in a patient with delayed-type hypersensitivity to heparins and heparinoids

Delayed-type hypersensitivity reactions ot subcutaneously (s.c) injected heparins are common. Since similar reactions usually occur to different heparin preparations, semisynthetic heparinoids might be a therapeutic alternative. We report a patient exhibiting eczematous reactions to heparins as well as heparinoids; delayed-type hypersensitivity was demonstrated by intracutaneous (i.c.) and patch tests, as well as by s.c. provocation. Remarkably, intravenous (i.v.) administration of heparin as well as heparinoid was well-tolerated.     

Cholesterol crystal embolism

Cholesterol crystal embolism (CCE) is an infrequent entity that primarily appears in males over the age of 60 with generalized arteriosclerosis after angiographic procedures, vascular surgery or, more rarely, with oral anticoagulant treatment with heparin or with fibrinolytics. We present the case of a patient with several risk factors for CCE, who presented with the pathognomonic triad of leg and foot pain, livedo reticularis and palpable pedal pulses. The diagnosis was based on the fact that cholesterol crystals were seen in the arterioles in the skin biopsy. Due to the frequency with which the skin manifestations appear and the importance of early diagnosis and treatment, an awareness of these crystals is fundamental in diagnosing these processes.     

IgG antibodies and early intradermal reactions to hydrocortisone in patients with cutaneous delayed-type hypersensitivity to hydrocortisone

Seven of 25 patients with cutaneous delayed-type hypersensitivity to hydrocortisone had an immediate reaction following the intradermal injection of hydrocortisone sodium succinate. Using an ELISA method, we found that these patients had significantly increased levels of IgG antibodies to hydrocortisone when compared with normal blood donors (P<0.005) and nickel-allergic patients (P<0.05). We suggest that these patients are at risk of developing type III and possibly type I reactions following the systemic administration of hydrocortisone and that, if needed, an alternative systemic corticosteroid should be used, for example betamethasone or dexamethasone.     

Frequency of thrombophilia determinant factors in patients with livedoid vasculopathy and treatment with anticoagulant drugs – a prospective study

Background Livedoid vasculopathy (LV) is a chronic idiopathic disease characterized by painful purpuric macules on lower extremities. Its exact aetiology remains uncertain, but thrombotic and microcirculatory phenomena have been implicated as possible pathogenic factors. Objectives To assess prospectively the frequency of thrombophilia and to verify the effectiveness of anticoagulant therapy among LV patients. Methods Thirty‐four LV patients were tested for prothrombin time, activated partial thromboplastin time, antithrombin activity, protein C and S activity, anticardiolipin antibodies, lupus anticoagulant, prothrombin gene mutation, factor V Leiden mutation, methylenetetrahydrofolate reductase mutation, plasma homocysteine and fibrinogen. Thirteen of these patients were treated with anticoagulant drugs (either warfarin or heparin). Results Of 34 patients, 18 (52%) presented laboratory abnormalities of procoagulant conditions. Positive treatment response to anticoagulant therapy was observed in 11 patients. Improvement of pain was obtained in 1–3 weeks, an average of 1.8 week. Complete healing of the lesions was observed in about 2.3 months. Remission was sustained even after treatment interruption and lasted an average 7.8 months. No severe adverse effects were noticed. Conclusion The authors suggest all patients with diagnosis of LV to be investigated for thrombophilic status. Anticoagulant drugs were well tolerated and seemed to be effective in treating not only LV symptoms but also its ulcerations.     

低分子肝素联合乌司他丁治疗急性胰腺炎的疗效分析

目的分析低分子肝素联合乌司他丁治疗急性胰腺炎（acutepancreatitis，AP）的效果。方法2004年6月～2008年3月收治的100例AP患者，随机分入数量相等的4组：A组（对照组）、B组（低分子肝素治疗组）、C组（乌司他丁治疗组）、D组（低分子肝素＋乌司他丁治疗组）。观察各组第1、3、7天时的血自细胞计数、动脉血氧分压统计平均治愈天数、手术治疗率、重症化率和病死率。结果治疗第1天时低分子肝素可降低白细胞计数；在治疗第3、7天时低分子肝素、乌司他丁、低分子肝素协同乌司他丁均可降低白细胞计数。在治疗第3、7天时低分子肝素、乌司他丁、低分子肝素协同乌司他丁均可提高动脉血氧分压。低分子肝素及乌司他丁可缩短治疗天数，低分子肝素与乌司他丁对治疗天数无协同作用。结论低分子肝素联合乌司他丁治疗急性胰腺炎，可改善动脉咖氢分乐．隆低白绅晌计狮．缩橱病耪．     

Livedoid vasculopathy: Clinical course and long‐term outcome in Asian patients with a review of the literature

Livedoid vasculopathy (LV) is an uncommon, chronic, and recurrent thrombo‐occlusive vascular disorder. Data specific to LV in Thai population remains scarce. This study aimed to evaluate the clinical course and treatment outcomes of LV in Thai patients, and to perform a literature review for studies that reported on anticoagulant treatment in LV. Seventy‐four patients with a mean age of 37.6 ± 14.7 years were included. The female to male ratio was 5.2:1, and the median follow‐up was 10.5 months. Most patients had primary LV disorder. Forty‐eight patients were improved with treatments, with a median duration of 11.4 months. Combination treatments were commonly used, including anti‐inflammatories, antiplatelets, and immunosuppressants. Add‐on therapy with anticoagulant or psoralen plus ultraviolet‐A (PUVA) led to disease improvement in a majority of the patients treated. Kaplan‐Meier analysis demonstrated that 38.5%, 53.7%, and 57.9% would have disease improvement at 1, 2, and 3 years, respectively. Of 39 studies (n = 219) that reported on anticoagulant treatment in LV, anticoagulant drug was used as monotherapy in 104 patients. The mean duration of anticoagulant treatment was 7.2 ± 3.8 months, which led to disease improvement in 97 patients (93.3%). Bleeding side effect was found in 9 patients (8.7%). The highest incidence of LV was found among females aged 30 to 40 years. Combination therapy with anti‐inflammatory drugs, antiplatelet drugs, and immunosuppressants led to disease improvement. The observed efficacy of add‐on PUVA or anticoagulant is promising and should be further investigated. Further studies are needed to guide the development of an LV management guideline.     

以晕厥为首发症状的肺栓塞30例临床分析

目的 探讨以晕厥为首发症状的肺栓塞临床特点及治疗。方法 对以晕厥为首发症状的30例肺栓塞患者（30～50岁），先给予低分子肝素或肝素抗凝治疗，低分子肝素5000U每日两次皮下注射，后行50万U尿激酶静脉注射溶栓治疗。结果 经抗凝，并行尿激酶溶栓治疗后，死亡4例，占13．33％；好转12例，占40．0％；治愈13例，占43．33％；无变化者1例，占3．33％。治愈及好转患者下肢肿胀、压痛及劳力性呼吸困难逐渐消失，恢复正常活动。结论 抗凝和尿激酶溶栓治疗对以晕厥为首发症状的肺栓塞有效。     

Treatment of severe cutaneous ulcerative lichen planus with low molecular weight heparin in a patient with hepatitis C

The ulcerative variant of lichen planus (LP) commonly involves the oral mucosa but is uncommon and difficult to treat when located on other areas. We describe an unusual case of ulcerative LP involving several surfaces, including the palms and scrotum, in a 50-year-old man with hepatitis C. The patient was recalcitrant to treatment with conventional therapy but obtained clearance with a sustained response using low molecular weight heparin (LMWH). This treatment is an option for patients with LP who are not ideal candidates for standard therapy.     

Lymphocyte proliferation response in patients with delayed hypersensitivity reactions to heparins

Background  Heparins can induce delayed-type hypersensitivity (DTH) reactions mediated by specific T lymphocytes. However, the interaction between heparins and lymphocytes has not been sufficiently studied.
Objectives  To analyse the lymphocyte response to heparins using different types of antigen-presenting cells in patients with DTH reactions to these drugs.
Methods  We studied seven patients with DTH reactions to heparins diagnosed by delayed reading of intradermal skin testing ( n  =   5) or drug provocation test ( n  =   2) and nine tolerant controls. Biopsies were obtained from intradermal testing or during the acute reaction. Peripheral blood mononuclear cells were used to obtain T and B lymphocytes, monocytes and monocyte-derived dendritic cells (DC). T-lymphocyte proliferation was assayed by means of ³H-thymidine incorporation.
Results  Skin testing showed a high degree of cross-reactivity within low molecular weight heparins with good tolerance to sodium heparin, fondaparinux and lepirudin in most cases. The proliferative response was positive in six patients to most of the heparins tested with both monocytes and B cells (the classical lymphocyte transformation test) or immature DC as antigen-presenting cells, giving a higher response with DC. At a second evaluation 1 year later, the proliferative response was found only with DC, and mainly to the culprit drug.
Conclusions  A model using DC in the lymphocyte proliferation test is a more appropriate way to assess the immunological response in DTH to heparins; additionally, it can detect a response over a longer time. These findings may be useful for the diagnostic evaluation of drug reactions.     

Delayed-type allergenicity of triforine (Saprol®)

The delayed-type allergenicity of triforine (Saprol®), 1,4-bis (2,2,2-trichloro-l-formamidoethyl) piperazine, was studied. In a mass examination of chrysanthemum growers among whom triforine was commonly used, the highest rate of positive patch test reaction was seen to triforine (17%) among the 7 pesticides and chrysanthemum extracts tested. A higher prevalence rate of work-related skin symptoms was seen in subjects with a positive patch test reaction to triforine (44%) than in those with negative reactions to all allergens tested (15%) ( p < 0.05). 12 subjects (67%) with positive patch test reactions to triforine were also positive to dichlorvos (DDVP®), with a high × coefficient (0.65). The grading of guinea pig maximization test to triforine was grade IV (66%), defined as "strong", Cross-sensitization between triforine and dichlorvos was also shown. The present results confirm that triforine is capable of including delayed-type allergy among chrysanthemum growers and of showing cross-reactivity with dichlorvos.