Delayed reactions to low-molecular weight heparins: Cross reactivity with unfractioned heparin

Low molecular weight heparins (LMWHs) are used for a variety of indications. The most common type of hypersensitivity reactions to LMWHs are delayed-type hypersensitivity reactions (DHR). Immediate-type hypersensitivity reactions (IHR) occur only sporadically. Cross-reactivity of different LMWHs is a common and unpredictable problem. We present 2 cases of patients who developed DHR to nadroparin and enoxaparin, respectively. The third case presents a patient who developed IHR to nadroparin. Skin tests confirmed the hypersensitivity in all cases. In the cases of DHR, a skin test negative LMWH was identified and was tolerated in a challenge test. In the IHR case, cross-reactivity to all tested LMWHs was established. We hypothesize that the degree of cross-reactivity might depend on the type of hypersensitivity reaction with immediate reactions linked to more extensive cross-reactivity than delayed reactions. This is important to consider because, at least in some cases, a safe alternative LMWH can be identified.

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Heparin-induced Thrombocytopenia: IgG Binding to PF4-Heparin Complexes in the Fluid Phase and Cross-reactivity with Low Molecular Weight Heparin and Heparinoid

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615190 ◽

1998 ◽

Vol 80 (08) ◽

pp. 292-297 ◽

Cited By ~ 80

Author(s):

Peter Newman ◽

Rebecca Swanson ◽

Beng Chong

Keyword(s):

Molecular Weight ◽

Fluid Phase ◽

Cross Reactivity ◽

Low Molecular Weight ◽

Absolute Contraindication ◽

Low Molecular Weight Heparins ◽

Heparin Induced Thrombocytopenia ◽

Igg Binding ◽

Heparin Complexes ◽

Low Levels

SummaryEarly diagnosis of heparin-induced thrombocytopenia (HIT) is essential to reduce morbidity and mortality. We report an enzyme immunoassay which detects the binding of HIT IgG to PF4-heparin in the fluid phase. Our fluid phase assay produces consistently low background and can detect low levels of anti-PF4-heparin. It is suited to testing alternative anticoagulants because, unlike in an ELISA, a clearly defined amount of antigen is available for antibody binding. We were able to detect anti-PF4-heparin IgG in 26/28 (93%) HIT patients. We investigated cross-reactivity of anti-PF4-heparin antibodies with PF4 complexed to alternative heparin-like anticoagulants. Low molecular weight heparins cross-reacted with 23/26 (88%) of the sera from HIT patients while half of the HIT sera weakly cross-reacted with PF4-danaparoid (Orgaran). The thrombocytopenia and thrombosis of most of these patients resolved during danaparoid therapy, indicating that detection of low affinity antibodies to PF4-danaparoid by immunoassay may not be an absolute contraindication for danaparoid administration.

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Cross-reactivity study of low molecular weight heparins and heparinoid in heparin-induced thrombocytopenia

Thrombosis Research ◽

10.1016/0049-3848(96)00027-8 ◽

1996 ◽

Vol 81 (5) ◽

pp. 525-532 ◽

Cited By ~ 51

Author(s):

Chee M Vun ◽

Sue Evans ◽

Beng H Chong

Keyword(s):

Molecular Weight ◽

Cross Reactivity ◽

Low Molecular Weight ◽

Low Molecular Weight Heparins ◽

Heparin Induced Thrombocytopenia ◽

Reactivity Study

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Lack of In Vitro Cross-Reactivity Predicts Safety of Low-Molecular Weight Heparins in Heparin-Induced Thrombocytopenia

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602969700300109 ◽

1997 ◽

Vol 3 (1) ◽

pp. 58-62 ◽

Cited By ~ 3

Author(s):

Sherif S. Farag ◽

Heten Savoia ◽

Cindy J. O'Malley ◽

Katherine M. McGrath

Keyword(s):

Molecular Weight ◽

Platelet Count ◽

Platelet Aggregation ◽

Unfractionated Heparin ◽

Cross Reactivity ◽

Low Molecular Weight ◽

Low Molecular Weight Heparins ◽

Aggregation Assay ◽

Heparin Induced Thrombocytopenia

Alternative anticoagulation in patients with heparin-induced thrombocytopenia (HIT) is often problematic. The relatively high cross-reactivity rate reported for the low-molecular-weight heparins (LMWH) has discouraged their use in this setting. This study has investigated the safety of using the LMWH Fragmin, based on a negative heparin-dependent platelet aggregation test using the latter, in patients with proven HIT. Fifty-three evaluable patients with clinical and laboratory evidence of HIT were evaluated for cross-reactivity with Fragmin using a Fragmin-dependent platelet aggregation test. In 20 of 38 patients who showed no in vitro cross-reactivity. Fragmin was substituted for unfractionated heparin. The outcome of these 20 patients was evaluated and compared to that of the remaining 33 patients, in whom anticoagulates were ceased or warfarin or Orgaran was used. Eighteen of 20 patients treated with Fragmin increased their platelet count by ≥50 x 109/l from a mean nadir of 57.9 ± 4.7 x 109/l within 2.8 ± 0.29 days following substitution of Fragmin for unfractionated heparin. Twenty-eight of the 33 remaining patients who did not receive Fragmin increased their platelet count by ≥50 x 109/l from a mean nadir of 53.0 ± 4.8 x 109/l within 3.0 ± 0.29 days. In seven patients (two treated with Fragmin), response could not be evaluated due to death within 36 h of cessation of heparin or discharge from hospital. The results indicate that in vitro cross-reactivity testing employing a heparin-dependent platelet aggregation assay can be safely used to select patients with HIT for further anticoagulation with LMWH. Key Words: Fragmin—Crossreactivity—Heparin-induced thrombocytopenia.

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Enoxaparin-Associated Dermal Necrosis: A Consequence of Cross-Reactivity with Heparin-Mediated Antibodies

Annals of Pharmacotherapy ◽

10.1177/106002809703100310 ◽

1997 ◽

Vol 31 (3) ◽

pp. 323-326 ◽

Cited By ~ 20

Author(s):

Michael E Tonn ◽

Robyn A Schaiff ◽

Marin H Kollef

Keyword(s):

Molecular Weight ◽

Previous History ◽

Subcutaneous Administration ◽

Cross Reactivity ◽

Low Molecular Weight ◽

Low Molecular Weight Heparins ◽

Heparin Induced Thrombocytopenia ◽

Heparin Administration ◽

History Of ◽

Subcutaneous Enoxaparin

Objective To describe a patient with enoxaparin-induced dermal necrosis and to review previously reported cases of skin manifestations associated with low-molecular-weight heparins. Case Summary A 43-year-old white woman with adult respiratory distress syndrome developed localized dermal necrosis and thrombocytopenia secondary to subcutaneous administration of unfractionated heparin. Upper extremity thrombi that had developed after administration of subcutaneous heparin at an outside hospital were treated with subcutaneous enoxaparin. Although platelet counts remained stable during enoxaparin therapy, dermal necrosis developed at the injection site. Parenteral anticoagulant therapy was discontinued and the necrotic lesions secondary to enoxaparin resolved with minimal local care. Discussion Numerous cases of dermal necrosis secondary to heparin administration have been reported while this reaction secondary to enoxaparin use has been reported only briefly. It has been postulated that dermal necrosis secondary to heparin is associated with heparin-induced thrombocytopenia and is a result of heparin-mediated thrombosis in the microvasculature. Antibodies to heparin have cross-reactivity with enoxaparin; therefore, dermal necrosis secondary to enoxaparin may occur by a similar mechanism. Conclusions Although enoxaparin-associated dermal necrosis appears to be a rare occurrence, we advise against the use of enoxaparin or other low-molecular-weight heparins in patients with a previous history of heparin-associated thrombocytopenia or heparin-induced dermal necrosis.

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