Antiplatelet Factor 4—Heparin Antibodies in Patients with Antiphospholipid Antibodies

doi:10.1016/S0049-3848(99)00057-2

Thrombosis Research

Volume 95, Issue 6, 15 September 1999, Pages 271-279

https://doi.org/10.1016/S0049-3848(99)00057-2 Get rights and content

Abstract

Antibodies directed against platelet factor 4-heparin are present in patients with heparin-induced thrombocytopenia (HIT). Additionally, it has been suggested that heparin can be an antigenic target of antiphospholipid antibodies (aPL). We investigated the presence of heparin-platelet factor 4-induced antibodies (HPIA) in 33 patients with aPL. There were 30 patients with lupus anticoagulant, 25 with anticardiolipin antibodies, 21 with anti-β₂ glycoprotein I, and 18 with antiprothrombin antibodies. 20 patients had a history of thrombosis and 19 had received heparin during the last 60 months. We found 7 (21.2%) who had HPIA; 5 of them also had anti-β₂ glycoprotein I antibodies. Four patients had severe thrombocytopenia and suspicion of HIT. Among them, two presented high positive HPIA results, one of them with positive platelet aggregation test. The third patient showed grey zone HPIA and borderline aggregation test and the fourth one had negative results. Among patients without a history of HIT, 2 who had never received heparin presented high positive, one a moderate positive, and one a grey zone HPIA result; all of them with negative aggregation tests. Five positive sera samples were incubated with cardiolipin liposomes in the presence of β₂ glycoprotein I, and whereas an inhibition greater than 50% was achieved in anticardiolipin and anti-β₂ glycoprotein I activities, HPIA results did not change. We demonstrate that HPIA could be frequently found in patients with aPL. They are responsible for HIT in some cases but can also be found in patients who have not received heparin. Whether they predispose patients with aPL to HIT is not known; nevertheless, a close follow-up of heparin treatment in these patients seems to be mandatory.

Section snippets

Patients

We studied 33 patients with aPL. Patients characteristics and clinical manifestations are shown in Table 1. Venous thrombotic events have been documented by venography and/or Doppler ultrasound for deep vein thrombosis and ventilation-perfusion lung scan and/or pulmonary angiography for pulmonary embolism. Chronic thromboembolic pulmonary hypertension was diagnosed when mean resting pulmonary artery pressure was above 25 mmHg during right heart catheterization with a mean pulmonary wedge

Results

Patients' characteristics and their clinical features are shown in Table 1. There were 20 patients with primary APS, four with APS secondary to systemic lupus erythematosus (SLE), two SLE without APS, three miscellaneous, and four asymptomatic. Among the 33 patients evaluated, there were four with severe thrombocytopenia (platelet count <80×10⁹/L) and high suspicion of HIT (patients one through four). Table 2 shows that HPIA ELISA gave a high positive result in two (patients one and two), one

Discussion

HIT should be diagnosed basically by two criteria: (1) one or more clinical event associated with this syndrome (isolated thrombocytopenia, or associated with a new thrombotic event) and (2) laboratory evidence for heparin-dependent immunoglobulin (usually IgG) using specific and sensitive tests [6]. Recently, an ELISA for HPIA that uses heparin-PF4 complex as antigen has been developed [13], and high but not complete concordance with functional assays has been found 13, 14, 15. We report here

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Cited by (34)

Similarities of antiphospholipid antibodies in HIT and APS patients with heparin-platelet factor 4 antibodies
2022, Thrombosis Update
Citation Excerpt :
On the other hand, this interference between anti-HPF4 and aPLs is supported by the fact that 7/31 patients referred for APS have HPF4 positive serology. Our results are in accordance with several studies [13–16]. Regarding to the specificity of the ELISA immunoassay the following question was raised: are the anti-HPF4 detected directed against the Heparin-Platelet Factor 4 complex or the Platelet Factor 4?
Heparin-induced thrombocytopenia (HIT) is a prothrombotic autoimmune disorder confirmed by the existence of Heparin-Platelet Factor 4 (HPF4) antibodies. The aim of this work is to study the possible relationship between anti-HPF4 and antiphospholipid antibodies (aPLs) that may explain the discrepancies observed in patients with a suspected HIT (HIT group) with positive immunoassay (HPF4-Elisa) and negative functional assay (heparin-induced platelet aggregation test). So, we performed H-PF4 antibodies research in 31 APS confirmed patients (APL group). All tests performed have been compared to normal controls (n = 34). We found anti-H-PF4 in 7/31 patients of APL group. In parallel, we search for aPLs in 9/34 patients tested positive for anti-HPF4 in HIT group, all of them were positive. All specificities were observed in the two anti-HPF4 positive groups (aβ2GP1 IgM/IgG/IgA, aCL (IgM/IgG/IgA, aPS-PT IgM/IgG). The most associated antibodies with anti-HPF4 are the anti ß2Glycoprotein1 (Odds ratio = 50.1). We suggest that the presence of aPLs in HIT group with anti-HPF4 could be the cause of the discrepancies. In addition, we performed the Heparin Neutralization Assay (HNA) which is specific for anti-HPF4, neutralization was obtained for patients exposed to heparin. Furthermore, we suggest that we should performed a larger cohort to confirm the causal relationship of aPLs and also to expand the tests allowing the differentiation between these autoantibodies.
Humoral immunity and thrombosis in COVID-19
2022, Autoimmunity, COVID-19, Post-COVID19 Syndrome and COVID-19 Vaccination
Coronavirus disease 2019 (COVID-19) is due to the infection of the upper and lower airways by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is characterized by different clinical manifestations ranging from paucisymptomatic conditions to life-threatening acute respiratory distress syndrome and may present multisystem involvement. A hyperinflammatory response to the virus and the associated prothrombotic state (immunothrombosis) are the major causes of tissue/organ damage. Several humoral mediators have been described to mediate the immunothrombosis in COVID-19; among them, a lot of attention has been paid to the synthesis of nonorgan specific procoagulant autoantibodies, the hyperproduction of proinflammatory cytokines, and to the activation of the complement cascade.
All the above-mentioned pathogenic pathways are affecting the endothelium as one of the main targets of the disease and contribute to the clinical manifestations.
False-positive tests for heparin-induced thrombocytopenia in patients with antiphospholipid syndrome and systemic lupus erythematosus: A rebuttal
2010, Journal of Thrombosis and Haemostasis
Heparin induced thrombocytopenia and thrombosis in a tertiary care hospital
2009, Thrombosis Research
Heparin-induced thrombocytopenia (HIT) results from development of an antibody to a complex of heparin and platelet factor 4 (PF4) resulting in thrombocytopenia and a prothrombotic state with serious clinical consequences. The diagnosis depends on a combination of both the clinical presentation and laboratory detection of an appropriate antibody.
To determine the frequency, clinical characteristics and laboratory correlates of HIT in a tertiary care hospital.
A retrospective review of all case of HIT over a thirty month period in a tertiary care hospital was conducted.
HIT was diagnosed in 136 patients including 114/28,091 (0.48%) of those receiving only unfractionated heparin, 22/6,559 (0.33%) of those that received both unfractionated and low-molecular-weight heparin (LMWH) and in 2/2498 (0.08%) of those receiving only LMWH (P = 0.02 compared to those receiving only unfractionated heparin). HIT occurred in 62/16,939 patients (0.39%) of patients receiving subcutaneous (SC) heparin or LMWH compared to 69/11,152 (0.62%) of patients receiving intravenous (IV) therapy (P = 0.003). Of all patients with exposure to heparin products, 41/34,650 (0.1%) developed symptomatic thrombosis. The optical density (OD) of the ELISA was significantly higher in patients with HIT and thrombosis (1.2 +/- 0.8) compared to those without thrombosis (0.9 +/- 0.6, P = 0.03).
HIT develops in approximately 0.4% of all patients exposed to heparin at a tertiary care hospital but is significantly less frequent in those treated with LMWH only than in those who receive unfractionated heparin. A higher antibody titer is associated with the development of thrombosis. The occurrence of HIT could be decreased by reducing exposure to unfractionated heparin, and the diagnosis could be improved by reporting the OD of the ELISA test result.
False-positive tests for heparin-induced thrombocytopenia in patients with antiphospholipid syndrome and systemic lupus erythematosus
2009, Journal of Thrombosis and Haemostasis
Background: Heparin‐induced thrombocytopenia (HIT) is a severe complication of heparin therapy that can be associated with arterial or venous thrombosis and is caused by antibodies against platelet factor 4 (PF4)–heparin complex. Patients with antiphospholipid syndrome (APS) have been reported with positive tests for PF4–heparin complex antibodies by antigen assay. Whether such patients can be treated with heparin is a dilemma. Objectives: To determine the incidence and nature of the HIT immune reaction in patients with APS and/or systemic lupus erythematosus (SLE). Methods: Antibodies against PF4–heparin complex were assayed by particle gel immunoassay (PaGIA), or enzyme immunoassay (EIA) with or without an excess of heparin. EIA for PF4 alone was also performed. Functional assays for HIT, that is, heparin‐induced platelet activation (HIPA) and heparin‐induced platelet aggregation, were also performed. Results: In 32 of 42 patients (76.2%) with APS, APS and SLE, SLE, or SLE with antiphospholipid antibodies, EIA IgG or PaGIA for PF4–heparin complex antibodies were positive. Of these 32 samples, 26 (81.3%) tested positive for anti‐PF4 antibodies. All 24 samples that were positive for PF4–heparin complex by EIA IgG were also positive for EIA IgG in the presence of heparin excess, and all were negative by the HIPA and heparin‐induced platelet aggregation tests. Conclusion: A large proportion of patients with APS and/or SLE give false‐positive HIT antigen test results that are presumably related to autoantibodies against PF4, which can be distinguished from true HIT antibodies by EIA for PF4–heparin complexes tested with heparin excess, and by functional assays.
A Spontaneous Prothrombotic Disorder Resembling Heparin-induced Thrombocytopenia
2008, American Journal of Medicine
Antibodies against the “self” protein, platelet factor 4 (PF4), bound to heparin—the cause of immune heparin-induced thrombocytopenia—are believed invariably to be triggered by preceding heparin therapy. We describe a novel syndrome, spontaneous heparin-induced thrombocytopenia, in which clinical and serologic features characteristic of this adverse drug reaction develop in patients despite the absence of preceding heparin therapy.
Three patients met the study criteria (clinical and serologic features of heparin-induced thrombocytopenia without preceding heparin exposure), of whom 2 patients were identified among 225 patients (0.89%, 95% confidence interval, 0.11%-3.17%) with serologically confirmed heparin-induced thrombocytopenia recognized during an 18-year period at 1 hospital. The platelet serotonin-release assay was used to detect heparin-dependent immunoglobulin G-induced platelet activation, and 2 enzyme immunoassays were used to detect antibodies against PF4/heparin.
Two patients presented with thrombocytopenia and multiple arterial thrombosis, and 1 patient presented with anaphylactoid reactions after 2 subcutaneous injections of low-molecular-weight heparin. All 3 patients had high levels of platelet-activating anti-PF4/heparin antibodies of immunoglobulin G class at presentation despite the absence of previous heparin exposure. However, each patient did have a preceding infectious or inflammatory event; 1 patient had concomitant antiphospholipid antibodies.
Circumstances other than heparin use can trigger a spontaneous disorder that closely mimics heparin-induced thrombocytopenia, further supporting the autoimmune nature of this adverse drug reaction.

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Regular articleAntiplatelet Factor 4—Heparin Antibodies in Patients with Antiphospholipid Antibodies

Abstract

Section snippets

Patients

Results

Discussion

Thromb Res

Am J Med

Thromb Res

Pathology

Thromb Res

Blood

Thromb Res

Thromb Res

Thromb Res

Clin Immunol Immunopathol

The anticardiolipin syndrome

J Rheumatol

The antiphospholipid syndrome—An introduction

Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies

Thromb Haemost

Regular article
Antiplatelet Factor 4—Heparin Antibodies in Patients with Antiphospholipid Antibodies