Determination of heparin-induced IgG antibody in heparin-induced thrombocytopenia type II

BACKGROUND: Heparin-induced thrombocytopenia is a relatively uncommon but severe side-effect of heparin therapy. Heparin-induced IgG antibody has been elucidated to be the main isotype and the most pathogenic antibody in the pathophysiology. As affected patients are at high risk of developing thrombotic events, confirmation of the clinical diagnosis and avoidance of heparin re-exposure are important and desirable. MATERIALS AND METHODS: In the present study, heparin-induced IgG was measured by the binding of neoantigens, which were prepared by incubating FITC-heparin with platelet factor 4 present in normal serum. The cross-reactivities of heparin-induced IgG with low-molecular-weight heparin and danaparoid were analysed by competitive binding. RESULTS: A total of 81 clinically suspected heparin-induced thrombocytopenia type II patients were analysed. Thirty-seven of 38 heparin-induced thrombocytopenia type II patients, in whom thromboembolism was confirmed by objective methods, had elevated relative fluorescence intensity ratios (patient normal control) and 36 had positive heparin-induced platelet activation results. The prevalence of heparin-induced IgG in heparin-induced thrombocytopenia type II patients was 97.4%. Positive heparin-induced IgG results were: 0/319 healthy volunteers, 0/38 other thrombo-cytopenia and 2/56 heparin/low-molecular-weight heparin-receiving patients without thrombocytopenia, 2/41 hyperbilirubinaemic patients and 2/50 hyperlipidaemic patients. A small amount of cross-reaction assays showed similar results as obtained in heparin-induced platelet activation. CONCLUSION: Our results suggest that a very high frequency of heparin-induced IgG in heparin-induced thrombocytopenia type II patients can be detected using a novel antigen assay. The rapid determination of pathogenic heparin-induced IgG may be a useful tool for the rapid diagnosis of heparin-induced thrombocytopenia type II that could facilitate further management of the patients.     

White clot syndrome

Heparin therapy is currently a vital component in the medical management of thromboembolic events. Despite its widespread use, it is associated with relatively few complications, and these are usually minor and quickly reversible. Recently a much more dramatic and serious complication of heparin therapy has been identified. In heparin-induced thrombocytopenia with associated thrombosis or "white clot syndrome," patients have paradoxic thromboembolic events while receiving heparin. These events are of acute onset and of major consequence, often resulting in limb loss or death. This paper describes our own experience with ten patients in whom the white clot syndrome occurred during heparin therapy for thrombotic or embolic events. Both porcine and bovine heparin preparations were being given through various routes. In the three cases in which platelet aggregation testing was completed, results were positive. Our ten patients ultimately had a 20% major limb amputation rate and an overall 50% mortality.     

Heparin-induced thrombocytopenia: how to manage it, how to avoid it

Heparin therapy has two potential adverse effects: bleeding and heparin-induced thrombocytopenia (HIT). There are two types of HIT: type I is more common but less severe; type II occurs less frequently but involves severe thrombocytopenia and a high risk for thrombotic events. Treatment involves discontinuing heparin, allowing the platelet count to return to normal, and treating any thrombosis. Lepirudin (Refludan) is the only agent currently approved for the treatment of HIT-related thrombosis, but other agents may have a role in combination therapy. Prevention includes using low molecular weight heparin instead of unfractionated heparin and limiting unfractionated heparin therapy to less than 5 days.     

Heparin-induced thrombocytopenia

A summary of heparin-induced thrombocytopenia (HIT) is presented. HIT is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. The frequency of HIT ranges from 1 to 5% of patients receiving heparin with exact frequencies ranging between specific agents. Interestingly, this immune-mediated syndrome is ironically associated with thrombosis, not bleeding, with thrombin formation playing a major role. It is caused by heparin-dependent, platelet-activating antibodies that identifies a self-protein, PF4, bound to heparin that results in an antibody formation. The resulting platelet activation is associated with increased thrombin generation. Typically, the platelet count fall begins 5–10 days after starting heparin, although a rapid platelet count fall can occur in a patient who has antibodies from recent heparin use. Typical causes of HIT as well as the best diagnostic studies and treatment are discussed in this review. HIT was reviewed using a pubmed? search; google scholar? using key words: “Heparin-induced thrombocytopenia”; “heparin”, and “drug AND thrombocytopenia.”     

Heparin-induced thrombocytopenia: a general review.

Unfractionated heparin is widely used for numerous clinical situations. A well-known adverse effect of heparin exposure is thrombocytopenia. Heparin-induced thrombocytopenia is a clinicopathologic syndrome that can be associated with severe complications and significant mortality. The pathophysiology of heparin-induced thrombocytopenia includes an immune-mediated reaction to heparin that activates platelets and results in an acquired hypercoagulability. Diagnosis of heparin-induced thrombocytopenia should incorporate clinical signs and symptoms and laboratory testing for heparin-induced thrombocytopenia antibodies. Therapy should include discontinuation of heparin, initiation of a direct thrombin inhibitor, and eventually therapy with warfarin (only after the platelet count is at least 100 x 10(9)/L).     

尿毒症血液透析时肝素导致血小板减少临床分析

目的：旨在初步探讨肝素导致血小板减少（HIT）在尿毒症血透患者中的特点。方法：研究对象为150例尿毒症血透患者,给予标准肝素体外抗凝治疗,每周血透2－3次,观察血小板计数及其它临床表现,比较标准肝素（SH）,低分子量肝素（LMWH）的治疗差别,结果：32例（21．33％）出现不同程度的血小板减少,其中出血18例,动静脉血栓形成6例,肝素抵抗2例,停用SH,给予LMWH抗凝治疗,血小板计数恢复正常15例。结论：HIT是尿毒症血透治疗的重要并发症。     

Low-molecular-weight heparin-induced thrombocytopenia in a child

OBJECTIVE: To report a case of probable acute venous thrombosis caused by heparin-induced thrombocytopenia (HIT) in a pediatric patient with a normal platelet count after prolonged enoxaparin therapy. CASE SUMMARY: An 11-year-old African American female with Crohn's disease developed extensive vena cava thrombosis. Her deep vein thrombosis (DVT) was treated with intravenous unfractionated heparin followed by extended outpatient warfarin therapy. Four months later, the warfarin was stopped and subcutaneous enoxaparin 1.5 mg/kg once daily was substituted prior to an elective colonoscopy. She was readmitted 6 weeks later with acute DVT with a platelet count of 233 x 10(3)/mm3, significantly lower than the count of 550-700 x 10(3)/mm3 5 months previously and the count of 433 x 10(3)/mm3 3 months earlier. An enzyme-linked immunosorbent assay for heparin-platelet factor 4 antibodies was strongly positive and a d-dimer was elevated at 2.9 mg/L (normal <1.5). She was treated with lepirudin followed by warfarin when repeat d-dimer on day 3 was normal. An ultrasound at that time showed no clot extension, and the platelet count had risen to >300 x 10(3)/mm3. Over the next 4 months, there was no further thrombosis. DISCUSSION: HIT appears to be rare in the pediatric population, and only a few cases treated with a direct thrombin inhibitor have been reported. This is the first case report to our knowledge of a pediatric patient developing HIT secondary to enoxaparin. An interesting feature of this case is the development of HIT in the face of a normal platelet count, which is rare but has been reported in adults. CONCLUSIONS: Pediatric patients receiving low-molecular-weight heparin are still at risk for developing HIT. Treatment of HIT should involve the initial use of a direct thrombin inhibitor to manage thrombosis until the platelet count returns to higher values. Once the platelet count returns, warfarin can be used for long-term thrombosis management.     

Heparin induced thrombocytopenia: case report with acute thrombotic complications and literature review]

PURPOSE: Review of the frequency, clinical and biological features and treatment of type II heparin-induced thrombocyopenia.METHODS: Case report and literature review.RESULTS: A 65 years old woman received as antithrombotic prophylaxis low molecular weight heparin (LMWH) after prosthetic knee replacement. Day 8, asymptomatic deep vein thrombosis was discovered after systematic echodoppler examination. Curative anticoagulation was started with LMWH. A fall in the platelet count (17 G/L) was noted day 12. Danaparoid was immediately introduced and heparin discontinued. However, day 16 a massive pulmonary embolism occurred which required transfer to an intensive care unit. Danaparoid was changed for lepirudin the same day. It took longer than three weeks for platelet count to return to normal value after heparin discontinuation. The suspicion of heparin-induced thrombocyopenia was confirmed by specific tests.DISCUSSION: HIT type II are rare but life-threatening and thrombosis events are the most frequent complications. The diagnosis is a high probability proved by both clinical and biological patterns. The treatment consists in alternative thrombin inhibitors such as danaparoid and lepirudin. The platelet count usually requires less than ten days to recover normal values after heparin withdrawal. Cases in which the delay to a normal platelet count exceeds 3 weeks have been reported specially after LMWH therapy.CONCLUSION: Type II HIT are rare but life-threatening events can occur. The platelet count check-up during heparin therapy must be systematic.     

肝素诱导的血小板减少症的临床研究

目的 观察应用肝素治疗患者肝素诱导的血小板减少症(HIT)发病情况,探索血小板计数监测HIT的可行性及HIT抗体检测对HIT诊断的意义.方法 对在血管外科应用普通肝素(UFH)治疗的145例患者进行临床观察,于应用UFH治疗前及治疗后进行血小板计数、HIT抗体ELISA检测及肝素诱导的血小板聚集试验(HIPA)等实验室检测.结果 145例患者中血小板减少40例(27.6%),HIT抗体阳性59例(40.7%),HIPA阳性26例(17.9%),诊断HIT 24例(16.5%),其中发生HIT并血栓形成综合征(HITTS)5例(发病率3.4%,占HIT患者的20.8%).多数HIT患者(15例,62.5%)血小板减少与HIT抗体阳性、HIPA阳性同时发生.24例HIT患者的血小板计数均在停用UFH后3～6 d恢复到正常或达到用UFH前水平.结论 通过动态监测血小板计数、联合HIT抗体ELISA法检测及HIPA,可以早期诊断HIT,及时停用UFH,换用抗凝剂,HITTS的发生率有望进一步下降,减少致残、死亡的发生.

Abstract：

Objective To observe the incidence of heparin-induced thrombocytopenia (HIT) in patients received unfractionated heparin ( UFH ) treatment, and explore the feasibility of monitoring HIT by platelet counts, as well as the significance of HIT-antibody test in HIT diagnosis. Methods 145 patients received UFH treatment in Vascular Surgery Department were studied. Before and after the UFH treatment,platelet counts, HIT-antibody ELISA test and heparin-induced platelet aggregation (HIPA) were tested.Results Among the 145 patients, thrombocytopenia occurred in 40 ( 27.6% ) cases, HIT-antibody ELISA test positive in 59(40.7% ) cases, HIPA test positive in 26( 17.9% ) cases. The HIT was diagnosed in 24 (16.5%) cases, and heparin-induced thrombocytopenia and thrombosis (HITTS) occurred in 5( 3.4% in all cases, and 20.8% in HIT patients). In HIT patients, 15 patients (62.5%) were thrombocytopenia, HITantibody positive and HIPA test positive. Platelet counts in all of the 24 patients recovered to normal or level before UFH treatment in 3 -6 days after heparin withdrawal therapy. Conclusion HIT can be early diagnosed by monitoring platelet counts, HIT-antibody ELISA test and HIPA test. Withdrawal of heparin therapy in time and use of alternative anticoagulant, HITTS rate might be expected to decline further.     

Diagnosis and management of heparin-induced thrombocytopenia

Heparin use is ubiquitous, wherein 1 to 5% of patients exposed to standard unfractionated heparin develop thrombocytopenia due to antibodies to a complex of heparin and platelet factor 4. Classic features include onset of thrombocytopenia after 5 to 10 days of ongoing heparin exposure, a 50% fall in the platelet count from baseline, resolution of the thrombocytopenia 5 to 10 days after cessation of heparin and a high risk of thrombosis noted in 30 to 75% of patients with heparin-induced thrombocytopenia (HIT) in terms of every-other-day platelet-count monitoring in patients on standard unfractionated heparin. And those patients developing thrombocytopenia necessitate an accurate, readily accessible diagnostic test for HIT. Diagnosis has been recently facilitated by the development of an enzyme-linked immunsorbent assay (ELISA) test for the heparin–P4 antibody complex, although this test carries a relatively low specificity. Widespread use of the ELISA demonstrates a relatively high prevalence of the antibody in patients exposed to heparin in certain settings, such as cardiopulmonary bypass, wherein a quarter of patients have a positive ELISA of unclear significance. Once HIT is diagnosed, the high risk of thrombosis necessitates empiric anticoagulation with an antithrombin such as argatroban or lepirudin, or the heparinoid danaparoid. Additional agents under further study include the antithrombin bivalirudin and the pentasaccharide fondaparinux. Future issues in HIT include increasing awareness for HIT, improving the specificity of HIT testing and the development of new anticoagulants for HIT that will enable out-patient management.     

Heparin-associated thrombocytopenia: observations on the mechanism of platelet aggregation

We investigated the mechanism of heparin-mediated platelet aggregation in 11 patients with heparin-associated thrombocytopenia. Severe thrombocytopenia (16,000 to 66,000 platelets/microliters) developed in each patient during heparin therapy, and platelet aggregation occurred in vitro when heparin was added to mixtures of patient plasma and normal platelet-rich plasma. In 10 patients, heparin-initiated platelet aggregation was inhibited by preincubation of mixtures of normal platelet-rich plasma and heparin-associated thrombocytopenia plasma with monoclonal antiglycoprotein Ib antibodies 6D1 or LJ-Ib1. Both antibodies are directed against the von Willebrand factor binding site on glycoprotein Ib and inhibit only ristocetin-induced platelet agglutination. Purified immunoglobulin G (IgG) from patients with heparin-associated thrombocytopenia also supported heparin-induced aggregation, but equivalent amounts of antigen-binding fragments [F(ab')2] did not. We also found that F(ab')2 of LJ-Lb1 did not inhibit heparin-induced platelet aggregation but retained inhibitory activity against ristocetin-induced platelet agglutination. The monoclonal antibody 3G6, directed against the alpha-chain of glycoprotein Ib but not inhibitory of ristocetin-induced platelet agglutination, had no effect on heparin-induced platelet aggregation. Antibodies to von Willebrand factor that inhibit ristocetin-induced platelet agglutination did not inhibit heparin-mediated platelet aggregation, but antibodies to glycoprotein IIb-IIIa blocked aggregation. These data suggest that platelet aggregation in heparin-associated thrombocytopenia may be initiated by an interaction between patient IgG, heparin, and the platelet surface. Platelet activation appears to be mediated by a platelet surface crystallizable fragment (Fc) receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnosis and management of heparin-induced thrombocytopenia

Heparin use is ubiquitous, wherein 1 to 5% of patients exposed to standard unfractionated heparin develop thrombocytopenia due to antibodies to a complex of heparin and platelet factor 4. Classic features include onset of thrombocytopenia after 5 to 10 days of ongoing heparin exposure, a 50% fall in the platelet count from baseline, resolution of the thrombocytopenia 5 to 10 days after cessation of heparin and a high risk of thrombosis noted in 30 to 75% of patients with heparin-induced thrombocytopenia (HIT) in terms of every-other-day platelet-count monitoring in patients on standard unfractionated heparin. And those patients developing thrombocytopenia necessitate an accurate, readily accessible diagnostic test for HIT. Diagnosis has been recently facilitated by the development of an enzyme-linked immunosorbent assay (ELISA) test for the heparin-P4 antibody complex, although this test carries a relatively low specificity. Widespread use of the ELISA demonstrates a relatively high prevalence of the antibody in patients exposed to heparin in certain settings, such as cardiopulmonary bypass, wherein a quarter of patients have a positive ELISA of unclear significance. Once HIT is diagnosed, the high risk of thrombosis necessitates empiric anticoagulation with an antithrombin such as argatroban or lepirudin, or the heparinoid danaparoid. Additional agents under further study include the antithrombin bivalirudin and the pentasaccharide fondaparinux. Future issues in HIT include increasing awareness for HIT, improving the specificity of HIT testing and the development of new anticoagulants for HIT that will enable out-patient management.     

Utility of thrombocytopenia as a marker for heparin allergy in adult ED patients

INTRODUCTION: Up to 5% of patients who receive heparin develop heparin allergy (HA), manifested by the presence of heparin antibodies (HAb) and/or the clinical syndrome of heparin-induced thrombocytopenia. As many as 10% of patients with HA develop serious thrombotic complications when reexposed to heparin. Heparin is often given empirically to emergency department (ED) patients, some of whom have been recently hospitalized and are at risk for HA/heparin-induced thrombocytopenia. Emergency department physicians should have a rapid means of determining which patients are at risk for heparin sensitivity. The prevalence of HA among ED patients is unknown; most are asymptomatic and unaware, and there is no bedside test available. OBJECTIVES: This study was designed to assess the prevalence of HA or thrombocytopenia in ED patients and to determine whether thrombocytopenia could serve as a useful marker for HA. METHODS: This was a prospective, observational study, done during the spring of 2004 in an 80000 adult visit inner-city ED. A convenience sample of 115 adult patients undergoing venipuncture had a blood specimen analyzed for platelet count using standard laboratory methods. The same blood sample was tested for the presence of antiheparin antibodies using an enzyme-linked immunosorbent assay test. RESULTS: Of 115 patients, 12 (10.4%; 95% CI, 6.1%-17.4%) had thrombocytopenia (platelets <150000). Six (5.2%; 95% CI, 2.5%-10.9%) had antiheparin antibodies. There was no overlap between the 2 groups of patients. CONCLUSIONS: (1) Thrombocytopenia occurs in 10% of a sample of 115 adult ED patients undergoing venipuncture in an inner-city ED. (2) Heparin allergy was present in 5% of patients in the same cohort. (3) Thrombocytopenia is neither sensitive nor specific as a marker for HA in ED patients. Heparin-allergic patients are at risk if given heparin; a method of rapid detection of patients with HA should be identified.     

Heparin-induced thrombocytopenia in patients requiring prolonged intensive care unit treatment after cardiopulmonary bypass

Summary.  Background:  The diagnosis of heparin-induced thrombocytopenia (HIT) is problematic in postcardiac surgery (CS) intensive care unit (ICU) patients, as there are multiple potential explanations for thrombocytopenia and the presence of anti-platelet factor 4/heparin antibodies is not highly specific for HIT. Two platelet count profiles for HIT – a 40% or greater fall in platelet count beginning on or after day 5 (pattern 1) and persisting thrombocytopenia (< 100 × 10⁹ L^–1) beyond day 7 (pattern 2) – have been described in post-CS patients. Methods and results:  We examined the platelet count profiles of 329 consecutive post-CS patients who required ICU treatment beyond 7 days. Although 70 patients (21.3%) developed thrombocytopenia (57.1% pattern 1, 42.9% pattern 2), the overall incidence of HIT was only 1.8% [6/329; 95% confidence interval (95% CI) 0.7–3.9%] in these ICU patients, with more HIT patients showing a pattern 2 than a pattern 1 platelet count decrease (four vs. two patients). Notably, pattern 2 patients with HIT also showed a new proportional fall of > 30% in platelet count between postoperative days 5 and 10. Among the remaining 2242 post-CS patients without a prolonged ICU stay, only three (0.1%; 95% CI 0.03–0.4%) developed symptomatic HIT (OR 0.07; 95% CI 0.01–0.3; P  =   0.0002 vs. ICU patients), all presenting with pattern 1. Conclusions:  Among post-CS ICU patients, a postoperative platelet count fall between days 5 and 10 increases diagnostic specificity for HIT, irrespective of whether this platelet count fall occurs after postoperative platelet count recovery (pattern 1) or is superimposed upon persisting postoperative thrombocytopenia (pattern 2). A prospective study is required in order to validate the findings of this retrospective analysis.     

Etiology and significance of thrombocytopenia in critically ill patients

Thrombocytopenia is common in critically ill patients and increases morbidity and mortality. A diagnosis of heparin-induced thrombocytopenia (HIT) is frequently considered in any ICU patient who develops thrombocytopenia in the context of ongoing heparin exposure. As the usual tests to diagnose HIT are often neither specific nor sensitive enough to be confirmatory, the intensivist must largely rely on clinical judgment in treatment decisions. Patients in the ICU may also develop thrombocytopenia resulting from non-HIT immune mechanisms, nonimmune platelet consumption, and from decreased platelet production due to preexisting disorders or as a result of their critical illness and/or drug therapy.     

Successful use of fondaparinux for bridging early after aortic and mitral mechanical heart valve replacement

OBJECTIVE : To report a case of successful use of fondaparinux for bridging early after aortic and mitral mechanical heart valve replacement (MHVR). CASE SUMMARY : A 71-year-old female underwent aortic and mitral valve replacements with St. Jude medical bileaflet prostheses, as well as DeVega tricuspid annuloplasty and coronary artery bypass graft. Anticoagulation was initially withheld following the procedure because of thrombocytopenia, large amount of chest tube drainage (~1 L/day), and concerns regarding postoperative bleeding. The thrombocytopenia (baseline platelet count 183 x 10(3)/μL; postoperative platelet count 44 × 10(3)/μL) was thought to be a consequence of the cardiopulmonary bypass; there was a low probability of heparin-induced thrombocytopenia. However, the care team preferred to avoid heparin products and initiated fondaparinux 7.5 mg subcutaneously once daily on postoperative day 8 once the patient's platelet count had recovered to >100 x 10(3)/μL. The treatment was bridged to warfarin on postoperative day 13 and the patient was discharged home after receiving 8 days of fondaparinux. Throughout the patient's hospitalization and upon follow-up on postoperative day 31, there were no signs or symptoms of thromboembolic events or bleeding. DISCUSSION : Unfractionated heparin and low-molecular-weight heparins are the standard of care for bridging to warfarin in patients with MHVR. The use of fondaparinux following MHVR has not been studied in randomized controlled trials. In vitro studies support the effectiveness of fondaparinux in preventing thrombus formation on mechanical heart valves. However, the only data available in humans as of December 2011 are 3 case reports. Two of these case reports described the successful use of fondaparinux for anticoagulation in a patient with an aortic valve replacement. In the third case report, the patient had an aortic and mitral valve replacement. Our case report is novel because it describes the use of fondaparinux early after MHVR, which is the most critical time period for effective thromboprophylaxis. CONCLUSIONS : The use of fondaparinux for postoperative bridging in our patient early after combined aortic and mitral MHVR was effective. However, until studies evaluate the efficacy and safety of fondaparinux in patients with MHVR, its use should be considered only when heparin products are contraindicated.     

In vitro detection of heparin-induced humoral antiplatelet activity

We investigated the etiology of thrombocytopenia, with or without platelet thrombi, occurring while patients are receiving parenteral heparin. We used two in vitro methods to detect possible humoral factors in the sera of patients who became thrombocytopenic while receiving heparin. In the presence of heparin, four of four such patients' serum caused platelet aggregation. Only serum from the patient most severely affected clinically caused release of platelet factor 3 (PF3). All control sera gave negative results by both methods. We propose that platelet aggregation studies may be a sensitive and reliable method of confirming that thrombocytopenia occurring during heparin therapy is due to a humoral factor requiring the presence of heparin.     

Cutaneous dalteparin reactions associated with antibodies of heparin-induced thrombocytopenia

OBJECTIVE: To report widespread cutaneous lesions due to low-molecular-weight heparin therapy associated with heparin-induced thrombocytopenia (HIT), but without evidence of thrombocytopenia, and to review previously reported cases of skin reactions related to heparin therapy. CASE SUMMARY: A 59-year-old white man with a subtotally resected glioblastoma developed febrile neutropenia and pneumonia secondary to chemotherapy. The development of an upper extremity thrombosis, following insertion of a peripherally inserted central venous catheter, was treated with subcutaneous dalteparin. Cutaneous lesions developed distant from the site of injection. The diagnosis of HIT was confirmed despite stable platelet counts. Dalteparin therapy was discontinued immediately, and anticoagulation was maintained with warfarin. The skin lesions resolved without further complications. DISCUSSION: Numerous cases of heparin-induced cutaneous reactions have been reported. The majority of these describe a local reaction at the heparin injection site with or without associated thrombocytopenia. The case presented here is unique in that the observed skin reaction was distant to the injection site and occurred without thrombocytopenia, but with detectable heparin-dependent antibodies. CONCLUSIONS: Although a skin reaction is a rare complication of heparin therapy, it can be a clinical indicator of HIT despite normal platelet counts. Patients who develop skin lesions should have their heparin therapy discontinued and a diagnosis of HIT investigated.     

False-positive tests for heparin-induced thrombocytopenia in patients with antiphospholipid syndrome and systemic lupus erythematosus

Summary.  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.     

Gold-induced thrombocytopenia responsive to cyclophosphamide.

Thrombocytopenia and nephrotic syndrome developed in a 51-year-old patient receiving gold therapy for rheumatoid arthritis. Marrrow findings and platelet infusion studies were consistent with a pattern of increased platelet destruction, known to occur in gold-induced thrombocytopenia. Improvement in the platelet count after therapy with dimercaprol was transient, and although steroids and splenectomy were not effective, a response was achieved with cyclophosphamide. The use of immunosuppressive drugs can be considered in refractory cases of gold-induced thrombocytopenia in which a significant hemorrhagic risk is present.