Antibodies to Heparin–Platelet Factor 4 Complex: Pathogenesis, Epidemiology, and Management of Heparin-Induced Thrombocytopenia in Hemodialysis

Abstract

An 83-year-old man treated with continuous ambulatory peritoneal dialysis for 3 years for end-stage renal disease caused by type 2 diabetes and hypertension was admitted with peritonitis. After 3 days, there had been no significant improvement, the peritoneal dialysis catheter was removed, and he was converted to treatment with intermittent hemodialysis using a right internal jugular catheter. His condition improved, and after 10 days, he was scheduled to be discharged home after a hemodialysis session. That morning, the patient was sent from the inpatient ward to the outpatient hemodialysis facility for his treatment. Within 3 minutes of the start of the hemodialysis session, he reported feeling unwell, dizzy, and short of breath. He rapidly became unconscious, with no recordable blood pressure or pulse, and died despite attempts at resuscitation. Because this was an unexpected death, the patient's charts and in-patient records were reviewed. In retrospect, it was observed that the peripheral platelet count had decreased since starting hemodialysis therapy (Fig 1); subsequent laboratory testing confirmed a positive result (optical density > 1.0) for an enzyme-linked immunosorbent assay (ELISA) for antibodies to the heparin–platelet factor 4 (PF4) complex, as well as a positive heparin-induced platelet aggregation test result. His pretest probability score was 8 (Table 1).1Warkentin T.E. Greinacher A. Heparin induced thrombocytopenia: Recognition, treatment, and prevention.Chest. 2004; 126: S311-S337Crossref PubMed Scopus (748) Google Scholar An assay for mast cell tryptase was negative. Although the initial hemodialysis sessions had not been performed with heparin, because he had been bed-bound, he had received prophylactic subcutaneous porcine unfractionated heparin (UFH), and the dialysis catheter had been locked with porcine UFH (1,000 IU/mL). He was then given a bolus of porcine UFH (1,000 IU) at the start of subsequent hemodialysis sessions. Review of his dialysis charts showed that although the flows through the catheter initially had been satisfactory, in the sessions before his collapse, arterial and venous pressures had increased, raising the suspicion of catheter-associated thrombus.Table 1Pretest Probability Score: Thrombocytopenia, Timing of Heparin Exposure, Thrombosis, and Other Causes (4T scoring system)Score (points)210ThrombocytopeniaNadir of 20-100 × 109/L or >50% ↓Nadir of 10-19 × 109/L or 30%-50% ↓Nadir of <10 × 109/L or <30% ↓Timing of onset of platelet ↓5-10 d⁎In patients previously exposed to heparins, heparin-induced thrombocytopenia type II can occur within 24 hours after reexposure. heparin exposure<10 d or timing not evident<1 d heparin exposureThrombosis or acute systemic symptomsProven thrombosis, skin necrosis, or acute systemic reactionProgressive, recurrent, silent thrombosis or erythematous skin lesionsNoneOther cause of thrombocytopeniaNone evidentPossibleProbableNote: Pretest probability of heparin-induced thrombocytopenia: high, 6 to 8; intermediate, 4 to 5; and low, 0 to 3.Based on Warkentin and Greinacher.1Warkentin T.E. Greinacher A. Heparin induced thrombocytopenia: Recognition, treatment, and prevention.Chest. 2004; 126: S311-S337Crossref PubMed Scopus (748) Google Scholar In patients previously exposed to heparins, heparin-induced thrombocytopenia type II can occur within 24 hours after reexposure. Open table in a new tab Note: Pretest probability of heparin-induced thrombocytopenia: high, 6 to 8; intermediate, 4 to 5; and low, 0 to 3. Based on Warkentin and Greinacher.1Warkentin T.E. Greinacher A. Heparin induced thrombocytopenia: Recognition, treatment, and prevention.Chest. 2004; 126: S311-S337Crossref PubMed Scopus (748) Google Scholar Postmortem examination excluded pulmonary embolus and acute myocardial infarction, but showed marked increased interstitial lung edema (Fig 2). This patient was presumed to have died of acute pseudo-pulmonary embolus syndrome associated with heparin-induced thrombocytopenia (HIT). HIT should be considered in patients newly starting hemodialysis treatment who develop peripheral thrombocytopenia, particularly in association with venous access catheter thrombus. Routine laboratory measurement of peripheral platelets was introduced only in the 1970s, and as such, the first published report of HIT complicated by thrombosis dates back to 1969,2Natelson E.A. Lynch E.C. Alfrey Jr, C.P. Gross J.B. Heparin induced thrombocytopenia An unexpected response to treatment of consumption coagulopathy.Ann Intern Med. 1969; 71: 1121-1125Crossref PubMed Scopus (93) Google Scholar although cases of HIT undoubtedly occurred many years before this report. Heparin is now recognized as the most common cause of drug-induced thrombocytopenia in clinical practice. However, not all patients who develop antibodies to the heparin-PF4 complex develop thrombocytopenia, and similarly, not all patients who develop HIT experience thrombotic consequences, which has led to the concept of an “iceberg” model3Chong B.H. Berndt M.C. Heparin induced thrombocytopenia.Blut. 1989; 58: 53-57Crossref PubMed Scopus (113) Google Scholar (Fig 3). The frequency of antibody formation depends on a variety of factors, including the chain length of the heparin molecule and degree of sulfation,4Nguyên P. Droullé C. Potron G. Comparison between platelet factor 4/heparin complexes ELISA and platelet aggregation test in heparin-induced thrombocytopenia.Thromb Haemost. 1995; 74: 804-805PubMed Google Scholar amount and frequency of heparin administration, clinical setting, and degree of nonimmune platelet activation.5Greinacher A. Heparin-induced thrombocytopenia: Frequency and pathogenesis.Pathophysiol Haemost Thromb. 2006; 35: 37-45Crossref PubMed Scopus (32) Google Scholar Whether patients then develop thrombocytopenia relates to the clinical setting,6Bream-Rouwenhorst H.R. Hobbs R.A. Heparin-dependent antibodies and thrombosis without heparin-induced thrombocytopenia.Pharmacotherapy. 2008; 28: 1401-1407Crossref PubMed Scopus (5) Google Scholar dose of heparin, platelet Fc receptor expression and also possibly Fc receptor polymorphisms,7Carlsson L.E. Lubenow N. Blumentritt C. et al.Platelet receptor and clotting factor polymorphisms as genetic risk factors for thromboembolic complications in heparin-induced thrombocytopenia.Pharmacogenetics. 2003; 13: 253-258Crossref PubMed Scopus (34) Google Scholar and concurrent inflammatory responses. Similarly, risk of thrombosis is then dependent on patient factors, including immobility, previous limb gangrene, peripheral vascular disease, presence of mutations disrupting levels or activity of natural anticoagulants such as protein C, treatment with coumarins, and degree of thrombocytopenia. Risk of thrombosis also is increased by the use of indwelling central venous catheters.8Hong A.P. Cook D.J. Sigouin C.S. Warkentin T.E. Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia.Blood. 2003; 101: 3049-3051Crossref PubMed Scopus (133) Google Scholar Patients who experience multiple thromboses or such severe systemic reactions as pseudo-pulmonary embolus typically have endothelial cell activation by HIT antibodies (Fig 4).Figure 4Schematic representation of the development of heparin-induced thrombocytopenia (HIT). Heparin binds to the platelet surface and leads to release of platelet factor 4 (PF4). If a critical stoichiometric ratio of heparin to PF4 is achieved, the heparin-PF4 complex undergoes a conformational change that exposes novel epitopes, leading to antibody (Ab) formation. The heparin-PF4 complex–bound antibody then binds to platelets, leading to activation and microparticle release, which activates the contact coagulation cascade to produce thrombin and further platelet activation. The antibody complex also binds endothelial cells through heparin sulfate and activates endothelial cells, leading to local thrombus and endothelial permeability, which causes the pseudo-pulmonary embolus syndrome. Abbreviation: ADP, adenosine diphosphate.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Heparins can bind surface-bound PF4, leading to platelet activation with a decrease in peripheral platelet count.3Chong B.H. Berndt M.C. Heparin induced thrombocytopenia.Blut. 1989; 58: 53-57Crossref PubMed Scopus (113) Google Scholar This usually occurs when patients are first exposed to heparins, such as initiating hemodialysis therapy9Davenport A. Heparin induced thrombocytopenia during renal replacement therapy.Hemodial Int. 2004; 8: 295-303Crossref PubMed Scopus (17) Google Scholar; typically is transitory; and is termed HIT type I (Table 2).10Warkentin T.E. History of heparin induced thrombocytopenia.in: Warkentin T.E. Greinacher A. Heparin Induced Thrombocytopenia. (ed 3). Dekker, New York, NY2004: 1-23Google ScholarTable 2General Differences Between HIT Types I and IIHIT Type IHIT Type IIFrequency (%)10-200.1-3Timing after heparin (d)1-35-10⁎In patients previously exposed to heparins, HIT type II can occur within 24 hours after reexposure.Peripheral platelet count (× 109/L)10030-50Antibody mediatedNoYesRisk of thrombosisNoYesRisk of hemorrhageNoYesManagementObserve, continue heparinWithdraw all heparinsData from Davenport.9Davenport A. Heparin induced thrombocytopenia during renal replacement therapy.Hemodial Int. 2004; 8: 295-303Crossref PubMed Scopus (17) Google ScholarAbbreviation: HIT, heparin-induced thrombocytopenia. In patients previously exposed to heparins, HIT type II can occur within 24 hours after reexposure. Open table in a new tab Data from Davenport.9Davenport A. Heparin induced thrombocytopenia during renal replacement therapy.Hemodial Int. 2004; 8: 295-303Crossref PubMed Scopus (17) Google Scholar Abbreviation: HIT, heparin-induced thrombocytopenia. When heparin binds to PF4 at a key stoichiometric ratio of 27 IU heparin to 1 mg of PF4, conformational change occurs within the PF4 molecule leading to exposure of novel epitopes, thus allowing the generation of autoantibodies to the heparin-PF4 complex.11Amiral J. Bridey F. Wolf M. et al.Antibodies to macromolecular platelet factor 4 heparin induced thrombocytopenia: A study of 44 cases.Thromb Haemost. 1995; 73: 21-28PubMed Google Scholar The affinity of heparin for PF4 depends on molecular weight, chain length, and degree of sulfation, thus accounting for the increased antibody formation with bovine to porcine UFH12Ahmad S. Heparin-induced thrombocytopenia: Impact of bovine versus porcine heparin in HIT pathogenesis.Front Biosci. 2007; 12: 3312-3320Crossref PubMed Scopus (10) Google Scholar and UFH compared with low-molecular-weight heparins. In 80% of cases, heparin-PF4 antibodies are of the immunoglobulin G (IgG) isotype13Greinacher A. Juhl D. Strobel U. et al.Heparin-induced thrombocytopenia: A prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes.J Thromb Haemost. 2007; 5: 1666-1673Crossref PubMed Scopus (195) Google Scholar because only IgG antibodies can bind to platelet FcγIIa receptors, although occasionally IgM and IgA antibodies have been reported to be pathogenic. The heparin-PF4-IgG complex then activates platelets through their FcγIIa receptors, and there is debate about whether some receptor isoforms predispose to HIT.14Palomo I. Pereira J. Alarcon M. et al.Prevalence of heparin induced antibodies in patients with chronic renal failure undergoing hemodialysis.J Clin Lab Anal. 2005; 19: 189-195Crossref PubMed Scopus (32) Google Scholar Platelet activation results in the release of platelet microparticles, platelet consumption, and peripheral thrombocytopenia, with generation of thrombin, activation of monocytes and other inflammatory cells, and also endothelial injury and activation (Fig 4). Because heparin can nonspecifically bind to plasma proteins, some patients can occasionally develop antibodies to heparin-chemokine complexes, resulting in HIT without typical heparin-PF4 antibodies.15Regnault V. de Maistre E. Carteaux J.P. et al.Platelet activation induced by human antibodies to interleukin-8.Blood. 2003; 101: 1419-1421Crossref PubMed Scopus (62) Google Scholar HIT typically occurs in incident hemodialysis patients, although late cases have been reported, particularly when heparin dosages and/or frequency have been increased.16Hutchinson C.A. Dasgupta I. National survey of heparin induced thrombocytopenia in the haemodialysis population of the UK population.Nephrol Dial Transplant. 2007; 22: 1680-1684Crossref PubMed Scopus (48) Google Scholar, 17Davenport A. Low molecular weight heparin as an alternative anticoagulant to unfractionated heparin for routine outpatient hemodialysis treatments.Nephrology. 2009; (in press)Google Scholar Clotting in the extracorporeal circuit18Matsuo T. Wanaka K. Management of uremic patients with heparin-induced thrombocytopenia requiring hemodialysis.Clin Appl Thromb Hemost. 2008; 14: 459-464Crossref PubMed Scopus (10) Google Scholar followed by catheter-associated thrombi are the most common clinical manifestations,19Gregorini G. Bellandi D. Martini G. Volpi R. Heparin induced thrombocytopenia syndrome and thrombosis in patients undergoing periodic haemodialysis.G Ital Nefrol. 2002; 19: 672-692PubMed Google Scholar particularly when patients with acute kidney injury are being dialyzed.20Lasocki S. Piednoir P. Ajzenberg N. Geffroy A. Benbara A. Montravers P. Anti-PF4/heparin antibodies associated with repeated hemofiltration-filter clotting: A retrospective study.Crit Care. 2008; 12: R84Crossref PubMed Scopus (19) Google Scholar In routine outpatient hemodialysis, other commonly reported manifestations include access thrombosis (arteriovenous fistulas and grafts) and central venous stenoses in patients undergoing dialysis with central venous catheters. In 1 survey, less than 10% of patients with HIT developed deep venous thrombosis and 4% developed pulmonary emboli. In addition, retroperitoneal hemorrhage was reported in 4%.16Hutchinson C.A. Dasgupta I. National survey of heparin induced thrombocytopenia in the haemodialysis population of the UK population.Nephrol Dial Transplant. 2007; 22: 1680-1684Crossref PubMed Scopus (48) Google Scholar Fortunately, myocardial infarction, multiple thromboses, and pseudo-pulmonary embolus syndrome occur in 1% or less of patients.21Hartman V. Malbrain M. Daelemans R. Meersman P. Zachée P: Pseudo-pulmonary embolism as a sign of acute heparin-induced thrombocytopenia in hemodialysis patients: Safety of resuming heparin after disappearance of HIT antibodies.Nephron Clin Pract. 2006; 104: c143-c148Crossref PubMed Scopus (30) Google Scholar, 22Davenport A. Sudden collapse during hemodialysis due to immune mediated heparin induced thrombocytopenia.Nephrol Dial Transplant. 2006; 21: 1721-1724Crossref PubMed Scopus (19) Google Scholar, 23Charif R. Davenport A. Heparin-induced thrombocytopenia: An uncommon but serious complication of heparin use in renal replacement therapy.Hemodial Int. 2006; 10: 235-240Crossref PubMed Scopus (21) Google Scholar There is debate about whether hemodialysis patients with heparin-PF4 antibodies, but without thrombocytopenia, are at increased risk of thrombosis, in particular, access thrombosis. Because these antibodies cause platelet activation, increased access thrombosis would be expected.24ElChoufani S.E. Bolin P. Waien S. Christiano C.R. Holbert D. Bode A.P. Platelet adhesion testing may predict early hemodialysis arteriovenous graft and fistula failure in end stage renal failure patients.Clin Appl Thromb Haemost. 2008; 14: 399-409Crossref PubMed Scopus (2) Google Scholar Although the majority of studies have reported an increased incidence of heparin-PF4 antibodies in patients with recurrent thrombosed accesses,16Hutchinson C.A. Dasgupta I. National survey of heparin induced thrombocytopenia in the haemodialysis population of the UK population.Nephrol Dial Transplant. 2007; 22: 1680-1684Crossref PubMed Scopus (48) Google Scholar, 25Nakamoto H. Shimada Y. Kanno T. Wanaka K. Matsuo T. Suzuki H. Role of platelet factor 4 heparin complex antibody (HIT antibody) in the pathogenesis of thrombotic episodes in patients on hemodialysis.Hemodial Int. 2005; 9: S2-S7Crossref PubMed Scopus (25) Google Scholar, 26O'Shea S.I. Lawson J.H. Reddan D. Murphy M. Ortel T.L. Hypercoagulable states and antihrombotic strategies in recurrent vascular access site thrombosis.J Vasc Surg. 2003; 38: 541-548Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar this has not been universal.27O'Shea S.I. Sands J.L. Nudo S.A. Ortel T.L. Frequency of anti heparin platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis.Am J Hematol. 2002; 69: 72-73Crossref PubMed Scopus (53) Google Scholar, 28Asmis L.M. Segal J.B. Plantinga L.C. et al.Heparin induced antibodies and cardiovascular risk in patients on dialysis.Thromb Haemost. 2008; 100: 498-504PubMed Google Scholar Three studies reported increased mortality in hemodialysis patients with anti–heparin-PF4 antibodies without thrombocytopenia.29Mureebe L. Coats R.D. Silliman W.R. Shuster T.A. Nicholls W.K. Silver D. Heparin associated antiplatelet antibodies increase morbidity and mortality in haemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 30Pena de la Vega L. Miller R.S. Benda M.M. et al.Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: A population-based study.Mayo Clin Proc. 2005; 8: 995-1000Abstract Full Text Full Text PDF Scopus (57) Google Scholar, 31Carrier M. Rodger M.A. Ferguson D. et al.Increased mortality in haemodialysis patients having specific antibodies to the platelet factor 4 heparin complex.Kidney Int. 2008; 73: 213-219Crossref PubMed Scopus (23) Google Scholar In these studies, there was an excess of thrombotic events, not only pulmonary emboli and mesenteric ischemia, but also cardiovascular deaths. However, a recent multicenter report28Asmis L.M. Segal J.B. Plantinga L.C. et al.Heparin induced antibodies and cardiovascular risk in patients on dialysis.Thromb Haemost. 2008; 100: 498-504PubMed Google Scholar did not show excess overall mortality or cardiovascular death in patients with antibodies to heparin-PF4. The diagnosis of HIT remains a clinical one supported by confirmatory laboratory testing. In the intensive care unit setting, there are many potential causes of thrombocytopenia,32Davenport A. Anticoagulation options for patients with heparin-induced thrombocytopenia requiring renal support in the intensive care unit.Contrib Nephrol. 2007; 156: 259-266Crossref PubMed Google Scholar and similarly, several drugs prescribed to outpatient hemodialysis patients, including such antibiotics as vancomycin, proton pump inhibitors, histamine2 blockers, and antidepressants, also can cause thrombocytopenia. Thus, to provide guidance, Warkentin and Greinacher1Warkentin T.E. Greinacher A. Heparin induced thrombocytopenia: Recognition, treatment, and prevention.Chest. 2004; 126: S311-S337Crossref PubMed Scopus (748) Google Scholar proposed a scoring system to assess the potential risk of patients having HIT, colloquially referred to as the 4Ts (Table 1). If HIT is suspected, all heparin exposure should be withdrawn while awaiting laboratory testing, and unless clinically contraindicated, the patient starts on an alternative systemic anticoagulant therapy.21Hartman V. Malbrain M. Daelemans R. Meersman P. Zachée P: Pseudo-pulmonary embolism as a sign of acute heparin-induced thrombocytopenia in hemodialysis patients: Safety of resuming heparin after disappearance of HIT antibodies.Nephron Clin Pract. 2006; 104: c143-c148Crossref PubMed Scopus (30) Google Scholar, 33Warkentin T.E. Greinacher A. Koster A. Lincoff A.M. American College of Chest PhysiciansTreatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (ed 8).Chest. 2008; 133: 40-380Crossref Scopus (715) Google Scholar Heparin-PF4 antibodies can be detected by means of either laboratory functional tests or immunoassays. Functional tests assess platelet activation in the presence of both heparin and the patient's serum. These include heparin-induced platelet aggregation, serotonin release assay (SRA), and flow cytometric assays that detect platelet microparticle release.34Warkentin T.E. Greinacher A. Laboratory testing for heparin induced thrombocytopenia.in: Warkentin T.E. Greinacher A. Heparin Induced Thrombocytopenia. (ed 3). Dekker, New York, NY2004: 313-334Google Scholar Activation assays should be confirmed by using heparin neutralization because at high concentrations of heparin, the test result should be negative because excess heparin leads to different heparin-PF4 binding so that the novel epitopes are not expressed. These activation assays also allow in vitro cross-reactivity to low-molecular-weight heparins and heparinoids to be assessed. Although the SRA is 95% sensitive and specific, when washed platelets are used, it is laborious and available in only a few laboratories worldwide. Thus, the heparin-induced platelet aggregation test, with variable sensitivity of 35% to 85%, is more commonly performed. During the last decade, a number of immunoenzymatic tests (solid-phase enzyme immunoassay, PF4-polyvinylsulfonate antigen assay, fluid-phase enzyme immunoassay, and gel particle immunoassay) have been developed to detect antibodies directed against the heparin-PF4 complex and have become readily available. These ELISAs have high sensitivity of 80% to 100%, but have low specificity because they detect a range of IgA and IgM antibodies that are not pathogenic. More recently, IgG isotype ELISAs have been introduced. No single assay has 100% sensitivity and specificity.29Mureebe L. Coats R.D. Silliman W.R. Shuster T.A. Nicholls W.K. Silver D. Heparin associated antiplatelet antibodies increase morbidity and mortality in haemodialysis patients.Surgery. 2004; 136: 848-853Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 35Suzuki S. Sakamoto S. Matsuo M. Shimano C. Kuroda T. Matsuo T. 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American College of Chest PhysiciansTreatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (ed 8).Chest. 2008; 133: 40-380Crossref Scopus (715) Google Scholar and there is value in repeated testing in clinically suspected cases.37Aster R.H. Heparin-induced immune thrombocytopenia—A clinical or laboratory diagnosis?.J Thromb Haemost. 2006; 4: 757-758Crossref PubMed Scopus (9) Google Scholar Mild thrombocytopenia can occur when patients first start dialysis therapy (Table 2) and are exposed to heparins. In addition to infections and alloantibodies, a substantial number of drugs have been reported to cause thrombocytopenia, ranging from antibiotics, including vancomycin and penicillins, to proton pump inhibitors, monoclonal immunosuppressants, and chemotherapeutic agents to antipsychotics.32Davenport A. Anticoagulation options for patients with heparin-induced thrombocytopenia requiring renal support in the intensive care unit.Contrib Nephrol. 2007; 156: 259-266Crossref PubMed Google Scholar, 38Kenney B. Stack G. Drug-induced thrombocytopenia.Arch Pathol Lab Med. 2009; 133: 309-314PubMed Google Scholar HIT can cause an acute collapse shortly after starting hemodialysis caused by heparin exposure by either priming the dialysis circuit with heparin, injection of the remaining heparin lock, and bolus administration.21Hartman V. Malbrain M. Daelemans R. Meersman P. Zachée P: Pseudo-pulmonary embolism as a sign of acute heparin-induced thrombocytopenia in hemodialysis patients: Safety of resuming heparin after disappearance of HIT antibodies.Nephron Clin Pract. 2006; 104: c143-c148Crossref PubMed Scopus (30) Google Scholar However, there are other causes of anaphylactoid-like reactions that can occur shortly after starting dialysis,39Davenport A. Heparin induced thrombocytopenia during renal replacement therapy in the intensive care unit.Crit Care. 2008; 12: 158Crossref PubMed Scopus (2) Google Scholar including air embolus, reactions to the dialyzer,40Chan M. Malynn E. Shaz B. Uhl L. Utility of consecutive repeat HIT ELISA testing for heparin induced thrombocytopenia.Am J Hematol. 2008; 83: 212-217Crossref PubMed Scopus (21) Google Scholar sterilization agents,41Davenport A. Intradialytic complications during hemodialysis.Hemodial Int. 2006; 10: 162-167Crossref PubMed Scopus (122) Google Scholar and anticoagulants. Some patients develop allergies to heparin as part of an allergy to porcine or bovine products or the stabilizing agents used in sodium and calcium heparin preparations. Mast cell tryptase and specific radioallergosorbent test assays for sterilization agents, plasticizers, and adhesives, including methacrylates, may be helpful in investigating such reactions. More recently, a series of fatal reactions have been reported with heparin preparations contaminated with oversulfated chondroitin sulfate.42Davenport A. Ahmad R. The effect of reuse of cuprophan dialysers on dialysis induced leukopenia and thrombocytopenia.Dial Transplant. 1988; 17: 132-134Google Scholar Heparin is negatively charged, which can cause activation of the contact coagulation cascade,43Davenport A. Pyrexia of unknown origin in a hemodialysis patient.Nephrol Dial Transplant Plus. 2008; 1: 109-111Google Scholar leading to kalikrein and bradykinin generation with complement activation and increased production of both nitric oxide and the anaphylatoxins C3a and C5a, potentially leading to profound hypotension. Contamination of heparin with oversulfated chondroitin sulfate increases the number of negative charges, thus increasing the potential to generate bradykinin and complement activation,44Kishimoto T.K. Viswanathan K. Ganguly T. et al.Contaminated heparin associated with adverse clinical events and activation of the contact system.N Engl J Med. 2008; 358: 2457-2467Crossref PubMed Scopus (531) Google Scholar leading to profound hypotension.45Davenport A. The coagulation system in the critically ill patient with acute renal failure and the effect of an extracorporeal circuit.Am J Kidney Dis. 1998; 30: S20-S27Google Scholar Increased heparin sulfation also increases the risk of developing HIT. Very few studies have prospectively measured antibodies to the heparin-PF4 complex in patients initiating hemodialysis. However, a UK survey on HIT reported an incidence of 1.6%.16Hutchinson C.A. Dasgupta I. 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Heparin-induced thrombocytopenia in hemodialysis patients.Am J Kidney Dis. 1996; 25: 82-85Abstract Full Text PDF Scopus (136) Google Scholar Differences between these reports can be explained by the differing assays used (functional versus antigen) and timing, in that the prevalence of antibodies is greater within the first 3 months after starting dialysis therapy (20%) and then decreases with dialysis vintage to 6% after 6 months.27O'Shea S.I. Sands J.L. Nudo S.A.