HEMATOLOGY: ISSUES IN THE DIALYSIS PATIENT: When Heparin Causes Thrombosis: Significance, Recognition, and Management of Heparin‐Induced Thrombocytopenia in Dialysis Patients

Heparin‐induced thrombocytopenia (HIT) is characterized by thrombocytopenia and paradoxical hypercoagulability. HIT occurs when an antibody (“HIT antibody”) produced against the complex of heparin and platelet factor 4 (PF4) causes systemic platelet consumption and activation. Nephrologists encounter HIT in the care of end‐stage renal disease (ESRD) patients because heparin is a routine anticoagulant in hemodialysis. The incidence of HIT in ESRD appears to be lower than in other clinical settings. However, HIT is equally life threatening in ESRD patients and therefore demands the same prompt recognition and aggressive treatment. Diagnosing HIT requires the detection of HIT antibodies. A functional assay (e.g., [14C] serotonin release assay) relies on the patient's HIT antibodies to activate donor platelets at pharmacologic heparin concentrations. The more common antigen assay (e.g., enzyme‐linked immunosorbent assay [ELISA]) detects the binding of the patient's HIT antibodies to antigens (e.g., heparin‐PF4 complex) in a microtiter well and does not involve platelets. The moment HIT is suspected, heparin should be stopped and an alternative anticoagulant initiated immediately, even before the result of a serologic test becomes available. The advent of several new anticoagulants in the last decade, especially argatroban and bivalirudin, has expanded treatment options for HIT in dialysis patients. This review discusses the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of HIT, with special emphasis on concepts relevant to the care of dialysis patients.

[1]  P. Prandoni,et al.  The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study. , 2005, Blood.

[2]  H. Nakamoto,et al.  Role of platelet factor 4–heparin complex antibody (HIT antibody) in the pathogenesis of thrombotic episodes in patients on hemodialysis , 2005, Hemodialysis international. International Symposium on Home Hemodialysis.

[3]  O. Samuelsson,et al.  Prevention of clot formation during haemodialysis using the direct thrombin inhibitor melagatran in patients with chronic uraemia. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[4]  Matthew G. Johnson,et al.  Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a population-based study. , 2005, Mayo Clinic proceedings.

[5]  Michael P Gulseth,et al.  Ximelagatran: an orally active direct thrombin inhibitor. , 2005, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[6]  P. Kam,et al.  Direct thrombin inhibitors: pharmacology and clinical relevance , 2005, Anaesthesia.

[7]  I. Jang,et al.  When heparins promote thrombosis: review of heparin-induced thrombocytopenia. , 2005, Circulation.

[8]  T. Warkentin.  New approaches to the diagnosis of heparin-induced thrombocytopenia. , 2005, Chest.

[9]  J. Bartholomew.  Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia. , 2005, Chest.

[10]  R. Bellomo,et al.  Use of fondaparinux (ARIXTRA) in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[11]  C. White,et al.  Thrombin-directed inhibitors: pharmacology and clinical use. , 2005, American heart journal.

[12]  S. Swan,et al.  A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. , 2004, Kidney international.

[13]  L. Rice.  Heparin-induced thrombocytopenia: myths and misconceptions (that will cause trouble for you and your patient). , 2004, Archives of internal medicine.

[14]  A. Greinacher,et al.  Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. , 2004, Chest.

[15]  C. Francis.  Ximelagatran: a new oral anticoagulant. , 2004, Best practice & research. Clinical haematology.

[16]  A. Greinacher,et al.  Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin. , 2004, Blood.

[17]  T. Warkentin.  Laboratory Testing for Heparin-Induced Thrombocytopenia , 2000, Journal of Thrombosis and Thrombolysis.

[18]  H. Breddin.  Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. , 2009, Archives of pathology & laboratory medicine.

[19]  H. Yatani,et al.  Deep venous thrombosis, myocardial infarction, and occlusion of vascular access associated with heparin-induced thrombocytopenia in a diabetic hemodialysis patient , 2003, Journal of Clinical and Experimental Nephrology.

[20]  J. Hirsh,et al.  An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. , 2003, Archives of internal medicine.

[21]  A. Greinacher,et al.  Anaphylactic and Anaphylactoid Reactions Associated With Lepirudin in Patients With Heparin-Induced Thrombocytopenia , 2003, Circulation.

[22]  N. N. Wong.  Fondaparinux: a synthetic selective factor-Xa inhibitor. , 2003, Heart disease.

[23]  P. Prandoni,et al.  The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. , 2003, Blood.

[24]  T. Ortel,et al.  HEPARIN‐INDUCED THROMBOCYTOPENIA IN DIALYSIS: Alternative Methods of Anticoagulation for Dialysis‐dependent Patients with Heparin‐induced Thrombocytopenia , 2003 .

[25]  R. Reilly.  HEPARIN‐INDUCED THROMBOCYTOPENIA IN DIALYSIS: The Pathophysiology of Immune‐mediated Heparin‐induced Thrombocytopenia , 2003, Seminars in dialysis.

[26]  T. Ortel,et al.  Alternative methods of anticoagulation for dialysis-dependent patients with heparin-induced thrombocytopenia. , 2003, Seminars in dialysis.

[27]  K. Mann,et al.  Thrombin formation. , 2003, Chest.

[28]  J. Francis,et al.  Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. , 2003, The Annals of thoracic surgery.

[29]  T. Warkentin.  Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. , 2002, Archives of pathology & laboratory medicine.

[30]  K. Fischer.  Hirudin In Renal Insufficiency , 2002, Seminars in thrombosis and hemostasis.

[31]  T. Ortel,et al.  Frequency of anti‐heparin‐platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis , 2002, American journal of hematology.

[32]  R. White,et al.  Use of Lepirudin in Patients with Heparin-Induced Thrombocytopenia and Renal Failure Requiring Hemodialysis , 2001, The Annals of pharmacotherapy.

[33]  C. Broelsch,et al.  Anticoagulation with hirudin for continuous veno‐venous hemodialysis in liver transplantation , 2001, Acta anaesthesiologica Scandinavica.

[34]  R. Reilly,et al.  A Case Review: Anticoagulation in Hemodialysis Patients with Heparin-Induced Thrombocytopenia , 2001, American Journal of Nephrology.

[35]  J. Kelton,et al.  Temporal aspects of heparin-induced thrombocytopenia. , 2001, The New England journal of medicine.

[36]  J. Bartholomew,et al.  Argatroban Anticoagulant Therapy in Patients With Heparin-Induced Thrombocytopenia , 2001, Circulation.

[37]  C. Ronco,et al.  Hirudin versus heparin for anticoagulation in continuous renal replacement therapy , 2001, Intensive Care Medicine.

[38]  J. Nawarskas,et al.  Bivalirudin: a new approach to anticoagulation. , 2001, Heart disease.

[39]  D. Jorkasky,et al.  Interpreting the International Normalized Ratio (INR) in Individuals Receiving Argatroban and Warfarin , 2001, Thrombosis and Haemostasis.

[40]  J. Kelton,et al.  Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis , 2001, Annals of Internal Medicine.

[41]  A. Greinacher,et al.  Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. , 2000, Blood.

[42]  A. Greinacher,et al.  Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. , 2000, Blood.

[43]  A. Deller,et al.  Continuous haemofiltration with r-hirudin (lepirudin) as anticoagulant in a patient with heparin induced thrombocytopenia (HIT II). , 2000, Wiener klinische Wochenschrift.

[44]  A. Mattioli,et al.  Heparin-induced thrombocytopenia in patients treated with unfractionated heparin: prevalence of thrombosis in a 1 year follow-up. , 2000, Italian heart journal : official journal of the Italian Federation of Cardiology.

[45]  W. Hörl,et al.  Recombinant tissue plasminogen activator is a useful alternative to heparin in priming quinton permcath. , 2000, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[46]  P J Simpson,et al.  Impact of the patient population on the risk for heparin-induced thrombocytopenia. , 2000, Blood.

[47]  K. Fischer,et al.  Recombinant hirudin (lepirudin) as anticoagulant in intensive care patients treated with continuous hemodialysis. , 1999, Kidney international. Supplement.

[48]  S. Ziemer,et al.  Bleeding after intermittent or continuous r-hirudin during CVVH , 1999, Intensive Care Medicine.

[49]  J. Harenberg,et al.  Generation of anti-hirudin antibodies in heparin-induced thrombocytopenic patients treated with r-hirudin. , 1999, Circulation.

[50]  F. J. van der Woude,et al.  Serious bleeding in a haemodialysis patient treated with recombinant hirudin. , 1999, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[51]  AndreasGreinacher,et al.  Lepirudin (Recombinant Hirudin) for Parenteral Anticoagulation in Patients With Heparin-Induced Thrombocytopenia , 1999 .

[52]  U. Janssens,et al.  Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) investigators. , 1999, Circulation.

[53]  G. Nowak,et al.  R-Hirudin as Anticoagulant in Regular Hemodialysis Therapy: Finding of Therapeutic R-Hirudin Blood/Plasma Concentrations and Respective Dosages , 1999, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[54]  J. Zehnder,et al.  The International Normalized Ratio during concurrent warfarin and argatroban anticoagulation: differential contributions of each agent and effects of the choice of thromboplastin used. , 1999, Clinical chemistry.

[55]  U. Janssens,et al.  Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. , 1999, Circulation.

[56]  B. Grabensee,et al.  Anticoagulation with r-hirudin in a patient with acute renal failure and heparin-induced thrombocytopenia. , 1999, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[57]  J. Buturović,et al.  Filling hemodialysis catheters in the interdialytic period: heparin versus citrate versus polygeline: a prospective randomized study. , 1998, Artificial organs.

[58]  B. Banas,et al.  Prevalence of Heparin-Induced PF4-Heparin Antibodies in Hemodialysis Patients , 1998, Nephron.

[59]  F. Fabris,et al.  Platelet count, anti-heparin/platelet factor 4 antibodies and tissue factor pathway inhibitor plasma antigen level in chronic dialysis. , 1998, Thrombosis research.

[60]  W. Hauck,et al.  Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. , 1997, Circulation.

[61]  P. Koudstaal,et al.  Heparin‐induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases , 1997, British journal of haematology.

[62]  J. Kelton,et al.  A 14-year study of heparin-induced thrombocytopenia. , 1996, The American journal of medicine.

[63]  A. Greinacher,et al.  Heparin-induced antibodies as a risk factor for thromboembolism and haemorrhage in patients undergoing chronic haemodialysis , 1996, The Lancet.

[64]  R. Zietse,et al.  The presence of antibodies against a PF4-heparin complex in patients on haemodialysis. , 1996, Thrombosis and haemostasis.

[65]  T. Matsuo,et al.  Heparin-induced thrombocytopenia in hemodialysis patients. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[66]  L. Pillsbury,et al.  Regional hemodialysis anticoagulation: hypertonic tri-sodium citrate or anticoagulant citrate dextrose-A. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[67]  J. Amiral,et al.  Pathogenicity of IgA and/or IgM antibodies to heparin–PF4 complexes in patients with heparin‐induced thrombocytopenia , 1996, British journal of haematology.

[68]  M. Samama,et al.  Absence of In Vitro Cross-Reaction of Pentasaccharide with the Plasma Heparin-Dependent Factor of Twenty-Five Patients with Heparin-Associated Thrombocytopenia , 1995, Thrombosis and Haemostasis.

[69]  T. Matsuo,et al.  Anticoagulation for heparin-induced thrombocytopenia with spontaneous platelet aggregation in a patient requiring haemodialysis. , 1995, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[70]  P. Badenhorst,et al.  A comparison between the use of recombinant hirudin and heparin during hemodialysis. , 1995, Kidney International.

[71]  J. Hirsh,et al.  Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. , 1995, The New England journal of medicine.

[72]  J. Miller,et al.  Clotting by heparin of hemoaccess for hemodialysis in an end-stage renal disease patient. , 1995, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[73]  J. Soria,et al.  Recombinant hirudin: a specific thrombin inhibiting anticoagulant for hemodialysis. , 1994, Kidney international.

[74]  K. Kario,et al.  TREATMENT OF HEPARIN‐INDUCED THROMBOCYTOPENIA BY USE OF ARGATROBAN, A SYNTHETIC THROMBIN INHIBITOR , 1992, British journal of haematology.

[75]  F. Markwardt,et al.  Pharmacology of r-hirudin in renal impairment. , 1992, Thrombosis research.

[76]  P. Comfurius,et al.  Platelet procoagulant activity: physiological significance and mechanisms of exposure. , 1991, Blood reviews.

[77]  T. Lubowski.  Heparin-induced thrombocytopenia and thrombosis. , 1990, Connecticut medicine.