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Thrombosis Journal
Published in: Thrombosis Journal 1/2013

Open Access 01-12-2013 | Review

Emphasis on the Role of PF4 in the Incidence, Pathophysiology and Treatment of Heparin Induced Thrombocytopenia

Authors: Margaret M Prechel, Jeanine M Walenga

Published in: Thrombosis Journal | Issue 1/2013

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Abstract

Heparin Induced Thrombocytopenia (HIT) is caused by antibodies that recognize platelet factor 4 (PF4) associated with polyanionic glycosaminoglycan drugs or displayed on vascular cell membranes. These antibodies are elicited by multimolecular complexes that can occur when heparin is administered in clinical settings associated with abundant PF4. Heparin binding alters native PF4 and elicits immune recognition and response. While the presence of heparin is integral to immunogenesis, the HIT antibody binding site is within PF4. Thus HIT antibodies develop and function to cause thrombocytopenia and/or thrombosis only in the presence of PF4. Future emphasis on understanding the biology, turnover and regulation of PF4 may lead to insights into the prevention and treatment of HIT.
Literature
1.
Messmore HL, Wehrmacher WH, Coyne E, Fareed J: Heparin to pentasaccharide and beyond: the end is not in sight. Semin Thromb Hemost 2004, 30(Suppl 1):81-88.PubMed
2.
Hirsh J, Raschke R: Heparin and low-molecular weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004, 126(3 Suppl):188S-203S.PubMedCrossRef
3.
Rice L, Nguyen PH, Vann AR: Preventing complications in heparin induced thrombocytopenia. Alternative anticoagulants are improving patient outcomes. Postgrad Med 2002, 112: 85-89.PubMedCrossRef
4.
Brieger DB, Mak KH, Kottke-Marchant K, Topol EJ: Heparin-induced thrombocytopenia. J Am Coll Cardiol 1998, 31: 1449-1459. 10.1016/S0735-1097(98)00134-XPubMedCrossRef
5.
Kelton JG, Warkentin TE: Heparin-induced thrombocytopenia: a historical perspective. Blood 2008, 112: 2607-2616. 10.1182/blood-2008-02-078014PubMedCrossRef
6.
Warkentin TE, Kelton JG: A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996, 101: 502-507. 10.1016/S0002-9343(96)00258-6PubMedCrossRef
7.
Levy JH, Tanaka KA, Hursting MJ: Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia. Anesth Analg 2008, 105: 570-582.CrossRef
8.
Cuker A, Cines DB: How I treat heparin-induced thrombocytopenia. Blood 2012, 119: 2209-2218. 10.1182/blood-2011-11-376293PubMedCrossRef
9.
Chong BH: Heparin-induced thrombocytopenia. Br J Haematol 1995, 89: 431-439. 10.1111/j.1365-2141.1995.tb08346.xPubMedCrossRef
10.
Chong BH, Pitney WR, Castaldi PA: Heparin-induced thrombocytopenia: association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis in platelet aggregation. Lancet 1982, 2: 1246-1249.PubMedCrossRef
11.
Chong BH, Fawaz I, Chesterman CN, Berndt MC: Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989, 73: 235-240. 10.1111/j.1365-2141.1989.tb00258.xPubMedCrossRef
12.
Green D, Harris K, Reynolds N, Roberts M, Patterson R: Heparin immune thrombocytopenia: Evidence for a heparin-platelet complex as the antigenic determinant. J Lab Clin Med 1978, 91: 167-175.PubMed
13.
Visentin GP, Ford SE, Scott JP, Aster RH: Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest 1994, 93: 81-88. 10.1172/JCI116987PubMedCentralPubMedCrossRef
14.
Greinacher A, Potzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C: Heparin-associated thrombocytopia: Isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994, 71: 247-251.PubMed
15.
Amiral J, Bridey F, Dreyfus M, Vissac M, Fressinaud E, Wolf M, Meyer D: Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992, 68: 95-96.PubMed
16.
Greinacher A, Ittermann T, Bagemühl J, Althaus K, Fürll B, Selleng S, Lubenow N, Schellong S, Sheppard JI, Warkentin TE: Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost 2010, 8: 2025-2031. 10.1111/j.1538-7836.2010.03974.xPubMedCrossRef
17.
Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG: Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost 2008, 6: 1304-1312. 10.1111/j.1538-7836.2008.03025.xPubMedCrossRef
18.
Greinacher A, Juhl D, Strobel U, Raschke R, Fueril B, Wessel A, Lubenow N, Eichler P, Warkentin TE: Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activation capacity and clinical significance of anti-platelet factor 4/heparin antibodies of the IgG, IgM, and IgA class. J Thromb Haemost 2007, 5: 1667-1673.
19.
Warkentin TE, Sheppard JA, Moore JC, Moore KM, Sigouin CS, Kelton JG: Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class to we need? J Lab Clin Med 2005, 146: 341-346. 10.1016/j.lab.2005.08.003PubMedCrossRef
20.
Greinacher A, Michels I, Mueller-Eckhardt C: Heparin-associated thrombocytopenia: The antibody is not heparin specific. Thromb Haemost 1992, 67: 545-549.PubMed
21.
Greinacher A, Alban S, Drummel V, Franz G, Mueller-Eckhardt C: Characterization of the structural requirements for a carbohydrate-based anticoagulant with a reduced risk of inducing the immunological type of heparin-associated thrombocytopenia. Thromb Haemost 1995, 74: 886.PubMed
22.
Haas S, Walenga JM, Jeske WP, Fareed J: Heparin-induced thrombocytopenia: Clinical considerations of alternative anticoagulation with various glycosaminoglycans and thrombin inhibitors. Clin Appl Thromb Hemost 1999, 5: 52-59.PubMedCrossRef
23.
Walenga JM, Koza MJ, Lewis BE, Pifarre R: Relative heparin-induced thrombocytopenic potential of low molecular weight heparins and new antithrombotic agents. Clin Appl Thromb Hemost 1996, 2(Suppl. 1):S21-S27.
24.
Mayo KH, Chen MJ: Human platelet factor 4 monomer-dimer-tetramer equilibria investigated by 1H NMR spectroscopy. Biochemistry 1989, 28: 9469-9478. 10.1021/bi00450a034PubMedCrossRef
25.
Moore S, Pepper DS, Cash JD: Platelet antiheparin activity. The isolation and characterisation of platelet factor 4 released from thrombin-aggregated washed human platelets and its dissociation into subunits and the isolation of membrane-bound antiheparin activity. Biochim Biophys Acta 1975, 379: 370-384. 10.1016/0005-2795(75)90144-0PubMedCrossRef
26.
Deuel TF, Keim PJ, Farmer M, Heinrikson RL: Amino acid sequence of human platelet factor 4. Proc Natl Acad Sci 1977, 74: 2256-2258. 10.1073/pnas.74.6.2256PubMedCentralPubMedCrossRef
27.
Huang SS, Huang JS, Deuel TF: Proteoglycan carrier of human platelet factor 4. J Biol Chem 1982, 257: 11546-11550.PubMed
28.
Barber AJ, Kaser-Glanzmann R, Jakabova M, Luscher EF: Characterization of a chondroitin 4-sulfate proteoglycan carrier for heparin neutralizing activity (platelet factor 4) released from human blood platelets. Biochim Biophys Acta 1972, 286: 312-329. 10.1016/0304-4165(72)90267-XPubMedCrossRef
29.
Stringer SE, Galagher JT: Specific binding of the chemokine platelet factor 4 to heparan sulfate. J Biol Chem 1997, 272: 20508-20514. 10.1074/jbc.272.33.20508PubMedCrossRef
30.
Handin RI, Cohen HJ: Purification and binding properties of human platelet factor four. J Biol Chem 1976, 251: 4273-4282.PubMed
31.
Luscombe M, Marshall S, Pepper DS, Holbrook JJ: The transfer of platelet factor 4 from its proteoglycan carrier to natural and synthetic polymers. Biochim Biophys Acta 1981, 18: 137-142.CrossRef
32.
Rybak ME, Gimbrone MA Jr, Davies PF, Handin RI: Interaction of platelet factor four with cultured vascular endothelial cells. Blood 1989, 73: 1534-1539.PubMed
33.
Cines DB: Disorders associated with antibodies to endothelial cells. Rev Infect Dis 1989, 11(4):705-711. 10.1093/clinids/11.Supplement_4.S705CrossRef
34.
Sachais BS, Higazi AA, Cines DB, Poncz M, Kowalska MA: Interactions of platelet factor 4 with the vessel wall. Semin Thromb Hemost 2004, 30: 351-358. 10.1055/s-2004-831048PubMedCrossRef
35.
Shi G, Morrell CN: Platelets as initiators and mediators of inflammation at the vessel wall. Thromb Res 2011, 127: 387-390. 10.1016/j.thromres.2010.10.019PubMedCentralPubMedCrossRef
36.
Slungaard A: Platelet factor 4: a chemokine enigma. Int J Biochem Cell Biol 2005, 37: 1162-1167. 10.1016/j.biocel.2004.12.003PubMedCrossRef
37.
Amiral J, Vissac AM: Generation and pathogenicity of anti-platelet factor 4 antibodies: Diagnostic implications. Clin Appl Thromb Hemost 1999, 5(Suppl 1):S28-S31.PubMedCrossRef
38.
Kaplan KL, Owen J: Plasma levels of beta-thromboglobulin and platelet factor 4 as indices of platelet activation in vivo. Blood 1981, 57: 199-202.PubMed
39.
Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S: Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 2003, 28: 451-457.CrossRef
40.
Nakamura T, Ebihara I, Shoji H, Ushiyama C, Suzuki S, Koide H: Treatment with polymyxin B-immobilized fiber reduces platelet activation in septic shock patients: decrease in plasma levels of soluble P-selectin, platelet factor 4 and beta-thromboglobulin. Inflamm Res 1999, 48: 171-175. 10.1007/s000110050442PubMedCrossRef
41.
Davi G, Gresele P, Violi F, Basili S, Catalano M, Giammarresi C, Volpato R, Nenci GG, Ciabattoni G, Patrono C: Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation 1997, 96: 69-75. 10.1161/01.CIR.96.1.69PubMedCrossRef
42.
Buyukasyk NS, Ileri M, Alper A, Senen K, Atak R, Hisar I, Yetkin E, Turhan H, Demirkan D: Increased blood coagulation and platelet activation in patients with infective endocarditis and embolic events. Clin Cardiol 2004, 27: 154-158. 10.1002/clc.4960270312PubMedCrossRef
43.
Laghrissi-Thode F, Wagner WR, Pollock PC, Finkel MS: Elevated platelet factor 4 and β-thromboglobulin plasma levels in depressed patients with ischemic heart disease. Biol Psychiatry 1997, 42: 290-295. 10.1016/S0006-3223(96)00345-9PubMedCrossRef
44.
Endo Y, Mamiya S, Satoh M, Takahashi K, Harada T: Plasma beta-thromboglobulin and platelet factor 4 in patients with chronic renal failure and effect of hemodialysis. Tohoku J Exp Med 1981, 135: 349-358. 10.1620/tjem.135.349PubMedCrossRef
45.
Pitsilos S, Hunt J, Mohler ER, Prabhaker AM, Poncz M, Dawicki J, Khalapyan TZ, Wolfe ML, Fairman R, Mitchell M: Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters. Thromb Haemost 2003, 6: 1120.
46.
Yamanishi J, Sano H, Saito K, Furata Y, Fukuzaki H: Plasma concentrations of platelet-specific proteins in different stages of essential hypertension: interactions between platelet aggregation, blood lipids and age. Thromb Haemost 1985, 30: 539-543.
47.
Gjesdal K, Kjeldsen SE, Lande K, Westheim A, Aakesson I, Foss OP, Leren P, Eide IK: Blood platelet release correlates with serum lipids in 50 year old men with essential hypertension. Acta Med Scand Suppl 1986, 714: 125-128.PubMed
48.
Ferroni P, Basili S, Davi G: Platelet activation, inflammatory mediators and hypercholesterolemia. Curr Vasc Pharmacol 2003, 1: 157-169. 10.2174/1570161033476772PubMedCrossRef
49.
Paramo JA, Rocha E: Deep vein thrombosis and related platelet changes after total hip replacement. Haemostasis 1985, 15: 389-394.PubMed
50.
Kageyama K, Nakajima Y, Shibasaki M, Hashimoto S, Mizobe T: Increased platelet, leukocyte, and endothelial cell activity are associated with increased coagulability in patients after total knee arthroplasty. J Thromb Haemost 2007, 5: 738-745. 10.1111/j.1538-7836.2007.02443.xPubMedCrossRef
51.
Lubenow N, Hinz P, Thomaschewski S, Lietz T, Vogler M, Ladwig A, Junter M, Nauck M, Schellong S, Wander K: The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood 2010, 115: 1797-1803. 10.1182/blood-2009-07-231506PubMedCrossRef
52.
Cella G, Vittadello O, Gallucci V, Girolami A: The release of β-thromboglobulin and platelet factor 4 during extracorporeal circulation for open heart surgery. Eur J Clin Invest 1981, 11: 165-169. 10.1111/j.1365-2362.1981.tb01836.xPubMedCrossRef
53.
Cofrancesco E, Colombi M, Cristoforetti G, Pogliani EM: Selective PF4 release in vitro induced by heparin and related glycosaminoglycans (GAGs) - correlation with beta TG-release and platelet aggregation. Thromb Haemost 1984, 28: 105-107.
54.
Cella G, Meyers CJ, Prosdocimi M, Sasahara AA: Human platelet factor 4 and protamine sulphate interaction with glycosaminoglycans in the rabbit. Eur J Clin Invest 1987, 17: 548-554. 10.1111/j.1365-2362.1987.tb01156.xPubMedCrossRef
55.
Cella G, Scattola N, Cappellato MG, Girolami A, Strauss WE, Sasahara AA: Platelet factor 4 release induced by intravenous administration of heparin. Folia Haematol Int Mag Klin Morphol Blutforsch 1985, 112: 165-174.PubMed
56.
Cella G, Scattola N, Vio C, Stevanato F, Lavagnini T, Padovan D, Girolami A: Platelet factor 4 (PF4) and heparin released platelet factor 4 (HR-PF4) in diabetes mellitus. Effect of the duration of the disease. Folia Haematol Int Mag Klin Morphol Blutforsch 1986, 113: 646-654.PubMed
57.
Cortellaro M, Cofrancesco E, Vicari A, Boshcetti C, Della Volpe A, Moreo G, Pozza G, Polli EE: High heparin released platelet factor 4 in uncomplicated type 1 diabetes mellitus. Thromb Res 1990, 58: 571-576. 10.1016/0049-3848(90)90303-TPubMedCrossRef
58.
O'Brien JR, Etherington MD, Pashley M: Intra-platelet platelet factor 4(IP-PF4) and the heparin-mobilisable pool of PF4 in health and atherosclerosis. Thromb Res 1984, 51: 354-357.
59.
Cella G, Colby SI, Taylor AD, McCracken L, Parisi AF, Sasahara AA: Platelet factor 4 (PF4) and heparin-released platelet factor 4 (HR-PF4) in patients with cardiovascular disorders. Thromb Res 1983, 29: 499-509. 10.1016/0049-3848(83)90345-6PubMedCrossRef
60.
Sadayasu T, Nakashima Y, Yashiro A, Kawashima T, Kuroiwa A: Heparin-releasable platelet factor 4 in patients with coronary artery disease. Clin Cardiol 1991, 14: 725-729. 10.1002/clc.4960140906PubMedCrossRef
61.
Abe S, Maruyama I, Arima S, Yamaguchi H, Okino H, Hamasaki S, Nomoto K, Tahara M, Atsuchi Y: Increased heparin-releasable platelet factor 4 and D dimer in patients one month after the onset of acute myocardial infarction:persistent activation of platelets and the coagulation/fibrinolytic system. Int J Cardiol 1994, 47: S7-S12. 10.1016/0167-5273(94)90320-4PubMedCrossRef
62.
Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC: Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000, 96: 1703-1708.PubMed
63.
Suvarna S, Espinasse B, Qi R, Lubica R, Poncz M, Cines DB, Wiesner MR: Determinants of PF4/heparin immunogenicity. Blood 2007, 110: 4253-4260. 10.1182/blood-2007-08-105098PubMedCentralPubMedCrossRef
64.
Warkentin TE, Cook RJ, Marder VJ, Greinacher A: Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization. J Thromb Haemost 2010, 8: 504-512. 10.1111/j.1538-7836.2009.03735.xPubMedCrossRef
65.
Rauova L, Zhai L, Kowalska MA, Arepally GM, Cines DB, Poncz M: Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood 2006, 107: 2346-2353. 10.1182/blood-2005-08-3122PubMedCentralPubMedCrossRef
66.
Cines DB, Rauova L, Arepally G, Reilly MP, McKenzie SE, Sachais BS, Poncz M: Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/disassembly. J Clin Apher 2007, 22: 31-36. 10.1002/jca.20109PubMedCrossRef
67.
Bauer TL, Arepally GM, Konkle BA, Mestichelli B, Shapiro SS, Cines DB, Poncz M, McNulty S, Amiral J, Hauck WW: Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 1997, 95: 1242-1246. 10.1161/01.CIR.95.5.1242PubMedCrossRef
68.
Pouplard C, May MA, Iochmann S, Amiral J, Vissac AM, Marchand M, Gruel Y: Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin: Clinical implications for heparin-induced thrombocytopenia. Circulation 1999, 99: 2530-2536. 10.1161/01.CIR.99.19.2530PubMedCrossRef
69.
Trossaert M, Gaillard A, Commin PL, Amiral J, Vissac A, Fressinaud E: High incidence of anti-heparin/platelet factor 4 antibodies after cardiopulmonary bypass surgery. Br J Haematol 1998, 101: 653-655. 10.1046/j.1365-2141.1998.00750.xPubMedCrossRef
70.
Greinacher A, Farner B, Kroll H, Kohlmann T, Warkentin TE, Eichler P: Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. Thromb Haemost 2005, 94: 132-135.PubMed
71.
Jackson MR, Neilson WJ, Lary M, Baay P, Web K, Clagett GP: Delayed-onset heparin-induced thrombocytopenia and thrombosis after intraoperative heparin anticoagulation: four case reports. Vasc Endovasc Surg 2006, 40: 67-70. 10.1177/153857440604000109CrossRef
72.
Omran AS, Karim A, Ahmadi H, Yazdanifard P: Delayed-onset heparin-induced thrombocytopenia presenting with multiple arteriovenous thromboses: case report. J Med Case Reports 2007, 1: 131-136. 10.1186/1752-1947-1-131PubMedCentralCrossRef
73.
Rice L, Attisha WK, Drexler A, Francis JL: Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med 2002, 136: 210-215. 10.7326/0003-4819-136-3-200202050-00009PubMedCrossRef
74.
Shah MR, Spencer JP: Heparin-induced thrombocytopenia occurring after discontinuation of heparin. J Am Board Fam Pract 2003, 16: 148-150. 10.3122/jabfm.16.2.148PubMedCrossRef
75.
Smythe MA, Stephens JL, Mattson JC: Delayed-onset heparin-induced thrombocytopenia. Ann Emerg Med 2005, 45: 417-419. 10.1016/j.annemergmed.2004.08.005PubMedCrossRef
76.
Warkentin TE, Kelton JG: Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001, 135: 502-506. 10.7326/0003-4819-135-7-200110020-00009PubMedCrossRef
77.
Rauova L, Hirsch JD, Greene TK, Zhai L, Hayes VM, Kowalska MA: Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia. Blood 2010, 116: 5021-5031. 10.1182/blood-2010-03-276964PubMedCentralPubMedCrossRef
78.
Prechel MM, Jeske WP, Walenga JM: Physiological changes in membrane-expressed platelet factor 4: implications in heparin-induced thrombocytopenia. Thromb Res 2010, 125: e143-e148. 10.1016/j.thromres.2009.10.021PubMedCrossRef
79.
Poncz M, Rauova L, Cines DB: The role of surface PF4:glycosaminoglycan complexes in the pathogenesis of heparin-induced thrombocytopenia (HIT). Pathophysiol Haemost Thromb 2006, 35: 46-49. 10.1159/000093543PubMedCrossRef
80.
Cines DB, Tomaski A, Tannenbaum S: Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987, 316: 581-589. 10.1056/NEJM198703053161004PubMedCrossRef
81.
Singer RL, Mannion JD, Bauer TL, Armenti FR, Edie RN: Complications from heparin-induced thrombocytopenia in patients undergoing cardiopulmonary bypass. Chest 1993, 104: 1436-1440. 10.1378/chest.104.5.1436PubMedCrossRef
82.
Makhoul RG, Greenberg CS, McCann RL: Heparin-induced thrombocytopenia and thrombosis: a serious clinical problem and potential solution. J Vasc Surg 1986, 4: 522-528.PubMedCrossRef
83.
Boshkov LK, Warkentin TE, Hayward CP, Andrew M, Kelton JG: Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol 1993, 84: 322-328. 10.1111/j.1365-2141.1993.tb03072.xPubMedCrossRef
84.
Liu JC, Lewis BE, Steen LH, Grassman ED, Bakhos M, Blakeman B, Wrona L, Leya F: Patency of coronary artery bypass grafts in patients with heparin-induced thrombocytopenia. Am J Cardiol 2002, 89: 979-981. 10.1016/S0002-9149(02)02252-XPubMedCrossRef
85.
Tremblay DM, Harris PG, Gagnon AR, Cordoba C, Brutus JP, Nikolis A: Heparin-induced thrombocytopenia syndrome as a cause of flap failure: a report of two cases. J Plas Reconstr Aesthet Surg 2008, 61: 78-83. 10.1016/j.bjps.2006.12.007CrossRef
86.
Refaai MA, Warkentin TE, Axelson M, Matevosyan K, Sarade R: Delayed-onset heparin-induced thrombocytopenia, venous thromboembolism, and cerebral venous thrombosis: A consequence of heparin "flushes". Thromb Haemost 2007, 98: 1139-1140.PubMed
87.
Amiral J, Vissac AM: Role of heparin-dependent antigens in immune heparin-induced thrombocytopenia. In Heparin-Induced Thrombocytopenia. 4th edition. Edited by: Warkentin TE, Greinacher A. New York: Informa Healthcare; 2007:131-147.CrossRef
88.
Warkentin TE, Heddle NM: Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003, 2: 148-157.PubMed
89.
Cuker A, Arepally G, Crowther MA, Rice L, Datko F, Hook K, Propert KJ, Kuter DJ, Ortel TL, Konkle BA: The HIT expert probability (HEP) score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinoin. J Thromb Haemost 2010, 8: 2642-2650. 10.1111/j.1538-7836.2010.04059.xPubMedCrossRef
90.
Messmore HL, Fabbrini N, Bird ML, Choudhury AM, Cerejo M, Prechel M, Jeske WP, Siddiqui A, Theti I, Wehrmacher WH: Simple scoring system for early management of heparin-induced thrombocytopia. Clin Appl Thromb Hemost 2011, 17: 197-201. 10.1177/1076029610387126PubMedCrossRef
91.
Greinacher A, Alban S, Omer-Adam MA, Weitschies W, Warkentin TE: Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings. Thromb Res 2008, 122: 211-220. 10.1016/j.thromres.2007.11.007PubMedCrossRef
92.
Kelton JG, Smith JW, Warkentin TE, Hayward CPM, Demonne GA, Horsewood P: Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4. Blood 1994, 83: 3232-3239.PubMed
93.
Maccarana M, Lindahl U: Model of interaction between platelet factor 4 and heparin. Glycobiology 1993, 3: 271-277. 10.1093/glycob/3.3.271PubMedCrossRef
94.
Visentin G, Moghaddam M, Beery SE, McFarland JG, Aster RH: Heparin is not required for detection of antibodies associated with heparin-induced thrombocytopenia/thrombosis. J Lab Clin Med 2001, 138: 22-31. 10.1067/mlc.2001.115525PubMedCrossRef
95.
Horne MK, Alkins BR: Platelet binding of IgG from patients with heparin-induced thrombocytopenia. J Lab Clin Med 1996, 127: 435-442. 10.1016/S0022-2143(96)90060-8PubMedCrossRef
96.
Suvarna S, Arepally G: Optimization of a murine immunization model for study of PF4/heparin antibodies. J Thromb Haemost 2009, 7: 857-864. 10.1111/j.1538-7836.2009.03330.xPubMedCentralPubMedCrossRef
97.
Rauova L, Poncz M, McKenzie SE, Reilly MP, Arepally G, Weisel JW, Nagaswami C, Cines DB, Sachais BS: Ultralarge complexes of heparin and PF4 are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 2005, 105: 131-138. 10.1182/blood-2004-04-1544PubMedCrossRef
98.
Bock PE, Luscombe M, Marshall SE, Pepper DS, Holbrook JJ: The multiple complexes formed by the interaction of platelet factor 4 with heparin. Biochem J 1980, 191: 769-776.PubMedCentralPubMedCrossRef
99.
Greinacher A, Gopinadhan M, Gunther J, Omer-Adam MA, Strobel U, Warkentin TE, Papastravrou G, Weitschies W, Helm CA: Close approximation of two platelet factor 4 tetramers by charge neutralization forms the antigens recognized by HIT antibodies. Arterioscler Thromb Vasc Biol 2006, 26: 2386-2393. 10.1161/01.ATV.0000238350.89477.88PubMedCrossRef
100.
Mikhailov D, Young JC, Linhardt RJ, Mayo KH: Heparin dodecasaccharide binding to platelet factor-4 and growth related protein-α. Induction of a partially folded state and implications for heparin-induced thrombocytopenia. J Biol Chem 1999, 274: 25317-25329. 10.1074/jbc.274.36.25317PubMedCrossRef
101.
Mayo KH, Ilyina E, Roongta V, Dundas M, Joseph J, Lai DK, Malone T, Daly TJ: Heparin binding to platelet factor-4. An NMR and site-directed mutagenesis study: arginine residues are crucial for binding. Biochem J 1995, 312: 357-365.PubMedCentralPubMedCrossRef
102.
Martel M, Lee J, Wells PS: Risk for heparin-induced thrombocytopenia with unfractionated heparin and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005, 2710.
103.
Greinacher A, Eichler P, Lietz T, Warkentin TE: Replacement of unfractionated heparin by low-molecular-weight heparin for postorthopedic surgery antithrombotic prophylaxis lowers the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia. Blood 2005, 106: 2921-2922. 10.1182/blood-2005-05-1824PubMedCrossRef
104.
Warkentin TE: Heparin-induced thrombocytopeina: pathogenesis and management. Br J Haematol 2003, 121: 535-555. 10.1046/j.1365-2141.2003.04334.xPubMedCrossRef
105.
Motokawa S, Takafumi T, Maeda Y, Maeda K, Jiuchi Y, Yamaguchi T, Someya S, Shindo H, Migita K: IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis. BMC Musculoskelet Disord 2011, 12: 22-29. 10.1186/1471-2474-12-22PubMedCentralPubMedCrossRef
106.
Warkentin TE, Cook RJ, Marder VJ, Sheppard JI, Moore JC, Eriksson BI, Greinacher A, Kelton JG: Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005, 106: 3791-3796. 10.1182/blood-2005-05-1938PubMedCentralPubMedCrossRef
107.
Savi P, Chong BH, Griesmacher A, Gruel Y, Kelton JG, Warkentin TE, Eichler P, Meuleman D, Petitou M, Herault J-P: Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood 2005, 105: 139-144. 10.1182/blood-2004-05-2010PubMedCrossRef
108.
Warkentin TE: Fondaparinux: does it cause HIT? Can it treat HIT? Expert Rev Hematol 2010, 3: 567-581. 10.1586/ehm.10.54PubMedCrossRef
109.
Cauwenberghs S, Feijge MAH, Hageman G, Hoylearts M, Akkeman JN, Curvers J, Heemskerk JWM: Plasma ectonucleotidases prevent desensitization of purinergic receptors in stored platelets: importance for platelet activity during thrombus formation. Transfusion 2006, 46: 1018-1028. 10.1111/j.1537-2995.2006.00837.xPubMedCrossRef
110.
Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U: Anticoagluant activities of heparin oligosaccharides and their neutralization by platelet factor 4. Biochem J 1984, 218: 725-732.PubMedCentralPubMedCrossRef
111.
Padilla A, Gray E, Pepper DS, Barrowcliffe TW: Inhibition of thrombin generation by heparin and low molecular weight (LMW) heparins in the absence and presence of platelet factor 4 (PF4). Br J Haematol 1992, 82: 406-413. 10.1111/j.1365-2141.1992.tb06437.xPubMedCrossRef
112.
Levy JH, Cormack JG, Morales A: Heparin neutralization by recombinant platelet factor 4 and protamine. Anest Analg 1995, 81: 35-37.
113.
Kadidal VV, Mayo KH, Horne MK: Heparin-induced thrombocytopenia (HIT) due to heparin flushes: a report of three cases. J Intern Med 1999, 246: 325-329. 10.1046/j.1365-2796.1999.00527.xPubMedCrossRef
114.
Dai MS, Hsieh AT, Chao TY: Catastrophic heparin-induced thrombocytopenia/thrombosis syndrome related to the use of a Port-A-Cath in a breast cancer patient receiving chemotherapy. Support Care Cancer 2004, 12: 537-539.PubMedCrossRef
115.
Amiral J, Bridey F, Wolf M, Boyer-Neumann C, Fressinaud E, Vissac M, Peynaud-Debayle E, Dreyfus M, Meyer D: Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: A study of 44 cases. Thromb Haemost 1995, 73: 21-28.PubMed
116.
Jeske WP, Jay AM, Haas S, Walenga JM: Heparin-induced thrombocytopenic potential of GAG and non-GAG antithrombotic agents. Clin Appl Thromb Hemost 1999, 5(1):556-562.
117.
Capitanio AM, Niewiarowski S, Rucinski B, Tuszynski GP, Cierniewski CS, Kornecki E: Interaction of platelet factor 4 with human platelets. Biochim Biophys Acta 1985, 839: 161-173. 10.1016/0304-4165(85)90033-9PubMedCrossRef
118.
Pötschke C, Selleng S, Bröker BM, Greinacher A: Heparin-induced thrombocytopenia: further evidence for a unique immune response. Blood 2012, 120: 4238-4245. 10.1182/blood-2012-04-419424PubMedCrossRef
119.
120.
Krauel K, Potschke C, Weber C, Kessler W, Furll B, Ittermann T, Maier S, Hammerschmidt S, Broker BM, Greinacher A: Platelet factor 4 binds to bacteria inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood 2011, 117: 1370-1378. 10.1182/blood-2010-08-301424PubMedCrossRef
121.
Krauel K, Weber C, Brandt S, Zähringer U, Mamat U, Greinacher A, Hammerschmidt S: Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes. Blood 2012, 120: 3345-3352. 10.1182/blood-2012-06-434985PubMedCrossRef
122.
Clemetson KJ: Platelets and pathogens. Cell Mol Life Sci 2010, 67: 495-498. 10.1007/s00018-009-0204-2PubMedCrossRef
123.
Levy O: Antimicrobial proteins and peptides of blood: templates for novel antimicrobial agents. Blood 2000, 96: 2664-2672.PubMed
124.
125.
Yeaman MR, Yount NY, Waring AJ, Gank KD, Kupferwasser D, Wiese R, Bayer AS, Welch WH: Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins. Biochem Biophys Acta 2007, 1768: 609-619. 10.1016/j.bbamem.2006.11.010PubMedCentralPubMedCrossRef
126.
Eliasson M, Egesten A: Antibacterial chemokines - actors in both innate and adaptive immunity. Contrib Microbiol 2008, 15: 101-117.PubMedCrossRef
127.
McMorran BJ, Wieczorski L, Drysdale KE, Chan JA, Huang HM, Smith C, Mitiku C, Beeson JG, Burgio G, Foote SJ: Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum . Science 2012, 338: 1348-1351. 10.1126/science.1228892PubMedCrossRef
128.
Love M, Millholland MG, Mishra S, Kulkarni S, Freeman KB, Pan W, Kavash RW, Costanzo MJ, Jo H, Daly TM: Platelet factor 4 activity against P . falciparum and its translation to nonpeptidic mimics as antimalarials. Cell Host Microbe 2012, 12: 815-823. 10.1016/j.chom.2012.10.017PubMedCentralPubMedCrossRef
129.
Yeaman MR, Yount NY: Unifying themes in host defence effector polypeptides. Nat Rev Microbiol 2007, 5: 727-740. 10.1038/nrmicro1744PubMedCrossRef
130.
Arepally GM, Hursting MJ: Platelet factor 4/heparin antibody (IgG/M/A) in healthy subjects: a literature analysis of commercial immunoassay results. J Thromb Thrombolysis 2008, 26: 55-61. 10.1007/s11239-008-0217-yPubMedCentralPubMedCrossRef
131.
Hursting MJ, Pai PJ, McCracken JE, Hwang F, Suvarna S, Lokhnygina Y, Bandarenko N, Arepally GM: Platelet factor 4/heparin antibodies in blood bank donors. Am J Clin Pathol 2010, 134: 774-780. 10.1309/AJCPG0MNR5NGKNFXPubMedCentralPubMedCrossRef
132.
Greinacher A, Holtfreter B, Krauel K, Gatke D, Weber C, Itterman T, Hammerschmidt S, Kocher T: Association of natural anti-platelet factor 4/heparin antibodies with periodontal disease. Blood 2011, 118: 1395-1401. 10.1182/blood-2011-03-342857PubMedCrossRef
133.
Warkentin TE, Makris M, Jay AM, Kelton JG: A spontaneous prothrombotic disorder resembling heparin-induced thrombocytopenia. Am J Med 2008, 121: 632-636. 10.1016/j.amjmed.2008.03.012PubMedCrossRef
134.
Ahmed A, Al-Mondhiry H, Milling TJ Jr, Campbell D: Heparin-induced thrombocytopenia associated with massive intracardiac thrombosis: a case report. Case Report Hematol 2012.
135.
Kerendi F, Thourani VH, Puskas JD, Kilgo PD, Osgood M, Guyton RA, Lattouf OM: Impact of heparin-induced thrombocytopenia on postoperative outcomes after cardiac surgery. Ann Thorac Surg 2007, 84: 1548-1555. 10.1016/j.athoracsur.2007.05.080PubMedCrossRef
136.
Olah Z, Kerenyi A, Kappelmayer J, Schlammadinger A, Razso K, Boda Z: Rapid-onset heparin-induced thrombocytopenia. Platelets 2012, 23: 495-498. 10.3109/09537104.2011.650245PubMedCrossRef
137.
138.
139.
Bachmann MF, Hengartner H, Zinkernagel RM: T helper cell-independent neutralizing B cell response against vesicular stomatitis virus: role of antigen patterns in B cell induction. Eur J Immunol 1995, 25: 3445-3451. 10.1002/eji.1830251236PubMedCrossRef
140.
Medzhitov R, Janeway CA: Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997, 91: 295-298. 10.1016/S0092-8674(00)80412-2PubMedCrossRef
141.
Mutwiri G, Gerdts V, Lopez M, Babuik LA: Innate immunity and new adjuvants. Rev Sci Tech 2007, 26: 147-156.PubMed
142.
Pone EJ, Zan H, Zhang J, Al-Qahtani A, Xu Z, Casali P: Toll-like receptors and B-cell receptors synergize to induce immunoglobulin class switch DNA recombination: relevance to microbial antibody response. Crit Rev Immunol 2012, 30: 1-29. 10.1146/annurev-immunol-100311-102839CrossRef
143.
144.
Amiral J, Marfaing-Koka M, Wolf M, Alessi MC, Tardy B, Boyer-Neumann C, Vissac AM, Fressinaud E, Poncz M, Meyer D: Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia. Blood 1996, 88: 410-416.PubMed
145.
Chudasama SL, Espinasse B, Hwang F, Qi R, Joglekar M, Afonina G, Wiesner MR, Welsby IJ, Ortel T, Arepally GM: Heparin modifies the immunogenicity of positively-charged proteins. Blood 2010, 116: 6046-6053. 10.1182/blood-2010-06-292938PubMedCentralPubMedCrossRef
146.
Amiral JJ, Vissac AM: Pseudo-HIT associated with antibodies to protamine sulfate. J Thromb Haemost 2009, 5(2):697.
147.
Xu W, Santini PA, Matthews AJ, Chiu A, Plebain A, He B, Chen K, Cerutti A: Viral double-sranded RNA triggers Ig Class switching by activating upper respiratory mucosa B cells through an innate TLR3 pathway involving BAFF. J Immunol 2008, 181: 276-287.PubMedCentralPubMedCrossRef
148.
Prechel MM, Walenga JM: Heparin-induced thrombocytopenia: an update. Semin Thromb Hemost 2012, 38: 483-496.PubMedCrossRef
149.
Cines DB, McCrae KR, Zheng XL, Sachais BS, Prak EL, Siegel DL: Antigen and substrate withdrawal in the management of autoimmune thrombotic disorders. Blood 2012, 120: 4134-4142. 10.1182/blood-2012-06-389445PubMedCentralPubMedCrossRef
150.
Tanhehco Y, Rux AH, Sachais BS: Low-density lipoprotein apheresis reduces platelet factor 4 on the surface of platelets: a possible protective mechanism against heparin-induced thrombocytopenia and thrombosis. Transfusion 2011, 51: 1022-1029. 10.1111/j.1537-2995.2010.02911.xPubMedCentralPubMedCrossRef
151.
Sachais BS, Litvinov RI, Yarovoi SV, Rauova L, Hinds JL, Rux AH, Arepally GM, Poncz M, Cuker A, Weisel JW: Dynamic antibody-binding properties in the pathogenesis of HIT. J Thromb Haemost 2012, 120: 1137-1142.
152.
Sachais BS, Rux AH, Cines DB, Yarovoi SV, Garner LI, Watson SP, Hinds JL, Rux JJ: Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia. Blood 2012, 119: 5955-5962. 10.1182/blood-2012-01-406801PubMedCentralPubMedCrossRef
153.
Aster RH: "Inactivating" PF4: a new approach to HIT treatment? Blood 2012, 119: 5951-5952. 10.1182/blood-2012-04-422535PubMedCrossRef
154.
Fryer A, Huang Y, Rao G, Jacoby D, Mancilla E, Whorton R, Piantadosi CA, Kennedy T, Hoidal J: Selective O-desulfation produces nonanticoagulant heparin that retains pharmacological activity in the lung. J Pharm Exp Therapeut 1997, 282: 208-219.
155.
Rao NV, Argyle B, Xu X, Reynolds PR, Walenga JM, Prechel MM, Prestwich GD, MacArthur RB, Walters BB, Hoidal JR: Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands. Am J Physiol Cell Physiol 2010, 299: C97-C110. 10.1152/ajpcell.00009.2010PubMedCrossRef
156.
Krauel K, Hackbarth C, Fürll B, Greinacher A: Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies. Blood 2012, 119: 1248-1255. 10.1182/blood-2011-05-353391PubMedCrossRef
157.
Joglekar MF, Quintana Diaz PM, Marcus S, Qi R, Espinasse B, Wiesner MR, Pempe E, Liu J, Monroe DM, Arepally GM: Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH). Thromb Haemost 2012, 107: 717-725. 10.1160/TH11-11-0795PubMedCentralPubMedCrossRef
158.
Barrowcliffe TW, Merton RE, Havercroft SJ, Thunberg L, Lindahl U, Thomas DP: Low-affinity heparin potentiates the action of high-affinity heparin oligosaccharides. Thromb Res 1984, 34: 125-133. 10.1016/0049-3848(84)90069-0PubMedCrossRef
159.
Greinacher A: Taking advantage of the non-anticoagulant effects of heparin. Blood 2012, 107: 717.
160.
Barry WH, Kennedy TP: Heparins with reduced anti-coagulant activity reduce myocardial reperfusion injury. Rec Pat Cardiovasc Drug Discov 2011, 6: 148-157. 10.2174/157489011795933855CrossRef
Metadata
Title
Emphasis on the Role of PF4 in the Incidence, Pathophysiology and Treatment of Heparin Induced Thrombocytopenia
Authors
Margaret M Prechel
Jeanine M Walenga
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Thrombosis Journal / Issue 1/2013
Electronic ISSN: 1477-9560
DOI
https://doi.org/10.1186/1477-9560-11-7

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