Download PDF
Thromb Haemost 2020; 120(07): 1096-1107
DOI: 10.1055/s-0040-1712957
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Comparative Analysis of a French Prospective Series of 144 Patients with Heparin-Induced Thrombocytopenia (FRIGTIH) and the Literature

Yves Gruel
1   EA 7501, GICC, Université de Tours, Tours, France
2   Service d'Hématologie-Hémostase, CHRU Tours, Tours, France
,
Caroline Vayne
1   EA 7501, GICC, Université de Tours, Tours, France
2   Service d'Hématologie-Hémostase, CHRU Tours, Tours, France
,
Jérôme Rollin
1   EA 7501, GICC, Université de Tours, Tours, France
2   Service d'Hématologie-Hémostase, CHRU Tours, Tours, France
,
Pierre Weber
2   Service d'Hématologie-Hémostase, CHRU Tours, Tours, France
,
Dorothée Faille
3   Laboratoire d'Hématologie, Hôpital Bichat, Paris, France
,
Anne Bauters
4   Département d'Hémostase et Transfusion, CHU Lille, Lille, France
,
Laurent Macchi
5   Laboratoire d'Hématologie, CHRU Angers, Angers, France
,
Martine Alhenc-Gelas
6   Laboratoire d'Hématologie, HEGP Paris, Paris, France
,
Aurélien Lebreton 
7   Laboratoire d'Hématologie, CHRU Clermont-Ferrand, Clermont-Ferrand, France
,
Emmanuel De Maistre
8   Laboratoire d'Hématologie, CHRU Dijon, Dijon, France
,
Sophie Voisin
9   Laboratoire d'Hématologie, CHRU Toulouse, Toulouse, France
,
Valérie Gouilleux-Gruart
1   EA 7501, GICC, Université de Tours, Tours, France
10   Laboratoire d'Immunologie, CHRU Tours, Tours, France
,
Julien Perrin
11   Laboratoire d'Hématologie, CHRU Nancy, Nancy, France
,
Brigitte Tardy-Poncet
12   Laboratoire d'Hématologie, CHRU Saint-Etienne, Saint-Etienne, France
,
Ismail Elalamy
13   Laboratoire d'Hématologie, Hôpital Tenon, Paris, France
,
Cécile Lavenu-Bombled
14   Laboratoire d'Hématologie, Hôpital Henri Mondor, Créteil, France
,
Christine Mouton
15   Laboratoire d'Hématologie, CHRU Bordeaux, Bordeaux, France
,
Christine Biron
16   Laboratoire d'Hématologie, CHRU Montpellier, Montpellier, France
,
Catherine Ternisien
17   Laboratoire d'Hématologie, CHRU Nantes, Nantes, France
,
Fabienne Nedelec-Gac
18   Laboratoire d'Hématologie, CHRU Rennes, Rennes, France
,
Jérôme Duchemin
19   Laboratoire d'Hématologie, CHRU Poitiers, Poitiers, France
,
Emmanuelle De Raucourt
20   Laboratoire d'Hématologie, Hopital Beaujon, Clichy, France
,
Isabelle Gouin-Thibault
21   Laboratoire d'Hématologie, Hopital Cochin, Paris, France
,
Lucia Rugeri
22   Laboratoire d'Hématologie, CHRU Lyon, Lyon, France
,
Bernard Tardy
23   INSERM CIC 1408, Unité de soins intensifs, CHRU Saint-Etienne, Saint-Etienne, France
,
Bruno Giraudeau
24   INSERM CIC, CHRU Tours, Tours, France
,
Théodora Bejan-Angoulvant
1   EA 7501, GICC, Université de Tours, Tours, France
25   Département de Pharmacologie Médicale, CHRU Tours, Tours, France
,
Claire Pouplard
1   EA 7501, GICC, Université de Tours, Tours, France
2   Service d'Hématologie-Hémostase, CHRU Tours, Tours, France
› Author Affiliations Funding The project FRIGTIH was supported by a PHRC grant (PHRN09-YG/FRIGTIH) and by the IRTH (Institut pour la Recherche sur la Thrombose et l'Hémostase).
Further Information

Publication History

09 January 2020

23 April 2020

Publication Date:
22 June 2020 (online)

Also available at
    Permissions and Reprints

Abstract

Background Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature.

Methods The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis.

Results Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries, p = 0.042) with a shorter recovery time (median = 3 vs. 5 days, p < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis, p = 0.03).

Conclusion This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.

Keywords

heparin - thrombocytopenia - thrombosis

Authors' Contributions

Y.G. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Y.G., B.G., and C.P. designed the research, C.V., J.R., and P.V. performed the research, Y.G., D.F., A.B., L.A., M.A.G., A.L., E.D.M., S.V., B.T., B.T.P., J.P., I.E., S.D., C.L.B., C.M., M.W., C.B., C.T., F.N., P.G., J.D., L.R., E.D.R., I.G.T., and C.P. provided patients samples and clinical follow-up. Y.G., C.V., J.R., P.V., B.G., T.B.A., and C.P. analyzed the data. Y.G. and C.P. supervised the study and wrote the paper.


Supplementary Material

 

  • References

  • 1 Amiral J, Bridey F, Dreyfus M. , et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992; 68 (01) 95-96
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101 (05) 502-507
    CrossrefPubMedSearch in Google Scholar
  • 3 Rollin J, Pouplard C, Sung HC. , et al. Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2. Blood 2015; 125 (15) 2397-2404
    CrossrefPubMedSearch in Google Scholar
  • 4 Pamela S, Anna Maria L, Elena D. , et al. Heparin-induced thrombocytopenia: the role of platelets genetic polymorphisms. Platelets 2013; 24 (05) 362-368
    CrossrefPubMedSearch in Google Scholar
  • 5 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67 (01) 27-30
    CrossrefPubMedSearch in Google Scholar
  • 6 Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH. ; scientific and standardization committee of the international society on thrombosis and haemostasis. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost 2011; 9 (12) 2498-2500
    CrossrefPubMedSearch in Google Scholar
  • 7 Boshkov LK, Warkentin TE, Hayward CPM, Andrew M, Kelton JG. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol 1993; 84 (02) 322-328
    CrossrefPubMedSearch in Google Scholar
  • 8 Gruel Y, Pouplard C, Nguyen P. , et al; French Heparin-Induced Thrombocytopenia Study Group. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol 2003; 121 (05) 786-792
    CrossrefPubMedSearch in Google Scholar
  • 9 Tardy B, Lecompte T, Boelhen F. , et al; GEHT-HIT Study Group. Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood 2006; 108 (05) 1492-1496
    PubMedSearch in Google Scholar
  • 10 Pouplard C, May MA, Iochmann S. , et al. 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 (19) 2530-2536
    CrossrefPubMedSearch in Google Scholar
  • 11 Walls JT, Curtis JJ, Silver D, Boley TM, Schmaltz RA, Nawarawong W. Heparin-induced thrombocytopenia in open heart surgical patients: sequelae of late recognition. Ann Thorac Surg 1992; 53 (05) 787-791
    CrossrefPubMedSearch in Google Scholar
  • 12 Look KA, Sahud M, Flaherty S, Zehnder JL. Heparin-induced platelet aggregation vs platelet factor 4 enzyme-linked immunosorbent assay in the diagnosis of heparin-induced thrombocytopenia-thrombosis. Am J Clin Pathol 1997; 108 (01) 78-82
    CrossrefPubMedSearch in Google Scholar
  • 13 Wallis DE, Quintos R, Wehrmacher W, Messmore H. Safety of warfarin anticoagulation in patients with heparin-induced thrombocytopenia. Chest 1999; 116 (05) 1333-1338
    CrossrefPubMedSearch in Google Scholar
  • 14 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344 (17) 1286-1292
    CrossrefPubMedSearch in Google Scholar
  • 15 Lindhoff-Last E, Gerdsen F, Ackermann H, Bauersachs R. Determination of heparin-platelet factor 4-IgG antibodies improves diagnosis of heparin-induced thrombocytopenia. Br J Haematol 2001; 113 (04) 886-890
    CrossrefPubMedSearch in Google Scholar
  • 16 Fabris F, Luzzatto G, Soini B. , et al. Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia. J Intern Med 2002; 252 (02) 149-154
    CrossrefPubMedSearch in Google Scholar
  • 17 Lillo-Le Louët A, Boutouyrie P, Alhenc-Gelas M. , et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004; 2 (11) 1882-1888
    CrossrefPubMedSearch in Google Scholar
  • 18 Pouplard C, Gueret P, Fouassier M. , et al. Prospective evaluation of the '4Ts' score and particle gel immunoassay specific to heparin/PF4 for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2007; 5 (07) 1373-1379
    CrossrefPubMedSearch in Google Scholar
  • 19 Thielmann M, Bunschkowski M, Tossios P. , et al. Perioperative thrombocytopenia in cardiac surgical patients - incidence of heparin-induced thrombocytopenia, morbidities and mortality. Eur J Cardiothorac Surg 2010; 37 (06) 1391-1395
    CrossrefPubMedSearch in Google Scholar
  • 20 Trehel-Tursis V, Louvain-Quintard V, Zarrouki Y, Imbert A, Doubine S, Stéphan F. Clinical and biologic features of patients suspected or confirmed to have heparin-induced thrombocytopenia in a cardiothoracic surgical ICU. Chest 2012; 142 (04) 837-844
    CrossrefPubMedSearch in Google Scholar
  • 21 Cuker A, Rux AH, Hinds JL. , et al. Novel diagnostic assays for heparin-induced thrombocytopenia. Blood 2013; 121 (18) 3727-3732
    CrossrefPubMedSearch in Google Scholar
  • 22 Leroux D, Hezard N, Lebreton A. , et al. Prospective evaluation of a rapid nanoparticle-based lateral flow immunoassay (STic Expert® HIT) for the diagnosis of heparin-induced thrombocytopenia. Br J Haematol 2014; 166 (05) 774-782
    CrossrefPubMedSearch in Google Scholar
  • 23 Joseph L, Casanegra AI, Dhariwal M. , et al. Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia. J Thromb Haemost 2014; 12 (07) 1044-1053
    CrossrefPubMedSearch in Google Scholar
  • 24 Linkins LA, Bates SM, Lee AY, Heddle NM, Wang G, Warkentin TE. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood 2015; 126 (05) 597-603
    PubMedSearch in Google Scholar
  • 25 Bayat M, Macedo FY, Ansari AS, Bracey AW, Akinyele S, Salazar M. Evaluation of clinical and laboratory data for early diagnosis of heparin-induced thrombocytopenia. Am J Health Syst Pharm 2015; 72 (19) 1649-1655
    CrossrefPubMedSearch in Google Scholar
  • 26 Vianello F, Sambado L, Scarparo P. , et al. Comparison of three different immunoassays in the diagnosis of heparin-induced thrombocytopenia. Clin Chem Lab Med 2015; 53 (02) 257-263
    PubMedSearch in Google Scholar
  • 27 Warkentin TE, Sheppard JI, Linkins LA, Arnold DM, Nazy I. Performance characteristics of an automated latex immunoturbidimetric assay [HemosIL® HIT-Ab(PF4-H)] for the diagnosis of immune heparin-induced thrombocytopenia. Thromb Res 2017; 153: 108-117
    CrossrefPubMedSearch in Google Scholar
  • 28 Ritchie BM, Connors JM, Sylvester KW. Comparison of an IgG-specific enzyme-linked immunosorbent assay cutoff of 0.4 versus 0.8 and 1.0 optical density units for heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2017; 23 (03) 282-286
    CrossrefPubMedSearch in Google Scholar
  • 29 Arangalage D, Lepage L, Faille D. , et al. Presentation, management and outcome of heparin-induced thrombocytopenia after valvular heart surgery. Eur J Cardiothorac Surg 2016; 50 (06) 1132-1138
    CrossrefPubMedSearch in Google Scholar
  • 30 Berry C, Tcherniantchouk O, Ley EJ. , et al. Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. J Am Coll Surg 2011; 213 (01) 10-17
    CrossrefPubMedSearch in Google Scholar
  • 31 Kelton JG, Warkentin TE. Heparin-induced thrombocytopenia: a historical perspective. Blood 2008; 112 (07) 2607-2616
    PubMedSearch in Google Scholar
  • 32 Cuker A, Arepally GM, Chong BH. , et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv 2018; 2 (22) 3360-3392
    CrossrefPubMedSearch in Google Scholar
  • 33 Bramer WM, Rethlefsen ML, Kleijnen J, Franco OH. Optimal database combinations for literature searches in systematic reviews: a prospective exploratory study. Syst Rev 2017; 6 (01) 245
    CrossrefPubMedSearch in Google Scholar
  • 34 Warkentin TE, Levine MN, Hirsh J. , et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332 (20) 1330-1335
    CrossrefPubMedSearch in Google Scholar
  • 35 Lindhoff-Last E, Nakov R, Misselwitz F, Breddin HK, Bauersachs R. Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight heparin. Br J Haematol 2002; 118 (04) 1137-1142
    CrossrefPubMedSearch in Google Scholar
  • 36 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106 (08) 2710-2715
    PubMedSearch in Google Scholar
  • 37 Bloemen A, Testroote MJ, Janssen-Heijnen ML, Janzing HM. Incidence and diagnosis of heparin-induced thrombocytopenia (HIT) in patients with traumatic injuries treated with unfractioned or low-molecular-weight heparin: a literature review. Injury 2012; 43 (05) 548-552
    CrossrefPubMedSearch in Google Scholar
  • 38 Pishko AM, Cuker A. Heparin-induced thrombocytopenia in cardiac surgery patients. Semin Thromb Hemost 2017; 43 (07) 691-698
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 Aguayo E, Sanaiha Y, Seo YJ. , et al. Heparin-induced thrombocytopenia in cardiac surgery: incidence, costs, and duration of stay. Surgery 2018; 164 (06) 1377-1381
    CrossrefPubMedSearch in Google Scholar
  • 40 Craik JD, Cobb AG. Heparin-induced thrombocytopenia following hip and knee arthroplasty. Br J Haematol 2013; 161 (02) 255-261
    CrossrefPubMedSearch in Google Scholar
  • 41 Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96 (05) 1703-1708
    CrossrefPubMedSearch in Google Scholar
  • 42 Kato S, Takahashi K, Ayabe K. , et al. Heparin-induced thrombocytopenia: analysis of risk factors in medical inpatients. Br J Haematol 2011; 154 (03) 373-377
    CrossrefPubMedSearch in Google Scholar
  • 43 Linkins LA, Dans AL, Moores LK. , et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e495S-e530S
    CrossrefPubMedSearch in Google Scholar
  • 44 Watson H, Davidson S, Keeling D. ; Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol 2012; 159 (05) 528-540
    PubMedSearch in Google Scholar
  • 45 Greinacher A, Farner B, Kroll H, Kohlmann T, Warkentin TE, Eichler P. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 2005; 94 (01) 132-135
    Thieme ConnectPubMedSearch in Google Scholar
  • 46 Gruel Y, Pouplard C. Post-operative platelet count profile: the most reliable tool for identifying patients with true heparin-induced thrombocytopenia after cardiac surgery. J Thromb Haemost 2010; 8 (01) 27-29
    CrossrefPubMedSearch in Google Scholar
  • 47 Tardy-Poncet B, Wolf M, Lasne D. , et al. Danaparoid cross-reactivity with heparin-induced thrombocytopenia antibodies: report of 12 cases. Intensive Care Med 2009; 35 (08) 1449-1453
    CrossrefPubMedSearch in Google Scholar
  • 48 Tardy-Poncet B, Nguyen P, Thiranos JC. , et al. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care 2015; 19: 396
    CrossrefPubMedSearch in Google Scholar
  • 49 Carlsson LE, Santoso S, Baurichter G. , et al. Heparin-induced thrombocytopenia: new insights into the impact of the FcgammaRIIa-R-H131 polymorphism. Blood 1998; 92 (05) 1526-1531
    CrossrefPubMedSearch in Google Scholar