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Table.  
Demographics of and Outcomes in Trauma Patients With and Without HIT
Demographics of and Outcomes in Trauma Patients With and Without HIT
1.
Rauova  L, Poncz  M, McKenzie  SE,  et al.  Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia.  Blood. 2005;105(1):131-138.PubMedGoogle ScholarCrossref
2.
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.  Injury. 2012;43(5):548-552.PubMedGoogle ScholarCrossref
3.
Krauel  K, Pötschke  C, Weber  C,  et al.  Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia.  Blood. 2011;117(4):1370-1378.PubMedGoogle ScholarCrossref
4.
Austin  PC.  Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies.  Pharm Stat. 2011;10(2):150-161.PubMedGoogle ScholarCrossref
5.
Linkins  LA, Dans  AL, Moores  LK, Bona  R, Davidson  BL, Schulman  S, Crowther  M.  Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.  Chest. 2012;141(2)(suppl):e495S-e530S.PubMedGoogle ScholarCrossref
6.
Jay  RM, Warkentin  TE.  Fatal heparin-induced thrombocytopenia (HIT) during warfarin thromboprophylaxis following orthopedic surgery.  J Thromb Haemost. 2008;6(9):1598-1600.PubMedGoogle ScholarCrossref
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    Research Letter
    October 2018

    Association of Heparin-Induced Thrombocytopenia With Bacterial Infection in Trauma Patients

    Author Affiliations
    • 1Division of Trauma, Burns, and Surgical Critical Care, Department of Surgery, University of California, Irvine, Medical Center, Orange
    JAMA Surg. 2018;153(10):964-965. doi:10.1001/jamasurg.2018.1652

    Heparin-induced thrombocytopenia (HIT) is a rare complication that has been reported to occur in 0.36% of trauma patients and is caused by antibody formation to complexes between heparin and platelet-factor 4 (PF4), leading to platelet activation and subsequent thrombosis.1,2 An earlier report demonstrated that PF4 can bind to bacteria, inducing an autoimmune response similar to the major antigen in HIT.3 We hypothesized that trauma patients with HIT have a higher incidence of bacterial infection during their hospitalization compared with patients without HIT. In addition, we provide a descriptive analysis of HIT in trauma patients.

    Methods

    This study was approved by the institutional review board of the University of California, Irvine. The need for informed consent was waived by the institutional review board of the University of California, Irvine. We queried the National Trauma Data Bank from 2008 through 2015 to identify patients with HIT using the International Classification of Diseases, Ninth Revision (289.84). Because of the observed imbalance in the sample size, we used a 1:2 ratio propensity score model to match patients with HIT to those without HIT using demographic and injury profile parameters (Table). Our analysis included only cases that were within 0.001 of the estimated logit.4 If a patient with HIT did not have a close match, they were excluded.

    A Student t test was used to compare continuous variables, and the χ2 test was used to compare categorical variables for bivariate analysis. The primary outcomes were incidence of bacterial infection, urinary tract infection, and pneumonia. Bacterial infection was defined as gastrointestinal tract bacterial infection or bacteremia. Analysis of outcomes was performed using a logistic regression model and reported with odds ratios (ORs) and 95% CIs; the statistical significance level was set at a 2-sided P < .05.

    Results

    We identified 120 patients with HIT (69 men and 51 women; annual incidence, 0.0037%; 120 of 3 243 243 individuals). There were 16 unmatched patients in our model, leaving 104 with HIT and 208 without HIT for analysis. Patients with HIT had a median age of 57.5 years (interquartile range, 42.5-72.5 years) and median injury severity score of 10 (interquartile range, 1-19), and most had experienced blunt trauma (93 of 104 patients [89.4%]). Mortality rate was similar in both groups (patients with HIT, 9 of 104 [8.7%]; patients without HIT, 25 of 208 [12.4%]; P = .33). Patients with HIT had greater odds of in-hospital bacterial infection (OR, 23.36; 95% CI, 7.99-68.25; P < .001), urinary tract infection (OR, 10.80; 95% CI, 2.32-50.25; P = .002), and pneumonia (OR, 5.58; 95% CI, 2.62-11.89; P < .001). The most common infective organism was Streptococcus species (6 of 33 patients with an organism identified [18%]).

    Discussion

    Heparin-induced thrombocytopenia is a prothrombotic complication caused by complexes of PF4 bound to heparin, which launches a cascade of events leading to thrombocytopenia and paradoxical platelet activation.1 Not all patients that develop anti-PF4/heparin antibodies develop clinical HIT.5 In addition, cases of spontaneous HIT have been reported without any exposure to heparin products, which suggests that an antigen distinct from heparin may induce anti-PF4/heparin antibodies.6 These spontaneous HIT cases have been associated with bacterial infection. Krauel et al3 demonstrated that certain bacteria can induce anti-PF4/heparin antibodies in a mouse model after PF4 binds to bacteria. Our study demonstrates that this may also occur in trauma patients, because patients with HIT were more likely to have a bacterial infection, urinary tract infection, or pneumonia during their hospitalization than were patients without HIT.

    Limitations to our study include those inherent to retrospective databases leading to reporting bias. As such, the true incidence of HIT may be several-fold higher than that reported here. The temporal relation of HIT and bacterial infection is not defined in the National Trauma Data Bank. It is therefore not possible to know which patients developed HIT after a bacterial infection, thus limiting us from drawing final conclusions.

    Conclusions

    The incidence of HIT among trauma patients may be lower than previously reported. Our study found an association between HIT and bacterial infection in trauma patients. A multicenter effort may prospectively validate our findings and determine whether the presence of bacterial infection can be used as an adjunct to current risk assessment tools for HIT.

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    Article Information

    Accepted for Publication: March 25, 2018.

    Corresponding Author: Areg Grigorian, MD, Division of Trauma, Burns, and Surgical Critical Care, Department of Surgery, University of California, Irvine, Medical Center, 333 The City Blvd W, Ste 1600, Orange, CA 92868 (agrigori@uci.edu).

    Published Online: June 27, 2018. doi:10.1001/jamasurg.2018.1652

    Author Contributions: Drs Grigorian and Nahmias had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Grigorian, Nahmias.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Grigorian.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Grigorian.

    Obtained funding: Lekawa.

    Administrative, technical, or material support: Lekawa, Nahmias.

    Supervision: Schubl, Joe, Lekawa, Nahmias.

    Conflict of Interest Disclosures: None reported.

    Meeting Presentation: This paper was presented at the 89th Annual Meeting of the Pacific Coast Surgical Association; February 17, 2018; Napa, California.

    References
    1.
    Rauova  L, Poncz  M, McKenzie  SE,  et al.  Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia.  Blood. 2005;105(1):131-138.PubMedGoogle ScholarCrossref
    2.
    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.  Injury. 2012;43(5):548-552.PubMedGoogle ScholarCrossref
    3.
    Krauel  K, Pötschke  C, Weber  C,  et al.  Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia.  Blood. 2011;117(4):1370-1378.PubMedGoogle ScholarCrossref
    4.
    Austin  PC.  Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies.  Pharm Stat. 2011;10(2):150-161.PubMedGoogle ScholarCrossref
    5.
    Linkins  LA, Dans  AL, Moores  LK, Bona  R, Davidson  BL, Schulman  S, Crowther  M.  Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.  Chest. 2012;141(2)(suppl):e495S-e530S.PubMedGoogle ScholarCrossref
    6.
    Jay  RM, Warkentin  TE.  Fatal heparin-induced thrombocytopenia (HIT) during warfarin thromboprophylaxis following orthopedic surgery.  J Thromb Haemost. 2008;6(9):1598-1600.PubMedGoogle ScholarCrossref
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