A case of heparin-induced thrombocytopenia (HIT) triggered by methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia
© The Author(s) 2016
Received: 9 May 2016
Accepted: 21 October 2016
Published: 8 December 2016
Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening complication of heparin anticoagulation. Recently, infection has been implicated in the development of HIT.
We herein present a case of HIT diagnosed by a repeated functional assay. A 67-year-old female with diabetic nephropathy was admitted to our hospital with hypoxemia caused by volume overload. Due to her diuretic-resistant condition, dialysis therapy anticoagulated with low-molecular-weight heparin (LMWH) was initiated. The coagulation of the whole extracorporeal blood circuit occurred on day 13. Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia derived from a catheter-related bloodstream infection (CRBSI) was detected on day 15. Based on the hypercoagulable state due to infection, we increased the heparin dose during dialysis therapy; however, coagulation of the dialysis circuit persisted. We suspected HIT on day 17 in spite of a normal platelet count and performed a functional assay, which was negative. Since thrombocytopenia subsequently developed, the functional assay was repeated and a positive result was obtained on day 27, which definitely established a diagnosis of HIT.
Based on the present clinical course, MSSA bacteremia appears to have contributed to the pathogenesis of HIT.
KeywordsHIT Functional assay Antigen assay Hypercoagulable state MSSA bacteremia
Heparin-induced thrombocytopenia (HIT) is a potentially critical complication of heparin therapy which results in thromboembolism. The HIT antibody test is frequently used to make a diagnosis. However, due to the relatively high rate of false-positive results, careful evaluations of clinical features and laboratory examinations are necessary. Therefore, a diagnosis of HIT is challenging, and the availability of functional assays is indicated. We herein present a case of HIT triggered by MSSA bacteremia. A functional assay exhibited the ability to explain the complex pathophysiology and interpret the relationship between HIT and infection.
320 × 104/μl
23.2 × 104/μl
HIT is a thrombotic immune-mediated response to UFH, LMWH, and other polyanions . Regarding the mechanisms underlying the development of HIT, platelet factor 4 (PF4) is released on the platelet membrane and into the bloodstream from the alpha granules of platelets. PF4 is positively charged and may combine with administered heparin to form a PF4/heparin complex. This complex was previously reported to be formed in vitro at molar ratios of heparin to PF4 of 1:1 to 1:4 [3, 4].
The PF4/heparin complex is recognized as an antigen, and a PF4/heparin complex antibody (HIT antibody) is produced, which forms an immune complex with the PF4-haparin complex; the Fc region of the HIT antibody combines with the FcγIIa receptor on the platelet membrane, which activates platelets and induces thrombocytopenia . A previous study reported that IgM, IgA, and IgG were almost simultaneously elevated around the fifth day after the exposure of HIT patients to heparin; however, only IgG exhibited an activation capacity for platelets, monocytes, and vascular endothelial cells and may be involved in the pathogenesis of HIT . In the case of intrinsic immune responses, IgM is produced, a class switch is then stimulated, and IgG increases 2 weeks later; therefore, the HIT IgG response is considered to be atypical . The production of pathogenic HIT IgG has been proposed as a misdirection of the immune defense system against negatively charged microorganisms. When bacterial infection occurs in the human body, platelets are activated and release positively charged PF4. PF4 binds charge dependently to various bacteria including Staphylococcus aureus . Especially in gram-negative bacteria, PF4 combines with lipid A and forms a PF4/bacteria complex . Also PF4 binds to nucleic acids generated from breakdown of bacteria and viruses, tissue damage, cell apoptosis, and the release from blood cells such as the formation of neutrophil extracellular traps . IgG against the PF4/bacteria complex has a defensive function such as the promotion of opsonization against bacteria and also combines with the PF4/heparin complex. In other words, when bacterial infection occurs, a PF4/bacteria complex similar to the PF4/heparin complex is formed, thereby exposing the PF4/heparin-like epitope recognized by antibodies which is induced in patients during heparin treatments. This theory may explain the formation of HIT IgG after approximately 5 days in the early period. In rare cases, HIT was recently shown to develop incidentally among patients with no history of heparin administration . These patients had auto-immune diseases such as SLE and/or recent microbial infection.
HIT 4Ts score
Platelet count decrease >50 % and platelet nadir >20 × 109 L−1
Platelet count decrease 30–50 % or platelet nadir 10–19 × 109 L−1
Platelet count decrease <30 % or platelet nadir <10 × 109 L−1
Timing of the platelet count decrease
Clear onset days 5–10 or platelet decrease <1 day (prior heparin exposure within 30 days)
Consistent with the day 5–10 decrease, but not clear; onset after day 10, or decrease <1 day (prior heparin exposure 30–100 days ago)
Platelet count decrease <4 days without recent heparin exposure
Thrombosis or other sequelae
New thrombosis (confirmed); skin necrosis; acute systemic reaction to the post-intravenous unfractionated heparin bolus
Progressive or recurrent thrombosis; non-necrotizing (erythematous) skin lesions; suspected thrombosis (not proven)
Other causes of thrombocytopenia
We encountered a case of HIT diagnosed by a repeated functional assay. Recent advances have been achieved in understanding the pathophysiology of HIT, particularly in the relationship between HIT and infection. To the best of our knowledge, this is the first case report to focus on the relationship between infection and the development of HIT, as proven using a repeated functional assay.
Catheter-related bloodstream infection
Methicillin-susceptible Staphylococcus aureus
Platelet factor 4
We are grateful to Dr. Takuma Maeda and Dr. Shigeki Miyata (National Cerebral and Cardiovascular Center, Japan) for performing the functional assay to diagnose HIT.
The authors declare that they did not receive any funding.
Availability of data and materials
The data sets supporting the conclusions of this report are included within the article.
SS wrote the initial draft. YD and AS contributed to the critical revision. SS, YD, TI, TA, KO, MK, and AS contributed to the interpretation of the pathological condition. All authors read and approved the final version of the manuscript.
Sayaka Sugioka: Clinical Fellow of the Department of Nephrology
Yohei Doi: Clinical Fellow of the Department of Nephrology
Takeshi Ishihara: Chief of the Department of Clinical Engineering
Tetsuya Arisato: Resident of the Department of Nephrology
Keisuke Osaki: Clinical Fellow of the Department of Nephrology
Masao Koshikawa: Assistant director of the Department of Nephrology
Akira Sugawara: Director of the Department of Nephrology.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.
Ethics approval and consent to participate
Based on the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan, Ethics approval is not necessary when submitting case reports.
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