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Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases
Burns Open xxx (xxxx) xxx
Contents lists available at ScienceDirect
Burns Open journal homepage: www.burnsopen.com
Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases Noriko Miyagawa a,⇑, Motoo Fujita a, Yu Kawazoe c, Shigeki Miyata b, Takuma Maeda b, Shigeki Kushimoto a,c a b c
Department of Emergency and Critical Care Medicine, Tohoku University Hospital, Japan Division of Transfusion Medical, National Cerebral and Cardiovascular Center, Japan Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Japan
a r t i c l e
i n f o
Article history: Received 4 August 2019 Received in revised form 21 October 2019 Accepted 25 October 2019 Available online xxxx Keywords: Heparin Thrombosis Heparin-induced thrombocytopenia antibodies Extensive burn
a b s t r a c t Patients with tissue injury due to severe trauma are at an increased risk for heparin-induced thrombocytopenia (HIT). However, HIT and its incidence have not been evaluated in patients with extensive burns. We describe two cases of extensive burn injuries with HIT in an attempt to recognize the pathology and clinical significance of HIT in patients with extensive burn injuries. Case 1 was a woman in her 50 s with burn injuries (total burn surface area, 60%). On day 9, her platelet count decreased significantly, and she was positive for the anti-platelet factor-4 immunoglobulin (Ig)-G antibody. On day 22, catheter-related iliac vein thrombosis was diagnosed. Case 2 was a man in his 40 s with burn injuries (total burn surface area, 77%). On day 5, he was diagnosed as having cerebellar infarction. His platelet count decreased significantly, and he was positive for the anti-platelet factor-4 IgG antibody on day 9. His condition was also complicated with pulmonary thrombosis. In both patients, heparin was used only to maintain arterial catheter patency. In conclusion, physicians must consider the possibility of HIT as a cause of thrombocytopenia in patients with burn, and it is necessary to discontinue all heparin and administer non-heparin-anticoagulant when HIT is clinically suspected. Further evaluation of HIT in patients with burn injuries is required. Ó 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
2. Case reports
Patients with extensive burns are considered at high risk of venous thrombosis [1,2], and heparin is used as a standard drug for prophylaxis against venous thrombosis. Heparin is often used not only for therapeutic drugs but also for maintaining the catheter patency required for respiratory and circulatory management in intensive care. Heparin-induced thrombocytopenia (HIT) is not a rare complication of heparin therapy in patients with tissue damage due to traumatic injury or invasive surgery [2,3]. The study of HIT in burn patients is limited to case reports, and the incidence of HIT has not been clarified [4,5,6]. Herein, we describe two consecutive cases of HIT in patients with extensive burns. The purposes of this report are to contribute to understanding this pathological condition of patients with burns and to emphasize the importance of specific rapid treatment.
Case 1: A 50 s years old woman, with past history of alcohol abuse, had total body surface area of 60% burn injury (second degree, 10% burn surface area and third degree, 50% burn surface area), complicated with inhalation injury due to a fire caused by a stove burner. Conservative treatment was performed in a local hospital where heparin was used solely to maintain arterial line patency, and continuous hemodiafiltration was introduced because of acute kidney injury (nafamostat mesilate alone was used as anticoagulant). She developed disseminated intravascular coagulation (DIC) and was transferred to our hospital on day 5. At the time of the initial examination, the oropharynx was carbonized, and a third degree burn with eschar was observed in an extensive region from her neck to the trunk. The wound on her trunk had a strong, foul odor and a large amount of pus, suggesting infection. Laboratory test results were as follows: White blood cell (WBC) count, 9900/lL; C-reactive protein (CRP), 14.2 mg/dL; Serum creatinine, 2.77 mg/dL; Platelet (Plt) count, 13.8 104/lL; Fibrin and fibrinogen degradation product (FDP), 17.9 lg/mL (reference
⇑ Corresponding author at: Department of Emergency and Critical Care Medicine, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai 980-8574, Japan. E-mail address: [email protected] (N. Miyagawa).
https://doi.org/10.1016/j.burnso.2019.10.002 2468-9122/Ó 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: N. Miyagawa, M. Fujita, Y. Kawazoe et al., Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases, Burns Open, https://doi.org/10.1016/j.burnso.2019.10.002
2
N. Miyagawa et al. / Burns Open xxx (xxxx) xxx
range, <0.5 lg/mL); and D-dimer, 7.5 lg/mL (reference range, <0.5 lg/mL). On day 9, her Plt count decreased from 12.7 104/lL (on day 8) to 4.5 104/lL, D-dimer level increased to 10 lg/mL (Fig. 1a), and her 4Ts score for HIT screening [7] was 5. On day 10, immunological testing for HIT evaluation showed that the patient had antiplatelet factor-4 (PF4)/heparin immunoglobulin (Ig)-G antibodies with a high optical density (OD) value of 2.354, and the functional assay was strongly positive (Table 1, Fig. 1b). We confirmed the diagnosis by washed platelet activation assay to quantify the extent of platelet activation induced by HIT antibodies using flow cytometry according to the previous publications [8,9]. The patient was diagnosed as having HIT; subsequently, all heparin was discontinued, and continuous infusion of argatroban was initiated. On day 22, she developed catheter-associated left common iliac vein thrombosis. Anticoagulant therapy with argatroban was continued, and her burn injuries were treated, after which her condition improved. After approximately 3 months, she was transferred to another hospital. Case 2: A 40 s years old man, with history of schizophrenia, had total body surface area of 77% burn injury (second degree, 55% burn surface area and third degree, 22% burn surface area) complicated by inhalation injury due to a home fire. In the previous hospital, he received conservative treatment, and heparin was administered only to maintain arterial line patency. On day 5, he
Table 1 Heparin exposure and diagnosis of HIT. Case 1 Heparin exposure Onset of Thrombocytopenia Start of treatment Location of thrombosis
Diagnosis of thrombosis IgG (OD, cut-off: 0.400) Functional assay
Case 2
Only in the arterial line Day 5 Day 8 Day 9 Day 9 CatheterMain branch of the right associated pulmonary artery thrombosis Day 22 Day 9 2.354 2.044 Strongly positive
HIT, heparin-induced thrombocytopenia; IgG, immunoglobulin G; OD, optical density.
developed cerebellar infarction and showed a decreased Plt count. On day 8, he was diagnosed as having DIC and transferred to our hospital. At the time of the initial examination, a third degree burn with eschar was observed in the region from his neck and anterior chest to upper limbs. The Plt count decreased from 32 104/lL (at the time of the first examination in the previous hospital) to 4.3 104/lL (on the day of admission to our hospital), and Ddimer level was high (10 lg/mL) (Fig. 2a). Computed tomography on admission to our hospital showed thrombus formation in the
Fig. 1. a: Time course changes in the platelet count and coagulation markers of case 1. UFH, unfractionated heparin; HIT, heparin-induced thrombocytopenia; Plt, platelet count. b: Functional assay of case 1. On day10, the functional assay was strongly positive. The patient’s serum had a high PAI at therapeutic concentrations of heparin (30 min and 60 min, 0.1 U/ml of UFH and 0.3 U/ml of LMWH), even in the absence of added heparin (No heparin), a pattern seen in patients with delayed-onset HIT. UFH, unfractionated heparin; LMWH, low-molecular-weight heparin.
Please cite this article as: N. Miyagawa, M. Fujita, Y. Kawazoe et al., Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases, Burns Open, https://doi.org/10.1016/j.burnso.2019.10.002
N. Miyagawa et al. / Burns Open xxx (xxxx) xxx
3
Fig. 2. a: Time course changes in the platelet count and coagulation markers of case 2. UFH, unfractionated heparin; HIT, heparin-induced thrombocytopenia; Plt, platelet count. b: Functional assay of case 2. On day9, the functional assay was strongly positive. The patient’s serum had a high PAI at therapeutic concentrations of heparin (30 min and 60 min, 0.1 U/ml of UFH and 0.3 U/ml of LMWH), even in the absence of added heparin (No heparin), a pattern seen in patients with delayed-onset HIT. UFH, unfractionated heparin; LMWH, low-molecular-weight heparin.
main branch of the right pulmonary artery, and he was diagnosed as having pulmonary thromboembolism. Laboratory test results were as follows: WBC count, 8000/lL; CRP, 18.4 mg/dL; Plt count, 4.3 104/lL; FDP, 21.2 lg/mL; D-dimer; 10 lg/mL, and 4Ts score, 7. Since HIT was strongly suspected based on the patient’s clinical course and the presence of thrombosis, heparin was discontinued, and continuous infusion of argatroban was initiated. On day 9, he had anti-PF4/heparin IgG antibodies with a high OD value of 2.044 (Table 1, Fig. 2b), and the functional assay was strongly positive, leading to a definitive diagnosis of HIT. Subsequently, his condition improved. After approximately 2 months, he was transferred to another hospital. Both patients were confirmed to be negative for IgG antibodies at 4 weeks after the diagnosis of HIT, and argatroban administration were changed to warfarin. 3. Discussion Patients requiring intensive care postoperatively and those with severe injury are considered at high risk of venous thrombosis. The incidence of venous thrombosis is 50% or more when preventive measures are not taken, and pulmonary thromboembolism is a main cause of death [10]. However, it was reported that the inci-
dence of venous thrombosis decreased to approximately 10% with appropriate preventive measures [11]. The incidence of HIT is reported to be 5% in patients receiving heparin for 4 days or longer [12]. If appropriate diagnosis and treatment are unavailable, approximately half of patients with HIT develop thrombosis, and the mortality rate reaches 5% [13]. It has also been reported that approximately 25% of patients with HIT developed thrombosis before the onset of thrombocytopenia [14]. The risk of HIT in patients with burn injury is considered substantial. HIT is more common in postsurgical patients than in medical patients [15]. In trauma, DNA fragments released into the blood due to tissue damage are rich in negative charges, so they form a complex with PF4, which is rich in positive charges. It has been pointed out that it is possible to produce an antibody without exposure to heparin by presenting the antigen [16,17]. There is also the theory that circulating DNA increases in burn patients [18,19]. In these 2 cases, there may be a mechanism that burn injury itself released DNA and resulted in antibody production against PF4/ DNA complex in burn patients. These findings suggest that HIT may not be a rare condition in patients with severe burns. Although thrombocytopenia following burns injury may result from several pathology, including sepsis, certain drug-induced thrombocytopenias, and even large burns themselves, heparin
Please cite this article as: N. Miyagawa, M. Fujita, Y. Kawazoe et al., Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases, Burns Open, https://doi.org/10.1016/j.burnso.2019.10.002
4
N. Miyagawa et al. / Burns Open xxx (xxxx) xxx
can be a cause of thrombosis in patients with burns; however, the risk is not fully understood. There is a possibility that thrombosis associated with HIT is a hidden cause of death. Physicians should consider the possibility of HIT when a burn patient develops thrombocytopenia and 4T’s score with intermediate to high probability [7]. If HIT is clinically suspected, heparin should be discontinued. In clinical practice, physicians should be aware that patients with burn are at high risk of HIT. If HIT is suspected, all heparin use should be immediately discontinued, and a non-heparin anticoagulant should be started to prevent thromboembolism. There is an insufficient number of studies about HIT in patients with burn. Larger multi-center studies are needed for further investigation. 4. Authors’ contributions All authors participated in the patients’ management and drafting of the manuscript. MF and SK revised the manuscript. All authors read and approved the final manuscript. 5. Consent for publication Consent for publication was obtained from the patients. 6. Formatting of funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Disclosure Personal information was handled according to the Guidelines on the Protection of Patient Privacy in Publishing and Presentation of Research Works including case reports by surgery-related associations in Japan. Source of funding The manuscript was supported by Tohoku-kyuikai and departmental funds of Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.burnso.2019.10.002. References [1] Guyatt G, Akl E, Crowther M, et al. SchuunemannAntithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(2). 7S–47S. [2] Sikora S, Papp A, et al. Venous thromboembolism in burn patients is not prevented by chemoprophylaxis. Burns 2017;43:1330–4. [3] Lubenow N, Hinz P, Thomaschewski S, et al. The severity of trauma determines the immune response to pf4/heparin and the frequency of heparin-induced thrombocytopenia. Blood 2010;115:1797–803. [4] Scott JR, Klein MB, Gernsheimer T, et al. Arterial and venous complications of heparin-induced thrombocytopenia in burn patients. J Burn Care Res 2007;28:71–5. [5] Kim J, Ho CH, Lewis KE, et al. Delayed-onset thrombocytopenia in a padiatric burn patients. Am J Hematol 2016;91:958–60. [6] Horner BM, Myers SR. Don’t miss HIT (heparin-induced thrombocytopenia). Burns 2004;30:88–90. [7] Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score(4T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759–65. [8] Maeda T, Noguchi T, Saito S, et al. Impact of heparin-induced thrombocytopenia on acute coronary artery thrombosis in patients undergoing PCI. Thromb Haemost. 2014 Sep 2;112(3):624–6. [9] Maeda T, Nakagawa K, Murata K, et al. Identifying patients at high risk of heparin-induced thrombocytopenia-associated thrombosis with a platelet activation assay using flow cytometry. Thromb Haemost 2017;117(1):127–38. [10] Turpie Alexander G G, Chin Bernard S P, Lip Gregory Y H, et al. Venous thromboembolism: pathophysiology, clinical features, and prevention. BMJ 2002;325:887–90. [11] Greinacher A, Eichler P, Lubenow N, 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 apttrange. Blood 2000;96:846–51. [12] Martel Naedine, Lee James, Philip S, et al. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106:2710–5. [13] Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996;101:502–7. [14] Greinacher A, Farner B, Kroll H, et al. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 2005;94:132–5. [15] Warkentin TE, Sheppard JA, Sigouin CS, et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006;108:2937–41. [16] Poudel DR, Ghimire S, Dhital R, et al. Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review. Platelets 2017;28(6):614–20. [17] Miyata S. Spontaneous heparin-induced thrombocytopenia (HIT) syndrome: HIT without any heparin exposure. Rinsho Ketsueki. 2016;57(10):2124–35. [18] Fox A, Gal S, Fisher N, et al. Quantification of circulating cell-free plasma DNA and endothelial gene RNA in patients with burns and relation to acute thermal injury. Burns 2008 Sep;34(6):809–16. [19] Shoham Y, Krieger Y, Perry ZH, et al. Admission cell free DNA as a prognostic factor in burns: quantification by use of a direct rapid fluorometric technique. Biomed Res Int 2014;2014. 306580.
Acknowledgments Not applicable.
Please cite this article as: N. Miyagawa, M. Fujita, Y. Kawazoe et al., Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases, Burns Open, https://doi.org/10.1016/j.burnso.2019.10.002
Contents lists available at ScienceDirect
Burns Open journal homepage: www.burnsopen.com
Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases Noriko Miyagawa a,⇑, Motoo Fujita a, Yu Kawazoe c, Shigeki Miyata b, Takuma Maeda b, Shigeki Kushimoto a,c a b c
Department of Emergency and Critical Care Medicine, Tohoku University Hospital, Japan Division of Transfusion Medical, National Cerebral and Cardiovascular Center, Japan Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Japan
a r t i c l e
i n f o
Article history: Received 4 August 2019 Received in revised form 21 October 2019 Accepted 25 October 2019 Available online xxxx Keywords: Heparin Thrombosis Heparin-induced thrombocytopenia antibodies Extensive burn
a b s t r a c t Patients with tissue injury due to severe trauma are at an increased risk for heparin-induced thrombocytopenia (HIT). However, HIT and its incidence have not been evaluated in patients with extensive burns. We describe two cases of extensive burn injuries with HIT in an attempt to recognize the pathology and clinical significance of HIT in patients with extensive burn injuries. Case 1 was a woman in her 50 s with burn injuries (total burn surface area, 60%). On day 9, her platelet count decreased significantly, and she was positive for the anti-platelet factor-4 immunoglobulin (Ig)-G antibody. On day 22, catheter-related iliac vein thrombosis was diagnosed. Case 2 was a man in his 40 s with burn injuries (total burn surface area, 77%). On day 5, he was diagnosed as having cerebellar infarction. His platelet count decreased significantly, and he was positive for the anti-platelet factor-4 IgG antibody on day 9. His condition was also complicated with pulmonary thrombosis. In both patients, heparin was used only to maintain arterial catheter patency. In conclusion, physicians must consider the possibility of HIT as a cause of thrombocytopenia in patients with burn, and it is necessary to discontinue all heparin and administer non-heparin-anticoagulant when HIT is clinically suspected. Further evaluation of HIT in patients with burn injuries is required. Ó 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
2. Case reports
Patients with extensive burns are considered at high risk of venous thrombosis [1,2], and heparin is used as a standard drug for prophylaxis against venous thrombosis. Heparin is often used not only for therapeutic drugs but also for maintaining the catheter patency required for respiratory and circulatory management in intensive care. Heparin-induced thrombocytopenia (HIT) is not a rare complication of heparin therapy in patients with tissue damage due to traumatic injury or invasive surgery [2,3]. The study of HIT in burn patients is limited to case reports, and the incidence of HIT has not been clarified [4,5,6]. Herein, we describe two consecutive cases of HIT in patients with extensive burns. The purposes of this report are to contribute to understanding this pathological condition of patients with burns and to emphasize the importance of specific rapid treatment.
Case 1: A 50 s years old woman, with past history of alcohol abuse, had total body surface area of 60% burn injury (second degree, 10% burn surface area and third degree, 50% burn surface area), complicated with inhalation injury due to a fire caused by a stove burner. Conservative treatment was performed in a local hospital where heparin was used solely to maintain arterial line patency, and continuous hemodiafiltration was introduced because of acute kidney injury (nafamostat mesilate alone was used as anticoagulant). She developed disseminated intravascular coagulation (DIC) and was transferred to our hospital on day 5. At the time of the initial examination, the oropharynx was carbonized, and a third degree burn with eschar was observed in an extensive region from her neck to the trunk. The wound on her trunk had a strong, foul odor and a large amount of pus, suggesting infection. Laboratory test results were as follows: White blood cell (WBC) count, 9900/lL; C-reactive protein (CRP), 14.2 mg/dL; Serum creatinine, 2.77 mg/dL; Platelet (Plt) count, 13.8 104/lL; Fibrin and fibrinogen degradation product (FDP), 17.9 lg/mL (reference
⇑ Corresponding author at: Department of Emergency and Critical Care Medicine, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai 980-8574, Japan. E-mail address: [email protected] (N. Miyagawa).
https://doi.org/10.1016/j.burnso.2019.10.002 2468-9122/Ó 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: N. Miyagawa, M. Fujita, Y. Kawazoe et al., Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases, Burns Open, https://doi.org/10.1016/j.burnso.2019.10.002
2
N. Miyagawa et al. / Burns Open xxx (xxxx) xxx
range, <0.5 lg/mL); and D-dimer, 7.5 lg/mL (reference range, <0.5 lg/mL). On day 9, her Plt count decreased from 12.7 104/lL (on day 8) to 4.5 104/lL, D-dimer level increased to 10 lg/mL (Fig. 1a), and her 4Ts score for HIT screening [7] was 5. On day 10, immunological testing for HIT evaluation showed that the patient had antiplatelet factor-4 (PF4)/heparin immunoglobulin (Ig)-G antibodies with a high optical density (OD) value of 2.354, and the functional assay was strongly positive (Table 1, Fig. 1b). We confirmed the diagnosis by washed platelet activation assay to quantify the extent of platelet activation induced by HIT antibodies using flow cytometry according to the previous publications [8,9]. The patient was diagnosed as having HIT; subsequently, all heparin was discontinued, and continuous infusion of argatroban was initiated. On day 22, she developed catheter-associated left common iliac vein thrombosis. Anticoagulant therapy with argatroban was continued, and her burn injuries were treated, after which her condition improved. After approximately 3 months, she was transferred to another hospital. Case 2: A 40 s years old man, with history of schizophrenia, had total body surface area of 77% burn injury (second degree, 55% burn surface area and third degree, 22% burn surface area) complicated by inhalation injury due to a home fire. In the previous hospital, he received conservative treatment, and heparin was administered only to maintain arterial line patency. On day 5, he
Table 1 Heparin exposure and diagnosis of HIT. Case 1 Heparin exposure Onset of Thrombocytopenia Start of treatment Location of thrombosis
Diagnosis of thrombosis IgG (OD, cut-off: 0.400) Functional assay
Case 2
Only in the arterial line Day 5 Day 8 Day 9 Day 9 CatheterMain branch of the right associated pulmonary artery thrombosis Day 22 Day 9 2.354 2.044 Strongly positive
HIT, heparin-induced thrombocytopenia; IgG, immunoglobulin G; OD, optical density.
developed cerebellar infarction and showed a decreased Plt count. On day 8, he was diagnosed as having DIC and transferred to our hospital. At the time of the initial examination, a third degree burn with eschar was observed in the region from his neck and anterior chest to upper limbs. The Plt count decreased from 32 104/lL (at the time of the first examination in the previous hospital) to 4.3 104/lL (on the day of admission to our hospital), and Ddimer level was high (10 lg/mL) (Fig. 2a). Computed tomography on admission to our hospital showed thrombus formation in the
Fig. 1. a: Time course changes in the platelet count and coagulation markers of case 1. UFH, unfractionated heparin; HIT, heparin-induced thrombocytopenia; Plt, platelet count. b: Functional assay of case 1. On day10, the functional assay was strongly positive. The patient’s serum had a high PAI at therapeutic concentrations of heparin (30 min and 60 min, 0.1 U/ml of UFH and 0.3 U/ml of LMWH), even in the absence of added heparin (No heparin), a pattern seen in patients with delayed-onset HIT. UFH, unfractionated heparin; LMWH, low-molecular-weight heparin.
Please cite this article as: N. Miyagawa, M. Fujita, Y. Kawazoe et al., Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases, Burns Open, https://doi.org/10.1016/j.burnso.2019.10.002
N. Miyagawa et al. / Burns Open xxx (xxxx) xxx
3
Fig. 2. a: Time course changes in the platelet count and coagulation markers of case 2. UFH, unfractionated heparin; HIT, heparin-induced thrombocytopenia; Plt, platelet count. b: Functional assay of case 2. On day9, the functional assay was strongly positive. The patient’s serum had a high PAI at therapeutic concentrations of heparin (30 min and 60 min, 0.1 U/ml of UFH and 0.3 U/ml of LMWH), even in the absence of added heparin (No heparin), a pattern seen in patients with delayed-onset HIT. UFH, unfractionated heparin; LMWH, low-molecular-weight heparin.
main branch of the right pulmonary artery, and he was diagnosed as having pulmonary thromboembolism. Laboratory test results were as follows: WBC count, 8000/lL; CRP, 18.4 mg/dL; Plt count, 4.3 104/lL; FDP, 21.2 lg/mL; D-dimer; 10 lg/mL, and 4Ts score, 7. Since HIT was strongly suspected based on the patient’s clinical course and the presence of thrombosis, heparin was discontinued, and continuous infusion of argatroban was initiated. On day 9, he had anti-PF4/heparin IgG antibodies with a high OD value of 2.044 (Table 1, Fig. 2b), and the functional assay was strongly positive, leading to a definitive diagnosis of HIT. Subsequently, his condition improved. After approximately 2 months, he was transferred to another hospital. Both patients were confirmed to be negative for IgG antibodies at 4 weeks after the diagnosis of HIT, and argatroban administration were changed to warfarin. 3. Discussion Patients requiring intensive care postoperatively and those with severe injury are considered at high risk of venous thrombosis. The incidence of venous thrombosis is 50% or more when preventive measures are not taken, and pulmonary thromboembolism is a main cause of death [10]. However, it was reported that the inci-
dence of venous thrombosis decreased to approximately 10% with appropriate preventive measures [11]. The incidence of HIT is reported to be 5% in patients receiving heparin for 4 days or longer [12]. If appropriate diagnosis and treatment are unavailable, approximately half of patients with HIT develop thrombosis, and the mortality rate reaches 5% [13]. It has also been reported that approximately 25% of patients with HIT developed thrombosis before the onset of thrombocytopenia [14]. The risk of HIT in patients with burn injury is considered substantial. HIT is more common in postsurgical patients than in medical patients [15]. In trauma, DNA fragments released into the blood due to tissue damage are rich in negative charges, so they form a complex with PF4, which is rich in positive charges. It has been pointed out that it is possible to produce an antibody without exposure to heparin by presenting the antigen [16,17]. There is also the theory that circulating DNA increases in burn patients [18,19]. In these 2 cases, there may be a mechanism that burn injury itself released DNA and resulted in antibody production against PF4/ DNA complex in burn patients. These findings suggest that HIT may not be a rare condition in patients with severe burns. Although thrombocytopenia following burns injury may result from several pathology, including sepsis, certain drug-induced thrombocytopenias, and even large burns themselves, heparin
Please cite this article as: N. Miyagawa, M. Fujita, Y. Kawazoe et al., Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases, Burns Open, https://doi.org/10.1016/j.burnso.2019.10.002
4
N. Miyagawa et al. / Burns Open xxx (xxxx) xxx
can be a cause of thrombosis in patients with burns; however, the risk is not fully understood. There is a possibility that thrombosis associated with HIT is a hidden cause of death. Physicians should consider the possibility of HIT when a burn patient develops thrombocytopenia and 4T’s score with intermediate to high probability [7]. If HIT is clinically suspected, heparin should be discontinued. In clinical practice, physicians should be aware that patients with burn are at high risk of HIT. If HIT is suspected, all heparin use should be immediately discontinued, and a non-heparin anticoagulant should be started to prevent thromboembolism. There is an insufficient number of studies about HIT in patients with burn. Larger multi-center studies are needed for further investigation. 4. Authors’ contributions All authors participated in the patients’ management and drafting of the manuscript. MF and SK revised the manuscript. All authors read and approved the final manuscript. 5. Consent for publication Consent for publication was obtained from the patients. 6. Formatting of funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Disclosure Personal information was handled according to the Guidelines on the Protection of Patient Privacy in Publishing and Presentation of Research Works including case reports by surgery-related associations in Japan. Source of funding The manuscript was supported by Tohoku-kyuikai and departmental funds of Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Acknowledgments Not applicable.
Please cite this article as: N. Miyagawa, M. Fujita, Y. Kawazoe et al., Extensive burns complicated with heparin-induced thrombocytopenia: A report of two cases, Burns Open, https://doi.org/10.1016/j.burnso.2019.10.002