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Can Heparin-Coated ECMO Cannulas Induce Thrombocytopenia in COVID-19 Patients?

Can Heparin-Coated ECMO Cannulas Induce Thrombocytopenia in COVID-19 Patients? Hindawi Case Reports in Immunology Volume 2021, Article ID 6624682, 5 pages https://doi.org/10.1155/2021/6624682 Case Report Can Heparin-Coated ECMO Cannulas Induce Thrombocytopenia in COVID-19 Patients? 1 1 1 1 Barbara Steinlechner , Gabriele Kargl, Christine Schlo¨mmer, Caroline Holaubek, 1 2 3 3 Georg Scheriau, Sabine Eichinger, Johannes Gratz, and Bernhard Ro¨ssler Division of Cardiothoracic and Vascular Anesthesia, Department of Anesthesia, Intensive Care Medicine and Pain Medicine, Medical University Vienna, Vienna, Austria Division of Hematology and Hemostaseology, Department of Medicine I, Medical University Vienna, Vienna, Austria Division of General Anesthesia and Intensive Care Medicine, Department of Anesthesia, Intensive Care Medicine and Pain Medicine, Medical University Vienna, Vienna, Austria Correspondence should be addressed to Barbara Steinlechner; barbara.steinlechner@meduniwien.ac.at Received 3 December 2020; Revised 27 April 2021; Accepted 21 May 2021; Published 7 June 2021 Academic Editor: Christian Drouet Copyright © 2021 Barbara Steinlechner et al. 'is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Extracorporeal membrane oxygenation (ECMO) is often used in the management of COVID-19-related severe respiratory failure. We report the first case of a patient with COVID-19-related ARDS on ECMO support who developed symptoms of heparin- induced thrombocytopenia (HIT) in the absence of heparin therapy. A low platelet count of 61 G/L was accompanied by the presence of circulating HIT antibodies 12 days after ECMO initiation. Replacement of the ECMO system including cannulas resulted in the normalization of the platelet count. However, the clinical situation did not improve, and the patient died 9 days later. Careful consideration of anticoagulant therapy and ECMO circuit, as well as routine HIT antibody testing, may prevent a fatal course in ECMO-supported COVID-19 patients. thromboembolic events [5]. HIT is the result of a severe 1. Introduction immune response mediated by the formation of IgG anti- About 5% of coronavirus disease 2019 (COVID-19) patients bodies against heparin/platelet factor 4 (PF4) complexes. become critically ill and develop acute respiratory distress 'ese immune complexes activate platelets and lead to syndrome (ARDS) [1]. platelet aggregation, thereby causing thrombocytopenia. In Extracorporeal membrane oxygenation (ECMO) is often addition, the release of PF4 by activated platelets induces a used to manage refractory hypoxemia in severe cases of massive production of thrombin, promoting a pro- respiratory failure [2, 3]. Vienna General Hospital is an thrombotic state [6, 7]. 'e incidence of HIT in severely ill expert, high-volume ECMO center with widely available patients may be higher than previously appreciated. In a ECMO devices, trained staff, and vast experience in the field study involving 300 ECMO-supported patients after cardiac of severe cardiorespiratory failure and lung transplant. surgery, Opfermann and colleagues found an HIT incidence Current Extracorporeal Life Support Organization of 7.3% with a 59% mortality rate [8]. A recent systematic (ELSO) guidelines recommend the continuous infusion of review of the literature revealed an HIT frequency of 17% in unfractionated heparin up to a rate of 20.0 units/kg/h as an patients on venoarterial or venovenous ECMO support [9]. anticoagulant therapy during ECMO [4]. However, heparin In COVID-19 patients treated with intravenous unfractio- may trigger heparin-induced thrombocytopenia (HIT), a nated heparin for at least five days (without ECMO support), potentially fatal condition characterized by a decline in the incidence of the positive HIT immunoassay was 12% platelet count and, puzzlingly, an increase in with a 60% mortality rate [10]. Surprisingly, there are few 2 Case Reports in Immunology degree of thrombocytopenia; (2) the timing of the platelet data available on HIT in ECMO-supported COVID-19 patients. decline after heparin administration; (3) the presence of new thrombosis; and (4) nonapparent other causes of thrombocytopenia. 2. Case Report Since the heparin-coated ECMO cannulas were sus- We report the case of a 69-year-old woman admitted to a pected to have triggered HIT, both the cannulas and the primary hospital in Vienna, Austria, presenting with fever, ECMO system were replaced by nonheparin-coated ECMO dry cough, headache, and diarrhea. 'e patient tested circuits (SOFTLINE circuits; Maquet Cardiopulmonary positive for COVID-19 by reverse transcription-polymerase GmbH; Rastatt, Germany), resulting in the normalization chain reaction of a nasopharyngeal swab specimen. Eight of the platelet count within 4 days (Figure 1(b)). However, days after admission, the patient’s respiratory state deteri- we could not revert the clinical situation. On day 22 after ICU admission, the ECMO indication was reevaluated, and orated rapidly resulting in severe hypoxemia. She was unresponsive to noninvasive continuous pos- the interdisciplinary team of the ICU and transplant sur- geons decided on therapy de-escalation as the patient did itive airway pressure (CPAP) ventilation and nasal high- flow oxygen and was transferred to the intensive care unit not qualify for lung transplantation. 'us, due to non- (ICU), intubated, and prone positioned. Because of an recovery and progressive organ dysfunction, the patient unaltered low oxygenation index indicating severe respi- was weaned from ECMO support and passed away within a ratory failure, she was transferred to Vienna General few hours Hospital for venovenous ECMO initiation (Cardiohelp Lung autopsy results described diffuse alveolar damage System, Maquet Cardiopulmonary GmbH; Rastatt, (DAD) and pulmonary fibrosis in organization. Germany). A heparin-coated, double venous cannula sys- tem (BIOLINE coating, Maquet Cardiopulmonary GmbH; Rastatt, Germany) was used, with one cannula inserted into 3. Discussion the right femoral vein and the other into the right internal Here, we report the first case of a patient with COVID-19 on jugular vein. Chest computed tomography scans showed multifocal bilateral patchy shadows indicative of COVID- venovenous ECMO support who developed symptoms of 19-related ARDS. Upon admission, the patient was on al- HIT in the absence of heparin therapy. 'e HITdiagnosis was ternative anticoagulation with the direct thrombin inhibitor based on clinical symptoms, including a low platelet count argatroban due to her allergy to low-molecular-weight and thromboembolic complications, and supported by a highly positive anti-PF4/heparin antibody immunoassay test heparins. Hence, the patient continued receiving argatroban at a rate between 0.33 and 0.73 µg/kg/min as an anticoag- result (OD � 2.63). 'e patient was already on the alternative anticoagulant argatroban at the time of the ECMO im- ulant therapy during ECMO provision. We relied on careful laboratory monitoring to guide argatroban dosage plantation. Hence, we suspect that the heparin-coated ECMO cannulas may have triggered HIT in our patient with (Figure 1(a)). Lung-protective ventilation and therapy in the sense of “compassionate use” of IV immunoglobulins, COVID-related ARDS. Consistently, the removal of heparin- coated cannulas led to a normalization of the platelet count anakinra (IL-1 inhibitor), and low-dose hydrocortisone were initiated. within 4 days. On day 11 after ECMO initiation, swelling of the right One complication of heparin therapy and heparin-coated circuits is HIT. Recently published data show that an OD leg was detected, caused by a nonocclusive thrombus within the right popliteal vein. Moreover, the patient presented with threshold of 1.0 in anti-PF4/heparin antibody ELISA testing has a specificity of 89% and a negative predictive value of 95% livid discolored fingertips. On day 12, the patient’s platelet count had decreased to a nadir of 61 G/L (Figure 1(b)). for detecting/excluding HIT in ECMO patients on unfrac- tionated heparin [12]. 'erefore, our ELISA OD result of 2.63 Platelet count was checked with a specific blood collection tube ('romboExact, Sarstedt, Numbrecht, ¨ Germany) together with the clinical features indicates a high likelihood of HIT. Until 2016, the functional heparin-induced platelet- confirming the results collected with the citrated blood tubes and to rule out pseudothrombocytopenia (PTCP), an in activation (HIPA) test was performed at our institution in vitro phenomenon of low platelet count caused by the ag- case of a positive ELISA test result. Based on receiver op- glutination of platelets, leading to false low platelet counts in erating characteristic curves (ELISA versus HIPA test), we automated cell counting [11]. Furthermore, anti- determined that the ZYMUTEST HIA IgG (HYPHEN BioMed) ELISA test had a sensitivity of 86% and specificity of phospholipid antibodies were excluded. 'e time course of the acute-phase proteins C-reactive protein and fibrinogen 81% at OD levels >0.8. 'erefore, an OD of 0.8 was estab- lished as a clinically relevant cutoff value for HIT, and HIPA and elevated D-dimer levels indicating active blood clotting is shown in Figure 1(c). testing was no longer performed [13]. Functional assays are still widely used as a confirmative test in the diagnosis of HIT. 'e patient was highly positive for anti-PF4/heparin antibodies (optical density (OD): 2.63) as determined by the One of the most common tests is the platelet serotonin- release assay (SRA). However, recent data from an overall enzyme-linked immunosorbent assay (Figures 1(a)–1(d)), indicating a high likelihood of HIT. 'e widely used 4T’s HIT cohort, without focusing on extracorporeal life support clinical scoring system was predicting a high probability of [14], and case reports indicate a certain unreliability of functional assays in ECMO patients [15]. HIT (in sum, 8 points: 2 points in each category as (1) the Case Reports in Immunology 3 120 0.8 250 0.7 0.6 0.5 60 0.4 0.3 0.2 0.1 0 0.0 0 123456789 1011121314151617181920212223 123456789 1011121314151617181920212223 ICU (days) ICU (days) aPTT Thrombin time Argatroban (a) (b) 800 80 700 350 700 650 600 60 600 500 550 400 40 500 275 300 450 200 20 400 100 350 0 0 300 200 123456789 1011121314151617181920212223 123456789 1011121314151617181920212223 ICU (days) ICU (days) Fibrinogen CT-ECA test CRP CT-IN test D-dimer (c) (d) Figure 1: Clinical course in the ECMO-supported COVID-19 patient. (a) Anticoagulant argatroban was administered throughout the provision of venovenous ECMO. Anticoagulation effect. (b) Time course of platelets and results of the ELISA test (ZYMUTEST HIA IgG). Anti-heparin/PF4 antibodies detected by optical density (OD) read on days 12, 14, and 20 were monitored by measuring activated partial thromboplastin time (aPTT) and thrombin time (TT). (c) Time course of fibrinogen, D-dimer, and C-reactive protein (CRP). (d) Un- dulating course of coagulation time (CT) in intrinsic (IN) and ecarin (ECA) tests in contrast to the relatively uniform course of aPTT measurement. Our patient was on alternative anticoagulation with when there are bleeding concerns [17]. Although heparin- argatroban, a reversible inhibitor of thrombin with a short bonded devices may contribute to the development of HITin previously unaffected patients, the medical guidelines are half-life. A major concern with argatroban is subtherapeutic anticoagulation in patients with confounding elevated not very clear regarding the routine change of heparin- partial thromboplastin time in the presence of a nonspecific coated devices in case of suspected HIT [18, 19]. Centers of inhibitor (such as lupus anticoagulant) and secondary to Excellence (ELSO) follow different strategies. In some fa- additional coagulopathy in COVID-19 patients (increased cilities, ECMO cannula and circuit change is performed very levels of the VWF antigen, FVIII, D-dimers, and fibrinogen) early after the suspicion of HIT and the detection of anti- [16]. For the first time at our institution, we have performed PF4/heparin antibodies, even if functional assays such as an ecarin (ECA) test at the later ICU stay of the patient serotonin-release assays are negative [15]. Our department (Figure 1(d)). Ecarin, a venom of the saw-scaled viper Echis (cardiac, thoracic, and vascular anesthesia and intensive care carinatus, activates prothrombin in ClotPro (Haemonetics medicine) changes the established ECMO circuit except GmbH, Munich, Austria), a new viscoelastic point-of-care cannulas in HIT-positive patients. 'is might be caused by the high percentage of VA-ECMOs at our ICU and thereby testing device. We think that coagulation time in the ECA test could improve laboratory monitoring in patients on increased risk of adverse events during the exchange of argatroban in addition to aPTT monitoring. 'is is being cannulas. In this particular case, we assumed that the evaluated in an ongoing study at our institution. heparin-coated tube system triggered HIT since the patient Our data suggest that the heparin-coated circuit is a was pretreated with argatroban and had no other docu- potential source of heparin exposure during ECMO pro- mented exposure to heparin during her stay. 'is made a vision. Covalently bonded heparin on the grafts and can- cannula and circuit change obligatory. Considering the nulas makes the circuits more biocompatible and limits the published data, it is not comprehensible to which extent need for anticoagulation therapy during ECMO, particularly ECMO cannulas and circuits are changed in HIT-positive Fibrinogen (mg/dl) aPTT; thrombin time (sec) OD 2.63 OD 2.63 OD 2.32 OD 2.32 OD 1.65 OD 1.65 CRP (mg/dl), D-dimer (µg/ml) Argatroban (µg/kg/min) CT-ECA test (sec) Platelets (10 ) OD 2.63 OD 2.63 OD 2.32 OD 2.32 OD 1.65 OD 1.65 CT-IN test (sec) 4 Case Reports in Immunology patients in general, and data considering COVID-19 Data Availability HIT-positive ECMO patients are scarce. However, there are 'e data used to support this study are available in the reports of regular and standardized exchanges of Patient Data Management System of the Vienna General heparin-coated systems for nonheparin-coated systems in Hospital, University Hospital, and the site of the Medical COVID-19 patients with a HIT diagnosis [20]. Given our University of Vienna. presented case, current recommendations and future treatment strategies need to be discussed and overthought. 'e medical history of the patient’s allergy to low-mo- Consent lecular-weight heparin and the infection with SARS-CoV-2, No written consent has been obtained from the patient as which is per se the cause of a procoagulant state, put her at there are no patient identifiable data included in this case high risk for the development of anti-PF4/heparin anti- report. bodies. Importantly, early HIT diagnosis may allow a timely change in the anticoagulant therapy and circuit and improve the clinical outcome. Conflicts of Interest Alternatively, endogenous heparin may have also been 'e authors declare no conflicts of interest. released by mast cells present in tissues in close contact with the external environment, including skin and airways, in response to the infection. Authors’ Contributions Intermittent flushing of heparin to prevent occlusion in long-term central venous catheters, heparin in the pres- Barbara Steinlechner wrote the article and provided clinical care for the patient. Gabriele Kargl, Georg Scheriau, Sabine surization system for arterial lines, and heparin in pro- Eichinger, and Johannes Gratz edited the article. Christine thrombin complex concentrates [21, 22] were all ruled out as Schlommer ¨ and Caroline Holaubek edited and revised the potential sources of heparin. article. Bernhard Rossler ¨ edited the article and provided We also considered other reasons for thrombocyto- clinical care for the patient. penia in COVID-19 patients on ECMO support. Patients requiring ECMO may also develop thrombocytopenia due to contact with foreign surfaces, sepsis, bleeding, or References medications. Furthermore, SARS-CoV-2 infection may [1] M. Baksh, V Ravat, A Zaidi, and R. S Patel, “A systematic affect the normal platelet biology in many ways, from review of cases of acute respiratory distress syndrome in the reducing platelet production to increasing platelet break- coronavirus disease 2019 pandemic,” Cureus, vol. 12, no. 5, down [23]. In summary, the origin of thrombocytopenia p. e8188, 2020. may have been multifactorial, reflecting both heparin-de- [2] K. Shekar, J. Badulak, G. Peek et al., “Extracorporeal life pendent and -independent mechanisms. Nevertheless, support organization coronavirus disease 2019 interim replacing the ECMO system and cannulas normalized the guidelines: a consensus document from an international platelet count, which led us to think of HIT as the most group of interdisciplinary extracorporeal membrane oxy- likely explanation in this particular case. genation providers,” ASAIO Journal, vol. 66, no. 7, COVID-19 and HIT are both prothrombotic conditions pp. 707–721, 2020. that, when intertwined, can have devastating consequences if [3] R. P. Barbaro, G. MacLaren, P. S. Boonstra et al., “Extra- corporeal membrane oxygenation support in COVID-19: an the HIT diagnosis is missed. If COVID-19 causes HIT, or if international cohort study of the Extracorporeal Life Support the procoagulant state during the infection is caused by Organization registry,” Lancet (London, England), vol. 396, other platelet-activating mechanisms, is currently the object no. 10257, pp. 1071–1078, 2020. of further research [24–26]. Several health organizations [4] 'e Extracorporeal Life Support Organization (ELSO) recommend the use of ECMO support in COVID-19-related Guidelines. 2014; Available from: https://www.elso.org/ refractory hypoxemic respiratory failure, yet the risk of Portals/0/Files/elsoanticoagulationguideline8-2014-table- complications such as HIT is not fully established. Early contents.pdf. reports suggested that mortality could be as high as 94% in [5] A. Cuker, G. M. Arepally, B. H. Chong et al., “American ECMO-supported COVID-19 patients, compared to 71% in Society of Hematology 2018 guidelines for management of conventional therapy patients [27]. In contrast, a recent venous thromboembolism: heparin-induced thrombocyto- study based on ELSO registry data estimated a 90-day penia,” Blood Advances, vol. 2, no. 22, pp. 3360–3392, 2018. [6] B. S. Salter, M. M. Weiner, M. A. Trinh et al., “Heparin-in- mortality of 38% in ECMO-supported COVID-19 patients, duced thrombocytopenia: a comprehensive clinical review,” supporting existing recommendations [3]. Unfortunately, Journal of the American College of Cardiology, vol. 67, no. 21, neither study provides data on anticoagulation therapy or pp. 2519–2532, 2016. thrombocytopenia occurrence. [7] A. Greinacher, “Heparin-induced thrombocytopenia,” New HIT monitoring could help to reconcile these apparently England Journal of Medicine, vol. 373, no. 3, pp. 252–261, conflicting results and, most importantly, prevent fatalities in ECMO-supported COVID-19 patients. [8] P. Opfermann, M. Bevilacqua, A. Felli et al., “Prognostic 'e way of confirming HIT diagnosis remains contro- impact of persistent thrombocytopenia during extracorporeal versial. In our case, functional confirmative assays for the membrane oxygenation,” Critical Care Medicine, vol. 44, diagnosis of HIT were not available. no. 12, pp. e1208–e1218, 2016. 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Moore et al., “Platelet-activating after cardiac surgery,” Case Report in Medicine, vol. 2021, immune complexes identified in critically ill COVID-19 pa- Article ID 3695407, 4 pages, 2021. tients suspected of heparin-induced thrombocytopenia,” [12] V. Kataria, L. Moore, S. Harrison, O. Hernandez, N. Vaughan, Journal of /rombosis and Haemostasis, vol. 19, no. 5, and G. Schwartz, “Evaluation of serotonin release assay and pp. 1342–1347, 2021. enzyme-linked immunosorbent assay optical density [27] B. M. Henry and G. Lippi, “Poor survival with extracorporeal thresholds for heparin-induced thrombocytopenia in patients membrane oxygenation in acute respiratory distress syn- on extracorporeal membrane oxygenation,” Critical Care drome (ARDS) due to coronavirus disease 2019 (COVID-19): pooled analysis of early reports,” Journal of Critical Care, Medicine, vol. 48, no. 2, pp. e82–e86, 2020. [13] A.-K. Schaefer, B. Donhauser, I. Kroeckel et al., “Heparin- vol. 58, pp. 27-28, 2020. induced thrombocytopaenia diagnostic testing after adult cardiac surgery: a single-centre experience and development,” European Journal of Cardio-/oracic Surgery, vol. 55, no. 4, pp. 722–728, 2019. [14] T. E. Warkentin, I. Nazy, J. A. I. Sheppard, J. W. Smith, J. G. Kelton, and D. M. Arnold, “Serotonin-release assay- negative heparin-induced thrombocytopenia,” American Journal of Hematology, vol. 95, no. 1, pp. 38–47, 2020. [15] B. Natt, C. Hypes, R. Basken, J. Malo, T. Kazui, and J. Mosier, “Suspected heparin-induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation,” /e Journal of Extra-corporeal Technology, vol. 49, no. 1, pp. 54–58, 2017. [16] G. Goshua, A. B. Pine, M. L. Meizlish et al., “Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study,” /e Lancet Haematology, vol. 7, no. 8, pp. e575–e582, 2020. [17] R. Biran and D. Pond, “Heparin coatings for improving blood compatibility of medical devices,” Advanced Drug Delivery Reviews, vol. 112, pp. 12–23, 2017. [18] F. Pappalardo, G. Maj, A. Scandroglio, F. Sampietro, A. Zangrillo, and A. Koster, “Bioline heparin-coated ECMO with bivalirudin anticoagulation in a patient with acute heparin-induced thrombocytopenia: the immune reaction appeared to continue unabated,” Perfusion, vol. 24, no. 2, pp. 135–137, 2009. [19] L. Mureebe, J. A. Graham, R. L. Bush, and D. Silver, “Risk of heparin-induced thrombocytopenia from heparin-bonded vascular prostheses,” Annals of Vascular Surgery, vol. 21, no. 6, pp. 719–722, 2007. [20] Z. N. Kon, D. E. Smith, S. H. Chang et al., “Extracorporeal membrane oxygenation support in severe COVID-19,” /e Annals of /oracic Surgery, vol. 111, no. 2, pp. 537–543, 2021. [21] N. K. Bradford, R. M. Edwards, and R. J. Chan, “Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children,” /e Cochrane Database of Systematic Reviews, vol. 11, p. CD010996, 2015. [22] A. Felli, P. Zeidler, B. Jilma et al., “Different heparin contents in prothrombin complex concentrates may impair blood clotting in outpatients with ventricular assist devices receiving phenprocoumon,” Journal of Cardiothoracic and Vascular Anesthesia, vol. 30, no. 1, pp. 96–101, 2016. [23] P. Xu, Q. Zhou, and J. Xu, “Mechanism of thrombocytopenia in COVID-19 patients,” Annals of Hematology, vol. 99, no. 6, pp. 1205–1208, 2020. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

Can Heparin-Coated ECMO Cannulas Induce Thrombocytopenia in COVID-19 Patients?

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Hindawi Case Reports in Immunology Volume 2021, Article ID 6624682, 5 pages https://doi.org/10.1155/2021/6624682 Case Report Can Heparin-Coated ECMO Cannulas Induce Thrombocytopenia in COVID-19 Patients? 1 1 1 1 Barbara Steinlechner , Gabriele Kargl, Christine Schlo¨mmer, Caroline Holaubek, 1 2 3 3 Georg Scheriau, Sabine Eichinger, Johannes Gratz, and Bernhard Ro¨ssler Division of Cardiothoracic and Vascular Anesthesia, Department of Anesthesia, Intensive Care Medicine and Pain Medicine, Medical University Vienna, Vienna, Austria Division of Hematology and Hemostaseology, Department of Medicine I, Medical University Vienna, Vienna, Austria Division of General Anesthesia and Intensive Care Medicine, Department of Anesthesia, Intensive Care Medicine and Pain Medicine, Medical University Vienna, Vienna, Austria Correspondence should be addressed to Barbara Steinlechner; barbara.steinlechner@meduniwien.ac.at Received 3 December 2020; Revised 27 April 2021; Accepted 21 May 2021; Published 7 June 2021 Academic Editor: Christian Drouet Copyright © 2021 Barbara Steinlechner et al. 'is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Extracorporeal membrane oxygenation (ECMO) is often used in the management of COVID-19-related severe respiratory failure. We report the first case of a patient with COVID-19-related ARDS on ECMO support who developed symptoms of heparin- induced thrombocytopenia (HIT) in the absence of heparin therapy. A low platelet count of 61 G/L was accompanied by the presence of circulating HIT antibodies 12 days after ECMO initiation. Replacement of the ECMO system including cannulas resulted in the normalization of the platelet count. However, the clinical situation did not improve, and the patient died 9 days later. Careful consideration of anticoagulant therapy and ECMO circuit, as well as routine HIT antibody testing, may prevent a fatal course in ECMO-supported COVID-19 patients. thromboembolic events [5]. HIT is the result of a severe 1. Introduction immune response mediated by the formation of IgG anti- About 5% of coronavirus disease 2019 (COVID-19) patients bodies against heparin/platelet factor 4 (PF4) complexes. become critically ill and develop acute respiratory distress 'ese immune complexes activate platelets and lead to syndrome (ARDS) [1]. platelet aggregation, thereby causing thrombocytopenia. In Extracorporeal membrane oxygenation (ECMO) is often addition, the release of PF4 by activated platelets induces a used to manage refractory hypoxemia in severe cases of massive production of thrombin, promoting a pro- respiratory failure [2, 3]. Vienna General Hospital is an thrombotic state [6, 7]. 'e incidence of HIT in severely ill expert, high-volume ECMO center with widely available patients may be higher than previously appreciated. In a ECMO devices, trained staff, and vast experience in the field study involving 300 ECMO-supported patients after cardiac of severe cardiorespiratory failure and lung transplant. surgery, Opfermann and colleagues found an HIT incidence Current Extracorporeal Life Support Organization of 7.3% with a 59% mortality rate [8]. A recent systematic (ELSO) guidelines recommend the continuous infusion of review of the literature revealed an HIT frequency of 17% in unfractionated heparin up to a rate of 20.0 units/kg/h as an patients on venoarterial or venovenous ECMO support [9]. anticoagulant therapy during ECMO [4]. However, heparin In COVID-19 patients treated with intravenous unfractio- may trigger heparin-induced thrombocytopenia (HIT), a nated heparin for at least five days (without ECMO support), potentially fatal condition characterized by a decline in the incidence of the positive HIT immunoassay was 12% platelet count and, puzzlingly, an increase in with a 60% mortality rate [10]. Surprisingly, there are few 2 Case Reports in Immunology degree of thrombocytopenia; (2) the timing of the platelet data available on HIT in ECMO-supported COVID-19 patients. decline after heparin administration; (3) the presence of new thrombosis; and (4) nonapparent other causes of thrombocytopenia. 2. Case Report Since the heparin-coated ECMO cannulas were sus- We report the case of a 69-year-old woman admitted to a pected to have triggered HIT, both the cannulas and the primary hospital in Vienna, Austria, presenting with fever, ECMO system were replaced by nonheparin-coated ECMO dry cough, headache, and diarrhea. 'e patient tested circuits (SOFTLINE circuits; Maquet Cardiopulmonary positive for COVID-19 by reverse transcription-polymerase GmbH; Rastatt, Germany), resulting in the normalization chain reaction of a nasopharyngeal swab specimen. Eight of the platelet count within 4 days (Figure 1(b)). However, days after admission, the patient’s respiratory state deteri- we could not revert the clinical situation. On day 22 after ICU admission, the ECMO indication was reevaluated, and orated rapidly resulting in severe hypoxemia. She was unresponsive to noninvasive continuous pos- the interdisciplinary team of the ICU and transplant sur- geons decided on therapy de-escalation as the patient did itive airway pressure (CPAP) ventilation and nasal high- flow oxygen and was transferred to the intensive care unit not qualify for lung transplantation. 'us, due to non- (ICU), intubated, and prone positioned. Because of an recovery and progressive organ dysfunction, the patient unaltered low oxygenation index indicating severe respi- was weaned from ECMO support and passed away within a ratory failure, she was transferred to Vienna General few hours Hospital for venovenous ECMO initiation (Cardiohelp Lung autopsy results described diffuse alveolar damage System, Maquet Cardiopulmonary GmbH; Rastatt, (DAD) and pulmonary fibrosis in organization. Germany). A heparin-coated, double venous cannula sys- tem (BIOLINE coating, Maquet Cardiopulmonary GmbH; Rastatt, Germany) was used, with one cannula inserted into 3. Discussion the right femoral vein and the other into the right internal Here, we report the first case of a patient with COVID-19 on jugular vein. Chest computed tomography scans showed multifocal bilateral patchy shadows indicative of COVID- venovenous ECMO support who developed symptoms of 19-related ARDS. Upon admission, the patient was on al- HIT in the absence of heparin therapy. 'e HITdiagnosis was ternative anticoagulation with the direct thrombin inhibitor based on clinical symptoms, including a low platelet count argatroban due to her allergy to low-molecular-weight and thromboembolic complications, and supported by a highly positive anti-PF4/heparin antibody immunoassay test heparins. Hence, the patient continued receiving argatroban at a rate between 0.33 and 0.73 µg/kg/min as an anticoag- result (OD � 2.63). 'e patient was already on the alternative anticoagulant argatroban at the time of the ECMO im- ulant therapy during ECMO provision. We relied on careful laboratory monitoring to guide argatroban dosage plantation. Hence, we suspect that the heparin-coated ECMO cannulas may have triggered HIT in our patient with (Figure 1(a)). Lung-protective ventilation and therapy in the sense of “compassionate use” of IV immunoglobulins, COVID-related ARDS. Consistently, the removal of heparin- coated cannulas led to a normalization of the platelet count anakinra (IL-1 inhibitor), and low-dose hydrocortisone were initiated. within 4 days. On day 11 after ECMO initiation, swelling of the right One complication of heparin therapy and heparin-coated circuits is HIT. Recently published data show that an OD leg was detected, caused by a nonocclusive thrombus within the right popliteal vein. Moreover, the patient presented with threshold of 1.0 in anti-PF4/heparin antibody ELISA testing has a specificity of 89% and a negative predictive value of 95% livid discolored fingertips. On day 12, the patient’s platelet count had decreased to a nadir of 61 G/L (Figure 1(b)). for detecting/excluding HIT in ECMO patients on unfrac- tionated heparin [12]. 'erefore, our ELISA OD result of 2.63 Platelet count was checked with a specific blood collection tube ('romboExact, Sarstedt, Numbrecht, ¨ Germany) together with the clinical features indicates a high likelihood of HIT. Until 2016, the functional heparin-induced platelet- confirming the results collected with the citrated blood tubes and to rule out pseudothrombocytopenia (PTCP), an in activation (HIPA) test was performed at our institution in vitro phenomenon of low platelet count caused by the ag- case of a positive ELISA test result. Based on receiver op- glutination of platelets, leading to false low platelet counts in erating characteristic curves (ELISA versus HIPA test), we automated cell counting [11]. Furthermore, anti- determined that the ZYMUTEST HIA IgG (HYPHEN BioMed) ELISA test had a sensitivity of 86% and specificity of phospholipid antibodies were excluded. 'e time course of the acute-phase proteins C-reactive protein and fibrinogen 81% at OD levels >0.8. 'erefore, an OD of 0.8 was estab- lished as a clinically relevant cutoff value for HIT, and HIPA and elevated D-dimer levels indicating active blood clotting is shown in Figure 1(c). testing was no longer performed [13]. Functional assays are still widely used as a confirmative test in the diagnosis of HIT. 'e patient was highly positive for anti-PF4/heparin antibodies (optical density (OD): 2.63) as determined by the One of the most common tests is the platelet serotonin- release assay (SRA). However, recent data from an overall enzyme-linked immunosorbent assay (Figures 1(a)–1(d)), indicating a high likelihood of HIT. 'e widely used 4T’s HIT cohort, without focusing on extracorporeal life support clinical scoring system was predicting a high probability of [14], and case reports indicate a certain unreliability of functional assays in ECMO patients [15]. HIT (in sum, 8 points: 2 points in each category as (1) the Case Reports in Immunology 3 120 0.8 250 0.7 0.6 0.5 60 0.4 0.3 0.2 0.1 0 0.0 0 123456789 1011121314151617181920212223 123456789 1011121314151617181920212223 ICU (days) ICU (days) aPTT Thrombin time Argatroban (a) (b) 800 80 700 350 700 650 600 60 600 500 550 400 40 500 275 300 450 200 20 400 100 350 0 0 300 200 123456789 1011121314151617181920212223 123456789 1011121314151617181920212223 ICU (days) ICU (days) Fibrinogen CT-ECA test CRP CT-IN test D-dimer (c) (d) Figure 1: Clinical course in the ECMO-supported COVID-19 patient. (a) Anticoagulant argatroban was administered throughout the provision of venovenous ECMO. Anticoagulation effect. (b) Time course of platelets and results of the ELISA test (ZYMUTEST HIA IgG). Anti-heparin/PF4 antibodies detected by optical density (OD) read on days 12, 14, and 20 were monitored by measuring activated partial thromboplastin time (aPTT) and thrombin time (TT). (c) Time course of fibrinogen, D-dimer, and C-reactive protein (CRP). (d) Un- dulating course of coagulation time (CT) in intrinsic (IN) and ecarin (ECA) tests in contrast to the relatively uniform course of aPTT measurement. Our patient was on alternative anticoagulation with when there are bleeding concerns [17]. Although heparin- argatroban, a reversible inhibitor of thrombin with a short bonded devices may contribute to the development of HITin previously unaffected patients, the medical guidelines are half-life. A major concern with argatroban is subtherapeutic anticoagulation in patients with confounding elevated not very clear regarding the routine change of heparin- partial thromboplastin time in the presence of a nonspecific coated devices in case of suspected HIT [18, 19]. Centers of inhibitor (such as lupus anticoagulant) and secondary to Excellence (ELSO) follow different strategies. In some fa- additional coagulopathy in COVID-19 patients (increased cilities, ECMO cannula and circuit change is performed very levels of the VWF antigen, FVIII, D-dimers, and fibrinogen) early after the suspicion of HIT and the detection of anti- [16]. For the first time at our institution, we have performed PF4/heparin antibodies, even if functional assays such as an ecarin (ECA) test at the later ICU stay of the patient serotonin-release assays are negative [15]. Our department (Figure 1(d)). Ecarin, a venom of the saw-scaled viper Echis (cardiac, thoracic, and vascular anesthesia and intensive care carinatus, activates prothrombin in ClotPro (Haemonetics medicine) changes the established ECMO circuit except GmbH, Munich, Austria), a new viscoelastic point-of-care cannulas in HIT-positive patients. 'is might be caused by the high percentage of VA-ECMOs at our ICU and thereby testing device. We think that coagulation time in the ECA test could improve laboratory monitoring in patients on increased risk of adverse events during the exchange of argatroban in addition to aPTT monitoring. 'is is being cannulas. In this particular case, we assumed that the evaluated in an ongoing study at our institution. heparin-coated tube system triggered HIT since the patient Our data suggest that the heparin-coated circuit is a was pretreated with argatroban and had no other docu- potential source of heparin exposure during ECMO pro- mented exposure to heparin during her stay. 'is made a vision. Covalently bonded heparin on the grafts and can- cannula and circuit change obligatory. Considering the nulas makes the circuits more biocompatible and limits the published data, it is not comprehensible to which extent need for anticoagulation therapy during ECMO, particularly ECMO cannulas and circuits are changed in HIT-positive Fibrinogen (mg/dl) aPTT; thrombin time (sec) OD 2.63 OD 2.63 OD 2.32 OD 2.32 OD 1.65 OD 1.65 CRP (mg/dl), D-dimer (µg/ml) Argatroban (µg/kg/min) CT-ECA test (sec) Platelets (10 ) OD 2.63 OD 2.63 OD 2.32 OD 2.32 OD 1.65 OD 1.65 CT-IN test (sec) 4 Case Reports in Immunology patients in general, and data considering COVID-19 Data Availability HIT-positive ECMO patients are scarce. However, there are 'e data used to support this study are available in the reports of regular and standardized exchanges of Patient Data Management System of the Vienna General heparin-coated systems for nonheparin-coated systems in Hospital, University Hospital, and the site of the Medical COVID-19 patients with a HIT diagnosis [20]. Given our University of Vienna. presented case, current recommendations and future treatment strategies need to be discussed and overthought. 'e medical history of the patient’s allergy to low-mo- Consent lecular-weight heparin and the infection with SARS-CoV-2, No written consent has been obtained from the patient as which is per se the cause of a procoagulant state, put her at there are no patient identifiable data included in this case high risk for the development of anti-PF4/heparin anti- report. bodies. Importantly, early HIT diagnosis may allow a timely change in the anticoagulant therapy and circuit and improve the clinical outcome. Conflicts of Interest Alternatively, endogenous heparin may have also been 'e authors declare no conflicts of interest. released by mast cells present in tissues in close contact with the external environment, including skin and airways, in response to the infection. Authors’ Contributions Intermittent flushing of heparin to prevent occlusion in long-term central venous catheters, heparin in the pres- Barbara Steinlechner wrote the article and provided clinical care for the patient. Gabriele Kargl, Georg Scheriau, Sabine surization system for arterial lines, and heparin in pro- Eichinger, and Johannes Gratz edited the article. Christine thrombin complex concentrates [21, 22] were all ruled out as Schlommer ¨ and Caroline Holaubek edited and revised the potential sources of heparin. article. Bernhard Rossler ¨ edited the article and provided We also considered other reasons for thrombocyto- clinical care for the patient. penia in COVID-19 patients on ECMO support. 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Published: Jun 7, 2021

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