Multisystem Inflammatory Syndrome in Children Requiring ECMO: Anticoagulation strategies and Lessons Learned

Intro: Multisystem Inflammatory Syndrome in Children (MIS-C) is a post-infectious inflammatory response after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which can cause acute cardiac dysfunction requiring mechanical circulatory support (MCS). MCS utilization for MIS-C is complicated by a propensity for thrombosis, which threatens circuit integrity. This study describes a cohort of MIS-C patients requiring MCS, their outcomes, and the anticoagulation strategies utilized. Method(s): A retrospective case series of patients diagnosed with MIS-C needing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) at Children's Healthcare of Atlanta from March 1, 2020 to June 30, 2022. VA-ECMO variables, laboratory data, complications, and outcomes were collected. Result(s): Seven patients (all male) with severe MIS-C required VA-ECMO for acute cardiac dysfunction. Median age was 13 years (range 4-15 years). Median ICU stay was 13 days (range 6-17 days) with a median ECMO duration of 7 days (IQR 3-8 days) and median mechanical ventilation duration of 8 days (IQR 5-11 days). All seven patients survived to hospital discharge with good neurologic outcomes. Median time to qualitatively normal ventricular function by echocardiogram was 9.5 days (IQR 3-21 days). Heparin was initially used in 6 patients, bivalrudin initially used in 1 patient, and 1 patient converted from heparin to bivalirudin for refractory systemic thrombosis. Median heparin dose was 206u/kg/d (IQR 192-276u/kg/d) with median anti-Xa levels of 0.75 (IQR 0.1-1.1) and median daily PTT 102 seconds (IQR 83-107 seconds). Median daily PTT of patients receiving bivalirudin was 86 seconds (80-93 seconds). Median R-values by thromboelastography were 38 seconds (IQR 25-55 seconds). Two patients required catheter directed thrombolysis with tissue plasminogen activator (t-PA) for refractory intracardiac thrombi, both were initially started on heparin. Significant cannula thrombosis occurred in 2 patients, 1 initially started on heparin and 1 initially on bivalrudin. Bleeding resulting in compartment syndrome occurred in one patient on heparin requiring fasciotomy of the upper extremities, this patient was not receiving t-PA. Conclusion(s): Anticoagulation management for MIS-C patients requiring ECMO is fraught with challenges. A successful management strategy may necessitate higher heparin assay levels, the use of direct thrombin inhibitors for refractory thrombosis, and the deployment of catheter directed thrombolysis. In this case series, CDT was safely and successfully used in two patients. Further studies are required to understand the optimal anticoagulation strategy for these patients to minimize complications.

Novel Monitoring and Dose Adjustment of Argatroban, a Direct Thrombin Inhibitor, to Maintain Therapeutic Anticoagulation in a Patient With Antiphospholipid Antibody Syndrome, Heparin-Induced Thrombocytopenia, and COVID-19 Pneumonia.

In patients who require systemic anticoagulation, a reliable monitoring method is required to ensure anticoagulation is maintained within the correct therapeutic window and patients are treated appropriately. When titrating direct thrombin inhibitors (DTIs), dilute thrombin time (dTT) measurements have been demonstrated to be more reliable and accurate than activated partial thromboplastin time (aPTT) measurements and thus often the preferred DTI assessment. However, a clinical need arises when both dTT measurements are not readily available and aPTT measurements are unreliable. CASE SUMMARY: A 57-year-old woman with a history of antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, and multiple prior deep venous thromboses and pulmonary emboli was admitted with COVID-19 pneumonia and intubated due to hypoxic respiratory failure. Argatroban was initiated in place of her home medication warfarin. However, the patient had a prolonged aPTT value at baseline and overnight dTT assay measurements were limited at our institution. A multidisciplinary team of hematology and pharmacy clinicians created a modified patient-specific aPTT target range and argatroban dosing was titrated accordingly. Subsequent aPTT values in the modified target range corresponded to therapeutic dTT values, indicating therapeutic anticoagulation was successfully achieved and maintained. Patient blood samples were additionally evaluated retrospectively using an investigational novel point-of-care test that detected and quantified the argatroban anticoagulant effect. CONCLUSIONS: Therapeutic anticoagulation with a DTI in a patient with unreliable aPTT measurements can be achieved with use of a modified patient-specific aPTT target range. Early validation of an investigational rapid testing alternative for DTI monitoring is promising.

Heparin-based versus bivalirudin-based anticoagulation in pediatric extracorporeal membrane oxygenation: A systematic review.

Introduction: Optimal anticoagulation therapy is essential for the prevention of thrombotic and hemorrhagic complications in pediatric patients supported with extracorporeal membrane oxygenation (ECMO). Recent data have demonstrated bivalirudin has the potential to surpass and replace heparin as the anticoagulant of choice. Methods: We conducted a systematic review comparing the outcomes of heparin-based versus bivalirudin-based anticoagulation in pediatric patients supported on ECMO to identify the preferred anticoagulant to minimize bleeding events, thrombotic complications, and associated mortality. We referenced the PubMed, Cochrane Library, and Embase databases. These databases were searched from inception through October 2022. Our initial search identified 422 studies. All records were screened by two independent reviewers using the Covidence software for adherence to our inclusion criteria, and seven retrospective cohort studies were identified as appropriate for inclusion. Results: In total, 196 pediatric patients were anticoagulated with heparin and 117 were anticoagulated with bivalirudin while on ECMO. Across the included studies, it was found that for patients treated with bivalirudin, trends were noted toward lower rates of bleeding, transfusion requirements, and thrombosis with no difference in mortality. Overall costs associated with bivalirudin therapy were lower. Time to therapeutic anticoagulation varied between studies though institutions had different anticoagulation targets. Conclusion: Bivalirudin may be a safe, cost-effective alternative to heparin in achieving anticoagulation in pediatric ECMO patients. Prospective multicenter studies and randomized control trials with standard anticoagulation targets are needed to accurately compare outcomes associated with heparin versus bivalirudin in pediatric ECMO patients.

Correlation between partial thromboplastin time and thromboelastography in adult critically ill patients requiring bivalirudin for extracorporeal membrane oxygenation.

STUDY OBJECTIVE: Thromboelastography (TEG) offers a more dynamic assessment of hemostasis over activated partial thromboplastin time (aPTT). However, the clinical utility of TEG in monitoring bivalirudin during extracorporeal membrane oxygenation (ECMO) remains unknown. The purpose of this study was to evaluate the correlation between aPTT and TEG in adult ECMO patients anticoagulated with bivalirudin. DESIGN: Multicenter, retrospective, cohort study conducted over a 2-year period. SETTING: Two academic university medical centers (Banner University Medical Center) in Phoenix and Tucson, AZ. PATIENTS: Adult patients requiring ECMO and bivalirudin therapy with ≥1 corresponding standard TEG and aPTT plasma samples drawn ≤4 h of each other were included. The primary endpoint was to determine the correlation coefficient between the standard TEG reaction (R) time and bivalirudin aPTT serum concentrations. MEASUREMENTS AND MAIN RESULTS: A total of 104 patients consisting of 848 concurrent laboratory assessments of R time and aPTT were included. A moderate correlation between TEG R time and aPTT was demonstrated in the study population (r = 0.41; p < 0.001). Overall, 502 (59.2%) concurrent assessments of TEG R time and aPTT values showed agreement on whether they were sub-, supra-, or therapeutic according to the institution's classification for bivalirudin. The 42.2% (n = 271/642) discordant TEG R times among "therapeutic" aPTT were almost equally distributed between subtherapeutic and supratherapeutic categories. CONCLUSIONS: Moderate correlation was found between TEG R time and aPTT associated with bivalirudin during ECMO in critically ill adults. Further research is warranted to address the optimal test to guide clinical decision-making for anticoagulation dosing in ECMO patients.

Anticoagulant Use During Extracorporeal Membrane Oxygenation Using Heparin and Direct Thrombin Inhibitors in COVID-19 and ARDS Patients.

Coagulopathies develop in patients supported with the use of extracorporeal membrane oxygenation (ECMO) and can be hemorrhagic and/or thrombophilic in spite of the use of systemic anticoagulation. The purpose this study was to examine the use of heparin and direct thrombin inhibitors (DTI) in COVID-19 patients with acute respiratory distress syndrome (ARDS) on ECMO, with a subset analysis by disease state. Following IRB approval, 570 consecutive records were reviewed of adult patients on venovenous ECMO between May 2020 and December 2021. Patients were grouped by anticoagulant use: Heparin Only (n = 373), DTI Only (bivalirudin or argatroban, n = 90), or DTI after Heparin (n = 107). The effect of anticoagulant grouping was assessed using Bayesian mixed-effects logistic regression adjusting for age, body mass index (BMI), gender, days of mechanical ventilation prior to ECMO, indication for ECMO support, hepatic and renal failure, hours on ECMO, hours off anticoagulation, coagulation monitoring target, and hospital. The primary endpoint was circuit failure requiring change-out with secondary endpoints of organ failure and mortality. Regression-adjusted probability of circuit change-outs were as follows: DTI after Heparin patients-32.7%, 95% Credible Interval [16.1-51.9%]; DTI Only patients-23.3% [7.5-40.8%]; and Heparin Only patients-19.8% [8.1-31.3%]. The posterior probability of difference between groups was strongest for DTI after Heparin vs. Heparin Only (97.0%), moderate for DTI after Heparin vs. DTI Only (88.2%), and weak for DTI Only vs. Heparin only (66.6%). The occurrence of both hepatic and renal failure for DTI Only and DTI after Heparin patients was higher than that of Heparin Only patients. Unadjusted mortality was highest for DTI after Heparin (64.5%) followed by DTI Only (56.7%), and Heparin Only (50.1%, p = 0.027). DTI after Heparin was associated with an increased likelihood of circuit change-out. Unadjusted hepatic failure, renal failure, and mortality were more frequent among DTI patients than Heparin Only patients.

Anticoagulants: dose control methods and inhibitors

These days, anticoagulants are in great demand. They are used as a prophylaxis for thromboembolic complications in various diseases and conditions in general therapeutic practice, cardiology, neurology, as well as obstetrics to manage high-risk pregnancies. The relevance of anticoagulants competent use has come to the fore in connection with the emergence of a new disease – COVID-19 and its serious complications such as developing thrombotic storm, in which the timely applied anticoagulant therapy is the key to the success of therapy. The risk of bleeding should be considered when using any anticoagulant. Age, impaired renal function and concomitant use of antiplatelet agents are common risk factors for bleeding. Moreover, only vitamin K antagonists and heparin have specific antidotes – vitamin K and protamine, respectively. Inhibitors of other anticoagulants are universal presented as inactivated or activated prothrombin complex concentrate and recombinant factor VIIa. Hemodialysis effectively reduces dabigatran concentration, activated charcoal is effective in the case of recent oral administration of lipophilic drugs. Research on new antidotes of currently available anticoagulants is under way, similar to testing of new types of anticoagulants that are sufficiently effective in preventing and treating thromboembolic complications with minimal risk of hemorrhagic. The main contraindication to anticoagulants use is the doctor's ignorance of the mechanisms of drug action and opportunities for suppressing its effect.

Novel monitoring and dose adjustment of argatroban to maintain therapeutic anticoagulation

INTRODUCTION: In patients with unreliable activated partial thromboplastin time (aPTT) measurements who require anticoagulation with a direct thrombin inhibitor (DTI), the only reliable alternative measurement at present is a dilute thrombin time (dTT). However, this assay is not always readily available, which limits accurate real-time dose adjustments necessary to maintain therapeutic anticoagulation. DESCRIPTION: A 57 year-old woman with a history of antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, and multiple prior deep venous thromboses and pulmonary emboli was admitted with COVID-19 pneumonia and intubated due to hypoxic respiratory failure. Argatroban was initiated in place of her home medication warfarin. This patient had a prolonged aPTT value at baseline and overnight dTT assay measurements were limited at our institution. To overcome this challenge, a multidisciplinary team of hematology and pharmacy clinicians created a modified aPTT algorithm. By measuring aPTT and dTT simultaneously from patient plasma samples, a patientspecific aPTT target range was derived and argatroban dosing was titrated accordingly. Subsequent aPTT values in the modified target range corresponded to therapeutic dTT values, indicating therapeutic anticoagulation was successfully achieved and maintained. Patient plasma samples were also evaluated retrospectively using a novel point-of-care (POC) coagulation test to detect and quantify the effect of argatroban. A Clotting Time Score (CTS) was derived for each sample tested. Comparison of CTS and dTT values demonstrated moderate positive correlation between test results. All CTS results accurately reflected if argatroban dosing achieved an appropriate level of anticoagulation. DISCUSSION: Therapeutic anticoagulation with a DTI in a patient with unreliable aPTT measurements is challenging but can be achieved with use of a modified aPTT scale, which in our case study was retrospectively confirmed by corresponding dTT measurements. Early validation of a novel test that could offer a rapid, POC alternative to dTT when dTT measurements are necessary but not readily available is promising. Such a technology could dramatically improve rapid accurate titration of DTIs to maintain therapeutic anticoagulation.

Extreme gamma prime fibrinogen levels in covid-19 patients

Introduction: COVID-19 disease progression can be accompanied by a 'cytokine storm' that leads to secondary sequelae such as thrombosis and acute respiratory distress syndrome. Several inflammatory cytokines have been associated with COVID-19 disease progression, but have far too much daily intra-individual variability to be useful in tracking the course of the disease. In contrast, we have shown that the inflammatory biomarker γ' fibrinogen (γ' Fbg) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP. The aims of the study were to measure γ' Fbg in serial blood samples from COVID-19 patients at a tertiary care medical center in order to investigate its association with clinical measures of disease progression. Hypothesis: Our hypothesis was that γ' Fbg levels would be elevated in COVID-19 patients compared to historical controls, and that the degree of elevation would be associated with disease severity. Methods: COVID-19 patients at a tertiary care medical center were retrospectively enrolled between 3/16/2020 and 8/1/2020. γ' Fbg was measured using the GammaCoeur ELISA (Gamma Diagnostics, Patent Pending). Results: Our results showed that ten out of the eighteen patients with COVID-19 had the highest levels of γ' Fbg ever recorded. The previous highest γ' Fbg level of 80.3 mg/dL was found in a study of 10,601 participants in the ARIC study. γ' Fbg levels were significantly associated with the need for ECMO and mortality. Conclusions: We found that COVID-19 patients can develop extraordinarily high levels of γ' Fbg. This has several important clinical implications. γ' Fbg contains a high affinity binding site for thrombin that binds to anion-binding exosite II on thrombin and protects it from inactivation by heparin. High levels of γ' Fbg therefore provide a reservoir of heparin-resistant clot-bound thrombin when the γ' Fbg is clotted. These findings have potential clinical implications regarding prophylactic anticoagulation of COVID-19 patients and suggest that heparin prophylaxis may be less effective than using other anticoagulants, particularly direct thrombin inhibitors.