Muhammad B. Ghbeis’s research while affiliated with Boston Children's Hospital and other places

Severe forms of pulmonary embolism (PE) in children are rare but cause significant morbidity and mortality. In this article, we review the pathophysiology of severe (high- and intermediate-risk) PE and suggest novel pediatric-specific risk stratifications and an acute treatment algorithm to expedite emergent decision making. We define pediatric high-risk PE as causing cardiopulmonary arrest, sustained hypotension or normotension with signs or symptoms of shock. Rapid primary reperfusion should be pursued with either surgical embolectomy or systemic thrombolysis in conjunction with a heparin infusion and supportive care as appropriate. We define pediatric intermediate-risk PE as those without systemic hypotension nor compensated shock but with evidence of right ventricular strain by imaging and/or myocardial necrosis by elevated cardiac troponin levels. The decision to pursue primary reperfusion in this group is complex and should be reserved for patients with more severe disease; anticoagulation alone may also be appropriate in some cases. If primary reperfusion is pursued, catheter-based therapies may be beneficial. In summary, acute management of severe PE in children may include systemic thrombolysis, surgical embolectomy, catheter-based therapies or anticoagulation alone, and may depend on patient and institutional factors. Pediatric emergency and intensive care physicians should be familiar with the risks and benefits of each therapy in order to expedite care. PE Response Teams may also have added benefit in streamlining care during these critical events.

Ventricular assist devices (VAD) are used more in children. Safe and effective anticoagulation is required for successful management of children supported with ventricular assist devices. Developmental hemostasis, device hemocompatibility, plastic to body ratio, surgical variable techniques, lack of knowledge on pharmacokinetics of anticoagulants, and wide variability in anticoagulation protocols have all contributed to increased incidence of bleeding and thromboembolic complications. New collaborative learning networks, such as the ACTION network, provide opportunities to define best practices, optimize, and reduce anticoagulation related adverse events. ACTION was established Dec 2017. It consists of expert clinicians in heart failure, as well as researchers, parents, and patients, with goals to improve outcomes, share data, improve education and standard practice for children with heart failure ( ¹ , n.d). Changes in pediatric VAD anticoagulation strategy from using mainly heparin to DTI such as bivalirudin have helped reduce bleeding and clotting complications.

Background Enoxaparin is a commonly used anticoagulant for treatment of thrombosis in pediatric patients. Its use in pediatric cardiac patients has not been well described. We sought to examine the utilization trends, dosing, and safety of enoxaparin in pediatric cardiac patients. Methods Retrospective study of pediatric cardiac patients treated with enoxaparin from 2011-2018. Starting and final doses of enoxaparin, number of dose adjustments, and time to therapeutic anti-factor Xa level were compared between age groups utilizing the Kruskal Wallis test with the Dunn test for pairwise comparisons. Results Seventy-one patients were treated with 77 courses of enoxaparin. Most enoxaparin courses were started on patients aged > 12 months (40%) and for arterial thrombosis (22 patients, 29%). The most common cardiac diagnosis was hypoplastic left heart syndrome (12 patients, 17%). The mean final dose of enoxaparin was significantly different when comparing patients 0-3-month, 3-12 month, and >12 months (2.1 ± 0.5 mg/kg vs. 1.5 ± 0.4 mg/kg vs. 1.2 ± 1.4 mg/kg, respectively; p < 0.02). Patients 0-3 months and 3-12 months had significantly higher final to initial enoxaparin dose differences than the > 12-month age group (0.4 ± 0.4 mg/kg vs. 0.4 ± 0.4 mg/kg vs. 0.1 ± 0.3 mg/kg, respectively; p < 0.01). All age groups needed 2-2.5 days to reach therapeutic anti-Xa levels. Patients aged 0-3 months had significantly more dose changes compared to those >12 months (2.2 ± 1.6 vs. 1.4 ± 1.4, p = 0.02). Antiplatelet therapy was used in 74% of courses. Adverse events were rare and had no relationship to antiplatelet use. Conclusions Enoxaparin is an effective and safe anticoagulant in pediatric cardiac patients. Initial enoxaparin dosing should be increased from current recommended doses in patients between 3 and 12 months of age to achieve more timely therapeutic anticoagulation.

Introduction: Thrombosis is a complication associated with Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), Corona Virus Disease 2019 (COVID-19). Although, abnormalities in coagulation markers have been reported in adults with COVID-19, coagulopathy in pediatric patients infected with coronavirus has not been elucidated. Hypothesis: In this study, we evaluated the coagulation profile in pediatric patients with COVID-19 using Thromboelastography (TEG). Methods: This is a retrospective study of pediatric (≤18yrs) patients with seropositive COVID-19 (N=35) regardless of symptom status. Coagulation markers including TEG were obtained from review of medical records under an IRB approved study. All TEG parameters were compared between patients with COVID-19 and age matched controls without COVID-19 (N=35). Results: Regardless of symptom status, COVID-19 patients had significantly lower R-time (5.3±2.7 min vs. 6.5±1.5 min; p=0.03 ), K-time (1.1±0.3 min vs. 1.8±1.1 min; p<0.001 ) and fibrinolysis (1.7±1.7% vs. 3.2±3.6%; p=0.04 ); and significantly elevated angle (73.6±4.8 deg vs.66.7±6.2 deg; p<0.001 ), maximum amplitude (68.9±6.1 mm vs. 59.5±8.7 mm; p<0.001 ) and overall clot strength G (11.7±3.3 Kdynes/cm ² vs. 7.8±2.4 Kdynes/cm ² ; p<0.001 ). Whereas the standard coagulation tests such as PT/INR, PTT, Thrombin time and Heparin levels were within the normal pediatric reference ranges. D-dimer expression was also higher (0.94 μg/ml) in COVID-19 patients compared to the normal pediatric reference range (<0.4 μg/ml). In patients with COVID-19 undergoing aspirin therapy, all patients responded to the treatment and platelet function was significantly inhibited compared to patients not given aspirin (85% vs. 8% platelet inhibition; p<0.001 ). Conclusions: Abnormal expression of all TEG parameters and D-dimer is consistent with a hypercoagulable profile. TEG may be useful in reducing thrombosis-risk in patients with COVID-19 by guiding anticoagulation management.

Purpose The use of bivalirudin has increased dramatically for primary thromboprophylaxis in pediatric paracorporeal ventricular assist device (VAD) support with limited data on optimal monitoring of effect. Partial thromboplastin time (aPTT) is commonly used for monitoring of bivalirudin, but can be impacted by line heparin, variability in assays and other patient factors. As such, we sought to examine the correlation of PTT to International Normalized Ratio (INR), as a possible monitoring tool for bivalirudin in in pediatric VAD patients. Methods Retrospective single center study of all children aged <19 years, treated with bivalirudin for anticoagulation of paracorporeal VAD support. Pearson correlation coefficient was calculated for aPTT -INR and heparin absorbed (HA) aPTT-INR paired samples for each patient over the course of their support with each sample drawn at the same time. Results From 2015-2019, eleven patients (4 female), median age 5 months (range 0.5-40 months), weighing 7.8 kg (3.4-17.0kg) and body surface area of 0.4 m2 (range 0.2-0.7 m2) at time of implant were treated with bivalirudin for paracorporeal VAD thromboprophylaxis, of which 6 were on EXCOR devices, 4 were transitioned between continuous flow and EXCOR devices, and 1 patients was on CardioHelp extracorporeal membrane oxygenator connected to EXCOR cannula. A total of 900 days of paracorporeal VAD support generated 3,143 laboratory values for correlation. Correlations varied between aPTT assays, with highest median correlation coefficient for HA aPTT to INR of 0.72 (min 0.57 to max 0.81) in 4 patients with a total of 662 paired samples, as compared to correlation coefficient for aPTT to INR of 0.56 (min 0.32-0.91) in 10 patients with a total of 1,188 paired samples. Correlations varied between patients, with no association to age, device type or survival outcomes. The most important determinant for lack of correlation between aPTT to INR was concomitant administration of line heparin. Conclusion Patients treated with bivalirudin demonstrate individual correlations of their INR to PTT, with highest correlation to HA PTT by accounting for exogenous line heparin. This preliminary data provides foundation for ongoing study into the utility of INR for bivalirudin dosing and possible future application of point of care INR testing in this population.