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.

Optimization of Thrombinemia Laboratory Diagnostics in COVID-19-Patients

Introduction. Currently used and available in real clinical practice, laboratory tests do not allow an objective and reliable assessment of risk and severity of thrombinemia, prothrombotic readiness, and, as a result, does not allow to choose the appropriate optimal antithrombotic therapy regimen (administration of prophylactic or therapeutic anticoagulant doses) in relation to the screening of this condition in severe COVID-19. Objective: analysis of prothrombotic readiness in COVID-19-patients by integral method — thrombin generation (kinetics) assay. Materials and Methods. A prospective clinical and laboratory study included 100 patients (average age was 63 [31–85] years, 60 women, 40 men) with an identified SARS-CoV-2 virus with moderate and severe course of novel coronovirus infection. Parameters of thrombin generation (kinetics) assay — clotting initiation time (tLag), time of thrombin peak formation (tPeak), thrombin peak (Peak), endogenous thrombin potential (ETR;area under the thrombin formation curve, AUC) were determined, as well as levels of fibrinogen, D-dimer, ferritin, C-reactive protein (CRP), activated partial thromboplastin time (APTT), prothrombin time (PT), international normalized ratio (INR). Results. The results of thrombin kinetics assay pointed to an increased blood procoagulant potential in COVID-19-patients on admission to the hospital;correlations were found between tLag and fibrinogen (rS = –0.7;p = 0.001), tLag and CRP (rS = –0.1;p = 0.01);between tPeak and all inflammation markers — D-dimer (rS = –0.4;p = 0.001), ferritin (rS = –0.2;p = 0.01), CRP (rS = –0.3;p = 0.05), fibrinogen (rS = –0.5;p = 0.001);between Peak and fibrinogen (rS = 0.3;p = 0.001);between rate index (VI) and fibrinogen (rS = 0.2;p < 0.001);between AUC and fibrinogen (rS = 0.4;p = 0.001), AUC and CRP (rS = 0.1;p = 0.001). Conclusion. Thrombin generation (kinetics) assay can be considered as a marker of thrombinemia — prothrombotic readiness in patients with moderate and severe course of novel coronovirus infection. © 2023, Hemostasis and Rheology LLC. All rights reserved.

Coagulation parameters predict COVID-19-related thrombosis in a neural network with a positive predictive value of 98.

Thrombosis is a major clinical complication of COVID-19 infection. COVID-19 patients show changes in coagulation factors that indicate an important role for the coagulation system in the pathogenesis of COVID-19. However, the multifactorial nature of thrombosis complicates the prediction of thrombotic events based on a single hemostatic variable. We developed and validated a neural net for the prediction of COVID-19-related thrombosis. The neural net was developed based on the hemostatic and general (laboratory) variables of 149 confirmed COVID-19 patients from two cohorts: at the time of hospital admission (cohort 1 including 133 patients) and at ICU admission (cohort 2 including 16 patients). Twenty-six patients suffered from thrombosis during their hospital stay: 19 patients in cohort 1 and 7 patients in cohort 2. The neural net predicts COVID-19 related thrombosis based on C-reactive protein (relative importance 14%), sex (10%), thrombin generation (TG) time-to-tail (10%), α2-Macroglobulin (9%), TG curve width (9%), thrombin-α2-Macroglobulin complexes (9%), plasmin generation lag time (8%), serum IgM (8%), TG lag time (7%), TG time-to-peak (7%), thrombin-antithrombin complexes (5%), and age (5%). This neural net can predict COVID-19-thrombosis at the time of hospital admission with a positive predictive value of 98%-100%.

Long COVID-19 syndrome: Association of cardiopulmonary impairment with a persistent platelet activation

Background: A considerable proportion of patients do not fully recover from COVID-19 infection and report symptoms that persist beyond the initial phase of infection: This condition is defined long-COVID-19 syndrome (LCS). LCS can involve lungs as well as several extrapulmonary organs, including the cardiovascular system. The risk and 1-year burden of cardiovascular diseases (CVD) is increased in COVID-19 survivors, even in subjects at low risk of CVD. Recently, we documented that acute COVID- 19 infection induces altered platelet activation state characterized by a prothrombotic phenotype and by the formation of platelet-leukocyte aggregates (PLA), that may be involved in the pulmonary microthrombi found in autoptic specimens. No data are yet available on the contribution of platelet activation to residual pulmonary impairment and procoagulant potential in LCS patients. Purpose(s): To study platelet activation status, microvesicle (MV) profile, platelet thrombin generation capacity (pTGC) in LCS patients enrolled at 6 months after resolution of the acute phase (6mo-FU), compared to acute COVID-19 infection patients. Method(s): 6mo-FU COVID-19 patients (n=24) with established LCS were enrolled at Centro Cardiologico Monzino. Residual pulmonary impairment was assessed by Cardiopulmonary Exercise Testing (CPET) and 64-rows- CT scan evaluation. Platelet activation (P-selectin, Tissue Factor [TF] and PLA) and MV profile were assessed by flow cytometry;pTGC by calibrated automated thrombogram. 46 patients enrolled during acute COVID-19 infection and 46 healthy subjects (HS) were used for comparison. Result(s): Dispnea in LCS patients was confirmed by CPET showing compromised alveolus-capillary membrane diffusion and residual pulmonary impairment. TF+-platelet and -MV levels were 3-fold (1.5% [1.2-2.9] vs 2.4% [1.6-5.7]) and 2-fold (217/mul [137-275] vs 435/mul [275-633]) lower at 6mo-FU compared to acute phase, being comparable to HS. pTGC behaved similarly. At 6mo-FU, the MV profile, in terms of total number and cell origin, returned to physiological levels. Conversely, although lower than that measured in acute phase, a 2.5-fold higher platelet P-selectin expression (6.9% [3-13.5] vs 11.7% [5.2-18.9]) and PLA formation (35.5% [27.4- 46.8] vs 67.7% [45.7-85.3]) was observed at 6mo-FU compared to HS. Interestingly, a significant correlation between PLA formation and residual pulmonary impairment was observed (r=-0.423;p=0.02). Conclusion(s): These data strengthen the hypothesis that the presence of PLA in the bloodstream, and thus also in the pulmonary microcirculation, may contribute to support pulmonary dysfunction still observed in LCS patients.

PERSONALIZED CORRECTION OF HEMOSTASIS SYSTEM DISORDERS IN PATIENTS WITH COVID-19.

Violations of the hemostasis (blood aggregation control, BAC) system in patients with COVID-19 in the acute period and at the stage of convalescence have been studied and methods of targeted correction of the identified disorders are considered. Prevention of serious complications related to COVID-19 infection requires complex assessment of the hemostasis system and prompt correction of disorders. Methods of clinical hemostasiograms and low-frequency piezothromboelastography (LPTEG) provide comprehensive and informative assessment of functional state of the BAC system and monitoring of the effectiveness of therapy, both in hospital and on outpatient basis. It was established that hemostasis system disorders had unspecified character with hyper- or hypocoagulation in the acute period and structural or chronometric hypercoagulation in the recovery period. Under LPTEG monitoring in hospital, the identified disorders were corrected by low-molecular-weight (LMW) heparins, blood-based preparations, and fibrinolysis inhibitors;at the outpatient stage, the therapy was supplemented with sulodexide and anticoagulants. Personalized correction of the hemostatic potential was based on the following LPTEG parameters. Prescription of the anti-aggregant and vasoprotective therapy required that the response time (t1) would be reduced below 0.9 min and thrombin activity (TA) constant increased above 40 relative units. The anticoagulant therapy was prescribed when the gelation point (t3) decreased to 4.7 min and the coagulation drive intensity (CDI) index was above 50 relative units. The fibrinolytic activity was corrected when the clot polymerization intensity (CPI) index was above 20 relative units, the cross-linked fibrin formation time (t5) decreased to 27 min, and the clot retraction and lysis intensity (CRLI) index exceeded 15%. The boundary values of these LPTEG parameters were adjusted at the levels of moderate hypercoagulation or reference normal coagulation. The LPTEG monitoring and personalization of the prescribed antithrombotic therapy allowed the risk of thrombo-hemorrhagic complications to be reduced at all stages of COVID-19 treatment.Copyright © 2021 Authors. All rights reserved.

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.

Evaluation of the protein C pathway in critically ill patients with severe COVID-19 as compared to bacterial sepsis

Introduction Endothelial dysfunction has been shown to play a role in severe COVID-19, the pathophysiology of which may be attributed to a myriad of factors including unmitigated immune and inflammatory response, viral-induced injury to the endothelium, end-stage organ failure, and coagulopathy. In addition, severe COVID-19 is most often seen in patients with multiple comorbidities, which themselves are often associated with endothelial dysfunction (such as myocardial and renal failure, as well as thrombotic disorders). However, the literature is still emerging on this topic and there appears to be no consensus on the extent to which endothelial dysfunction plays a role in severe COVID-19. Method The aim of this study was to assess the functionality of the endothelial protein C pathway in hospitalized patients > 18 years of age with severe COVID-19 as compared to those hospitalized with bacterial sepsis. COVID-19 (n = 31) and sepsis (n = 47) patients who were admitted to the ICU were assessed for rates of thrombin and activated protein C (APC) generation. Indirect markers of thrombin formation, including thrombin-antithrombin (TAT) complex, prothrombin fragment 1 + 2 (F1 + 2), as well as D-dimer, and protein C (PC) were measured additionally. Statistical analysis was performed via the Mann-Whitney test and a p value of < 0.05 was considered statistically significant. Results Plasma levels of free thrombin in COVID-19 and sepsis patients did not differ significantly, with (median, IQR) 0.59 (0.46-1.21) vs 0.57 (0.46-1.10) pmol/L, respectively. TAT was also increased at similar extent in both cohorts (192;111-325 pmol/L in COVID-19 patients, 148;73-213 pmol/L in sepsis patients), whereas F1 + 2 was higher in COVID-19 than in sepsis patients, with 850 (440-1940) vs 380 (130-620) pmol/L (p = 1.3 x 10-5). Interestingly, rates of APC formation did not significantly differ between the two groups, with 7.47 (1.99- 19.14) vs 9.87 (2.08-16.87) pmol/L ( Fig. 1). D-dimer and protein C were significantly higher in the COVID-19 patients than in those with sepsis (14.3 vs 8.1 mg/L, p = 0.01, and 92.9 % vs 58.5 %, p = 3x10-8, respectively). Conclusion We hypothesized that APC formation rates in response to thrombin formation would be significantly lower in patients with severe COVID-19 as compared to those with bacterial sepsis due to the well-known association between severe COVID-19 disease burden and endothelial dysfunction due to the downregulation of thrombomodulin expression. However, our results indicate that this may not be universally true in this patient population, as our observations suggest a largely intact functionality of the protein C pathway. Further studies are warranted to investigate the pathophysiology of severe COVID-19. (Figure Presented).

Characteristics of coagulation hemostasis in corona virus infection

Studying the activity of coagulation hemostasis in the main groups of coronavirus infection helps to prevent life-threatening complications. In the clinical study, 350 patients were examined, including 100 patients with mild, 150 moderate and 100 severe coronavirus infections. Coagulation hemostasis indicators did not reliably change in patients with mild coronavirus infection, but hypercoagulation was detected in moderate and severe coronavirus infection: active partial thromboplastin time decreased by 26 - 40%, INR decreased to 0.79 +or- 0.05*, thrombin time 22, decreased by 3-45.2%, fibrinogen increased by 37.4 - 58.6%, D dimer increased by 69% and more.

Review: Coagulation Panel in Patients with SARS-CoV2 Infection (COVID-19)

The 2019 novel coronavirus (SARS-CoV2) is the causal agent of the newly-termed Coronavirus Disease 2019 (COVID-19). In January 2020, the World Health Association (WHO) declared the COVID-19 as an epidemic. Abnormal coagulation parameters in COVID-19 patients currently are considered as prognostic factors of severity. Our aim is to summarize the current data available in the literature. Materials and Methods. An electronic search was performed in the Database of publications on coronavirus disease (COVID-19) of the World Health Organization. Thrombin Time (TT), Prothrombin Time (PT), Fibrinogen (FIB), Activated Partial Thromboplastin Time (APPT), and D-Dimer have been detected as parameters to study in every COVID-19 patient. Clinical Application. The coagulation function panel has been described to be altered in critical COVID-2019 patients. DIC, which plays an important role in advanced stage, is known to be associated with sepsis. Anticoagulant therapy, mainly with low molecular weight heparin (LMWH), appears to be associated with better prognosis in patients with severe COVID-19. Discussion. Coagulation function in patients with SARS-CoV2 infection is significantly deranged compared with normal patients. FIB and D-Dimer/FDP are the most significantly altered values and the early deetection of alteration could be useful to address therapies. D-Dimer/FDP (DD/FDP) alteration correlates with severity. Markedly elevated D-Dimer can be used to guide the introduction of anticoagulation therapy and evaluate prognosis of COVID-19. In every patient admitted with SARS-CoV2 infection PT, FIB, D-Dimer/FDP, and platelets must be ordered. We suggest daily extraction for every patient admitted and tested positive for COVID-19.Copyright © 2020 by the Association of Clinical Scientists, Inc.

COVID-19 Mortality and the Cytokine Storm: An Added Value for APOE Genotyping

The new COVID-19 presents some comorbidities, such as obesity, Alzheimer's, and coronary risk, among others. We argue that the current understanding of some of these clinical conditions may illuminate the design of future COVID-19 studies to account for a bias that may be the cause of the para-doxical associations between COVID-19 mortality and cytokine storm. Given that we know some of the genetic mechanisms behind these diseases, it is possible to circumscribe these studies to some key genes that help us understand why some patients experience a cytokine storm and what the treatment strategies might be. In this paper, we discuss the role of A2M and APOE genes. A2M encodes a multifaceted protein which is highly expressed in the liver and released to the bloodstream associated with the apolipopro-tein E. This association depends on the APOE genotype. A2M has protease-clearing activity binding of a broad range of proteases, such as thrombin and Factor Xa. It also presents the ability to bind to proin-flammatory ligands, like cytokines. Further, A2M acts as chaperone of misfolded substrates, like beta-amyloid peptide. The last two molecular functions grant it a key role in regulating both inflammatory processes, as well as extracellular protein homeostasis. For these reasons, we conclude that A2M-APOE association will have prophylactic, therapeutic, and prognostic implications;and the proper understanding of the physiological role of APOE and A2M in controlling inflammatory processes can shed further light on the putative treatment of COVID-19-derived cytokine storm.Copyright © 2022 Bentham Science Publishers.

Acute Mesenteric Thrombosis, Small Intestine Necrosis and Peritonitis as a Complication of Covid-19 - a Case Report

Introduction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to a family of ribonucleic acid (RNA) viruses, causing novel coronavirus disease 2019 (COVID-19). Because of a global inflammatory response and endothelial damage, COVID-19 may predispose to coagulation disorders and severe thrombotic events. Case presentation. A 62-year-old man patient was admitted for COVID-19 pneumonia and abdominal pain for 10 days. Because of the rapid deterioration of the clinical status, shock and evidence of peritoneal irritation, the patient was consulted by a surgeon. The native spiral computed tomography (CT) of the abdomen detected enlarged colon filled with air collections and hydro-aeric levels. The surgical intervention revealed diffuse peritonitis with necrosis of the distal ileum secondary to mesenteric thrombosis. A partial resection of the ileum was done. The histological examination showed an infarcted small bowel, with hemorrhage, vascular thrombosis, and signs of necrotizing endovasculitis. Conclusions. SARS-CoV-2 binds to ACE2 receptor, which results in increased signalling by thrombin receptors on platelet and endothelial cells, leading to coagulopathy. In older patients presenting with abdominal pain, shock and peritonitis, the most common underlying cause is mesenteric thrombosis which could be a complication of COVID-19.Copyright © 2022 Balkan Medical Union.

Monitoring of argatroban in COVID-19 ICU patients: A prospective study comparing aPTT, point-of-care viscoelastic testing with ECA-test and dTT to LC/MS/MS

Introduction Argatroban is indicated for treatment of heparin-induced thrombocytopenia, but is also used in critical ill COVID-19 patients presenting with extensive thrombin overload. Direct drug monitoring is not available and argatroban dosing is mainly based on activated partial plasmin time (aPTT), which has limitations in hypercoagulable patients with increased FVIII [1, 2]. The aim of this study was to compare correlation of routine clotting tests (aPTT, ecarin clotting time [ECA-CT] and diluted thrombin time [dTT]) [3] to argatroban plasma levels measured by gold standard mass spectrometry (LC/MS/MS). Method From 06/2021 to 03/2022, 205 samples from 22 COVID-19 ICU patients were analyzed: aPTT and dTT on STA R Max3-Analyzer (Stago Deutschland GmbH, Germany) using the BIOPHEN DTI Kit with Argatroban-calibration (CoaChrom Diagnostica GmbH, Austria);ECA-CT was measured using ClotPro ecarin assay. LC/MS/MS was performed using an RP column, a solvent gradient and an API4000 mass spectrometer with electrospray. Correlation was analyzed using Pearson correlation coefficient r in R version 3.2.4. This study was approved by the Ethics Committee of the Technical University of Dresden, Germany (BO-EK-64022022) and registered with German Clinical Trials Register DRKS00028689. Results From 205 samples with LC/MS/MS analysis, 195 were compared to aPTT, 153 to ECA-CT and 105 to dTT. In 40 samples, dTT was not measureable due high bilirubin values. Compared to LC/MS/MS, correlation of dTT was highest (r = 0.924), followed by ECA-CT (r 0.609) and aPTT (r 0.367;p < 0.001;Fig. 1). When recommended cut-offs for argatroban plasma levels (500-1000 ng/ml according to SmPC) were applied, dTT (when measurable) and ECA-CT better identified critical values of argatroban plasma values > 1000ng/ml than aPTT (Fig. 2). Conclusion Argatroban in critical ill COVID-19 patients should be monitored using dTT. If dTT is not possible or measurements are highly time-sensitive, point-of-care ClotPro ECA-test should be preferably used instead of aPTT. (Table Presented).

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.

Percutaneous thrombin injection under contrast-enhanced ultrasound guidance to control active extravasation not associated with pseudoaneurysm.

The technique of percutaneous thrombin injection (PTI) under contrast-enhanced ultrasound (CEUS) guidance for control of acute hemorrhage-active extravasation not associated with (pseudo) aneurysm is demonstrated in three cases: 1) massive spontaneous retroperitoneal hematoma in a patient with multiple comorbidities. Contrast-enhanced computed tomography (CT) showed extensive active extravasation, which was only partially controlled by transarterial embolization. CEUS was performed in the angiography suite. Contrary to unenhanced US and color Doppler (CD), CEUS confirmed persistent extravasation; CEUS-guided PTI was performed immediately thereafter. 2) Large rectus sheath hematoma in a patient on anticoagulant therapy. Contrast-enhanced CT and unenhanced US/CD could not definitely diagnose extravasation. CEUS clearly showed extravasation and was used for guidance of PTI. 3) Chest wall hematoma complicating central venous catheter placement in a patient with coronavirus on anticoagulant therapy. CD was inconclusive. CEUS was performed at the bedside, clearly showed active extravasation, and was used for guidance of PTI. In all three cases, post-PTI CEUS confirmed the absence of residual enhancement of the hematomas, and the hemodynamic status of the patients improved. PTI appears to be effective in selected cases of hematomas associated with active extravasation. In this context, CEUS may be the most suitable modality for guidance and for an immediate evaluation of the treatment effect.

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.

SARS-CoV-2 vaccines are not associated with hypercoagulability in apparently healthy people.

Background: SARS-CoV-2 adenoviral-vector-DNA vaccines have been linked to the rare but serious thrombotic post-vaccine complication vaccine-induced immune thrombotic thrombocytopenia (VITT). This has raised concerns regarding the possibility of increased thrombotic risk after any SARS-CoV-2 vaccines. Objectives: To investigate whether SARS-CoV-2 vaccines cause coagulation activation leading to a hypercoagulable state. Methods: This observational study included 567 healthcare personnel, 521 were recruited post-vaccination after a first dose of adenoviral vector ChAdOx1-S (Vaxzevria®, AstraZeneca) vaccine, and 46 prospectively before vaccination with an mRNA vaccine, either Spikevax® (Moderna, n=38) or Comirnaty® (Pfizer-BioNTech, n=8). In the mRNA group, samples were acquired before and 1-2 weeks after vaccination. In addition to pre-vaccination samples, 56 unvaccinated blood donors were recruited as controls (total n=102). Thrombin generation, D-dimer and free tissue factor pathway inhibitor (TFPI) were analyzed. Results: No participant experienced thrombosis, VITT or thrombocytopenia (platelet count <100·109/L) one week to one month post-vaccination. There was no increase in thrombin generation, D-dimer or TFPI in the ChAdOx1-S vaccine group compared with controls, or after the mRNA vaccines compared with baseline values. Eleven of 513 vaccinated with ChAdOx1-S (2.1%) had anti-PF4/polyanion antibodies without concomitant increase in thrombin generation. Conclusion: In this study, SARS-CoV-2 vaccines were not associated with thrombosis, thrombocytopenia, increased thrombin generation, D-dimer or TFPI levels compared with baseline or unvaccinated controls. These findings argue against subclinical activation of coagulation post-COVID-19 vaccination.

Surface control approach for growth of cerium oxide on flower-like molybdenum disulfide nanosheets enables superior removal of uremic toxins

Due to the high incidence of kidney disease, there is an urgent need to develop wearable artificial kidneys. This need is further exacerbated by the coronavirus disease 2019 pandemic. However, the dialysate regeneration system of the wearable artificial kidney has a low adsorption capacity for urea, which severely limits its application. Therefore, nanomaterials that can effectively remove uremic toxins, especially urea, to regenerate dialysate are required and should be further investigated and developed. Herein, flower-like molybdenum disulphide (MoS2) nanosheets decorated with highly dispersed cerium oxide (CeO2) were prepared (MoS2/CeO2), and their adsorption performances for urea, creatinine, and uric acid were studied in detail. Due to the open interlayer structures and the combination of MoS2 and CeO2, which can provide abundant adsorption active sites, the MoS2/CeO2 nanomaterials present excellent uremic toxin adsorption activities. Further, uremic toxin adsorption capacities were also assessed using a self-made fixed bed device under dynamic conditions, with the aim of developing MoS2/CeO2 for the practical adsorption of uremic toxins. In addition, the biocompatibility of MoS2/CeO2 was systematically analyzed using hemocompatibility and cytotoxicity assays. Our data suggest that MoS2/CeO2 can be safely used for applications requiring close contact with blood. Our findings confirm that novel 2-dimensional nanomaterial adsorbents have significant potential for dialysis fluid regeneration. © 2022

Only Subclinical Alterations in the Haemostatic System of People with Diabetes after COVID-19 Vaccination.

People with diabetes have an increased risk of experiencing adverse COVID-19 outcomes. COVID-19 vaccination is, therefore, highly recommended. However, people with diabetes have an inherently elevated risk of thrombotic events and the impact of the vaccination on the coagulation system in this patient population remains to be elucidated. The aim of this study was to investigate the impact of COVID-19 vaccination on the haemostatic system in people with type 1 or type 2 diabetes. We evaluated the effects of COVID-19 vaccination (BioNTech Pfizer, Moderna, AstraZeneca) on standard coagulation parameters, whole blood coagulation (Thrombelastometry), platelet function (impedance aggregation), and thrombin generation (calibrated automated thrombography) in people with type 1 diabetes mellitus (n = 41) and type 2 diabetes mellitus (n = 37). Blood sampling points were prior to vaccination and two weeks after the respective vaccination. Thrombelastometry measurements indicated moderately increased clot formation post-vaccination in people with type 1, as well as with type 2, diabetes: "Clot formation times" were significantly shorter, and both "maximum clot firmness" and "alpha angles" were significantly higher, as compared to the respective pre-vaccination values. Therefore, TEM parameters were not altered after vaccination in patients receiving ASA. Moreover, platelet aggregation was enhanced in people with type 1 diabetes, and plasma levels of D-Dimer were increased in people with type 2 diabetes, following COVID-19 vaccination. All other standard coagulation parameters, as well as thrombin generation, were not affected by the vaccination. The coagulation responses of people with diabetes to COVID-19 vaccination were only subclinical and comparable to those observed in healthy individuals. Our findings suggest that people with diabetes do not face an increased activation of the coagulation post-vaccination.

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.

Decreased protein C activity, lower ADAMTS13 antigen and free protein S levels accompanied by unchanged thrombin generation potential in hospitalized COVID-19 patients.

INTRODUCTION: COVID-19 is associated with an increased thromboembolic risk. However, the mechanisms triggering clot formation in those patients remain unknown. PATIENTS AND METHODS: In 118 adult Caucasian severe but non-critically ill COVID-19 patients (median age 58 years; 73 % men) and 46 controls, we analyzed in vitro plasma thrombin generation profile (calibrated automated thrombogram [CAT assay]) and investigated thrombophilia-related factors, such as protein C and antithrombin activity, free protein S level, presence of antiphospholipid antibodies and factor V Leiden R506Q and prothrombin G20210A mutations. We also measured circulating von Willebrand factor (vWF) antigen and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) antigen and activity. In patients, blood samples were collected on admission to the hospital before starting any therapy, including heparin. Finally, we examined the relationship between observed alterations and disease follow-up, such as thromboembolic complications. RESULTS: COVID-19 patients showed 17 % lower protein C activity, 22 % decreased free protein S levels, and a higher prevalence of positive results for IgM anticardiolipin antibodies. They also had 151 % increased vWF, and 27 % decreased ADAMTS13 antigens compared with controls (p < 0.001, all). On the contrary, thrombin generation potential was similar to controls. In the follow-up, pulmonary embolism (PE) occurred in thirteen (11 %) patients. They were characterized by a 55 % elevated D-dimer (p = 0.04) and 2.7-fold higher troponin I (p = 0.002) during hospitalization and 29 % shorter time to thrombin peak in CAT assay (p = 0.009) compared to patients without PE. CONCLUSIONS: In COVID-19, we documented prothrombotic abnormalities of peripheral blood. PE was characterized by more dynamic thrombin generation growth in CAT assay performed on admittance to the hospital.