Heparin Resistance Research Articles

The Rise and Fall of Antithrombin Supplementation in Cardiac Surgery.

Various cohort studies, both retrospective and prospective, showed that low antithrombin levels after cardiac surgery (at the arrival in the intensive care unit and during the next days) were associated with a number of adverse outcomes, including surgical reexploration and thromboembolic events, eventually leading to prolonged stay in the intensive care. Values lower than 58% to 64% of antithrombin activity were indicative of this higher morbidity with good sensitivity and specificity. The scenario generated the hypothesis that low antithrombin levels needed to be corrected by supplementation to improve postoperative outcome. However, randomized controlled studies run to test this idea failed to demonstrate any benefit of antithrombin supplementation, showing no effects on outcome, neither as preemptive preoperative strategy nor for treating postoperative low antithrombin values. In addition, randomized trials highlighted that those patients who received antithrombin experienced significantly higher incidence of acute kidney injury with a pooled odds ratio of 4.41 (95% CI, 1.90-10.23; P = .001). A strongly decreased thrombin activity after antithrombin correction may eventually affect the efficiency of the glomerular filtration and cause the deterioration of kidney function, but underlying biological mechanisms remain unclear. In conclusion, low levels of antithrombin activity after cardiac surgery should be considered as a marker of greater severity of the patient's conditions and/or of the complexity of the surgical procedure. There are no indications for antithrombin supplementation in cardiac surgery unless for correcting heparin resistance.

Low-Molecular-Weight Heparin Resistance and Its Viscoelastic Assessment in Critically Ill COVID-19 Patients.

Critically ill COVID-19 patients present an inflammatory and procoagulant status with a high rate of relevant macro- and microvascular thrombosis. Furthermore, high rates of heparin resistance have been described; yet, individualized anticoagulation by drug monitoring has not been sufficiently researched. We analyzed data from critically ill COVID-19 patients treated at Innsbruck Medical University Hospital with routinely adapted low-molecular-weight heparin (LMWH) doses according to anti-Xa peak levels, and regularly performed ClotPro analyses (a viscoelastic hemostatic whole blood test). A total of 509 anti-Xa peak measurements in 91 patients were categorized as below (<0.008 IU/mL/mg), within (0.008-0-012 IU/mL/mg) or above (> 0.012 IU/mL/mg) expected ranges with respect to the administered LMWH doses. Besides intergroup comparisons, correlations between anti-Xa levels and ClotPro clotting times (CTs) were performed (226 time points in 84 patients). Anti-Xa peak levels remained below the expected range in the majority of performed measurements (63.7%). Corresponding patients presented with higher C-reactive protein and D-dimer but lower antithrombin levels when compared with patients achieving or exceeding the expected range. Consequently, higher enoxaparin doses were applied in the sub-expected anti-Xa range group. Importantly, 47 (51.6%) patients switched between groups during their intensive care unit (ICU) stay. Anti-Xa levels correlated weakly with IN test CT and moderately with Russell's viper venom (RVV) test CT. Critically ill COVID-19 patients present with a high rate of LMWH resistance but with a variable LMWH response during their ICU stay. Therefore, LMWH-anti-Xa monitoring seems inevitable to achieve adequate target ranges. Furthermore, we propose the use of ClotPro's RVV test to assess the coagulation status during LMWH administration, as it correlates well with anti-Xa levels but more holistically reflects the coagulation cascade than anti-Xa activity alone.

A case of COVID‐19 with pernio‐like skin lesions and increased red blood cell distribution width

Heparin resistance has been observed in patients with active severe COVID‐19 infection. The red blood cell distribution (RDW), a component of the complete blood count that reflects cellular volume variation, has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases. Cutaneous manifestations, RDW, and levels of LD and D‐dimer might be useful biomarkers in triage of patients with COVID‐19.

Andexanet-Alfa-Associated Heparin Resistance in the Context of Hemorrhagic Stroke

BackgroundWith a growing number of patients on new oral anticoagulants, interest in reversal agents is rising. Andexanet alfa is used for reversal of factor Xa inhibitors in intracranial hemorrhage.MethodsWe provide a brief review on andexanet-alfa-associated heparin resistance and discuss potentially critical situations from different clinical perspectives.ResultsCase reports point out that andexanet alfa can cause unresponsiveness to heparin, leading to catastrophic events. As a result, regulatory bodies have issued warning notices to avoid heparinization parallel to the use of andexanet alfa.ConclusionsAlthough well known to hematologists, the phenomenon is underrecognized among stroke clinicians. However, patients with intracranial hemorrhage frequently undergo endovascular or surgical interventions that require periprocedural administration of heparin.

Heparin Resistance in SARS-CoV-2 Infected Patients with Venous Thromboembolism.

Introduction: Heparin resistance has been reported in coronavirus disease 2019 (COVID-19) patients receiving intravenous unfractionated heparin (IV UFH). Anti-Xa monitoring of IV UFH has been suggested over activated partial thromboplastin times due to laboratory interference from elevated factor VIII and fibrinogen levels in COVID-19 patients. Information on heparin resistance with anti-Xa monitoring in COVID-19 patients with confirmed venous thromboembolism (VTE) is lacking. Methods: In this retrospective cohort study of patients with radiographically confirmed VTE, IV UFH dosage requirements in COVID-19 positive patients were compared with COVID-19 negative patients. The primary endpoint was the IV UFH dose needed to achieve a therapeutic anti-Xa level. Secondary endpoints included time to therapeutic anti-Xa, number of dose adjustments to achieve therapeutic anti-Xa, and bleeding. Results: Sixty-four patients with confirmed VTE were included (20 patients COVID-19 positive, 44 patients COVID-19 negative). Eighty-five percent (17 of 20) of COVID-19 positive patients achieved anti-Xa ≥ 0.3 units/mL with the first anti-Xa level drawn post-IV UFH infusion initiation. The median UFH dose needed to achieve first therapeutic anti-Xa was similar between COVID-19 positive and COVID-19 negative patients (median [IQR]: 18 units/kg/hour [18-18] vs 18 units/kg/hour [18-18], P = .423). The median number of dose adjustments and time to achieve therapeutic anti-Xa were also similar between the 2 groups. The frequency of patients receiving IV UFH of more 35 000 units/day did not differ between the 2 groups. Two cases of clinically significant heparin resistance in the COVID-19 positive group were identified. Conclusions: During the first wave of COVID-19, heparin dose and time to therapeutic anticoagulation appeared to be similar between COVID-19 positive and COVID-19 negative patients monitored by anti-Xa at our institution. More studies are required to evaluate clinically significant heparin resistance in the context of the wide range of viral variants which developed, and beyond the population observed in this single center retrospective study.

The Changing Landscape of Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation: Use of the Direct Thrombin Inhibitors

Bleeding and thrombosis frequently occur in pediatric patients with extracorporeal membrane oxygenation (ECMO) therapy. Until now, most patients are anticoagulated with unfractionated heparin (UFH). However, heparin has many disadvantages, such as binding to other plasma proteins and endothelial cells in addition to antithrombin, causing an unpredictable response, challenging monitoring, development of heparin resistance, and risk of heparin-induced thrombocytopenia (HIT). Direct thrombin inhibitors (DTIs), such as bivalirudin and argatroban, might be a good alternative. This review will discuss the use of both UFH and DTIs in pediatric patients with ECMO therapy.

A Review of Pharmacogenetics of Anticoagulant Therapy

Variances in the patients’ outcomes have been a well-documented challenge in anticoagulant therapy. A clinical encounter with a thromboembolic or a hemorrhagic event, due to subtherapeutic or adverse effects of an anticoagulant, is often managed by switching the anticoagulant agent into another, which is more specific and direct-acting. This management approach is usually associated with a financial burden. Additionally, the certainty of achieving better efficacy and safety profile is still questionable. Genetic variants affecting the protein sites that are involved in the anticoagulant pharmacokinetic and pharmacodynamics interactions have been suggested to contribute to the variability in the response to anticoagulant therapy. The current work reviewed the studies investigating the response variability associated with the anticoagulant therapy (heparins, rivaroxaban, apixaban, and dabigatran) and the potential pharmacogenes contributing to such response variability. Several genetic polymorphisms were reported as potential contributors to variances in response to anticoagulant therapy and were associated with adverse events. A link has been proposed for heparin resistance with single nucleotide polymorphisms (SNPs) of the anti-thrombin-encoding gene (SERPINC1) as well as heparin-induced thrombocytopenia with human leukocyte antigen (HLA) variant allele (HLA-DRB3*01:01). Several investigations also remarked variations in the serum drug level of direct oral anticoagulants (DOACs) that are associated with SNPs in the proteins contributing to the pharmacokinetics of the anticoagulant agent. Several studies discerned significant associations between SNPs in the ABCB1 gene and elevations in the serum levels of rivaroxaban, apixaban, and dabigatran. Moreover, carriers of the variant genotype of the SNP (rs776746) in the cytochrome P450 3A5 enzyme-encoding gene (CYP3A5) had significantly higher drug levels when compared with the non-carriers. In contrast, some SNPs were reported to impart a protective phenotype to the carrier. The SNP (rs2244613) in the carboxylesterase-encoding gene (CES1) has been significantly associated with a decline in dabigatran trough levels and a lower risk of hemorrhage. Further investigations are essential to elucidate the extent of pharmacogenetics-based alterations in the drug levels as well as the subsequent clinical outcomes of anticoagulant therapy.

Incidence of Heparin resistance after preoperative heparin therapy in patients undergoing open heart surgery

Aim: Incidence of Heparin Resistance after preoperative heparin therapy in patients undergoing open heart surgery. Methods: The Prospective Observational study included 124 patients of different heart diseases undergoing open heart surgery, at cardiac surgery department of Punjab Institute of Cardiology; Lahore Pakistan was performed between 5th October 2013 to 16 March 2014. Both genders age 18-75 were included. All those patients who present with diseases other than heart diseases, age &lt;18 and &gt; 75 were excluded in the study. Data was analyzed using Statistical Package for Social Sciences (SPSS) version 16.0. P-value ≤ 0.05 were considered significant. Results: Our results showed that out of 124 patients, 87(70.16%) were male while 37(29.84%) were females. Clinical characteristics i.e. (hypertension, diabetes mellitus, emergency bypass, smoking, alcohol intake, hyperlipidemias, obesity and family history) were insignificantly associated with heparin resistance. The clinical characteristics i.e. (baseline activated clotting time, albumin and cross clamp time) were significantly associated with the development of heparin resistance as (p-value &lt;0.05 .015, .041 and .025 respectively). Conclusion: The results indicate that the incidence of heparin resistance after preoperative heparin therapy was 8.06%.

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review.

During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.

CONCURRENT CEREBRAL VENOUS THROMBOSIS AND PULMONARY THROMBOEMBOLISM ASSOCIATED TO HEPARIN RESISTANCE

TYPE: Late Breaking Case Report TOPIC: Critical Care INTRODUCTION: Thrombosis arising from unusual or multiple locations warrant a thorough search for a cause. The causes are usually underlying pathologies such as cancer, antiphospholipid syndrome, and inherited thrombophilias. CASE PRESENTATION: A 19-year-old patient with obesity presented with a persistent headache. A head CT showed a right transverse sinus thrombosis. Unfractionated heparin was started as first-line treatment, but reaching a therapeutic range of activated partial-thromboplastin time was difficult. Evolution was favorable, and anticoagulation continued with LMWH. Anti-Xa levels were requested and found to be borderline low, requiring modification of therapy. With no other relevant complications, the patient was discharged from ICU. Later, he presented with fever, shortness of breath, dry cough, and pleuritic pain in the right subcostal region. Imaging revealed a pulmonary embolism with thrombosis of the right main and inferior lobar arteries. He persisted with low anti-Xa levels. An antithrombin (AT) study was requested, showing activity of 44% and prompting supplementation. The patient had a favorable clinical evolution and was discharged after 14 days. DISCUSSION: AT deficiency may cause heparin resistance, complicating the thrombotic scenario. Inherited deficiencies are rare, and acquired causes can result from impaired production and reductions from extracorporeal circuits, especially in ECMO support. AT replacement therapy may be used besides anticoagulation in cases of AT deficiency and acute thromboembolism with or without evidence of heparin resistance. CONCLUSIONS: The patient had regular follow-ups, with no new thrombotic episodes and adequate control with vitamin K antagonists. Careful consideration needs to be taken regarding risk factors for heparin resistance in the ICU. DISCLOSURE: Nothing to declare. KEYWORD: heparin resistance

Critical coronavirus disease 2019 complicated with heparin resistance in 2 patients

To explore the diagnosis process and treatment experience of severe coronavirus disease 2019 (COVID-19) patients with heparin resistance (HR). The medical team of the First People's Hospital of Lianyungang admitted 2 severe COVID-19 patients with HR in intensive care unit (ICU) during their support to the designated hospital for the treatment of COVID-19 patients in Lianyungang City in November 2021. The clinical features, laboratory examinations, imaging features, treatment and prognosis of the two patients were analyzed. Both severe COVID-19 patients received mechanical ventilation, 1 patient was treated with extracorporeal membrane oxygenation (ECMO) support. Both patients were complicated with lower extremity deep venous thrombosis and HR phenomenon under routine dose anticoagulant therapy. The maximum daily dose of unfractionated heparin exceeded 35 000 U (up to 43 200 U), the 2 patients failed to meet the standard of anticoagulation treatment, and the course of disease was prolonged. After that, argatroban was given 0.4 μg×kg-1×min-1 combined with anticoagulant therapy, the activated partial thromboplastin time (APTT) of patients undergoing ECMO could be maintained at 55-60 seconds and the activated coagulation time (ACT) of them could be maintained at 180-200 seconds. After ECMO support or later sequential mechanical ventilation, both patients recovered and were discharged, and deep venous thrombosis was also effectively controlled. HR phenomenon often occurs during the treatment of severe COVID-19 patients, the anticoagulation regimen should be adjusted in time, and the anticoagulation effect combined with argatroban is clear.

The Efficacy and Safety of Bivalirudin Versus Heparin in the Anticoagulation Therapy of Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis.

Background: Bivalirudin is a direct thrombin inhibitor (DTI) that can be an alternative to unfractionated heparin (UFH). The efficacy and safety of bivalirudin in anticoagulation therapy in extracorporeal membrane oxygenation (ECMO) remain unknown. Methods: This study followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. A systematic literature search was performed in PubMed, EMBASE, and The Cochrane Library databases to identify all relevant original studies estimating bivalirudin’s efficacy and safety versus UFH as anticoagulation therapy in ECMO. The time limit for searching is from the search beginning to June 2021. Two researchers independently screened the literature, extracted data and evaluated the risk of bias of the included studies. The meta-analysis (CRD42020214713) was performed via the RevMan version 5.3.5 Software and STATA version 15.1 Software. Results: Ten articles with 847 patients were included for the quantitative analysis. Bivalirudin can significantly reduce the incidence of major bleeding in children (I 2 = 48%, p = 0.01, odd ratio (OR) = 0.17, 95% confidence interval (CI): 0.04–0.66), patient thrombosis (I 2 = 0%, p = 0.02, OR = 0.58, 95% CI: 0.37–0.93), in-circuit thrombosis/interventions (I 2 = 0%, p = 0.0005, OR = 0.40, 95% CI: 0.24–0.68), and in-hospital mortality (I 2 = 0%, p = 0.007, OR = 0.64, 95% CI: 0.46–0.88). Also, comparable clinical outcomes were observed in the incidence of major bleeding in adults (I 2 = 48%, p = 0.65, OR = 0.87, 95% CI: 0.46–1.62), 30-day mortality (I 2 = 0%, p = 0.61, OR = 0.83, 95% CI: 0.41–1.68), and ECMO duration in adults (I 2 = 41%, p = 0.75, mean difference (MD) = −3.19, 95% CI: −23.01–16.63) and children (I 2 = 76%, p = 0.65, MD = 40.33, 95% CI:−135.45–216.12). Conclusions: Compared with UFH, bivalirudin can be a safe and feasible alternative anticoagulant option to UFH as anticoagulation therapy in ECMO, especially for heparin resistance (HR) and heparin-induced thrombocytopenia (HIT) cases.

The addition of Tirofiban infusion to heparin for intraoperative heparin resistance associated with Marfan Syndrome

Marfan syndrome classically presents with aortic root aneurysms. Aortic ectasia causes diverse blood flow alterations, influencing the behavior of coagulation factors and platelet activity. Heparin resistance has also been reported associated with Marfan Syndrome in a small number of patients, probably due to antithrombin III (ATIII) deficiency or various mutations. The ascending aorta and the aortic valve are replaced with prosthetic material during Bentall- de Bonno procedures. Resistance to anticoagulation during extracorporeal circulation, represents a significant challenge for both anesthesiologists and the surgical team. Resistance to heparin was observed in a patient with Marfan syndrome undergoing a Bentall procedure. ATIII concentrate was not available, and ACT did not increase despite high doses of heparin. An alternate anticoagulation approach was used successfully.

Review of Case Study: Chowdhry, Moshman, and Caroll (2021). A Case of COVID-19 Related Coagulopathy Complications and Heparin Resistance

Review of Case Study: Chowdhry, Moshman, and Caroll (2021). A Case of COVID-19 Related Coagulopathy Complications and Heparin Resistance

Nticoagulant therapy monitoring in COVID-19 patients in the intensive care unit: thromboelastometry and echocardiography

Aim. To determine the effectiveness of thromboelastometry (TEM) and echocardiography for anticoagulant therapy monitoring in patients with COVID-19.Material and methods. We analyzed treatment regimen of 92 patients with COVID-19. The patients were divided into two groups. In the control group (n=30), anticoagulant therapy with unfractionated heparin (UFH) was carried out under laboratory control of coagulation parameters. In the experimental group (n=62), anticoagulation was maintained by intravenous UFH under control of coagulation, echocardiography (Philips, Epiq 5) and TEM (ROTEM® delta). Echocardiography determined the pulmonary artery acceleration time (AT), mid-systolic notching (SN). The TEM method was used to study external (EXTEM) and internal (INTEM) pathways, differential tests (FIBTEM, HEPTEM) of coagulation. Statistical analysis was performed by calculating non-parametric statistics parameters, comparisons of differences in groups (Mann-Whitney test), area under the curve (AUC), and regression equations.Results. A high correlation level between echocardiographic and TEM parameters was determined. Their levels associated with a positive prognosis were calculated (AT&gt;113,5 ms., AUC 0,979; p&lt;0,0001; no SN, AUC 0,931; p&lt;0,0001; FIBTEM ML (60 min) &gt;1,12%, AUC 0,971, p&lt;0,0001; INTEM ML (60 min) &gt;2,01%, AUC 0,941, p&lt;0,0001, EXTEM ML (60 min) &gt;1,4%, AUC 0,934, p&lt;0,0001; MCFfib not &gt;26 mm, AUC 0,954; p&lt;0,0001; MCFin not &gt;56,6 mm, AUC 0,938; p&lt;0,0001; MCFex not &gt;47,9 mm, AUC 0,838, p&lt;0,0001). In 33,9% of patients in the experimental group, heparin resistance was detected. In this connection, combined therapy with UFH and direct oral anticoagulants (DOACs) was used, followed by the switch to DOACs. In the control group, artificial ventilation was used in 50% of patients, mortality — 36,6%, myocardial infarction — 13,3%, deep vein thrombosis — 6,6%, pulmonary embolism — 6,6%, while in the experimental group, mechanical ventilation — 12,9%, myocardial infarction — 4,8%, mortality — 8,1%.Conclusion. The dynamic assessment of echocardiography and TEM parameters made it possible to monitor pulmonary thrombosis processes, significantly reduce complications, the use of artificial ventilation and mortality in COVID-19 patients.

Potential mechanisms of resistance to current anti-thrombotic strategies in Multiple Myeloma.

Multiple Myeloma (MM) is a common haematological malignancy that is associated with a high rate of venous thromboembolism (VTE) with almost 10% of patients suffering thrombosis during their disease course. Recent studies have shown that, despite current thromboprophylaxis strategies, VTE rates in MM remain disappointingly high. The pathophysiology behind this consistently high rate of VTE is likely multifactorial. A number of factors such as anti-thrombin deficiency or raised coagulation Factor VIII levels may confer resistance to heparin in these patients, however, the optimal method of clinically evaluating this is unclear at present, though some groups have attempted its characterisation with thrombin generation testing (TGT). In addition to testing for heparin resistance, TGT in patients with MM has shown markedly varied abnormalities in both endogenous thrombin potential and serum thrombomodulin levels. Apart from these thrombin-mediated processes, other mechanisms potentially contributing to thromboprophylaxis failure include activated protein C resistance, endothelial toxicity secondary to chemotherapy agents, tissue factor abnormalities and the effect of immunoglobulins/“M-proteins” on both the endothelium and on fibrin fibre polymerisation. It thus appears clear that there are a multitude of factors contributing to the prothrombotic milieu seen in MM and further work is necessitated to elucidate which factors may directly affect and inhibit response to anticoagulation and which factors are contributing in a broader fashion to the hypercoagulability phenotype observed in these patients so that effective thromboprophylaxis strategies can be employed.

Evaluation of heparin infusion rates in patients with intravenous drug misuse.

To evaluate the hypothesis that patients with a history of intravenous drug misuse (IVDM) initiated on weight-based heparin infusions require higher than expected infusion rates to achieve therapeutic activated partial thromboplastin time (aPTT). This study is a multicenter, retrospective chart review of patients with a history of IVDM who were admitted to an acute care site between 10/1/2015 and 9/30/2020 and treated with continuous heparin infusions. Patients were identified using ICD9 and ICD10 codes and included if they had a documented history of IVDM within the past six months. Variables of particular interest included: median heparin infusion rates to maintain therapeutic aPTT, average time to reach therapeutic aPTT, and International Society of Thrombosis and Haemostasis Criteria for moderate to severe bleeding. Of the 41 patients who met the inclusion and exclusion criteria, 39 achieved therapeutic aPTT while on a weight-based heparin infusion. All heparin infusions were initiated at a rate of 18 units/kg/hr then titrated per institutional heparin infusion protocols. The mean time to therapeutic aPTT was 38.48 h ± 26.4 h with a mean infusion rate of 27.64 ± 7.14 units/kg/hr. To maintain therapeutic anticoagulation, infusion rates 150% higher than the initial rate were required. Of the 39 patients who achieved therapeutic aPTT, 85% (33) met criteria for heparin resistance, defined as greater than 35,000 units of heparin daily. No statistical significance could be derived from this retrospective chart review as therapeutic heparin rates were evaluated in comparison to initial infusion rate, rather than a control group. The findings in this study demonstrate a possible clinical association of the reduced antithrombin activity previously described in opiate misusers. To efficiently achieve therapeutic anticoagulation, it may be appropriate to consider use of heparin antiXa monitoring in place of aPTT or utilization of increased initial heparin infusion rates.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11239-021-02615-z.

Abstract 11378: Reference Intervals of Activated Clotting Time in Pediatric Patients Undergoing Cardiac Surgery

Introduction: Monitoring the anticoagulant effect of heparin is critical to prevent thrombosis and/or bleeding during cardiac surgery. This evaluation is usually performed by assessing the activated clotting time (ACT) with a POC device. Despite the relevance and widespread use of ACT, there are currently limited reference values to use as a target. Furthermore, compared to the adult population, infants have been described with a longer ACT, reinforcing the need to establish a separate reference interval for this segment of the population. Aim: The present work aims to propose reference intervals of ACT in pediatric patients. Methods: We collected data on 155 consecutive patients, ranging in age from 1 day to 18 years, undergoing cardiac surgery from 01-2019 to 01-2021 at Sainte-Justine hospital. Prior to surgery, patients were given UFH as a bolus of 3 mg/kg, and Hemochron Signature Elite ACT+ (Accriva Diagnostics, Inc.) was used to measure ACT before and promptly after heparin injection. Data were subsequently analyzed by using a parametric method. Lower and upper reference limits are the values at the 2.5 and 97.5 percentile, respectively. Results: The ACT before heparin injection followed a normal distribution with a lower reference limit at 85 seconds and an upper limit at 147 seconds compared to the range of 70-120 seconds proposed for the general population. Interestingly, the ACT after heparin bolus exhibited a non-gaussian distribution. Since neonates have been previously described with a greater heparin resistance compared to older infants; patients were separated into two age groups: patients &lt; 1-month of age (Group A; n=31) and patients &gt; 1-month (group B; n=124). Afterward, we performed a log transformation of the ACT values after heparin injection to approximate a Gaussian distribution, yielding mean ACT value of 392 seconds (limits 291-529 seconds) for Group A and 473 seconds (limits 314-996 seconds) for Group B (Welch test p value = 4.4 10 -6 ). No significant difference in ACT values prior to heparin bolus was found between the two groups. Conclusion: Overall, our results provide reference values of ACT measured using an Hemochron device, in a pediatric context, paving the way for improved patient care during cardiac surgery.

Emergency cardiac surgery in patients on oral anticoagulants and antiplatelet medications.

Emergency surgery, blood transfusion, and reoperation for bleeding have been associated with increased operative morbidity and mortality. The recent increased use of direct oral anticoagulants and antiplatelet medications has made the above more challenging. In addition, cardiopulmonary bypass (CPB), with its associated hemodilution, fibrinolysis, and platelet consumption, may exacerbate the pre-existing coagulopathy and increase the risk of bleeding. The aim of this study was to examine available literature with regard to treating patients who are on the above medications and require emergency cardiac surgery. Management decisions are typically made on a case-by-case basis. Surgery is delayed when possible, and less invasive percutaneous options should be considered if feasible. Attention is paid to exercising meticulous techniques, avoiding excessive hypothermia, and treating coexisting issues such as sepsis. Ensuring a dry operative field upon entry by correcting the coagulopathy with reversal agents is offset by the concern of potentially hindering efforts to anticoagulate the patient (heparin resistance) in preparation for CPB, in addition to possibly increasing the risk of thromboembolism. Proper knowledge of anticoagulants, their reversal agents, and the usefulness of laboratory testing are all essential. Platelet transfusion remains the mainstay for antiplatelet medications. Four-factor prothrombin complex concentrate is considered in patients on oral anticoagulants if CPB needs to be instituted quickly. Specific reversal agents such as idarucizumab and andexanet alfa can be considered if significant tissue dissection is anticipated, such as redo sternotomy, but are costly and may lead to heparin resistance and anticoagulant rebound.

Arterial Thrombosis Induced By Coagulopathy Due To Coronavirus Infection Concomitant With Heparin Resistance: A Case Report

Background : A newly emerging pandemic of Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory coronavirus 2 is responsible for significant morbidity and mortality worldwide. As one of the effects is hematological changes related to the COVID-19 infection causing patient tend to thrombosis than hemorrhagic. Current review of evidence and statements on management of coagulopathy and thrombotic complications related to this novel disease is needs to be explored Case : Male 53 years old referred from Private Hospital, due to Severe pneumonia due to COVID-19 and Acute Limb Ischemia. This patient was assessed as Pneumonia COVID-19 severe with acute limb ischemia bilateral grade IIB and performed bilateral surgical thrombectomy with antegrade approach using fogarty catheter with the result was thrombus 10cm along the left femoral artery and thrombus 2cm in the right femoral artery. Discussion : With consideration of atherosclerotic diseases in this patient, we decided to give rivaroxaban as an anticoagulant combined with aspilet and statin high dose. But due to lack of source in our hospital, and patient also denied for further management, treatment for the patient cannot be optimal, so the patient discharge with unresolved limb ischemia. Conclusion : This case showed that the increase risk of heparin resistance in SARS-CoV-2 patient, it is recommend- ed to monitor heparin activity of UFH treatment based on anti-Xa levels instead of aPTT alone.