Antithrombin III infusion improves anticoagulation in congenital diaphragmatic hernia patients on extracorporeal membrane oxygenation

Purpose Achieving effective anticoagulation during neonatal extracorporeal membrane oxygenation (ECMO) without increasing the risk of hemorrhage remains challenging. The use of antithrombin III (AT-III) for this purpose has been examined, but studies have been limited to intermittent bolus dosing. We aimed to evaluate the efficacy and safety of an institutionally developed AT-III continuous infusion protocol in neonates receiving ECMO for the treatment of congenital diaphragmatic hernia (CDH). Methods In this single center, retrospective study, all neonates with a CDH who received ECMO support during the study period were included. Data on anticoagulation labs and therapy, life-threatening bleeding, and circuit changes were analyzed. Results Eleven patients were divided into two groups: patients with AT-III continuous infusion ( n = 5) and without ( n = 6). There were no differences in the gestational age ( p = 0.29), sex ( p = 1.00), ECMO duration ( p = 0.59), or initial AT-III levels ( p = 0.76) between groups. Patients in the AT-III infusion group had on average 18.5% higher AT-III levels ( p < 0.0001). Patients receiving continuous AT-III infusions spent a significantly higher percentage of ECMO time within the therapeutic range, measured using anti-Factor Xa levels (64.9±4.2% vs. 29.1±8.57%, p = 0.008), and required fewer changes to the heparin infusion rate (6.48±0.88 vs 2.38±0.36 changes/day changes/day, p = 0.005). Multivariate analysis revealed continuous infusion of AT-III did not increase the rate of intracranial or surgical bleeding ( p = 0.27). Conclusion AT-III as a continuous infusion in CDH neonates on ECMO provides a decreased need to modify heparin infusion and more consistent therapeutic anticoagulation without increasing the risk of life-threatening bleeding.

Antimicrobial Prophylaxis and Anticoagulation Therapy in Pediatric ECMO: A Survey Study

OBJECTIVE The purpose was to characterize antimicrobial and anticoagulation therapies used in health systems with children receiving extracorporeal membrane oxygenation (ECMO). METHODS An anonymous electronic survey assessing health system demographics and antimicrobial and anticoagulation therapies during ECMO was distributed to the American College of Clinical Pharmacy Pediatric Practice and Research Network and the Pediatric Pharmacy Association Critical Care Special Interest Group. The primary objective was to identify the number of respondents using antimicrobial prophylaxis for ECMO cannulation and ECMO runs. Secondary objectives included the first- and second-line anticoagulants and anticoagulation laboratory parameters. Additionally, the antimicrobial regimens and the dosing and administration of antithrombin III (AT III) with systemic anticoagulation were collected. Descriptive statistics were employed. RESULTS The questionnaire was completed by 38 respondents from 33 health systems; respondents practiced in the pediatric ICU (n = 20; 52.6%), cardiovascular ICU (n = 14; 36.8%), and neonatal ICU (n = 4; 10.5%). Twenty-eight (73.6%) respondents use antimicrobial prophylaxis during ECMO cannulation or ECMO runs, with most units using cefazolin monotherapy. Thirty-five (92.1%) respondents use heparin as the first-line anticoagulant and used a variety of laboratory tests including anti-factor Xa, activated clotting time, and activated partial thromboplastin time. The most common second-line anticoagulant was bivalirudin (n = 24; 63.2%). Thirty-six (94.7%) respondents use AT III with heparin, with most patients receiving AT III dosing calculated based on a formula for the desired AT III concentration. CONCLUSIONS The majority of respondents use antimicrobial prophylaxis, but variations in the regimens were noted. Heparin was the most common anticoagulant, but variations in laboratory monitoring and concomitant use of AT III were found.

Management of hemostasis in a patient with liver cirrhosis in the perioperative period.

Для пациентов с циррозом печени характерны существенные изменения в системе гемостаза. Описан клинический случай ведения пациента с циррозом печени, портальной гипертензией, варикозными венами желудка, оперированного на высоте желудочно-кишечного кровотечения, на фоне выявленных тромбоэмболических осложнений (тромбоэмболия легочной артерии и тромбоз глубоких вен голеней). В предоперационном периоде был установлен кава-фильтр. В первые двое суток послеоперационного периода в качестве антикоагулянта вводили концентрат антитромбина III (АТ-III) по 1000 ЕД в связи с исходным его дефицитом (64%) и для дальнейшего обеспечения эффективности терапии низкомолекулярными гепаринами (НМГ). По мере увеличения уровня тромбоцитов с 66×109/л до 200×109/л в качестве антикоагулянта был назначен парнапарин натрия в лечебной дозе. Эффективность терапии НМГ оценивали с помощью тромбоэластографии (ТЭГ). На 9-е сутки после операции диагностировано развитие гепаринорезистентности на фоне тромбоцитоза более 1 млн, гиперфибриногенемии, высокой активности фактора VIII и вновь выявленного дефицита АТ-III (53%). Клинически гепаринорезистентность проявилась образованием флотирующего тромба в правой бедренной вене. К максимальной лечебной дозе парнапарина (17000 анти- Ха) добавлен антиагрегант клопидогрел (75 мг) и начато введение концентрата АТ-III по 1000 МЕ в течение 3 сут. Преодолена гепаринорезистентность с нормализацией уровня АТ-III (89%), достигнута дезагрегация тромбоцитов. Через 7 сут диагностирован полный лизис флотирующего тромба в правой бедренной вене. В дальнейшем пациент в течение 1 мес амбулаторно находился на терапии парнапарином (17000 анти- Ха активность в сутки) и клопидогрелом (75 мг/сут). По данным компьютерной ангиопульмонографии: полный лизис тромба в легочной артерии, кава-фильтр удален. Заключение. Мониторинг системы гемостаза у пациента с циррозом печени позволил контролировать адекватность проводимой антикоагулянтной терапии и использовать арсенал имеющихся в распоряжении клинициста препаратов. Patients with liver cirrhosis are characterized by significant hemostasis changes. A clinical case is described of patient management with liver cirrhosis, portal hypertension, stomach varicose veins, operated at the height of gastrointestinal bleeding, with revealed thromboembolic complications (pulmonary embolism and deep vein thrombosis of the lower legs). Cava filter was installed in preoperative period. In the first 2 days of the postoperative period, antithrombin III (AT-III) concentrate was administered as an anticoagulant, 1000 units each due to its initial deficiency (64%) and to further ensure the therapy efficacy with low molecular weight heparins (LMWH). By increasing the platelet count from 66×109/L to 200×109/L, a therapeutic dose of parnaparin sodium was prescribed as an anticoagulant. The efficacy of LMWH therapy was assessed by thromboelastography (TEG). On the day 9 after surgery heparin resistance was diagnosed with thrombocytosis (more than 1 million), hyperfibrinogenemia, high activity of VIII factor and re-identified AT-III deficiency (53%). Clinically, heparin resistance was manifested by floating thrombus in the right femoral vein. The antiaggregant clopidogrel (75 mg) was added to the maximum therapeutic dose of parnaparin (17,000 anti- Xa), and the administration of AT-III concentrate (1000 IU) was started for 3 days. Heparin resistance was overcome with normalization of AT-III level (89%), platelet disaggregation was achieved. Complete lysis of floating thrombus in the right femoral vein was diagnosed after 7 days. Later the patient was treated with parnaparin (17,000 anti- Xa activity per day) and clopidogrel (75 mg/day) during 1 month outpatiently. According to computer pulmonary angiography, complete thrombus lysis in the pulmonary artery was revealed, the cava filter was removed. Conclusions. Hemostasis monitoring in patient with liver cirrhosis made it possible to control the adequacy of the anticoagulant therapy and to use the arsenal of drugs available to the clinician.

On-chip light detection using integrated microdisk laser and photodetector bonded onto Si board

Characteristics of a compact III–V optocoupler heterogeneously integrated on a silicon substrate and formed by a 31 µm in diameter microdisk (MD) laser with a closely-spaced 50 µm × 200 µm waveguide photodetector are presented. Both optoelectronic devices were fabricated from the epitaxial heterostroctructures with InGaAs/GaAs quantum well-dot layers. The measured dark current density of the photodetector was as low as 2.1 µA cm−2. The maximum link efficiency determined as the ratio of the photodiode photocurrent increment to the increment of the microlaser bias current was 1%–1.4%. The developed heterogeneous integration of III–V devices to silicon boards by Au-Au thermocompression bonding is useful for avoiding the difficulties associated with III–V epitaxial growth on Si and facilitates integration of several devices with different active layers and waveguides. The application of MD lasers with their lateral light output is promising for simplifying requirements for optical loss at III–V/Si interface.

High Mortality and Risk of Severe Sepsis in in-Hospital Cardiac Arrest Patients with Antithrombin Deficiency: Analysis of National Inpatient Sample Database

Background: Previous studies found the association between hereditary thrombophilia (HT) and increased risk of inpatient arterial thromboembolism, such as myocardial infarction and ischemic stroke. Nevertheless, the outcomes of hospitalized HT patients with cardiac arrest remains unclear. We aim to investigate the outcomes of inherited thrombophilia after in-hospital cardiac arrest (IHCA). Methods: This is a retrospective analysis of National Inpatient Sample database with 2016-2018 data years. We included adult (age above 18 years old) who had IHCA. IHCA, various types of HT (Factor V Leiden/activated protein C resistance, prothrombin mutation, deficiencies of antithrombin [AT] III, protein C or S deficiencies, other inherited thrombophilia), and other comorbidities were identified with International Classification of Diseases, 10th Revision, Clinical Modification Procedure Codes and Diagnosis Codes. Charlson Comorbidity Index (CCI) was used to adjust for comorbidities. Age distribution was analyzed with unpaired two-samples t-test. Gender and racial group distribution were compared with Chi-square test. Primary outcome was mortality. All independent factors associated with IHCA in inherited thrombophilia were determined by weighted multivariable logistic regression. SAS and R were used for statistical analysis. Results: Among 67,351 adult patients with IHCA, 620 patients had at least one diagnosis of HT (Factor V Leiden: 86; antithrombin III deficiency: 235; protein C/S deficiencies: 301; prothrombin gene mutation: 6; 5 cases have both factor V Leiden and protein C/S deficiencies; 3 cases have both antithrombin III and protein C/S deficiencies). Patients with HT were significant younger (mean age: 60.6 vs 65.9, p value &lt; 0.0001) with fewer comorbidities (mean CCI: 5.32 vs 5.81, p value &lt;0.0005). There was no significant difference in gender and racial groups distribution. HT was not associated with risk of mortality after IHCA (adjusted odds ratio (aOR): 0.98, Confidence interval (CI): 0.82 - 1.16, p value = 0.75). Nevertheless, subgroup analysis with different types of HT revealed increased mortality in AT III deficiency group (aOR: 1.40, CI: 1.02 - 1.91 p value &lt; 0.05). On the contrary, factor V Leiden and protein C/S deficiencies had a weak association of lower mortality (aOR: 0.70, p value &lt; 0.1; aOR: 0.80, p value = 0.06). AT III deficiency was also associated with higher risk of developing severe sepsis (aOR: 1.56, p &lt; 0.005). Myocardial infarction, ischemic stroke, pulmonary embolism, and deep venous thrombosis were not significantly associated with HT after adjusted for other potential confounders. Conclusion: HT patients who developed IHCA were younger with fewer underlying comorbidities. Only AT III deficiency subgroup was associated with higher odds of mortality and severe sepsis. Factor V Leiden and protein C/S deficiencies had a tendency of favorable outcomes. The unfavorable outcome of AT III deficiency subgroup couldn't be attributed to either arterial or venous thromboembolism. Disclosures No relevant conflicts of interest to declare.

Chemical Structure and Anticoagulant Property of a Novel Sulfated Polysaccharide from the Green Alga Cladophora oligoclada

Marine macroalgae are efficient producers of sulfated polysaccharides. The algal sulfated polysaccharides possess diverse bioactivities and peculiar chemical structures, and represent a great potential source to be explored. In the present study, a heparinoid-active sulfated polysaccharide was isolated from the green alga Cladophora oligoclada. Results of chemical and spectroscopic analyses indicated that the sulfated polysaccharide was composed of →6)-β-d-Galp-(1→, β-d-Galp-(1→, →6)-α-d-Glcp-(1→ and →3)-β-d-Galp-(1→ units with sulfate esters at C-2/C-4 of →6)-β-d-Galp-(1→, C-6 of →3)-β-d-Galp-(1→ and C-3 of →6)-α-d-Glcp-(1→ units. The branches consisting of β-d-Galp-(1→ and →6)-β-d-Galp-(1→ units were located in C-3 of →6)-β-d-Galp-(1→ units. The sulfated polysaccharide exhibited potent anticoagulant activity in vitro and in vivo as evaluated by activated partial thromboplastin time (APTT), thrombin time, and the fibrinogen level. For the APTT, the signal for clotting time was more than 200 s at 100 μg/mL in vitro and at 15 mg/kg in vivo. The obvious thrombolytic activity of the sulfated polysaccharide in vitro was also found. The mechanism analysis of anticoagulant action demonstrated that the sulfated polysaccharide significantly inhibited the activities of all intrinsic coagulation factors, which were less than 1.0% at 50 μg/mL, but selectively inhibited common coagulation factors. Furthermore, the sulfated polysaccharide strongly stimulated the inhibition of thrombin by potentiating antithrombin-III (AT-III) or heparin cofactor-II, and it also largely promoted the inhibition of factor Xa mediated by AT-III. These results revealed that the sulfated polysaccharide from C. oligoclada had potential to become an anticoagulant agent for prevention and therapy of thrombotic diseases.

Management of antithrombin III deficiency in pregnancy: a representative case and a literature review

The work is aimed at discussing pregnancy management for the most thrombogenic genetic thrombophilia - antithrombin III (AT-III) deficiency. A detailed analysis of the literature and clinical case of pregnancy management in a patient with AT-III deficiency, pulmonary embolism and habitual history of miscarriage has been performed and presented. Patients with AT-III deficiency are at high risk for developing thrombotic and obstetric complications even despite using therapeutic doses of anticoagulants. Indications for use and modes of administration of AT-III concentrate have not been currently defined clearly. Monitoring therapy with low molecular weight heparin is largely complicated because a test for determining anti-Xa activity is AT-III-dependent. In addition to standard methods for controlling antithrombotic therapy, we used tests characterizing the dynamic blood clot parameters: thromboelastography and thrombin generation test. The peak risk resulting in both thrombotic and hemorrhagic complications in such patients occurs during period of labor and the postpartum period, when a change in the regimen of anticoagulant therapy is required with its temporary withdrawal and additional administration of AT-III concentrate.

Validation of a Prospective Urinalysis-Based Prediction Model for ICU Resources and Outcome of COVID-19 Disease: A Multicenter Cohort Study

In COVID-19, guidelines recommend a urinalysis on hospital admission as SARS-CoV-2 renal tropism, post-mortem, was associated with disease severity and mortality. Following the hypothesis from our pilot study, we now validate an algorithm harnessing urinalysis to predict the outcome and the need for ICU resources on admission to hospital. Patients were screened for urinalysis, serum albumin (SA) and antithrombin III activity (AT-III) obtained prospectively on admission. The risk for an unfavorable course was categorized as (1) “low”, (2) “intermediate” or (3) “high”, depending on (1) normal urinalysis, (2) abnormal urinalysis with SA ≥ 2 g/dL and AT-III ≥ 70%, or (3) abnormal urinalysis with SA or AT-III abnormality. Time to ICU admission or death served as the primary endpoint. Among 223 screened patients, 145 were eligible for enrollment, 43 falling into the low, 84 intermediate, and 18 into high-risk categories. An abnormal urinalysis significantly elevated the risk for ICU admission or death (63.7% vs. 27.9%; HR 2.6; 95%-CI 1.4 to 4.9; p = 0.0020) and was 100% in the high-risk group. Having an abnormal urinalysis was associated with mortality, a need for mechanical ventilation, extra-corporeal membrane oxygenation or renal replacement therapy. In conclusion, our data confirm that COVID-19-associated urine abnormalities on admission predict disease aggravation and the need for ICU (ClinicalTrials.gov number NCT04347824).

Scalable Bio Marker Combinations for Early Stroke Diagnosis: A Systematic Review

Background: Acute stroke treatment is a time-critical process in which every minute counts. Laboratory biomarkers are needed to aid clinical decisions in the diagnosis. Although imaging is critical for this process, these biomarkers may provide additional information to distinguish actual stroke from its mimics and monitor patient condition and the effect of potential neuroprotective strategies. For such biomarkers to be effectively scalable to public health in any economic setting, these must be cost-effective and non-invasive. We hypothesized that blood-based combinations (panels) of proteins might be the key to this approach and explored this possibility through a systematic review.Methods: We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines for systematic review. Initially, the broader search for biomarkers for early stroke diagnosis yielded 704 hits, and five were added manually. We then narrowed the search to combinations (panels) of the protein markers obtained from the blood.Results: Twelve articles dealing with blood-based panels of protein biomarkers for stroke were included in the systematic review. We observed that NR2 peptide (antibody against the NR2 fragment) and glial fibrillary acidic protein (GFAP) are brain-specific markers related to stroke. Von Willebrand factor (vWF), matrix metalloproteinase 9 (MMP-9), and S100β have been widely used as biomarkers, whereas others such as the ischemia-modified albumin (IMA) index, antithrombin III (AT-III), and fibrinogen have not been evaluated in combination. We herein propose the following new combination of biomarkers for future validation: panel 1 (NR2 + GFAP + MMP-9 + vWF + S100β), panel 2 (NR2 + GFAP + MMP-9 + vWF + IMA index), and panel 3 (NR2 + GFAP + AT-III + fibrinogen).Conclusions: More research is needed to validate, identify, and introduce these panels of biomarkers into medical practice for stroke recurrence and diagnosis in a scalable manner. The evidence indicates that the most promising approach is to combine different blood-based proteins to provide diagnostic precision for health interventions. Through our systematic review, we suggest three novel biomarker panels based on the results in the literature and an interpretation based on stroke pathophysiology.

COAGULATION ASSAYS AND AT-III ON LEVONORGESTREL IMPLANT ACCEPTORS

Background: Indonesia is the fourth most populous country in the world, so the government has focused Family Planning Program using contraception. Implants and IUDs are two most effective reversible contraceptive methods and often used in Indonesia. Implant releases progestin, with most common reported side effect of abnormal bleeding. Specically for levonorgestrel implants, changes in menstrual intervals, duration, volume of menstrual ow can occur. Progestins are believed to cause changes in platelet and blood vessel, leading to hypercoagulability state, which can be assessed through coagulation assays (PT, TT, aPTT) and level of AT-III. Objective: This aims to determine the differences in coagulation assays and AT-III levels between levonorgestrel implant versus IUD acceptors. Methods: This study was an observational analytic study with retrospective cross-sectional design. The population were case population (levonorgestrel implant acceptors) and control population (IUD). A total of 74 respondents were chosen by consecutive sampling. Characteristics data were obtained by interview, anthropometric measurements, and medical records; PT, TT, aPTT, and AT-III data were obtained from blood samples by ELISA method. An independent T-test was used to analyze the data. Results: Mean PT was the same for implant and IUD users, 13.11 seconds (SD=0.81 seconds) (p=0.1,000). Mean TT of implant users was 14.78 seconds (SD=1.18 seconds) and IUD 14.58 seconds. (SD=1.18 seconds) (p=0.75). Mean aPTT for implant users was 30.22 seconds (SD=4.65 seconds) and IUD 30.55 seconds (SD=2.79 seconds) (p=0.200). Mean of ATIII in implant users was 92.18% (SD=9.72%) and IUD 84.79% (SD=14.74%) (p=0.250). Conclusion: No signicant mean differences for PT, TT, aPTT, and AT-III between groups of levonorgestrel implant and IUD acceptors (p value> 0.05).