Unfractionated Heparin For Treatment Research Articles

Early unfractionated heparin treatment in patients with STEMI – trial design and rationale

The early unfractionated heparin (UFH) treatment in patients with ST-elevation myocardial infarction (STEMI) is a single-center, open-label, randomized controlled trial. The study population are patients with STEMI that undergo primary percutaneous coronary intervention (PPCI). The trial was designed to investigate whether early administration of unfractionated heparin immediately after diagnosis of STEMI is beneficial in terms of patency of infarct-related coronary artery (IRA) when compared to established UFH administration at the time of coronary intervention. The patients will be randomized in 1:1 fashion in one of the two groups. The primary efficacy endpoint of the study is Thrombolysis in myocardial infarction (TIMI) flow grades 2 and 3 on diagnostic coronary angiography. Secondary outcome measures are: TIMI flow after PPCI, progression to cardiogenic shock, 30-day mortality, ST-segment resolution, highest Troponin I and Troponin I values at 24 hours. The safety outcome is bleeding complications. The study of early heparin administration in patients with STEMI will address whether pretreatment with UFH can increase the rate of spontaneous reperfusion of infarct-related coronary artery.

Management of prosthetic valve thrombosis with unfractionated heparin

BackgroundProsthetic valve thrombosis (PVT) is a severe and life-threatening complication. Surgery and thrombolytic therapy (TT) carry a high risk, and in several circumstances, optimal anticoagulation with unfractionated heparin (UFH) infusion may be an alternative treatment. This study aimed to assess the results of UFH in patients diagnosed with both obstructive and non-obstructive PVT. MethodsThis observational retrospective study enrolled patients who had contraindications for TT and surgery underwent UFH therapy. ResultsA total of 136 patients were enrolled [male: 55 (40.4%), mean age: 50.3 ± 14.6 years] in the study. In the successful group, 66 patients (48,5%) showed >75% regression in the thrombus burden without facing death or major non-fatal complications.In the unsuccessful group, 56 had less than a 50% reduction in thrombus load and 14 (10.3%) suffered major complications. The presence of obstruction (27.1% vs. 12.1%; p = 0.028), thrombus area 1.1 cm2 vs. 0.8 cm2; p = 0.005] and the duration of UFH treatment (15.1 vs. 11.8 (days); p = 0.005) were significantly higher in the unsuccessful UFH group.In multivariate regression analyses the presence of obstruction (RR: 3.088, p = 0.020), increased thrombus area (RR: 2.400; p = 0.015), and increased duration of UFH therapy (RR: 1.073 95%, p = 0.012) were identified as independent predictive parameters for a failed UFH therapy. ConclusionsThis study suggests that UFH therapy may be considered a relatively beneficial treatment strategy for some patients with PVT. The most significant factors affecting success are the obstructive nature and area of the thrombus.

In-hospital mortality and associated factors among patients admitted with venous thromboembolism at selected public hospitals of Harar Town, Eastern Ethiopia.

Venous thromboembolism is the third most common cause of cardiovascular death and is responsible for more than 3 million deaths annually worldwide. Despite high rates of morbidity and mortality associated with venous thromboembolism, limited studies have been conducted on in-hospital mortality and its associated factors in Ethiopia, particularly in study settings. To assess in-hospital mortality and associated factors among patients admitted with venous thromboembolism at selected public hospitals of Harar town, Eastern Ethiopia, from 10 March 2018 to 8 March 2022. A retrospective cohort study design was conducted among 502 patients admitted with venous thromboembolism at Hiwot Fana Comprehensive Specialized Hospital and Jugal General Hospital using a simple random sampling technique. Data extraction formats were used to collect data from patient medical record cards. Then data were coded and entered into EpiData version 3.1 computer programs and exported to SPSS version 26 for analysis. Bivariate and multivariate backward Cox regression analysis was used to verify the associated factors of in-hospital mortality among venous thromboembolism patients. A p-value of less than 0.05 at a 95% confidence interval was used to establish a statistically significant association. A total of 502 patient medical record cards with outcome variables were included in the study. More than half of the patients 350 (69.7%) were females. Among the 502 patients who were admitted with venous thromboembolism, 8.2% (95% CI: 5.6-10.6) of patients had in-hospital mortality. DM (AHR = 4.28, 95% CI: 1.80-10.15, p = 0.001) and unfractionated heparin duration (AHR = 10.26, 95% CI: 2.45-43.01, p = 0.001) were statistically significant association with venous thromboembolism mortality. Approximately 8.2% of venous thromboembolism patients died in the hospital. Diabetes and heparin were independently associated with higher mortality. Therefore, it is better to give more attention to the patients co-morbid with diabetes mellitus and for unfractionated heparin treatment duration to reduce venous thromboembolism mortality.

No Association Between Outcomes And Anti-Factor Xa Levels For Heparin Monitoring In Patients With Cerebral Venous Thrombosis (P14-5.012)

<h3>Objective:</h3> We sought to determine whether Anti-factor-Xa (AFXa) values are associated with outcomes in cerebral venous thrombosis (CVT). <h3>Background:</h3> Intravenous unfractionated heparin (UFH) is a cornerstone of anticoagulant therapy for patients with CVT, but frequent monitoring is needed because of dose-response variability. The AFXa assay is used to monitor UFH treatment. <h3>Design/Methods:</h3> This pilot study included adults (≥18y) admitted to a comprehensive stroke center from 2018 through 2020 who were initially treated for CVT with low-intensity UFH drip and had at least one AFXa assay. AFXa therapeutic values were defined as 0.25 – 0.5 IU/mL. We examined percent of patients who became therapeutic within 24h of arrival, and time (hours, h) to reach therapeutic range. Outcomes included hospital LOS, bleeding event, and discharge disposition. Continuous data are presented as median (interquartile range). <h3>Results:</h3> There were 51 CVT patients included. The time to start UFH was 2h (1–6) from arrival and the time to the first AFXa assay was 8h (4–11) from arrival. AFXa were drawn 4 (2–8) times per patient. AFXa assays were performed within 24h for 45 (88%) patients and 30(67%) patients were in the therapeutic range. There was no association between study outcomes and AFXa being therapeutic or not: bleeding events were 17.2% and 13.3%, respectively (p=1.0), discharge to home was 77% vs. 80% (p=1.0), and hospital LOS was 5 days for each group (p=0.95). There was also no association between study outcomes and the time (h) to reach therapeutic range: discharge home vs. other location (11h vs. 14h, p=0.49), development of a bleed vs. no bleed (9h vs. 12h, p=0.44), and no correlation with hospital LOS (p=0.55). <h3>Conclusions:</h3> The time to achieve therapeutic AFXa was not associated with outcomes, although most patients were within the target AFXa range within 24h of arrival and had favorable outcomes. <b>Disclosure:</b> Dr. Pirahanchi has nothing to disclose. Ms. Salottolo has nothing to disclose. Dr. Burrell has nothing to disclose. Dr. Tang has nothing to disclose. Dr. DiSalvo has nothing to disclose. David Bar-Or has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Ampio Pharmaceuticals. David Bar-Or has stock in Ampio Pharmaceuticals. Dr. Bartt has nothing to disclose.

Transitioning to Unfractionated Heparin in Treatment of Non-ST-Segment Elevation Myocardial Infarction Patients on Direct Oral Anti-Xa Inhibitors.

The heparin anti-Xa assay is affected by the use of direct oral anticoagulants (DOACs) and is utilized in the management of intravenous unfractionated heparin. Patients with non-ST-segment myocardial infarction (NSTEMI) receive intravenous unfractionated heparin with prior administration of DOACs poses challenges given these laboratory abnormalities. On this background, we evaluate if an elevated heparin anti-Xa assay may lead to the decision to delay heparin in the management of NSTEMI patients and the outcome of in-hospital mortality. This is a single-center chart review study with patients admitted between January 2019 and December 2020. Patients with a documented DOAC home medication and a diagnosis of NSTEMI were included.Data was collected for heparin anti-Xa levels at baseline, after 6 and 12 hours of hospitalization, in addition to the reason for the delay in the administration of heparin. Statistical analysis included the determination of r-squared correlation and one-way ANOVA using GraphPad Prism 8.0. A total of 44 patients were divided into three groups based on baseline Xa levels of patients. Elevated Xa level was noted more in patients who were taking apixaban. Heparin infusion was delayed among this sub-group of patients. Elevated baseline heparin anti-Xa levels were significantly improved after 12 hours. There was no correlation between elevated anti-Xa levels and activated partial thromboplastin time. No in-hospital mortality was observed among any of the subgroups. Collectively, this study demonstrates that the high sensitivity of heparin anti-Xa assay to DOACs affect assay accuracy and result in elevated heparin anti-Xa level with the use of DOACs resulting in delayed start of heparin therapy in treating NSTEMI patients.

Abstract TP12: No Association Between Outcomes And Anti-Factor Xa Levels For Heparin Monitoring In Patients With Cerebral Venous Thrombosis

Introduction: For patients with cerebral venous thrombosis (CVT), intravenous unfractionated heparin (UFH) is a cornerstone of anticoagulant therapy. Drawbacks of UFH include difficulty in reaching an optimal dose. Anti-factor-Xa (AFXa) assay is used to monitor UFH treatment. We sought to determine whether AFXa values are associated with outcomes in CVT. Methods: This pilot study included adults (≥18y) admitted to a CSC between 1/1/2018-12/31/2020 who were initially treated for CVT with low-intensity UFH drip and had at least one AFXa assay. AFXa therapeutic values were defined as 0.25 - 0.5 IU/mL. We examined percent of patients who became therapeutic within 24h of arrival, and time (hours) to reach therapeutic range. Outcomes included hospital LOS, bleeding event, and discharge disposition. Continuous data are presented as median (interquartile range). Significance was p&lt;0.20. Results: 51 CVT patients were included. The hospital LOS was 5 (4-9) days, 40 (78%) patients were discharged home, and 7 (14%) developed a bleed; 4 bleeds required no action. The time to start UFH was 2h (1-6) from arrival and the time to the first AFXa assay was 8h (4-11) from arrival. AFXa were drawn 4 (2-8) times per patient. AFXa assays were performed within 24h for 45 (88%) patients and 30 (67%) patients were in the therapeutic range. There was no association between study outcomes and therapeutic AFXa ( Table 1 ). There was also no association between study outcomes and the time (h) to reach therapeutic range: discharge home vs. other location (11h vs. 14h, p=0.49), development of a bleed vs. no bleed (9h vs. 12h, p=0.44), and no correlation with hospital LOS (p=0.55). Conclusions: Most CVT patients were within the target AFXa range within 24h of arrival. The time to achieve therapeutic AFXa was not associated with better outcomes, although most patients had a favorable disposition and bleeding complications were infrequent.

Management Strategies in Septic Coagulopathy: A Review of the Current Literature.

One of the 'organs' that can be affected by sepsis is the coagulation system. Coagulopathy in sepsis may take the form of sepsis-induced coagulopathy (SIC) or sepsis-associated disseminated intravascular coagulation (DIC). It is important to identify SIC early, as at this stage of coagulopathy anticoagulants may be of the greatest benefit. The most recent diagnostic scoring systems for septic coagulopathy come from the International Society on Thrombosis and Hemostasis and the Japanese Association for Acute Medicine. Recommendations regarding the management of septic coagulopathy differ between organizations. Moreover, septic coagulopathy is an area of intense research in recent years. Therefore we searched three databases to review the most recent management strategies in septic coagulopathy. The mainstream management strategies in septic coagulopathy include the causal treatment of sepsis, unfractionated heparin, low-molecular-weight heparin, antithrombin, and recombinant human thrombomodulin. The last two have been associated with the highest survival benefit. Nevertheless, the indiscriminate use of these anticoagulants should be avoided due to the lack of mortality benefit and increased risk of bleeding. The early diagnosis of SIC and monitoring of coagulation status during sepsis is crucial for the timely management and selection of the most suitable treatment at a time. New directions in septic coagulopathy include new diagnostic biomarkers, dynamic diagnostic models, genetic markers for SIC management, and new therapeutic agents. These new research avenues may potentially result in timelier SIC diagnosis and improved management of all stages of septic coagulopathy by making it more effective, safe, and personalized.

Effect of heparin on recurrent IVF-ET failure patients

Objective: To elucidate the possible role of unfractionated heparin in patients with failed repeated in in vitro fertilization and embryo transfer (IVF-ET) and thrombophilia.Methods: This case control study evaluated the efficacy of the unfractionated heparin in increasing the pregnancy and implantation ratio in women with recurrent IVF-ET failures. Eighty-six women received in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) with a record of three or more previous IVF-ET failures. Participants were randomly distributed into two groups. Group A (n=43) received unfractionated heparin 5 000 IU twice daily, and group B (n=43) did not take any antithrombotic drugs. Coagulation abnormalities such as factor V Leiden (FVL) mutation, methylene tetra hydro folate reductase (MTHFR) mutation and prothrombin mutation (FII) were evaluated. Age, body mass index, basal follicular stimulating hormone, basal estradiol, duration of infertility, and number of IVF-ET failures were compared between two groups.Results: 45.0% and 17.4% of women were pregnant with and without MTHFR and prothrombin mutation, respectively, when they received unfractionated heparin treatment. The implantation rate was more in group A (12.5%) than group B (4.3%) and differences in the fertilization rate of the two groups were observed (27.7% vs. 35.9%). The clinical pregnancy rate per cycle was remarkably more in group A (30.2%) than group B (14.0%).Conclusions: Heparin is a safe and valuable treatment for patients with repeated IVF-ET failures. The clinical pregnancy and implantation rates are higher in the heparin-treated group in contrast with the control group.Trial registration: The trial registration was done with clinical registration number of “ IRCT138807202575N1”.

The Effect of Polybrene on an aPTT-based Lupus Anticoagulant Test in the Plasma of Patients Receiving Unfractionated Heparin

Objective: Heparins can interfere with lupus anticoagulant (LA) testing, especially when the detection assays do not contain a heparin neutralizer. In this study we evaluated whether hexadimethrine bromide commonly known as polybrene was able to neutralize the effects of unfractionated heparin (UFH) on activated partial thromboplastin time (aPTT)-based LA determination. Material and Methods: The influence of polybrene on the aPTT-based LA testing results of 14 patients receiving UFH therapy was studied. Measurements were performed using Dade Actin FSL (aPTT-LA screen) and Dade Actin FS (aPTT-LA confirm) reagents on a Sysmex CS-1600 analyzer. The aPTT-LA screen/confirm ratios before and after the polybrene treatments were compared. Results: The UFH treatment affected the aPTT-LA screen/confirm ratio in four patterns, 1) no coagulation (NC code), 2) false positive, 3) false low, and 4) unchanged interpretation. After adding polybrene in the patient plasmas, the aPTT-LA screen/confirm ratios returned nearly to baseline without false positive or negative results. Conclusion: The best practice for LA testing should be done outside anticoagulant therapies, but if necessary, the tests can be performed by adding the proper concentration of polybrene.

Unfractionated Heparin Protects Microcirculation in Endotoxemic Rats by Antagonizing Histones

IntroductionLevels of extracellular histones are highly increased in sepsis and may facilitate microcirculatory dysfunction. Unfractionated heparin (UFH) binds histones and neutralizes their cytotoxicity. We investigated the effect of UFH on microcirculatory dysfunction by interacting with extracellular histones in endotoxemic rats. MethodsTwenty-four Wistar rats were randomly divided into three groups: control, lipopolysaccharide (LPS) group, and LPS + UFH group. In the LPS and LPS + UFH groups, 10 mg/kg LPS was injected to induce endotoxemia, and 100 IU/kg/h UFH was administered intravenously in the LPS + UFH group. The rats underwent midline laparotomy, and then intestinal microcirculation was evaluated using an incident dark field microscope. Circulating histones and microstructures of the rat intestinal microvascular endothelium were also detected. Additionally, the antagonistic effect of UFH on histone-induced cytotoxicity was investigated in human intestinal microvascular endothelial cells. ResultsUFH protected the microcirculation of the intestinal serosa and mucosa in endotoxemic rats, as evidenced by increased total vessel density, perfused vessel density, and proportion of perfused vessels of both the serosa and mucosa, and increased microcirculatory flow index of the mucosa in the LPS + UFH group. UFH treatment decreased the levels of circulating histones and alleviated intestinal microvascular endothelial injuries in endotoxemic rats. Furthermore, UFH inhibited histone cytotoxicity in vitro. ConclusionsUFH attenuated microcirculatory dysfunction in endotoxemic rats by antagonizing extracellular histones, thereby providing a potential therapeutic strategy for sepsis.

Clinical Study of Deep Vein Thrombosis of Lower Limbs

Understanding the natural history of venous thrombosis is important for optimal management of this condition. Once risk factors are recognized it is possible to avoid these risk factors or to use active prophylaxis to reduce the morbidity and mortality. This study is targeted at identifying the risk factors of deep vein thrombosis in our set up, the role of Heparin in prophylaxis and to do a comparative study of low molecular weight Heparin with unfractionated Heparin in treatment of deep vein thrombosis of lower limb in Guru Gobind Singh Government hospital, Jamnagar. Material and Methods: Study population consisted of 50 consecutive patients with deep vein thrombosis, admitted to Guru Gobind Singh hospital, Jamnagar. We have studied 50 patients above 18 years of age with proven deep venous thrombosis by Doppler ultrasound. A complete clinical history was taken to assess risk factors, level of immobility if present and thorough physical examination was done. Routine investigations such as hemogram, haematocrit, blood indices, and liver and renal function tests were done. Diagnosis of deep vein thrombosis was detected by radiographic imaging like Doppler ultrasonography. Results: In our study, most of patients presented with complaints of swelling (70%) and pain (48%) of the affected lower limb. Few patients (4%) had symptoms of breathlessness (SOB), chest pain and orthopnea suggestive of pulmonary embolism. 34 patients in our study were having reasonably good level of haemoglobin while rests of all were having anaemia of different degree4 patients had haemoglobin below 8gm/dl and that needed separate treatment also. Leukocytosis was present in 16 patients. 16 patients had smoking as associated risk factor along with other acquired risk factors and 5 patients had obesity along with other risk factors. The most common complication of DVT is pulmonary embolism which occurs due to dislodgement of thrombus. Conclusion: Even though it is grievous, DVT can be prevented and treatable. Better and regular availability of drugs like LMWH and safer oral anticoagulants in the smallest possible region of the country can do wonders to save lives. Larger studies focusing more on coagulation cascade, molecular biology and genetics will be even bigger help to mankind.

Anticoagulation with unfractionated heparin in patients with prosthetic valve thrombosis- a single center study

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND Surgical and thrombolytic therapy (TT) are used as effective treatment methods to treat obstructive Prosthetic valve thrombosis (PVT). However, TT is usually contraindicated in patients who suffer PVT in the early postoperative period (first three weeks) or those who present with an acute cerebral thromboembolism. Unfractionated heparin (UFH) infusion seems to be one of the appropriate treatment options in such patients. PURPOSE In this single-center study, we aimed to investigate the efficacy of UFH therapy in patients with PVT. METHODS This retrospective, observational, single center study included 136 PVT patients (mean age: 50.3 ± 14.6 years; female: 81, male: 55) who did meet the following criteria: (i) PVT with &amp;gt;10 mm thrombus lenght; (ii) a thrombus with embolic risk despite no thrombolytic indication, accompanied with clinical entities such as gradient increase on the valve, acute coronary syndrome, infective endocarditis, and TIA.The success criteria of the treatment was defined as a 75% reduction in the thrombus burden in the absence of major non-fatal complications. Patients with a 50 75% reduction in the thrombus burden were considered as partially successful. The development of major complications indicated treatment failure. RESULTS The study included 16 (11.8%) aortic, 97 (71.3%) mitral, 19 (14%) aortic and mitral, 4 (2.9%) tricuspid prosthesis, with 27 (19.9%) obstructive and 109 (80.1%) non-obstructive thrombosis. During the follow-up, 66 (48,5%) patients showed a regression &amp;gt; 50% in the thrombus burden without facing death or major non-fatal complications; therefore the UFH therapy was considered successful in these patients. Fifty-six patients had a &amp;lt; 50% reduction in thrombus load despite the UFH treatment. Furthermore, 14 (10.3 %) patients suffered major complications. UFH treatment was assumed unsuccessful in these 70 patients (51.5%). Nature of the thrombus (27.1% vs. 12.1%; p = 0.028), thrombus area (1.1 (in a range of 0.7-1.6) cm2 vs. 0.8 (in a range of 0.6-1.2) cm2; p = 0.005] and the duration of UFH treatment (15.1 ± 6.7 days vs. 11.8 ± 7.2 days; p = 0.005) were significantly higher in the unsuccessful UFH group. The parameters that were found to be significantly different in the univariate analyses between patients with successful and unsuccessful UFH treatment were further evaluated in multivariate regression analysis. As a result, the obstructive nature of the thrombus (RR: 3.088, 95% CI: 1.191-8.006; p = 0.020), increased thrombus area (RR: 2.400, 95% CI: 1.184-4.864; p = 0.015), and increased duration of UFH therapy (RR: 1.073 95% CI: 1.016-1.133; p = 0.012) were identified as independent predictive parameters for a failed UFH therapy. CONCLUSIONS In this study, we have demonstrated that UFH treatment may be beneficial in patients with PVT that are unsuitable for surgical and TT. Our findings have revealed that the most significant factor affecting the success of UFH treatment is the thrombus burden. Abstract table 1 Abstract table 2

The usage and outcomes of dextran in the treatment of acute deep venous thrombosis.

In this study, we retrospectively compared the outcomes of patients with acute deep vein thrombosis treated with dextran 40 infusion and unfractionated heparin with those of patients treated with unfractionated heparin alone. We evaluated 104 patients with the diagnosis of acute deep vein thrombosis. The pain complaints of the patients at the time of admission and the pain complaints in the calf with dorsiflexion of the foot were evaluated with the visual analogue pain scale, and the calf diameter of affected limbs was measured. Fifty five patients had dextran 40 infusion and unfractionated heparin treatment concomitantly (Group HD), while 49 patients had unfractionated heparin treatment (Group H). Heparin dose was adjusted to obtain 1.5- to 2.5-fold of normal activated partial thromboplastin time in both groups. Oral anticoagulant, warfarin sodium, was administered in the first day and resumed. Unfractionated heparin infusion therapy was resumed until international normalized ratio values of 2-2.5 were obtained. Dextran 40 infusion therapy was administered for 3 days. Calf diameters, current pain, and calf pain at foot dorsiflexion were recorded at 48 h and 72 h. 65 patients were distal, and 39 patients were proximal and popliteal acute DVT. None of the patients had phlegmasia. All were acute DVT. At 48 and 72 h of therapy, it was determined that the decrease of the calf diameter and the pain were more significant both at 48th and 72nd hours in the Group HD. The calf circumference change, especially at 72 h, was 2.58 ± 0.39cm in the group receiving heparin + dextran, while it was 1.76 ± 0.56cm in the group receiving only heparin. (p = 0.000). While there were only 1.24 ± 1.02 people in the group that received dextran at 72 h, leg pain persisted in 3.35 ± 1.11 people in the other group. (p = 0.000). Evaluation was made only with calf vein diameter measurement. When patients with Homan's sign were evaluated for their calf pain at foot dorsiflexion; both groups had decreased pain at 48th and 72nd hours. In this study, we observed that the use of dextran 40 infusion therapy concomitantly with unfractionated heparin accelerates recovery substantially and decreases patient complaints significantly in early stages. In particular, reduction in leg pain and calf circumference reduction were more adequate in the dextran group. The early decrease in the calf circumference will have clinical consequences such as less heparin intake, earlier return to normal life, and a decrease in the total cost of treatment. Since the antithrombotic and anticoagulant effects of dextran are well known, we think that its use in this treatment as well as venous thromboembolism prophylaxis should be discussed.

Long-term follow-up results of unfractionated heparin infusion treatment for submassive pulmonary thromboembolism.

Treatment options for submassive pulmonary thromboembolism cases vary depending on the patient's hemodynamic stability, comorbidities, and bleeding risk. The long-term effect of unfractionated heparin treatment on pulmonary hypertension and mortality is unclear. The aim of this study was to investigate the long-term effect of unfractionated heparin treatment on pulmonary thromboembolism. This is a cross-sectional study with 22 patients who were diagnosed with submassive pulmonary thromboembolism and followed up at the outpatient clinic between 2016 and 2020 and received unfractionated heparin treatment. Mean pulmonary artery pressure was 53±13.6 mmHg during hospital admission and 42.7±13.4 mmHg at hospital discharge. There was a statistically significant decrease in d-dimer and pulmonary artery pressure levels before and after treatment (p=0.001). At the end of one year, pulmonary artery pressure was considered high in three patients of this study. Our study suggests that unfractionated heparin is safe in the treatment of submassive pulmonary thromboembolism in terms of bleeding risk and reduces pulmonary artery pressure.

Unfractionated Heparin Attenuated Histone-Induced Pulmonary Syndecan-1 Degradation in Mice: a Preliminary Study on the Roles of Heparinase Pathway.

Endothelial glycocalyx degradation is thought to facilitate the development of sepsis. Histone is a significant mediator in sepsis. Unfractionated heparin (UFH) possessed beneficial effects on sepsis. Thereby, this study aims to figure out whether histone can disrupt glycocalyx and to investigate the protective effect and mechanism of UFH. Male mice (C57BL/6, 8-10weeks old, weighing 20-25g) were randomly divided into five groups including control group, histone group, histone + UFH group, histone + heparinase (HPA) inhibitor group, and histone + UFH + HPA inhibitor group. The mice were treated with histone (50mg/kg) via tail vein immediately after HPA (20mg/kg) injection. UFH (400 U/kg) was injected 1h after histone administration. The other groups were injected with equal volume of sterile saline accordingly. UFH alleviated histone-induced lung injury and pulmonary edema. UFH inhibited histone-induced lung coagulation activation and inflammatory response. UFH treatment markedly inhibited pulmonary glycocalyx degradation by reducing the histone-induced decrease in the levels of lung syndecan-1 mRNA and protein. UFH downregulated histone-induced expression of HPA mRNA and protein, and thus alleviated glycocalyx degradation. UFH protects against histone-induced pulmonary glycocalyx injury partly by heparinase pathway.

Lack of Inter-Laboratory Agreement in the Monitoring of Unfractionated Heparin Using the Anti-Factor Xa Activity and the Anti-Factor Xa-Correlated Activated Partial Thromboplastin Time

Background: Unfractionated heparin (UFH) has been in clinical use for more than half a century. Due to the risk of hemorrhage in case of over dosage and the risk of thrombosis in case of under dosage, monitoring UFH treatments is mandatory. The activated partial thromboplastin time (aPTT) is the most widely used method as it is simple, cheap, and readily available. However, it is also poorly standardized and affected by many parameters, both analytic and pre-analytic, that are unrelated to the heparin effect. Particularly, the UFH-induced prolongation of aPTT is highly dependent on the reagent and analyzer used. In an effort to improve inter-laboratory agreement in the monitoring of UFH, the College of American Pathologists (CAP) recommends that the aPTT therapeutic range must be defined in each laboratory through correlation with a direct measure of heparin activity such as the factor Xa (FXa) inhibition assay. Such a strategy was endorsed years ago by the American College of Chest Physicians (ACCP) and the 9thACCP Consensus guideline recommends monitoring UFH treatments by using either the anti-FXa activity, with the therapeutic range between 0.30 and 0.70 IU/mL, or the anti-FXa-correlated aPTT. However, whether and to what extent this approach enhances the inter-laboratory agreement of UFH monitoring has been weakly evaluated, so far.Objectives: To compare the inter-laboratory agreement of the anti-FXa activity and the anti-FXa-correlated aPTT for monitoring therapeutic UFH treatment, we conducted a cross-validation study among 3 accredited coagulation laboratories that used different technical conditions.Patients and Methods: 125 inpatients treated with UFH were sampled in one of the centers. Blood was collected into evacuated polymer tubes containing 3.2% tri-Na citrate. Tubes were centrifuged twice within 2 h after collection, and plasma was stored frozen in aliquots at -70°C that were shipped in dry ice to the 2 other centers to be locally evaluated. Anti-FXa activity (in IU/mL) was evaluated using 4 chromogenic assays i.e. Biophen Heparin LRT (Hyphen BioMed), HemosIL Liquid Anti-Xa (Instrumentation Laboratory, IL), Innovance Heparin (Siemens), and STA-Liquid Anti-Xa (Stago). APTT (expressed as the patient-to-control ratio) was evaluated using 4 reagents i.e. HemosIL SynthASil and HemosIL APTT SP (IL), Pathromtin SL (Siemens), and STA-PTT Automate 5 (Stago). With some exceptions, participating centers used combinations of reagents and analyzers from the same manufacturer i.e. ACL TOP 700 (IL), CS-5100 (Siemens) and STAR (Stago).Results: In the studied population, anti-FXa test results were found to be highly variable depending of the assay used, with the median activity ranging from 0.57 IU/mL with one reagent to 0.37 IU/mL with another, the two other reagents giving intermediate results (Table). Test results obtained using the different reagents were well correlated (r>0.91 in all cases) even though some comparisons performed according to Bland-Altman demonstrated unacceptable bias. If 0.30 to 0.70 IU/mL was used as the therapeutic range of anti-FXa activity, such a discrepancy in test results led to a lack of agreement as to whether a sample was subtherapeutic, therapeutic or supratherapeutic in more than 25% of the patients.The median aPTT test result (ratio) ranged from 2.22 with the less sensitive to 2.93 with the most sensitive reagent. Using the anti-FXa-correlation method, aPTT therapeutic ranges were found to be highly different from one combination of reagent/analyzer to another (Table), and the same applied when correlations were made between one single aPTT reagent and different anti-FXa assays performed on the same analyzer. Consequently, agreement among all aPTT reagents was found in in less than 40% of the patient samples.Conclusions: The reported discrepancy between test results evaluated using commercially available anti-FXa assays are consistent with the results of various national and international EQA programs, and clearly suggests a lack of standardization of that assay. As the consequence, the anti-FXa-correlated aPTT therapeutic range could be significantly impacted. In addition, the anti-FXa-correlation method did not appear to enhance interlaboratory agreement in UFH monitoring as it produces considerable disparity in UFH dosing decisions among different centers, although the clinical impact of this disparity is not known. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Additional Treatment with Low-Molecular-Weight Heparin Provides a Better Patient Outcome for Neonatal Pulmonary Hemorrhage with Unfractionated Heparin Treatment

Pulmonary hemorrhage occurring in preterm newborns is a catastrophic event and is significantly associated with neonatal deaths. Low-weight-molecular heparin is a medical agent usually used as anticoagulants during pregnancy and has the advantages of good absorption, long half-life, and high bioavailability. This study evaluated the pulmonary function and coagulation function in neonates with pulmonary hemorrhage following intravenous drip of low-molecular-weight heparin and the effects of low-molecular-weight heparin on serum prealbumin and retinol-binding protein levels. A total of 96 neonates with pulmonary hemorrhage were included as study subjects and arranged into the control group and the observation group, 48 per group, based on intravenous drip of unfractionated heparin with or without low-molecular-weight heparin. The neonates receiving intravenous drip of unfractionated heparin and low-molecular-weight heparin exhibited elevated partial pressure of oxygen (PaO2) concomitant with declined partial pressure of carbon (PaCO2) compared to those receiving unfractionated heparin treatment alone. With regard to pulmonary function, neonates receiving combined treatment of unfractionated heparin and low-molecular-weight heparin displayed increased forced expiratory volume in the first second (FEV1), FEV1/forced expiratory vital capacity (FVC), and peak expiratory flow (PEF) ( P &lt; 0.05 ) when comparable to neonates receiving unfractionated heparin treatment alone. As for coagulation function, neonates with pulmonary hemorrhage had decreased activated partial thromboplastin time (APTT), prothrombin time (PT), thromboplastin time (TT), and fibrinogen (FIB) after treatment. Expectedly, these decreases were more significantly in neonates undergoing unfractionated heparin coupled with low-molecular-weight heparin ( P &lt; 0.05 ). The control group was given unfractionated heparin, and the observation group was given unfractionated heparin coupled with low-molecular-weight heparin. In addition to pulmonary function and coagulation function, it was also observed that neonates undergoing unfractionated heparin coupled with low-molecular-weight heparin exhibited higher serum levels of serum prealbumin and retinol-binding protein than those treated with unfractionated heparin alone. Finally, higher recovery rate and lower incidence rate of complications, such as pulmonary infection, intracranial hemorrhage, and respiratory distress, were found in the observation group than the control group ( P &lt; 0.05 ). In conclusion, additional treatment with low-molecular-weight heparin could provide a better patient outcome for neonatal pulmonary hemorrhage with unfractionated heparin treatment, as it could notably improve pulmonary function and coagulation function and reduce the incidence of complications.

Low-molecular-weight heparin administered by subcutaneous catheter is a safe and effective anti-coagulation regimen in selected inpatient infants and children with complex congenital heart disease.

Disadvantages of intravenous therapeutic unfractionated heparin, the first-line anti-coagulant agent in children with complex congenital heart disease, include unpredictable pharmacokinetics requiring frequent phlebotomies and the need for continuous intravenous access. To compare efficacy and safety of low-molecular-weight heparin administered by a subcutaneous indwelling catheter with intravenous unfractionated heparin. Clinical data from 31 inpatients prospectively enrolled to receive subcutaneous low-molecular-weight heparin were compared with those from a historical group of 44 inpatients receiving intravenous unfractionated heparin. Investigation of parents' satisfaction by telephone survey. The percentage of anti-factor Xa levels outside therapeutic range was lower in the subcutaneous low-molecular-weight heparin group compared with the percentage of activated partial thromboplastin times outside therapeutic range in the intravenous unfractionated heparin group (40% versus 90%, p < 0.001). Neither group had a major complication. Transient local reactions occurred in 19% of patients of the subcutaneous low-molecular-weight heparin group. The number of needle punctures and that of placement of indwelling catheters were significantly lower in the subcutaneous low-molecular-weight heparin compared with the intravenous unfractionated heparin group (p < 0.001). In total, 84.2% of parents in the subcutaneous low-molecular-weight heparin group reported a positive experience when asked about comparison with prior intravenous unfractionated heparin treatment. Subcutaneous low-molecular-weight heparin offers a safe anti-coagulation regimen for children with complex congenital heart disease providing more efficient therapeutic anti-coagulation and a reduction in needle punctures, thus causing less pain and anxiety in this children.

Individual variation in unfractionated heparin dosing after pediatric cardiac surgery

We aimed to identify attributing factors to the interindividual variabilities of the infusion rates in unfractionated heparin therapy. We included patients who required unfractionated heparin therapy to achieve the target APTT after cardiac surgery between May 2014 and February 2018. Fifty-nine patients were included, of whom 8 underwent Blalock-Taussig shunt; 27, Glenn procedure; 19, Fontan procedure; 3, mechanical valve replacement; and 2, Rastelli procedure. Previously reported variables that influenced the response to unfractionated heparin treatment were initially compared, which included age; weight; sex; type of surgery; platelet count; fibrinogen, antithrombin III, total protein, albumin, alanine transaminase, and creatinine levels; and use of fresh frozen plasma. The type of surgical procedure was found to be significantly associated with the differences in heparin infusion rate (P = 0.00073). Subsequently, the variance explained by these factors was estimated through a selection based on the minimum Akaike information criterion value; models constructed by various combinations of the surgery types were compared. The model including the Blalock-Taussig shunt, Glenn procedure, and mechanical valve replacement showed the highest summed variance explained (29.1%). More than 70% of the interindividual variability in initial heparin maintenance dosing was unexplained.

Monitoring of Unfractionated Heparin in Severe COVID-19: An Observational Study of Patients on CRRT and ECMO.

Objective Severe cases of coronavirus disease 2019 (COVID-19) can require continuous renal replacement therapy (CRRT) and/or extracorporeal membrane oxygenation (ECMO). Unfractionated heparin (UFH) to prevent circuit clotting is mandatory but monitoring is complicated by (pseudo)-heparin resistance. In this observational study, we compared two different activated partial thromboplastin time (aPTT) assays and a chromogenic anti-Xa assay in COVID-19 patients on CRRT or ECMO in relation to their UFH dosages and acute phase reactants. Materials and Methods The aPTT (optical [aPTT-CS] and/or mechanical [aPTT-STA] clot detection methods were used), anti-Xa, factor VIII (FVIII), antithrombin III (ATIII), and fibrinogen were measured in 342 samples from 7 COVID-19 patients on CRRT or ECMO during their UFH treatment. Dosage of UFH was primarily based on the aPTT-CS with a heparin therapeutic range (HTR) of 50–80s. Associations between different variables were made using linear regression and Bland–Altman analysis. Results Dosage of UFH was above 35,000IU/24 hours in all patients. aPTT-CS and aPTT-STA were predominantly within the HTR. Anti-Xa was predominantly above the HTR (0.3–0.7 IU/mL) and ATIII concentration was >70% for all patients; mean FVIII and fibrinogen were 606% and 7.5 g/L, respectively. aPTT-CS correlated with aPTT-STA ( r 2 = 0.68) with a bias of 39.3%. Correlation between aPTT and anti-Xa was better for aPTT-CS (0.78 ≤ r 2 ≤ 0.94) than for aPTT-STA (0.34 ≤ r 2 ≤ 0.81). There was no general correlation between the aPTT-CS and ATIII, FVIII, fibrinogen, thrombocytes, C-reactive protein, or ferritin. Conclusion All included COVID-19 patients on CRRT or ECMO conformed to the definition of heparin resistance. A patient-specific association was found between aPTT and anti-Xa. This association could not be explained by FVIII or fibrinogen.