Levels Of Coagulation Factors Research Articles

Developmental adcyap1b loss leads to hemorrhage, disrupted hemostasis, and a blood coagulation cascade in zebrafish

BackgroundPituitary adenylate cyclase–activating polypeptide is a neuropeptide with diverse roles in biological processes. Its involvement in the blood coagulation cascade is unclear. ObjectivesThis study unraveled adcyap1b’s role in blood coagulation using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 in zebrafish. Effects were validated via adcyap1b knockdown. Gene expression changes in adcyap1b mutants were explored, linking them to clotting disorders. An analysis of proca gene splicing illuminated its role in adcyap1b-related anticoagulation deficiencies. MethodsZebrafish were genetically modified using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to induce adcyap1b knockout. Morpholino-mediated gene knockdown was employed for validation. Expression levels of coagulation factors, anticoagulant proteins, and fibrinolytic system genes were assessed in adcyap1b mutant zebrafish. Alternative splicing of proca gene was analyzed. ResultsAdcyap1b mutant zebrafish exhibited severe hemorrhage, clotting disorders, and disrupted blood coagulation. Morpholino-mediated knockdown replicated observed phenotypes. Downregulation in transcripts related to coagulation factors V and IX, anticoagulation protein C, and plasminogen was observed. Abnormal alternative splicing of the proca gene was identified, providing a mechanistic explanation for anticoagulation system deficiencies. ConclusionAdcyap1b plays a crucial role in maintaining zebrafish blood coagulation and hemostasis. Its influence extends to the regulation of procoagulant and anticoagulant pathways, with abnormal alternative splicing contributing to observed deficiencies. These findings unveil a novel aspect of adcyap1b function, offering potential insights into similar processes in mammalian systems.

Adherence tool for prophylactic haemophilia treatment in adult and adolescent patients: A systematic review and meta-analysis protocol

Hemophilia is a congenital bleeding disorder resulting from a low level or deficiency of clotting factors. It is an x-linked recessive disease and happens almost exclusively in males whereas females are the carrier of the affected gene. The most common types of hemophilia are hemophilia A and Hemophilia B. Hemophilia is classified into mild, moderate and severe. Prophylaxis treatment has more advantages clinically compare to on-demand therapy. It may reduce the bleeding frequency, gives protection from joint damage, may lower the number of total bleeding episodes per year, and may reduce annualised spontaneous and trauma related bleeding events. However, prophylaxis treatment needs regular weekly infusions therefore it is painful to administer especially if the vein is difficult to access. It may cause pain at the site of injections and may lead to non-adherence to treatment. Non-adherence to a regimen will result in insufficient clotting factor levels in the body. The efficacy of the medication is reduced and may lead to a high bleeding tendency. Thus far, the study on adult haemophilic patient adherence tool is scarce and limited; and therefore this review is warranted. The study protocol is conducted as per the PRISMA-P guideline. There are 4 concepts in this systematic review which are Haemophilia, adult and adolescence, preventive treatment and adherence. Articles will be sought from electronic databases PUBMED, Ovid EMBASE, CINAHL, and SCOPUS using the MeSH term, synonym free-text word, truncation, and proximity operators as per each database. The proposed keywords within each concept will be joined using the Boolean operator “OR “and the 4 different concepts combined using the Boolean operator “AND”. Search will be limited to Human, English language, and publication until 2022. Studies will be included if they meet the study inclusion criteria. The quality of the studies will be appraised using the Newcastle-Ottawa quality assessment scale (NOS) for observation-based studies. This systematic review does not require formal ethical approval as data will be extracted from selected published studies. The results will be disseminated through a peer-reviewed publication and relevant conference presentations.(PROSPERO registration CRD42021273813)

Hemostatic balance between pro- and anticoagulant is maintained during glucocorticoid treatment.

Glucocorticoids are associated with an increased risk of venous thrombosis. Glucocorticoid treatment increases coagulation factor and anticoagulant levels; however, its effect on hemostatic function remains unclear. This study aimed to investigate the changes in comprehensive coagulation profiles after glucocorticoid treatment in noninflammatory diseases to elucidate the direct contribution of glucocorticoids to hemostatic function. Patients diagnosed with primary immune thrombocytopenia requiring glucocorticoid treatment were prospectively enrolled in this study. Changes in coagulation factors and anticoagulants during glucocorticoid treatment and changes in thrombin generation potential were determined in the absence and presence of soluble thrombomodulin (sTM). Seven treatment cases (four for steroid pulse therapy and three for oral glucocorticoid therapy) in six patients with immune thrombocytopenia were examined. After glucocorticoid treatment, activated partial thromboplastin time significantly shortened, and activities of factor VIII, IX, XI, and XII significantly increased, except for von Willebrand factor antigen. Moreover, antithrombin and protein C (PC) activities significantly increased after glucocorticoid treatment. Two major parameters of thrombin generation potential, endogenous thrombin potential (ETP) and peak thrombin (Peak), significantly increased in the absence of sTM after glucocorticoid treatment. However, no significant increases in either parameter were observed in the presence of sTM. ETP-TM and Peak-TM ratios, which represent resistance to the anticoagulant effect of the PC pathway, significantly decreased after glucocorticoid treatment, suggesting that anticoagulant function via the PC pathway is elevated after glucocorticoid treatment. As glucocorticoids increase intrinsic coagulation factor and anticoagulant levels, hemostatic balance between pro- and anticoagulant functions is maintained.

Management of pregnant women who have bleeding disorders.

Bleeding disorders, including von Willebrand disease (VWD), hemophilia, other coagulation factor deficiencies, platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Successful management of bleeding disorders in pregnant women requires not only an understanding of bleeding disorders but also an understanding of when and how bleeding occurs in pregnancy. Bleeding does not occur during a normal pregnancy with a healthy placenta. Bleeding occurs during pregnancy when there is an interruption of the normal utero-placental interface, during miscarriage, during an ectopic pregnancy, or at the time of placental separation at the conclusion of pregnancy. Although mild platelet defects may be more prevalent, the most commonly diagnosed bleeding disorder among women is VWD. Other bleeding disorders are less common, but hemophilia carriers are unique in that they are at risk of bleeding themselves and of giving birth to an affected male infant. General guidance for maternal management of a woman who is moderately or severely affected includes obtaining coagulation factor levels at a minimum in the third trimester; planning for delivery at a center with hemostasis expertise; and anticipating the need for hemostatic agents. General guidance for fetal management includes pre-pregnancy counseling; the option of preimplantation genetic testing for hemophilia; delivery at a tertiary care center with pediatric hematology and newborn intensive care; consideration of cesarean delivery of a potentially severely affected infant; and avoidance of invasive procedures such as scalp electrodes and operative vaginal delivery in any potentially affected infant.

Time for a Paradigm Shift in Vitamin K Antagonist Reversal - Embracing TGA over INR for Optimal Outcomes?

Introduction: Vitamin K antagonist (VKA) anticoagulation reversal has relied on International Normalized Ratio (INR) as a standard parameter of coagulation status. Reversal of anticoagulation within INR ranges of 2 - 3 is usually achieved by 25 IU/kg of 4-Factor PCC (4F-PCC), resulting in INR <1.5. However, emerging evidence suggests that increases in coagulation factor activities may be more accurately reflected by the thrombin generation assay (TGA), paving the way for a different approach to assessing effectiveness of VKA reversal. To this effect, a Phase I/II clinical study was conducted to assess dose response of 4F-PCC in healthy subjects anticoagulated with a VKA agent. Methods: This was a prospective, randomized, open-label, placebo-controlled study involving healthy subjects aged 18 to 55 years. Participants were pre-treated for 10 days with acenocoumarol to achieve an INR between 2 and 3 (± 10% inclusive). Subsequently, they received a single iv bolus of 4F-PCC at doses of 12.5 IU/kg or 25 IU/kg, or placebo. Blood samples for TGA, INR, and blood clotting factors (FII, FVII, FIX, FX, protein C, and protein S) were assessed at specified intervals from pre-dose VKA (baseline) up to 15 days after 4F-PCC dose. Results: VKA for 10 days decreased plasma activities of blood clotting factors II, VII, IX and X as expected. Thirty minutes after infusion with 4F-PCC, clotting factor levels were increased in a dose-dependent manner, relative to pre-infusion levels. Placebo had no significant effect on any of the clotting factors. 4F-PCC at 12.5 IU/kg, or 25 IU/kg decreased mean INR values within 30 min after dosing from 2.39 to 1.37, and 2.45 to 1.17, respectively. Infusion with 25 IU/kg fully restored peak thrombin generation at 30 min after dosing compared to baseline (mean ratio: 1.08), while 12.5 IU/kg achieved partial restoration (mean ratio: 0.75). Factor II: Doses of 12.5 IU/kg or 25 IU/kg 4F-PCC increased mean FII values at 30 min post-dose from 32% to 65% and 32% to 89%, respectively (Figure 1). The median maximum concentration (Emax 0-12h) was 68% for 12.5 IU/kg, and 92% for 25 IU/kg (Table 1). Factor VII: Doses of 12.5 IU/kg and 25 IU/kg 4F-PCC increased mean FVII values at 30 min from 15% to 30%, and from 14% to 46%, respectively. The median Emax 0-12h was 32% for 12.5 IU/kg, and 46% for 25 IU/kg. Factor IX: Doses of 12.5 IU/kg and 25 IU/kg 4F-PCC increased mean FIX values at 30 min from 29% to 41% and from 29% to 52%, respectively. The median Emax 0-12h was 45% for 12.5 IU/kg, and 56% for 25 IU/kg. Factor X: Doses of 12.5 IU/kg and 25.0 IU/kg 4F-PCC increased mean FX values at 30 min, from 18% to 42% and 18% to 64%, respectively. The median Emax 0-12h was 45% for 12.5 IU/kg, and 66% for 25 IU/kg. Conclusion: After 4F-PCC infusion, clotting factors II, VII, IX and X showed dose-dependent increases at 30 min post-dose. Correspondingly, a dose-dependent TGA response was observed; 4F-PCC resulted in restoration to levels measured before anticoagulation with VKA. The degree of INR normalization appeared to be slightly more pronounced in the higher dosed 4F-PCC group. Factor II was almost normalized after 4F-PCC infusion and is known to be a main driver of the TGA response. Even though the other clotting factors, such as factor VII, remain in the range of approx. 50%, this does not represent a limitation for adequate activation of the coagulation system. Considering 4F-PCC characteristics and the mechanisms underlying either TGA or INR, the choice of TGA rather than INR appears to be more suitable to monitor appropriate restoration of the overall clotting potential after VKA reversal with 4F-PCC.

Proactive Systematic Hemophilia Carrier Screening: A Step Towards Gender Equity in Hemophilia Care

Introduction Despite multiple awareness-raising initiatives, and in contrast with male persons with hemophilia (PwH), a considerable number of carriers and female PwH still go undiagnosed. We here present the findings of a proactive and extensive hemophilia carrier screening project. Methods From May 2021 until April 2023, potential and obligate carriers of hemophilia A (HA) and B (HB) were identified by updating family trees of all PwH regularly followed at the Cliniques universitaires Saint-Luc. Data from previously screened female individuals (bleeding history, coagulation factor assays and testing for the index patient's pathological genetic variant) were collected retrospectively through electronic medical records (EMRs). Female individuals who had not been previously screened or with missing data were provided with a total of 125 invitation letters by related index hemophilia patients. The study protocol received approval of the local ethics committee. Results All 287 male PwH (226 HA, 61 HB) from 228 families (180 HA, 48 HB) were included in the analysis. Seven female PwH (3 HA, 4 HB) were considered as index cases in their families. In total, based on the family trees, there were 900 females, among which 454 were obligate and/or genetically proven carriers of hemophilia and 118 were found to be non-carriers (Figure 1). Mean age at diagnosis was 30.7 years (range 1-82) in families with HA and 30.1 years (range 0.5-93) in families with HB, without significant difference between these two groups (p=0.809) or between families with severe, moderate or mild hemophilia (p=0.535). Genetic testing for pathological variants has been conducted in 133 obligate, 237 potential and 4 sporadic carriers, and remains to be performed in 190 obligate and 328 potential carriers. Eight females were obligate non-carriers. The group of mothers, sisters and daughters of PwH comprised 543 females, of which at least 178 (35.7% of those with known date of birth) were of reproductive age (18-49 years). Seventy-three percent of females in the latter group have had genetic testing. The proportion of female individuals genetically tested did not significantly differ between families of different severities of HA (p=0.132). In families with moderate HB, female individuals were more likely to be tested (genetic status known in 59.4%) than in other HB severity groups (p=0.01), yet this may be attributed to the presence of one large family comprising 6 male persons with moderate HB and 22 female individuals, of whom a large proportion (n=18, 82%) has had genetic testing. Among carriers with known coagulation factor levels (261/454), 42 (23.0%) and 23 (29.5%) carriers of HA and HB, respectively, had a factor level below 40 IU/dL, and 65 (35.5 %) and 32 (41.0%) had a factor level below 50 IU/dL. The proportion of carriers with a factor level below 40 IU/dL did not significantly differ between families with severe, moderate and mild hemophilia (22.6%, 34.7% and 22.7% respectively, p=0.213), neither did mean coagulation factor levels in carriers with a factor deficiency in these groups (26.2, 30.4 and 27.1 IU/dL in families with severe, moderate and mild HA and HB, p=0.344). Carriers with a coagulation factor deficiency of less than 40 IU/dL were screened earlier than other female individuals (mean age at diagnosis 25.8 and 31.8 years, respectively, p=0.034). Conclusions This study represents the first reported attempt to systematically identify all (potential) hemophilia carriers within families of all PwH followed at a single hemophilia treatment center. To date, this initiative has allowed 44% of the entire cohort to be screened, and carrier status to be genetically confirmed in 73% of mothers, sisters and daughters of PwH who are of childbearing age, based on the date of birth documented in their EMR. Although original and promising, these data reflect the major challenges and difficulties in reaching out and providing appropriate screening to all women genetically linked to one or more PwH. The carrier screening efforts that have been initiated in our center, and which should ideally be replicated across the hemophilia community globally, appear as a critical step towards providing equal access to haemophilia diagnosis and care to all potentially affected individuals, regardless of their gender.

Trend in Von Willebrand Factor Profile in Women With Von Willebrand Disease During Pregnancy and Postpartum

Introduction: Pregnancy is considered a hypercoagulable state, with levels of multiple coagulation factors including Factor VIII (FVIII) and von Willebrand Factor (VWF), progressively increasing throughout, reaching their peak levels during the third trimester. However, in women with von Willebrand disease (VWD), these changes are variable and could be blunted or absent due to the wide heterogeneity of phenotypes and pathophysiological mechanisms linked to this disorder, posing a significant clinical challenge. This study aims to describe the trend in the VWF profile in women with VWD during each trimester of pregnancy and in the postpartum period. Methods: This is a retrospective single-center study that included adult pregnant women diagnosed with VWD, who were followed at Henry Ford Health between 03/2012 and 11/2022. Patients with other bleeding disorders were excluded from the study. Data on baseline characteristics, including age, race, age at childbirth, and parity were collected. Additional data collected included VWF antigen (VWF:Ag) level, FVIII activity level, and VWF ristocetin cofactor (VWF:Rco) activity during the first, second, and third trimesters, as well as in the postpartum period. Results: A total of 33 cases were included in our study. At baseline, the mean VWF:Ag level in our patients was 50.5% (reference range 50%-150%). Compared to baseline, the VWF:Ag level increased by 48.71% in the first trimester, 80.59% in the second trimester, and 168.71% in the third trimester. Postpartum, the VWF:Ag level decreased by 51.29% compared to the third trimester; however, it remained 30.89% higher than baseline levels. While the FVIII level (reference range 50%-150%) was an average of 64.8% at baseline, it increased by 21.91% in the first trimester, 74.23% in the second trimester, and 143.67% in the third trimester, compared to baseline. Postpartum, the FVIII level decreased by 48.45% from the third trimester but remained 25.62% higher than baseline. Additionally, the VWF:Rco level was an average of 44.3% (reference range 51%-215%) at baseline. Compared to baseline, the VWF:Rco level increased by 61.85% in the first trimester, 90.52% in the second trimester, and 142.66% in the third trimester. It decreased by 49.12% postpartum compared to the third trimester but remained 23.48% higher than baseline. Conclusion: In women with VWD, VWF:Ag level, FVIII level, and VWF:Rco levels steadily increase during pregnancy, reaching their maximum levels during the third trimester. All three levels decreased in the postpartum period; however, they remain higher compared to baseline at a median follow up of 105 days after delivery.

Atherosclerosis in Patients with Congenital Hemophilia: A Focus on Peripheral Artery Disease.

Advances in the treatment of hemophilia have increased the life expectancy of this population and we are currently facing diseases associated with aging, including cardiovascular ones. Coronary atherosclerosis, with acute myocardial infarction as the most severe form of manifestation, has been recognized as part of the comorbidities of hemophiliacs. However, little is known about peripheral artery disease. Available data show that hemophiliacs have cardiovascular risk factors and atherosclerosis similar to the general population. Impaired thrombus formation and phenotype of atheroma plaque rather than the burden of atherosclerosis explains their lower cardiovascular mortality. Since the effect of traditional cardiovascular risk factors overpowers that of decreased coagulability and promotes the onset and progression of atherosclerotic lesions, screening for traditional cardiovascular risk factors and peripheral artery disease should be integrated into standard hemophilia care. There is evidence that invasive treatments and long-term antithrombotic therapy are generally safe, provided that coagulation factor levels are taken into account and replacement therapy is given when necessary.

Changes in the Fibrinolytic System of Patients Infected with Severe Acute Respiratory Syndrome Coronavirus 2

Introduction: In this study, coagulation and fibrinolysis parameters and their association with disease severity were investigated in coronavirus disease (COVID-19) patients. Materials and Methods: COVID-19 patients (n=446) admitted to our institute between February 21, 2021 and March 17, 2022, were recruited. Clinical data and staging were collected from all patients. Blood samples were collected and analyzed for several parameters of fibrinolysis and coagulation, including alpha-2-antiplasmin(α2AP) and plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), D dimer, and fibrinogen levels. Results: The TAFI, fibrinogen, and tPA levels were significantly higher in participants who died compared to that of patients who recovered (P<0.001). However, PAI-1, tPA, and TAFI were significantly higher in patients admitted to the ICU than those of the healthy controls (P<0.001 for PAI-1 and tPA; P=0.0331 for TAFI). Our results showed that stage C and D COVID-19 patients had significantly higher levels of PAI-1 (P = 0.003). Furthermore, the stage D COVID-19 patients had significantly higher tPA and TAFI values (P=0.003). Conclusions: Hypofibrinolysis was the most prevalent condition among patients with severe COVID-19. In this study, several coagulation markers were elevated, making them suitable prognostic markers for hypofibrinolysis. Figure 1. Plasma levels of different coagulation factors in COVID-19 patients. Plasma isolated from patients that had died due to COVID-19 and those recovering from the disease (top panel).

Clinical and Laboratory Presentation and Underlying Mechanism in Patients with Low VWF.

Low von Willebrand factor (VWF) refers to subjects with plasma levels of 30 to 50 IU/dL. The mechanism of low VWF is poorly understood. We chose to determine the clinical presentation, laboratory phenotype, and underlying mechanisms of low VWF. We included 250 patients characterized with low VWF. The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) was used to assess clinical symptoms. To determine the underlying mechanisms of low VWF, we used as markers the VWF propeptide (VWFpp) assay and FVIII:C/VWF:Ag ratio for VWF synthesis and the VWFpp/VWF:Ag ratio for VWF clearance. Results were compared with those of 120 healthy controls. Cases with abnormal screening tests were further evaluated for coagulation factor levels and platelet disorders. The median age of the cohort was 35 years (range 3-85), 21% were children (n = 53), 34% were adult males (n = 85), and 45% (n = 112) were adult females. According to the ISTH-BAT, abnormal bleeding was found in 35% of children, 47% of males, and 49% of females. No association was found between VWF activity levels and ISTH-BAT. Patients showed an overall decreased VWF synthesis/secretion and an enhanced VWF clearance was identified in 33% of them. In 89 patients (36%), there were other hemostasis-related defects, but there was no difference in the ISTH-BAT between the two groups. Our findings indicate that reduced VWF synthesis/secretion and enhanced VWF clearance are major mechanisms of low VWF levels. Patients with low VWF have significant bleeding manifestations. While other hemostasis defects occurred together with low VWF, this combination did not exacerbate clinical symptoms.

Abstract 061: Identification of Proteins Predictive of Post‐Thrombectomy Outcome Based on an Appalachian vs. Non‐Appalachian Cohort

Introduction The Appalachia region of North America is known to have significant health disparities, specifically, worse risk factors and outcomes for stroke. Appalachians are more likely to have comorbidities related to stroke, such as diabetes, obesity, and tobacco use, and are often less likely to have stroke interventions such as mechanical thrombectomy (MT) for emergent large vessel occlusion (ELVO). As our Comprehensive Stroke Center directly serves stroke subjects from both Appalachian and non‐Appalachian areas, we set out to identify proteomic biomarkers predictive of stroke outcomes specific to subjects residing in Appalachia. Methods Eighty‐one subjects met inclusion criteria for this study. These subjects underwent MT for ELVO, and during the procedure, carotid arterial blood samples were acquired and subsequently sent for proteomic analysis. Samples were processed in accordance with the Blood And Clot Thrombectomy Registry And Collaboration (BACTRAC; clinicaltrials.gov; NCT 03153683). Statistical analyses were utilized to examine whether relationships between protein expression and outcomes differed by Appalachian status for functional outcomes (NIH Stroke Scale; NIHSS and Modified Rankin Score; mRS), cognitive outcomes (Montreal Cognitive Assessment; MoCA), and mortality. Results No significant differences were found in demographic data nor co‐morbidities when comparing Appalachia to non‐Appalachia subjects. However, time from stroke onset to treatment (last known normal) was significantly longer in patients from Appalachia, so this datapoint was entered as a co‐variate in all predictive models. A comprehensive analysis of 184 cardiometabolic and inflammatory proteins revealed seven Appalachia‐specific proteins predictive of NIHSS, fourteen predictive of MoCA, six predictive of mRS, and seven proteins related to mortality. Specifically, within the Appalachian group, the protein multiple epidermal growth factor‐like domains protein 9 (MEGF9) was positively correlated to discharge NIHSS, elevated levels of the proteins coagulation factor XI (F11) and mannose binding protein (MBL2) were found to have an increased likelihood of worse mRS, but there were no proteins identified from the Appalachian cohort that were predictive of worse MoCA score, nor worse mortality. Conclusion Appalachia is an underserved population with significantly worse health disparities, specifically related to ischemic stroke. Our study found that patients who presented from Appalachian regions have a different proteomic response at time of MT when compared to otherwise similar subjects presenting from non‐Appalachian communities. These differentially expressed proteins could be used as prognostic biomarkers as well as novel therapies targeted at an underserved population. Lastly, expression differences may be in part related to environmental exposures, such as coal pollution, which will require additional studies moving forward.

Levels of Some Blood Clotting Factors in COVID-19 Patients: Comparative Study Before and After Pfizer- BioNTech Vaccinations

One of the health issues that a coronavirus can induce is blood clotting. Coronavirus can be prevented in a number of ways. Vaccination is one of the critical methods for preventing illness or lessening its impact. This study seeks to estimate a few blood coagulation variables. 147 samples were collected from the Baghdad Governorate in the autumn of 2021. The samples were split into three groups: COVID-19 patients, healthy individuals before and after receiving the (Pfizer-BioNTech) vaccine, and healthy individuals only. Prothrombin Time (PT), Partial Thromboplastin Time (PTT), Protein C (PTN-C), Protein S (PTN-S), and International Normalized Ratio (INR) for 49 samples were measured and computed for each group. The results have shown that the PTN-C and PTN-S concentrations were significantly decreased in the COVID-19 patients compared to unvaccinated healthy individuals. While INR of COVID-19 patients showed a highly significant increase when compared with unvaccinated healthy individuals. At the same time, there was no significant difference for each PT and PTT between these studied groups. The parameters exhibit identical findings when COVID-19 patients are compared to those who have had vaccinations, with the exception of PT, which reveals a highly significant rise in COVID-19 patients when compared to those who have received vaccinations. Conclusion: COVID-19 causes blood clots and may be recognized by a decrease in PTN-C and PTN-S content.

Evaluation of hemostasis parameters in recipients following related transplantation of the right lobe of the liver

Objective: to study the dynamics of hemostasis parameters in the early postoperative period and to identify the timing of restoration of the level of procoagulants and anticoagulants synthesized by the liver (received from a living related donor) in liver lobe recipients.Materials and methods. Under observation were 31 recipients and 31 related donors of liver lobe. They were treated at the Republican Specialized Scientific and Practical Medical Center for Surgery in Tashkent, Uzbekistan, from August 2022 to August 2023. Hemostasis parameters were determined in recipients, whose postoperative period was uneventful.Results. It was revealed that compensation in the hemostasis system occurs even at low levels of coagulation factors on day 10 after liver transplantation (LT). In recipients, a decrease in anticoagulants was more pronounced than that of procoagulants. In general, the hemostasis system was in an unstable equilibrium, which, under the influence of external and internal factors, can easily shift both towards hypercoagulable and hypocoagulable state. Activity of the fibrinolytic system and fibrinogen level are significant influencing factors. Gradual recovery of fibrinogen levels by the end of day 1 after surgery is the result of activation of the synthetic function of the liver. After LT, there were signs of endothelium activation, but not endothelial damage, which regress and normalize by postoperative day 10. At the same time, in the initial status, recipients had an increase in both the amount and activity of von Willebrand factor, which indicates endothelial damage and dysfunction. The low level of homocysteine in recipients is probably a protective factor against the development of thrombotic complications, and homocysteine dynamics reflects the gradual restoration of the functional activity of the liver, adaptation of the donor liver to functioning.Conclusion. Monitoring of hemostasis system in recipients after liver transplantation allows to prevent thrombohemorrhagic complications in time but also to assess the dynamic equilibrium of procoagulants and anticoagulants, the timing of restoration of the activity of the main hemostasis factors and, according to this, to vary the administration regimes of anticoagulants, antiplatelet medications, and fibrinolysis inhibitors, to carry out replacement therapy and to realize the concept of hemostasis management.

Coagulation profiles during and after anabolic androgenic steroid use: data from the HAARLEM study

BackgroundAnabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk. ObjectivesWe investigated whether AAS influence coagulation parameters associated with VTE by assessing their changes during and after AAS use. MethodsThe HAARLEM study enrolled 100 male amateur athletes voluntarily starting an AAS cycle between 2015 and 2018. We measured procoagulant and anticoagulant protein levels, D-dimer levels, endogenous thrombin potential (ETP), and clot lysis time (CLT) at baseline and during 2 years of follow-up. Changes in coagulation during AAS cycle, 3 months after its discontinuation, and 1 year after its inclusion compared with baseline were estimated using linear mixed models. The associations between AAS dose and duration of use with these outcomes were studied through adjusted multivariable linear regression. ResultsParticipants used AAS for a median of 13 weeks (IQR: 10-23) with a median weekly dose of 901 mg (IQR: 634-1345 mg). Mean levels of multiple coagulation factors (F) increased during use compared with baseline, whereas FVIII and von Willebrand factor levels remained unchanged. Protein S and D-dimer showed the biggest increase (22% [95% CI: 15-29] and 1.3-fold [95% CI: 1.2-1.5], respectively). CLT was 8 minutes longer (95% CI: 5-10) and ETP was 165 nM∗min (95% CI: −205 to −124) lower during the AAS cycle. A high weekly AAS dose and short cycle duration were associated with changes in protein S and ETP during use. All parameters returned to baseline values 3 months after discontinuation and remained similar after. ConclusionDuring AAS use, procoagulant and anticoagulant protein levels increased in a reversible manner. The overall balance did not suggest a clear procoagulant state.

A Global Assessment of Coagulation Profile and a Novel Insight into Adamts-13 Implication in Neonatal Sepsis.

Neonatal sepsis is a life-threatening condition associated with significant morbidity and mortality. Sepsis-induced coagulopathy is a well-recognized entity, signifying the strong cross-talk between inflammation and coagulation. The aim of the present study was to compare the coagulation profile between the acute phase of sepsis and recovery in term and preterm neonates. Additional comparisons to healthy neonates were undertaken. Levels of clotting, anti-clotting factors and ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type-1 motives), the cleaving protein of von Willebrand factor (VWF), were measured in 16 term and preterm neonates in the acute phase of infection and following recovery, as well as in 18 healthy neonates. Clotting times were prolonged, while levels of particular clotting factors were lower in the acute phase of infection compared to controls and recovery. On the other hand, levels of fibrinogen, factor VIII (FVIII) and VWF were significantly higher in the acute phase in comparison to controls and recovery, while they remained persistently higher in the infection group compared to controls. In regard to the anticlotting mechanism, a clear suppression was observed in septic neonates. ADAMTS-13 levels were significantly lower in the acute phase of infection in comparison to controls and recovery (p = 0.015 and 0.004, respectively), while a trend toward superimposed normalization was demonstrated post infection, as higher ADAMTS-13 levels were measured in recovered neonates compared to controls (p = 0.002). The coagulation profile is considerably deranged in neonatal sepsis. ADAMTS-13 deficiency in septic neonates is a novel finding with promising future implications, as ADAMTS-13 substitution may serve as a useful therapeutic option in neonatal sepsis, prompting further investigation in future studies.

Effect of carboprost tromethamine and carbetocin on coagulation factors and prognosis in puerpera with postpartum hemorrhage due to uterine inertia

Purpose: To determine the effect of carboprost tromethamine and carbetocin on coagulation factors and prognosis in puerpera with postpartum hemorrhage due to uterine inertia.Methods: A total of 80 high-risk pregnant women with postpartum hemorrhage due to uterine inertia admitted to Longyan First Hospital Affiliated of Fujian Medical University, Longyan, China from June 2021 to June 2022 were randomly divided into control group (oxytocin + carboprost tromethamine, n = 40) and study group (oxytocin + carboprost tromethamine + carbetocin, n = 40). Vaginal bleeding volume was recorded for both groups at delivery, and 2 and 24 h after delivery. Decrease in hemoglobin level 24 h after delivery, as well as levels of coagulation factors, and adverse drug reactions before and after treatment were assessed.Results: The third stage of labor, postpartum hemorrhage at 2 and 24 h, and decrease in hemoglobin 24 h after delivery in the study group were lower (p < 0.05). Compared with that before treatment, PLT and FIB levels also fell, while APTT and PT levels rose in both groups after treatment for 24 h (p < 0.05). Platelet count and fibrinogen levels in the study group were lower after treatment for 24 h, but APTT and PT levels were higher (p < 0.05). There was no statistically significant difference in the incidence of adverse drug reactions between both groups (15.00 vs 12.50 %; p > 0.05).Conclusion: Co-administration of carboprost tromethamine with carbetocin prevents high-risk postpartum hemorrhage in pregnant women due to uterine inertia. It also reduces the level of bleeding, and promotes recovery of coagulation function. However, further clinical trials on a larger scale are recommended prior to the application of this treatment strategy in clinical practice.

Peculiarities of orthotopic liver transplantation in patients with liver cirrhosis and severe hemophilia A

In the presented clinical case reports, patients with decompensated liver cirrhosis resulted from chronic viral hepatitis C, being stable responders to antiviral therapy and having severe hemophilia A, underwent orthotopic liver transplantation from a post-mortem donor. The volume of intraoperative blood loss and the course of the immediate postoperative period on the background of the replacement therapy with recombinant VIII coagulation factors did not differ from other liver transplant recipients of the City Clinical Hospital n.a. S.P. Botkin. In the late postoperative period, the level of coagulation factor VIII returned to normal in patients, which made it possible to cancel the replacement therapy.

Surgery in rare bleeding disorders: the prospective MARACHI study

BackgroundDespite the wide use of bleeding scores and the reliability of clotting factor level measurement, bleeding risk stratification before surgery remains challenging in patients with rare inherited bleeding disorders. ObjectivesThis multicenter observational prospective study assessed in patients with rare coagulation factor deficiency, the perioperative hemostatic management choices by hemostasis experts and the bleeding outcomes after surgery. MethodsOne hundred seventy-eight patients with low coagulation activity level (factor [F] II, FV, combined FV-FVIII, FVII, FX, or FXI <50%) underwent 207 surgical procedures. The bleeding outcome, Tosetto’s bleeding score, and perioperative hemostatic protocols were collected. ResultsAmong the 81 procedures performed in patients with severe factor deficiency (level ≤10%), 27 were done without factor replacement (including 6 in patients at high bleeding risk), without any bleeding event. Factor replacement therapy was used mainly for orthopedic procedures. In patients with mild deficiency, 100/126 surgical procedures were carried out without perioperative hemostatic treatment. In patients with FVII or FXI deficiency, factor replacement therapy was in function of the procedure, bleeding risk, and to a lesser extent previous bleeding history. Tranexamic acid was used in almost half of the procedures, particularly in case of surgery in tissues with high fibrinolytic activity (76.8%). ConclusionsThe current perioperative hemostatic management of patients with rare bleeding disorders appears to be adapted. Among the 207 procedures, only 6 were associated with excessive bleeding. Our findings suggest that rather than the bleeding score, factor level and surgery type are the most relevant criteria for perioperative factor replacement therapy.

Preparation of Fibrinogen-Depleted Human Platelet Lysate to Support Heparin-Free Expansion of Umbilical Cord-Derived Mesenchymal Stem Cells.

Human platelet lysate (hPL) has high levels of fibrinogen and coagulation factors, which can lead to gel and precipitate formation during storage and cell culture. Heparin derived from animals is commonly added to minimize these risks, but cannot completely eliminate them. Thus, this study proposes an alternative method to prepare fibrinogen-depleted hPL (Fd-hPL) that supports heparin-free expansion of mesenchymal stem cells (MSCs). hPL was added to heparin to prepare heparin-hPL (H-hPL), whilst Fd-hPL was prepared by adding calcium salt to hPL to remove the fibrin clot. The concentrations of calcium, fibrinogen, and growth factors in H-hPL and Fd-hPL were compared. The effects of H-hPL and Fd-hPL on umbilical cord-derived MSCs (UC-MSCs) were assessed. The results showed that Fd-hPL possessed a significantly higher calcium concentration and a lower fibrinogen level than H-hPL. The concentrations of BDNF, TGF-β1, and PDGF-BB showed no significant difference between H-hPL and Fd-hPL, but Fd-hPL had a lower VEGF concentration. Fd-hPL retained the characteristics of UC-MSCs, as it did not affect the cell viability, proliferation, multilineage differentiation potential, or surface marker expression. In conclusion, Fd-hPL effectively supported the in vitro expansion of MSCs without compromising their characteristics, positioning it as a potential substitute for FBS in MSC culture.

Need to determine the residual concentrations of direct oral anticoagulants in patients with atrial fibrillation undergoing transcatheter implantation of the aortic valve

Introduction. Lengthening the period of direct oral anticoagulant (DOAC) withdrawal before intervention is not allowed. Chronic kidney disease (CKD), impaired liver function, extremely low or high body mass, chronic heart failure (CHF), and age &gt; 90 years can increase blood DOAC levels. DOAC therapy does not require routine laboratory monitoring. However, there are coagulation tests that can be used to detect the presence of a drug in blood. Duration of DOAC discontinuation and the appropriateness of assessing residual anticoagulant concentrations before intervention with a high bleeding risk in a special category of patients is to be defined.Aim. To measure residual concentrations of anticoagulants and their association with perioperative bleeding risk in patients with AF using DOACs in blood samples collected immediately before TAVI.Materials and methods. The 94 patients with atrial fibrillation (AF) included in the study were characterized by senile age, a high risk of thromboembolic complication (ТС), many comorbidities, and a high prevalence of senile asthenia. The apixaban and rivaroxaban concentrations were measured according to the value of anti-Xa activity and control plasmas with normal levels of coagulation factors (Diagnostica Stago, France).Results. The median time of DOAC withdrawal before TAVI was 60 hours [47.5; 72]. However, the DOAC concentration exceeded 30 ng/ml in 1/5 patients (19.2%), and stage 3 or more CKD was more common in these patients. Our study showed the relationship between DOAC concentration and the duration of DOAC withdrawal period. However, the relationship between DOAC concentration and bleeding that occurred in the perioperative period could not be found. Patients with signs of CKD were older and had a lower BMI as compared to patients without CKD.Conclusion. Our data showed the relationship between the DOAC concentration and the duration of DOAC withdrawal period. No relationship was found between DOAC concentrations and bleeding.