Prolonged aPTT Research Articles

Effect of Age, Sex, Renal Impairment and Hepatic Impairment on the Safety, Pharmacokinetics and Pharmacodynamics of Asundexian.

Asundexian is a reversible and selective inhibitor of activated factor XI. It is currently under investigation for the prevention of secondary stroke in at-risk patients; these patients are often characterised by advanced age, impaired organ function and comorbidities. This article summarises results from three Phase I studies that investigated the effects of age and sex (study 1), chronic kidney disease including end-stage kidney disease (ESKD) on dialysis and dialysis-free days (study 2) and Child-Pugh A and B liver disease (study 3) on the safety, pharmacokinetics and pharmacodynamics of a single oral dose of asundexian 25mg. Study 1 was a multicentre, randomised, single-blind, placebo-controlled group-stratification design; study 2 was a single-centre, non-randomised, non-placebo-controlled, non-blinded group-stratification design; and study 3 had a non-randomised, non-blinded, non-placebo-controlled group-stratification design. Single doses of asundexian 25 mg were generally well tolerated in all three studies, with no asundexian-related bleeding events or treatment-emergent adverse events of special interest. Point estimates (geometric least squares [LS] means) (90% confidence intervals [CIs]) for the total asundexian area under the plasma concentration-time curve (AUC) for participants aged ≥65 to< 75 years versus ≥18 to <45 yearsand ≥75 to ≤80 years versus ≥18 to <45years were 1.257 (1.134-1.393) and 1.288 (1.158-1.433), respectively, and for females versus males, it was 1.084 (0.995-1.182). Point estimates (geometric LS means) (90% CIs) for unbound AUC in participants in estimated glomerular filtration rate (eGFR) categories G2 (60-89 mL/min/1.73 m2), G3 (30-59 mL/min/1.73 m2) and G4 (15-29 mL/min/1.73 m2) versus control were 1.003 (0.698-1.443), 0.791 (0.550-1.138) and 0.882 (0.606-1.285), respectively, and in participants with ESKD on dialysis-free day versus control was 0.597 (0.406-0.877). There was no effect of the dialysis procedure on the pharmacokinetics of asundexian. In participants deemed Child-Pugh class A and Child-Pugh class B, geometric LS means (90% CIs) for unbound AUC were 0.834 (0.597-1.164) and 1.143 (0.810-1.612), respectively, when compared to participants with normal liver function. Activated partial thromboplastin time (aPTT) was assessed as a pharmacodynamic variable of interest. Geometric mean maximum aPTT prolongation as a ratio to baseline after administration of asundexian 25 mg ranged from 1.45 to 1.55 in all age and sex groups, 1.49-1.59 in the control and eGFR G2 to G4 groups, 1.38-1.54 in the control and ESKD groups on dialysis and dialysis-free day and 1.38-1.89 in the healthy control and liver impairment groups. The effects of the investigated intrinsic factors on the exposure of asundexian were small and not considered clinically relevant. The impact of lower exposure in participants with ESKD requires further investigation. Pharmacodynamics were as expected. EudraCT 2022-000196-38 and 2020-000626-25.

A study of clinical profile and outcome of patients with snake bite-induced acute kidney injury

ABSTRACT Background: Snake bite is a well-known occupational hazard amongst farmers, plantation workers, and other outdoor workers and results in much morbidity and mortality throughout the world. The complications related to kidneys are observed in most patients with snake bites admitted to a hospital. The current study aimed to study the renal involvement in patients with snake bites with reference to clinical features and the time of onset of acute renal failure. Methods: A prospective clinical study of 68 patients of snake bite was done to know the clinical profile and outcome in Gandhi Hospital Secunderabad and cases were particularly looked for development of acute kidney injury. Later each case was studied and investigated with respect to onset, clinical features, course in the hospital, need for renal replacement therapy including dialysis, and mortality due to AKI. Patients were followed up till discharge or death. They were treated as per protocol. Results: The incidence of AKI was 29.1%. Common signs and symptoms were fang mark (100%), swelling (91.2%), tenderness (91.2%), bleeding manifestations (79.4%) oliguria (26.47%), anuria (5.8%), and haematuria (8.8%). Hypotension was present in 73%, which may be the cause of AKI. All the AKI patients showed coagulation abnormalities in the form of prolonged BT, CT, PT, and aPTT. Thrombocytopenia was seen in 29.4%. All the AKI patients were given ASV for 2 to 3 days. The mean ASV vials used in the present study is 15 ± 5. Hemodialysis was done in 29.4% of patients. Conclusion: The cause of AKI in snakebite was multifactorial in origin. Bleeding and hypotension were among the important causes. Thrombocytopenia was significantly related to clinical bleeding. The type of snakebite is an important factor in the development of AKI and Russell’s viper bite is more commonly associated with it. AKI is usually associated with oliguria and generally occurs within 48 hours.

Characterisation of the pharmacokinetic and pharmacodynamic relationship of milvexian in total knee replacement patients

Abstract Background Milvexian, an oral factor XIa inhibitor, is currently being evaluated in patients at risk for thrombotic events due to atrial fibrillation, ischaemic stroke, or acute coronary syndrome. The exposure-response relationship between clinical efficacy and safety endpoints and milvexian pharmacokinetic (PK) metrics was recently submitted as a separate publication. Characterisation of the relationship between the coagulation pharmacodynamic (PD) markers versus milvexian PK metrics at the patient level has yet to be reported. Purpose This analysis characterised the relationship between the coagulation biomarkers, activated partial thromboplastin time (aPTT) and prothrombin time (PT), and milvexian systemic exposure in patients undergoing total knee replacement (TKR) evaluated in the AXIOMATIC-TKR study. Methods A population pharmacokinetic (PopPK) model was previously developed and characterised the PK of milvexian in TKR patients well. The PK/PD relationships between observed aPTT and PT versus PopPK model estimated time-matched milvexian plasma concentrations via nonlinear mixed effects modeling. The relationship between key clinical safety endpoints (e.g., any bleeding or clinically relevant non-major bleeding) and individual PD marker change (e.g., aPTT ratio to baseline) was also explored. Results The aPTT increased with increasing plasma concentration of milvexian over the range of doses evaluated in the study (25mg QD to 200mg BID). An Emax type of model reasonably characterised the PK/PD relationship between the aPTT and model predicted time-matched milvexian plasma concentration, which is consistent with previously observed relationships in healthy volunteers. No change was observed in PT with increased milvexian exposure. No obvious relationship was identified between any (including clinically relevant non-major) bleeding and aPTT ratio to baseline. Conclusions Increased milvexian exposure is directly correlated with aPTT prolongation over the range of doses evaluated in the TKR study. There was no obvious relationship between any (including clinically relevant non-major) bleeding and aPTT ratio. The PK/PD relationship of aPTT without a parallel relationship in PT distinguishes milvexian, a FXIa inhibitor, from previously studied FXa inhibitors. These analyses were a complementary component in dose selection for the milvexian Phase 3 program. Figure 1. PK/PD relationship between aPTT (left) and PT (right) and estimated time-matched plasma concentration (AXIOMATIC-TKR study)

Preclinical characterisation and first-in-human results on the tolerability and pharmacodynamic effect of REGN9933, a monoclonal antibody targeting the factor XI/activated factor XI apple 2 domain

Abstract Background/Introduction Standard-of-care anticoagulants are associated with increased bleeding risk. Genetic/pharmacological data suggest coagulation factor XI (FXI) inhibition can prevent thrombosis with minimal increased bleeding risk. We present preclinical and first-in-human (FIH) data on REGN9933, a FXI-binding monoclonal Ab. Purpose To characterise REGN9933 epitope binding sites, affinities for FXI and activated FXI (FXIa), and effect on high molecular weight kininogen (HMWK)’s interaction with FXI. Also, to assess safety, tolerability and pharmacodynamics in healthy human participants (pts). Methods Epitope binding sites mapped with cryogenic electron microscopy, binding affinities determined with plasmon resonance techniques, effect on thrombin generation assessed with a thrombin generation assay, and impact on HMWK:FXI interaction analysed using ELISAs. In the FIH, Ph 1, randomised, double-blind, single-centre study, pts received a single dose of REGN9933 intravenously (IV; 3–300 mg) or subcutaneously (SC; 100 mg &amp; 300 mg), or placebo (PBO). Primary endpoint: incidence and severity of treatment-emergent AEs (TEAEs). Other endpoints: effect of REGN9933 on activated partial thromboplastin time (aPTT) and prothrombin time (PT) to assess intrinsic and extrinsic pathway-triggered coagulation, respectively; and FXI activity. Results REGN9933 was found to bind the FXI apple 2 domain, with subnanomolar binding affinities for FXI and FXIa at 37°C, resulting in reduced thrombin generation from the intrinsic (not extrinsic) pathway. REGN9933 competed with HMWK for FXI binding in a dose-related manner. In the Ph 1 study, 56 pts received REGN9933 (IV, n=30; SC, n=12) or PBO (n=14); 42.9% and 21.4% had ≥1 TEAE, respectively (most common with REGN9933: headache, 12%; oropharyngeal pain, 5%). No serious/severe TEAEs, or TEAEs of special interest (inc. moderate/severe bleeding) reported. Laboratory tests revealed no clinically meaningful differences in the number/type of treatment-emergent potentially clinically significant values with REGN9933 vs PBO. REGN9933 resulted in dose-dependent prolongation of aPTT; aPTT mean fold change from baseline was highest with IV 300 mg after 8 hrs (2.7) and remained &amp;gt;2 for 36 days (Fig 1). There was no detectable effect on PT or clinically meaningful effect on bleeding time. REGN9933 supressed FXI activity in a dose-dependent manner, with suppression to approx. the lower limit of assay quantification (5%) with IV ≥30 mg (Fig 2). Conclusion(s) REGN9933 binds the FXI apple 2 domain and inhibits HMWK:FXI interaction, preventing intrinsic pathway-triggered FXI activation. FIH data showed dose-dependent inhibition of the intrinsic coagulation pathway by REGN9933, without affecting the extrinsic or common pathways. Pharmacodynamic and safety findings support continued development of REGN9933 as an anticoagulant that may carry less bleeding risk than currently approved agents.

Prevalence of High Activated Partial Thromboplastin Time (aPTT) among Patients with Liver Cirrhosis Department of Medicine at Saidu Group of Teaching Hospital, Swat

Introduction: Chronic liver disease or liver cirrhosis is a disease condition in which fibrosis and the creasing of the liver are not functioning correctly. The severity of cirrhosis depends upon the extent of liver failure. Advanced stages of liver failure that create an abnormal coagulation profile have increased the tendency towards bleeding and have consequently increased the hospitalization rates and mortality among cirrhotic patients. Activated partial thromboplastin time is a test that measures activity of Factors VII, IX, XI, and XII. An increased aPTT is due to decreased synthesis of measuring clotting factors in the sample indirectly decreases synthesis from the liver. Department of Medicine, Saidu Group of Teaching Hospital Swat Duration of study: From 13 August 2020 to 14 Feb 2021. Total 195 cases of cirrhosis are consecutively selected from OPD and activated partial thromboplastin time (aPTT). Results: The mean age of sample was 45.2 + 7.3 years. 68.2% was male gender while 31.8% is female gender. The mean duration of the disease was 7.1 + 2.5 years. The results showed acute decompensation in 34.9% and 30.8% had hospitalization history due to decompensation. Cardiac drug use history was present in 34.9%. The results further showed that 45.1% patients were diagnosed with prolonged aPTT. Conclusion: Prolongation of aPTT is a frequent problem in our local cirrhotic population. Further studies are needed to develop an association of factors that lead to the prolongation of aPTT, its control, and its effect on morbidity and mortality of patients with cirrhosis. Keywords. Liver cirrhosis, coagulation disorders, activated partial thromboplastin time, acute decompensation

A Tale of Two Cases: Acquired Hemophilia A and/or Lupus Anticoagulant?

Abstract Distinguishing between acquired hemophilia A (AHA) and lupus anticoagulant (LA) is essential for effective clinical management. This can be challenging due to similarities in laboratory tests and potential interference between their diagnostic tests. Here we present two complex cases. Case 1 is a 69-year-old female with PNH presenting with a subdural hematoma. Prolonged aPTT with no correction on mixing raised clinical suspicion of AHA. Factor VIII activity was low (2%) across three dilutions in the factor assay. A Bethesda assay revealed a low factor VIII inhibitor (1%). LA was negative by DRVVT. Antiphospholipid antibodies (Cardiolipin and Beta-2-Glycoprotein 1) were also negative. Treatment with prednisone and intravenous immunoglobulin was initiated with presumptive diagnosis of AHA. Subsequent samples to check other factor levels uncovered low Factor IX as well. Higher dilutions in factor assays exhibited non-parallelism in Factor IX and VIII, suggesting a non-specific inhibitor. Chromogenic Factor VIII was within the normal range. Another LA test, Staclot-LA was positive. Overall, this case was consistent with LA rather than AHA. The initial ‘positive’ Bethesda assay was attributed to interference by LA. Case 2 is a 20-year-old female with no significant medical history who was admitted elsewhere for a complicated C-section with intraabdominal hemorrhage. She had prolonged aPTT and positive LA by platelet neutralization test there. Upon transfer, the initial assessment confirmed prolonged aPTT and a time-dependent inhibitor pattern in mixing studies. Factor studies revealed significantly diminished factor VIII activity (&amp;lt;1%) using both one-stage clotting and chromogenic assays. A strong factor VIII inhibitor was identified through chromogenic Bethesda assay (126 BU). Non-parallelism was observed in other factors (Factor IX, XI, XII). LA was negative by DRVVT but positive by Staclot-LA. Cardiolipin and beta2-glycoprotein-1 antibodies were negative. The diagnosis of AHA was evident. But is there concurrent LA present? Both Staclot-LA and platelet neutralization tests are PTT-based and susceptible to interference from factor VIII inhibitor. The patient underwent treatment, and factor VIII inhibitor disappeared in 3 months. Staclot-LA also turned negative, suggesting that the initially ‘positive’ LA test was likely a result of interference. In both cases, adopting a holistic approach to differentiate between AHA and LA is beneficial. Relying solely on individual tests may lead to false interpretations, as LA can inhibit FVIII activity assays and produce false positives in the Bethesda assay. It is advisable to include higher dilutions in factor assays and/or chromogenic assays to mitigate interference. The presence of factor VIII inhibitor can also result in false-positive LA results such as Staclot-LA assay. For more reliable results, DRVVT and antibody tests are preferable. If the aPTT-based assay is the sole positive LA test, the presence of LA is suggested when it occurs before and/or after the presence of a factor inhibitor.

Evaluating preoperative coagulation panels in dogs undergoing liver lobectomy for primary liver tumors: A multi-institutional retrospective study.

The objectives of this study were to: (i) Determine whether operable primary liver tumors were associated with prolongations in prothrombin time (PT) and activated partial thromboplastin time (aPTT) and (ii) determine if these secondary hemostatic abnormalities were more prevalent with specific liver tumors. Multi-institutional retrospective study. Dogs (n = 359) undergoing liver lobectomy for a primary liver tumor with a preoperative coagulation panel. Data was identified via electronic medical record review at eight veterinary teaching hospitals. Baseline dog characteristics, coagulation panel values, platelet count, emergency versus non-emergency procedure, whether the dogs received transfusion(s) of a blood product, liver lobe removed, and histopathological diagnosis were extracted from the medical record. Chi-square analysis was used to compare categorical variables between groups. Continuous variables were assessed for normality using the Shapiro-Wilk test. A total of 74 of 359 dogs (20.6%) had a prolongation in either PT or aPTT preoperatively. A total of 20 of 359 dogs (5.6%) were found to have prolongation of both PT and aPTT. Hemangiosarcoma was the only histopathological diagnosis associated with concurrent prolongations of both PT and aPTT (p < .001) in 6/16 (37.5%) dogs. Coagulation panels including PT and aPTT are unlikely to detect substantial deficiencies in secondary hemostasis in most dogs with primary liver tumors except in dogs with a histopathological diagnosis of hemangiosarcoma. PT and aPTT testing is low yield as an elective preoperative screening test in dogs with primary liver tumors except in dogs where there is a hemoabdomen or high suspicion for hepatic hemangiosarcoma.

A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis.

Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre-clinical studies showed benefit with a histone-neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose-adjusted, open-label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady-state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug-related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half-life values ranged from 5 to 7 h. The mean (±SD) terminal half-life for non-RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.

Basic coagulation parameters and platelet count among malaria patients attending at Addis Zemen Primary Hospital, Northwest Ethiopia.

Malaria is an intravascular parasitic-related blood disease that causes bleeding, coagulopathy, and thrombocytopenia. However, limited data shows the effect of Plasmodium species infection on basic coagulation parameters and platelet count. Thus, this study aimed to assess basic coagulation parameters and platelet count among malaria patients. A cross-sectional study was conducted among 240 study participants (120 cases and 120 controls) from June 1, 2021, to February 30, 2022. A convenient sampling technique was employed to select study participants. The blood sample was collected by a trained laboratory technologist for platelet counts, prothrombin time (PT), partial thromboplastin time (PTT), international normalization ratio (INR), blood film, and serological testing. The collected data were analyzed in SPSS version 23. Data were analyzed by the Mann-Whitney U test, Kruskal Wallis H, and Spearman's rank-order correlation tests. Descriptive findings were presented through median, tables, and chart. In all cases, a P-value < 0.05 was considered statistically significant. The percentage of mild, moderate, and high malaria parasitemia levels per microliter of blood was 21.7%, 20%, and 58.3%, respectively. The overall median malaria parasitemia was 10,304 per microliter of blood. Among malaria patients, 77.5%, 61.7%, and 51.7% had prolonged PT, INR, and APTT, respectively as compared to control. Moreover, 26.7% of Plasmodium-infected participants had mild thrombocytopenia as compared to the control group (P < 0.001). The value of PT, APTT, and INR were significantly elevated, whereas the level of platelet count was inversely reduced when the malaria parasitemia level increased as compared to controls (p < 0.001).

Antiphospholipid syndrome autoantibodies induction after treatment with anti-TNF alpha therapy in patients with IBD

IntroductionAnt-iTNF treatment has been broadly linked with autoantibodies and autoimmune disorders development. After the clinical observation of aPTT (activated partial thromboplastin clotting time) prolongation in our cohort of IBD patients treated with anti-TNF, we sought to determine the presence of antiphospolipid antibodies in our population, along with antiphospholipid syndrome (APS) occurrence. MethodsWe included in the study 289 patients treated with anti-TNFα antibodies. ResultsTwenty four of 289 patients presented a prolonged aPPT (8.3%) after starting anti-TNF treatment. We found antiphospholipid antibodies in 70.8% (17/24) of patients with aPTT prolongation. No major thrombotic events were reported although one patient met criteria for APS because of persistent antiphospolipid antibodies and two miscarriages. Another patient was diagnosed with lupus-like syndrome. ConclusionAnti-TNF treatment is associated with the induction of various antibodies, among them, antiphospholipid antibodies. However, a very low number of patients develop APS. Testing for antiphospholipid antibodies patients with prolonged aPPT could identify those at risk and lead to individualized treatment. Additional prospective studies are necessary to acquire more information.

Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies.

The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single-blinded, placebo-controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1-3 h and 4-6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose-proportional pharmacokinetics for AUC but not Cmax; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose-dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1-4 h and 2-6 days after IV and SC administration, respectively. Anti-drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose-proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated.

A retrospective cohort study of coagulation function in patients with liver cirrhosis receiving cefoperazone/sulbactam with and without vitamin K1 supplementation.

Cefoperazone/sulbactam is commonly prescribed for the treatment of infected patients with cirrhosis. To investigate the effect of cefoperazone/sulbactam on coagulation in cirrhotic patients and assess the effectiveness of vitamin K1 supplementation in preventing cefoperazone/sulbactam-induced coagulation disorders. This retrospective cohort study compared coagulation function in 217 cirrhotic patients who received cefoperazone/sulbactam with and without vitamin K1 supplementation (vitamin K1 group, n = 108; non-vitamin K1 group, n = 109). Propensity score matching (PSM) was used to to reduce confounders' influence, the SHapley additive exPlanations (SHAP) model to explore the importance of each variable in coagulation disorders. In the non-vitamin K1 group, the post-treatment prothrombin time (PT) was 16.5 ± 6.5s and the activated partial thromboplastin time (aPTT) was 34.8 ± 9.4s. These were significantly higher than pre-treatment values (PT: 14.6 ± 2.4s, p = 0.005; aPTT: 30.4 ± 5.9s, p < 0.001). In the vitamin K1 group, no differences were observed in PT, thrombin time, or platelet count, except for a slightly elevated post-treatment aPTT (37.0 ± 10.4s) compared to that of pre-treatment (34.4 ± 7.2s, p = 0.033). The vitamin K1 group exhibited a lower risk of PT prolongation (OR: 0.211, 95% CI: 0.047-0.678) and coagulation disorders (OR: 0.257, 95% CI: 0.126-0.499) compared to that of the non-vitamin K1 group. Propensity score matching analysis confirmed a reduced risk in the vitamin K1 group for prolonged PT (OR: 0.128, 95% CI: 0.007-0.754) and coagulation disorders (OR: 0.222, 95% CI: 0.076-0.575). Additionally, the vitamin K1 group exhibited lower incidences of PT prolongation, aPTT prolongation, bleeding, and coagulation dysfunction compared to the non-vitamin K1 group. Cefoperazone/sulbactam use may be linked to a higher risk of PT prolongation and coagulation disorders in cirrhotic patients. Prophylactic use of vitamin K1 can effectively reduce the risk.

Clot waveform analysis of prolonged activated partial thromboplastin time in various disorders.

The prolongation in APTT reflects various disorders affecting the blood coagulation system. Automated coagulation analyzers such as ACL TOP, help in evaluating the clotting cascade by displaying clot reaction curves or waveforms. The fibrin formation curve forms S-shaped curve showing the changes in the absorbance on X-axis and time in seconds on Y-axis. The clotting data is processed to obtain derivatives. This observational study analyzed 80 samples including 20 samples from normal healthy individuals as control. The parameters studied were time (secs), height (mAbs), and width (secs) of first derivative (FD), fibrin clot time at ½ height, height (mAbs), and width (secs) of both first and second peaks of second derivative (SD). Hemophilia (n = 13) that consisted of factor VIII deficiency (n = 11) and factor IX deficiency (n = 2) showed biphasic patterns in both first DC and second DC. Cases with thrombosis (n = 8) showed marked elevation in first DC. Various other disorders (n = 39) that consisted of mainly hepatic dysfunction (n = 24) showed prolongation in fibrin formation, first DC, and second DC peak time. The atypical derivative curve analysis helps in determining the interferences in clotting cascade. It gives significant information and provides direction for further testing.

DNA/RNA heteroduplex technology with cationic oligopeptide reduces class-related adverse effects of nucleic acid drugs

Antisense oligonucleotides (ASOs) are a therapeutic modality for incurable diseases. However, systemic injection of gapmer-type ASOs causes class-related toxicities, including prolongation of activated partial thromboplastin time (aPTT) and thrombocytopenia. We previously reported that cholesterol-conjugated DNA/RNA heteroduplex oligonucleotides (Chol-HDOs) exhibit significantly enhanced gene silencing effects compared to ASOs, even in the central nervous system, through crossing the blood-brain barrier. In the present study, we initially evaluated the effect of the HDO structure on class-related toxicities. The HDO structure ameliorated the class-related toxicities associated with ASOs, but they remained to some extent. As a further antidote, we have developed artificial cationic oligopeptides, L-2,4-diaminobutanoic acid oligomers (DabOs), which bind to the phosphates in the major groove of A-type double helical structure of HDOs. DabO/Chol-HDO complex showed significantly improved aPTT prolongation and thrombocytopenia in mice while maintaining gene silencing efficacy. Moreover, the conjugation with DabOs effectively prevented cerebral infarction, a condition frequently observed in mice intravenously injected with high-dose Chol-HDO. These approaches, combining HDO technology with DabOs, offer distinct advantages over conventional strategies in reducing toxicities. Consequently, the DabO/HDO complex represents a promising platform for overcoming the class-related toxicities associated with therapeutic ASOs.

Is lupus anticoagulant testing with dilute Russell’s viper venom clotting times reliable in the presence of inflammation?

BackgroundTesting for lupus anticoagulant (LA) is not recommended in case of inflammation as C-reactive protein (CRP) can interfere in vitro with the phospholipids present in the activated partial thromboplastin time test used to detect an LA. However, the potential interference of an acute phase protein (ie, CRP) in LA testing using the dilute Russell’s viper venom (DRVV) test is poorly studied. ObjectivesTo study the effect of inflammation, as evidenced by increased CRP levels, on DRVV tests. MethodsFirst, a retrospective analysis (2013-2023) was performed: data on all LA workups were retrieved, and the association between CRP levels and DRVV screen, mix, and confirm clotting times was studied. Second, data on DRVV panels and CRP levels were extracted from 2 prospective studies involving intensive care unit patients to study the association between both variables. Third, CRP was added to normal pooled plasma at 6 relevant concentrations (up to 416 mg/L) to study the association between CRP itself and DRVV coagulation times. ResultsIn the retrospective analysis, DRVV screen and confirm clotting times significantly increased as CRP increased (increase of 0.11 seconds and 0.03 seconds per 1 mg/L increase of CRP level, respectively). In the prospective analysis, only DRVV screen was prolonged with high CRP levels (increase of 0.06 seconds for a 1 mg/L increase in CRP level); DRVV screen/confirm ratio was also increased with high CRP levels. In vitro, the addition of CRP did not significantly increase any DRVV clotting times. ConclusionLA testing should be performed with much caution in the presence of inflammation as it may be associated with prolongation of both activated partial thromboplastin time and DRVV clotting times.

Purification and Structural Analyses of Sulfated Polysaccharides from Low-Value Sea Cucumber Stichopus naso and Anticoagulant Activities of Its Oligosaccharides.

Three polysaccharides (SnNG, SnFS and SnFG) were purified from the body wall of Stichopus naso. The physicochemical properties, including monosaccharide composition, molecular weight, sulfate content, and optical rotation, were analyzed, confirming that SnFS and SnFG are sulfated polysaccharides commonly found in sea cucumbers. The highly regular structure {3)-L-Fuc2S-(α1,}n of SnFS was determined via a detailed NMR analysis of its oxidative degradation product. By employing β-elimination depolymerization of SnFG, tri-, penta-, octa-, hendeca-, tetradeca-, and heptadeca-saccharides were obtained from the low-molecular-weight product. Their well-defined structures confirmed that SnFG possessed the backbone of {D-GalNAc4S6S-β(1,4)-D-GlcA}, and each GlcA residue was branched with Fuc2S4S. SnFS and SnFG are both structurally the simplest version of natural fucan sulfate and fucosylated glycosaminoglycan, facilitating the application of low-value sea cucumbers S. naso. Bioactivity assays showed that SnFG and its derived oligosaccharides exhibited potent anticoagulation and intrinsic factor Xase (iXase) inhibition. Moreover, a comparative analysis with the series of oligosaccharides solely branched with Fuc3S4S showed that in oligosaccharides with lower degrees of polymerization, such as octasaccharides, Fuc2S4S led to a greater increase in APTT prolongation and iXase inhibition. As the degree of polymerization increases, the influence from the sulfation pattern diminishes, until it is overshadowed by the effects of molecular weight.

CLINICAL AND LABORATORY PROFILE OF ADMITTED PATIENTS PRESENTING WITH FEBRILE ILLNESS DUE TO DENGUE AND SCRUB TYPHUS COINFECTION FROM A TERTIARY CARE HOSPITAL IN SOUTH RAJASTHAN, INDIA

Objective: The present study aims at describing the clinical features, laboratory diagnosis, and complications in patients presenting with febrile illness due to scrub typhus and dengue coinfection from Southern Rajasthan, India. Method: This present prospective, observational, and hospital-based study conducted in the Department of Microbiology of AIMS &amp; RC, Rajsamand, located in Southern Rajasthan, from January 2021 to December 2021. Scrub typhus was diagnosed in the microbiology laboratory by performing SD Bioline, one-step scrub typhus for the detection of IgM antibody, and dengue fever using J.mitra and Co. Pvt. Ltd., rapid card test for the detection of NS1 antigen and IgM antibody. Result: Out of 500 patients suspected of AUFI, 25 (5%) patients diagnosed of having dengue and scrub typhus coinfection. Fever was present in all 25 (100%) patients and 13 (52%) of patients had arthralgia, nausea, and vomiting. The most common sign noticed in our study was pallor and icterus in 10 (40%) patients each followed by shock/hypotension in 8 (32%) and hepatosplenomegaly in 5 (20%). The most predominant laboratory finding was thrombocytopenia (&lt;1.0 × 106/cumm) in 23 (92%) patients, while elevated bilirubin (&gt;2 mg/dl) in 22 (88%) and elevated transaminase and prolonged aPTT in 21 (84%) patients each. The majority of patients 23 (92%) had hepatic dysfunction, i.e., in followed by multi-organ dysfunction (MODS) in 15 (60%). Conclusion: In developing countries like India, particularly in tropical areas, dengue, and scrub typhus coinfection is under-recognized entity. Additional investigation should be carried out in cases of AUFI patients with features such as hypotension, leukocytosis, early drop in platelet counts, and hypoalbuminemia.

Distinctive patterns of sequential platelet counts following blunt traumatic brain injury predict outcomes

ABSTRACT Objective To determine the role of platelet counts in the context of the decision to treat patients with non-compounded, non-surgically-treated blunt traumatic brain injury (NCNS-bTBI) with anticoagulants/antiaggregants. Methods A retrospective analysis of 141 anticoagulants/antiaggregants-naïve patients with NCNS-bTBI. Changes in PT-INR and prolonged aPTT were examined and correlated with Marshall and Rotterdam scores, clinical and neuroradiological outcomes. Results Three groups of platelet counts were identified. Group 1 (83% of patients) had normal platelet counts (150,000–450,000 platelets/mm3) from admission to discharge. Group 2 (13%) developed transient thrombocytopenia (<150,000 platelets/mm3) 2–3 days post-trauma. Group 3 (4%) developed extreme thrombocytosis > 1,000,000/mm3 platelets 6–9 days post-trauma. Neither acute coagulopathy of trauma nor progressive hemorrhagic insults followed NCNS-bTBI. Moreover, while patients with thrombocytosis/extreme thrombocytosis presented with a worse Glasgow coma score (GCS) on admission (8.8 ± 2.9 vs. 13 ± 2, p < 0.01) and had longer hospitalization (13.5 ± 10.4 vs. 4.5 ± 2.1 days), their improvement at discharge was the highest (delta GCS, 4 ± 2.8 vs. 1.2 ± 2.1, p = 0.05). Traumatic subarachnoid hemorrhage was associated with isolated thrombocytosis and ‘best improvement.’ No thromboembolic or hemorrhagic complications occurred. Conclusion NCNS-bTBI, thrombocytosis was correlated with better outcomes and was not associated with an increased risk for developing thromboembolism or hemorrhage, precluding the immediate need for any additional antiaggregates.

Course of coronavirus infection in patients with type 2 diabetes mellitus

The coronavirus infection (COVID-19) pandemic remains a hot topic of study to this day. According to studies, mortality in patients with COVID-19 and a history of diabetes mellitus (DM) is 2-3 times higher than in patients without DM.The purpose of the study is to analyze the course of coronavirus infection in patients with T2DM.Material and methods: A prospective observation of 381 patients with T2DM and COVID-19 in the intensive care unit was carried out in 2020-2021. 2 groups were formed: Group I (comparison group) – patients with a fatal outcome, Group II (control group) – patients discharged from the hospital with an improvement in their condition. An assessment was made of changes in the dynamics of clinical and laboratory parameters upon admission and before discharge in both groups.Results and discussion: Patients with a fatal outcome were more often admitted in a serious condition (75% vs. 12.7% at p ≤ 0.0001). Significantly more often than aches (92.5% vs. 69.58%, p=0.0044), shortness of breath on exertion (92.5% vs. 75.17%, p=0.0245), grade 3 DN (62.5%, p&lt;0.0001), the need for non-invasive lung ventilation (28.95% versus 1.39%, p &lt;0.0001) artificial lung ventilation (81.1% versus 1.75% ( p&lt;0.0001) was noted in group I. In the comparison group, the Charlson comorbidity index was higher: 6.0 [5.0;7.0] versus 4 [4; 4], at p&lt;0.0001. In the group of patients who were discharged with improvement, they more often took metformin and sulfonylureas, in the group of patients who died, they were more often on insulin therapy. In dynamics, the levels of intracellular enzymes such as alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase in the group with an unfavorable outcome significantly increased, in contrast to the group with a positive outcome. Also, in a fatal outcome, there is a deterioration in kidney function, laboratory characterized by an increase in the level of creatinine and urea, a decrease in the glomerular filtration rate and blood albumin. Despite the ongoing anticoagulant therapy, patients with a fatal outcome showed pronounced signs of activation of the hemostasis system, which are characterized by an increase in INR, prolongation of prothrombin time and aPTT, and thrombocytopenia.Conclusion. The risk of death from coronavirus infection in people with diabetes increases with age. DM 2 is a comorbid disease and acute multiple organ disorders develop with the addition of a coronavirus infection. Coronavirus-induced coagulopathy in patients with DM2 and COVID-19 with a fatal outcome is characterized by poor controllability and low efficacy of anticoagulant therapy.

Risk Factors for Death in Patients with Severe Acute Pancreatitis in Guizhou Province, China.

To compare the clinical characteristics of survival and nonsurvival patients with severe acute pancreatitis (SAP) and explore the risk of mortality in SAP patients. This was a single-center retrospective study performed in a severe acute pancreatitis diagnosis and treatment center. According to the outcome, SAP patients were divided into survival group and nonsurvival group. One-way ANOVA or independent t-test was used to compare the clinical characteristics of two groups of patients. Multivariate retrospective analysis was used to identify risk factors for mortality in SAP patients. A total of 486 SAP patients were included in the study, and the 90-day mortality for SAP patients was 13.58%. The common etiologies of SAP are biliary tract diseases (69.75%) and hyperlipidemia (17.28%). The most common complications caused by SAP were organ failure (55.14%), ARDS (50.62%), AKI (30.45%), sepsis (27.16%), and abdominal fluid collection (27.57%). There were differences in age, complications, and medical intervention between the nonsurvival group and the survival group. The main causes of death were infection (46.97%), abdominal bleeding (28.79%), and organ failure (9.09%). The binary logistic regression analysis showed that there were significant differences in age, AKI, sepsis, abdominal hemorrhage, organ failure, laparotomy, creatinine, and APTT between the nonsurvival group and the survival group. Age, AKI, sepsis, abdominal hemorrhage, and organ failure are risk factors for mortality in SAP patients. SAP patients with high creatinine and prolonged APTT upon admission require doctors to be vigilant. The main cause of death in SAP patients is pancreatitis-related organ failure and secondary infection.