Pharmacokinetics, pharmacodynamics, and safety of frunexian in healthy Chinese volunteer adults: A randomized dose-escalation phase I study.

The purpose of this study was to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of frunexian (formerly known as EP-7041 and HSK36273) injection, a small molecule inhibitor of activated coagulation factor XI (FXIa), in healthy Chinese adult volunteers. This study was a randomized, placebo- and positive-controlled, sequential, ascending-dose (0.3/0.6/1.0/1.5/2.25 mg/kg/h) study of 5-day continuous intravenous infusions of frunexian. Frunexian administration exhibited an acceptable safety profile with no bleeding events. Steady state was rapidly reached with a median time ranging from 1.02 to 1.50 h. The mean half-life ranged from 1.15 to 1.43 h. Frunexian plasma concentration at a steady state and area under the concentration-time curve exhibited dose-proportional increases. The dose-escalation study of frunexian demonstrated its progressively enhanced capacities to prolong activated partial thromboplastin time (aPTT) and inhibit FXIa activity. The correlations between PK and PD biomarkers (aPTT/baseline and FXI clotting activity/baseline) were described by the two Emax models, with the EC50 values of 8940 and 1300 ng/mL, respectively. Frunexian exhibits good safety and PK/PD properties, suggesting it is a promising candidate for anticoagulant drug.

Pharmacokinetics, pharmacodynamics, and safety of fesomersen, a novel antisense inhibitor of factor XI, in healthy Chinese, Japanese, and Caucasian volunteers.

The inhibition of coagulation factor XI (FXI) presents an attractive approach for anticoagulation as it is not expected to increase the risk of clinically relevant bleeding and is anticipated to be at least as effective as currently available anticoagulants. Fesomersen is a conjugated antisense oligonucleotide that selectively inhibits the expression of FXI. The article describes three clinical studies that investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of fesomersen after subcutaneous (s.c.) injection to healthy participants. The studies included participants from diverse ethnic backgrounds (Caucasian, Japanese, and Chinese). Fesomersen demonstrated good safety and tolerability in all three studies. No major bleeding events were observed. After single-dose s.c. injection, fesomersen was rapidly absorbed into the systemic circulation, with maximum fesomersen-equivalent (fesomersen-eq) concentrations (Cmax) in plasma observed within a few hours. After reaching Cmax, plasma fesomersen-eq concentrations declined in a biphasic fashion. The PD analyses showed that the injection of fesomersen led to dose-dependent reductions in FXI activity and increases in activated partial thromboplastin time (aPTT). The maximum observed PD effects were reached between Day 15 and 30, and FXI activity and aPTT returned to near-baseline levels by Day 90 after a single dose. The PK/PD profiles after a single injection were similar among the various ethnic groups. Collectively, the study results suggest that fesomersen has a favorable safety profile and predictable and similar PK and PD profiles across Chinese, Japanese, and Caucasian participants.

[Vertebral fractures combined with prolonged activated partial prothrombin time: A case report].

With the development of modern medical standards, autoimmune diseases and their associated successive osteoporosis have received increasing attention in recent years. Patients with autoimmune diseases, due to the characteristics of the disease and the prolonged use of glucocorticoid hormone therapy, may affect the bone formation and bone absorption of the patient, followed by severe successive osteoporosis, thereby increasing the risk of osteoporotic vertebral fractures. Vertebral compression fractures of the spine are common fracture types in patients with osteoporotic fractures. Osteoporosis is a common complication after glucocorticoid therapy in patients with autoimmune diseases. Percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) are minimally invasive operation and are commonly used surgical methods for the treatment of osteoporotic vertebral compression fractures. However, due to the operation of spinal puncture during the operation, there are serious surgical risks such as bone cement leakage, spinal epidural hemorrhage, subdural hemorrhage, and subarachnoid hemorrhage in both PVP and PKP. As a result, it is necessary to evaluate the patient' s body before surgery carefully, especially in the case of blood coagulation. This article reports a case of autoimmune disease patient admitted to Peking University People' s Hospital due to lumbar 4 vertebral compression fracture combined with Sjögren' s syndrome. The patient' s preoperative examination showed that the activated partial thromboplastin time (APTT) was significantly prolonged. After completing the APTT extended screening experiment and lupus anticoagulant factor testing, the multi-disciplinary team (MDT) of Peking University People' s Hospital jointly discussed the conclusion that the patient' s test results were caused by an abnormal self-immunity anti-copulant lupus (LAC). Based on the results of the laboratory examination, the patient was considered to be diagnosed with combined antiphospholipid syndrome (APS). For such patients, compared with the patient' s tendency to bleed, we should pay more attention to the risk of high blood clotting in the lower limbs of the patient, pulmonary clots and so on. With timely anti-coagulation treatment, the patient safely passed the peripheral period and was successfully discharged from the hospital. Therefore, for patients with autoimmune diseases with prolonged APTT in the perioperative period, doctors need to carefully identify the actual cause and carry out targeted treatment in order to minimize the risk of surgical and perioperative complications and bring satisfactory treatment results to the patients.

Exploring coagulation parameters as predictive biomarkers of Plasmodium infection: A comprehensive analysis of coagulation parameters.

BACKGROUND: Malaria affects the intravascular environment, leading to abnormal coagulation activation, prolonged prothrombin time, and activated partial thromboplastin time. Despite the high prevalence of malaria in the study area, there has been little published research on the effects of Plasmodium infection on coagulation parameters. OBJECTIVE: The aim was to assess the effect of malaria on basic coagulation parameters among patients attending Dembia Primary Hospital and Makisegnit Health Center. METHODS: A cross-sectional study was carried out from January to March 2020. The study involved 120 participants. Blood specimens were collected, which were analyzed using a Huma Clot Due Plus analyzer. The collected data were entered into EpiData and exported to SPSS version 21 for analysis. Non-parametric statistical methods were employed to analyze the data. The results were considered statistically significant if the p-value was less than 0.05. RESULTS: Individuals infected with Plasmodium exhibit coagulation disorders with elevated levels of PT (Prothrombin Time), APTT (Activated Partial Thromboplastin Time), and INR (International Normalization Ratio) in comparison to healthy controls. The median PT, APTT, and INR values for infected cases were measured at 20.5 [8.6], 39.5 [17.9], and 1.8 [0.9], respectively, while healthy controls had measurements of 15.1 [2.5], 28.8 [8.3], and 1.3 [0.2] (p ≤ 0.001). The severity of coagulation disorders increased with an increase in parasitemia levels. The type of Plasmodium species present had a significant impact on PT and INR values (p ≤ 0.001), whereas APTT did not show any significant impact across the Plasmodium species (p > 0.05). CONCLUSION: The results of this study found that malaria has a substantial impact on various blood clotting parameters, including PT, APTT, and INR. Parasitemia severity is significantly associated with extended PT and INR, implying that the higher the parasitemia, the longer it takes for blood to clot. Furthermore, the study discovered that the PT and INR levels differed based on the type of Plasmodium species responsible for the infection.

Effect of Reduced INR in Early Pregnancy on the Occurrence of Preeclampsia: A Retrospective Cohort Study.

To investigate the effect of reduced early-pregnancy activated partial thrombin time (APTT), prothrombin time (PT), and international standardized ratio (INR) on the risk of preeclampsia. A total of 8549 pregnant women with singleton births were included. Early pregnancy APTT, PT, and INR levels, with age, birth, prepregnancy body mass index, fibrinogen (FBG), thrombin time (TT), D-dimer (DD2), antithrombin III (ATIII), fibrin degradation products (FDP) as confounders, generalized linear model of APTT, the relative risk of PT and INR when INR reduction. After adequate adjustment for confounders, the relative risk of preeclampsia was 0.703 for every 1 s increase in plasma PT results in early pregnancy, and for every 0.1 increase in plasma INR results, the relative risk of preeclampsia was 0.767. With a PT less than the P25 quantile (<11 s), the relative risk of preeclampsia was 1.328. The relative risk of preeclampsia at an INR less than the P25 quantile (<0.92) was 1.24. There was no statistical association between APTT on the risk of preeclampsia. The relative risk of preeclampsia is strongly associated with a decrease in PT and INR in early pregnancy. PT and INR in early pregnancy were a potential marker in the risk stratification of preeclampsia. Focusing on reduced PT and INR levels in early pregnancy can help to identify early pregnancies at risk for preeclampsia.

Coagulation Testing in Real-World Setting: Insights From a Comprehensive Survey.

The objective of this survey was to gain a real-world perspective on coagulation testing by evaluating the availability of various coagulation laboratory tests, assessing specific analytic and postanalytic steps in clinical laboratories in Korea.Participants were surveyed using a 65-question questionnaire specifically focused on their coagulation testing practices related to prothrombin time (PT), activated partial thromboplastin time (aPTT), plasma-mixing studies, lupus anticoagulant (LA) tests, platelet function tests, coagulation factor assays, and the composition of hemostasis and thrombosis test panels. The survey was performed between July and September 2022.The survey achieved a 77.9% (81 of 104) response rate. PT or aPTT tests were performed directly at all participating institutions, followed by D-dimer and fibrinogen tests, platelet function test, and plasma-mixing studies in order of frequency. Variations existed in the performance of mixing test and LA assessment. Patterns of coagulating testing differed depending on the size of the hospital. The survey revealed that most laboratories conducted coagulation tests following the international guidelines such as Clinical Laboratory Standards Institute guidelines and the Korean Laboratory Certification system. However, some coagulation tests, including mixing test and LA tests, are yet to be standardized in Korea.Continuous education on coagulation test methods and internal and external quality control are required to encourage laboratories to enhance the performance of coagulation testing.

Ascorbic acid prevents stress-induced hypercoagulability in overweight and obese individuals.

Ascorbic acid (AA) may contribute to restoring hemostatic balance after mental stress (MS) in overweight/obese adults. We aimed to determine the effects of AA administration on hemostatic responses to MS in overweight/obese men. Fourteen overweight/obesity men (27 ± 7 years; BMI: 29.7 ± 2.6 kg m-2) performed the Stroop color-word stress task for 5 min after non-simultaneous infusion of placebo (PL, 0.9% NaCl) and AA (3 g). Blood was collected at baseline, during MS, and 60 min after MS to measure: activated partial thromboplastin time, prothrombin time, and fibrinogen concentration, by coagulometer; platelet-derived microvesicles (PMV, mv/µL), by flow cytometry; nitrite (µM), by chemiluminescence. In PL session, MS led to decreases in PTs (stress, p = 0.03; 60 min, p < 0.001), PT-INR (stress, p < 0.001; 60 min, p < 0.01), aPTTs (60 min, p = 0.03), aPTT ratio (60 min, p = 0.04) and fibrinogen (60 min, p = 0.04), while increased PT activity (60 min, p = 0.01) when compared to baseline. Furthermore, AA increased PTs (60 min, p < 0.001), PT-INR (60 min, p = 0.03) and decreased PT activity (60 min, p < 0.001) and fibrinogen (stress, p = 0.04) when compared to PL. Nitrite was increased in response to stress during AA session (p < 0.001 vs PL). There was no difference in PMV. Ascorbic acid prevented the impaired hemostatic profile and improved nitrite response to stress in the overweight and obese adults.

The influence of dead space in blood sampling needle on FVIII level and pharmacokinetic profiles in children with hemophilia.

OBJECTIVE: To investigate the influence of the dead space in disposable blood sampling needle on activated partial thromboplastin time (APTT), FVIII level and pharmacokinetic (PK) profiles in children with hemophilia. METHODS: Children (<18 years) with severe hemophilia A were enrolled. After three days' washout-period, blood samples were collected at pre-dose, 1 h, 3 h, 9 h, 24 h and 48 h post-infusion. At each timepoint, two 2 mL vacuum tubes with 3.2% trisodium citrate were used. The first tube was signed as 'non-standard' (NS) and the second tube was signed as 'standard' (S). FVIII activities were evaluated by one-stage assay. WAPPS-Hemo was used to generate PK profiles like half-life time (t1/2), clearance (CL), trough level and time to 1, 2 and 5IU/dL after a dose of 50 ± 10IU/dL. The FVIII activities at 9 h and 24 h post-infusion were put into WAPPS and thus brought four combinations by true or biased FVIII level that used. RESULT: Compared with standard-collected blood samples, prolonged APTT results (P-values < 0.01) and decreased FVIII activity (P-values < 0.05) were revealed in those non-standard blood samples. The corresponding bias was in positive relation to both APTT-S (r = 0.44, P < 0.0001) and FVIII-S level(r = 0.68, P < 0.001). The FVIII bias percentage got larger as FVIII-S level reduced (r = -0.24, P < 0.01). During the four combinations of FVIII activity at 9 h and 24 h, statistically longer t1/2, lower CL and longer time to 1, 2 or 5IU/dL were observed in 9H-S&24H-S group and 9H-NS&24H-S group. CONCLUSION: While using vacuum tubes for clotting indicators and PK profiles, the dead space of blood sampling needle should be eliminated in advance.

Establishment of Normal Reference Intervals for Coagulation Test Indicators in Children.

BACKGROUND: The objective of this study is to determine the standard reference intervals for coagulation function and coagulation factors in children across various age groups. METHODS: A statistical analysis was conducted on prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), thrombin time (TT), and coagulation factors (II, V, VII, X, VIII, IX, XI, and XII) in 389 healthy children who underwent health checkups and presurgical examinations at the Children's Hospital of Zhejiang University School of Medicine. The children were categorized into four age groups. RESULTS: The established normal reference ranges are as follows: PT (seconds): 10.00 - 12.26 for 1 month - 3 years, 10.24 - 12.66 for 3 - 18 years; APTT (seconds) : 24.82 - 35.65 for 1 month - 1 year, 25.20 - 32.30 for 1 - 18 years; Fib (g/L): 1.21 - 2.44 for 1 month - 1 year, 1.48 - 2.70 for 1 - 3 years, 1.69 - 3.60 for 3 - 18 years; TT (seconds): 18.48 - 23.06 for 1 month - 1 year, 17.80 - 21.26 for 1 - 18 years; coagulation factor II (%): 68.77 - 105.07 for 1 month - 1 year, 78.20 - 119.40 for 1 - 18 years; V (%): 74.24 - 140.96 for 1 month - 3 years, 70.64 - 132.01 for 3 - 18 years; VII (%): 56.34 - 113.00 for 1 month - 18 years; X (%): 49.17 - 105.57 for 1 month - 1 year, 64.34 - 115.24 for 1 - 18 years; VIII (%): 43.53 - 130.07 for 1 month - 1 year, 45.92 - 144.90 for 1 - 18 years; IX (%): 28.55 - 69.17 for 1 month - 1 year, 46.29 - 97.48 for 1 - 18 years; XI (%): 44.64 - 139.00 for 1 month - 1 year, 57.50 - 139.98 for 1 - 18 years; XII (%): 30.16 - 94.48 for 1 month - 1 year, 36.88 - 115.50 for 1 - 18 years. CONCLUSIONS: This study successfully established standard reference intervals for coagulation function and coagulation factors in children of various age groups in Hangzhou, China.

Pulmonary hypertension is associated with hypocoagulability in dogs: a retrospective analysis of 66 cases (2013-2021).

OBJECTIVE: To describe coagulation profiles in dogs with echocardiographic evidence of pulmonary hypertension (PH), to compare them to coagulation profiles in dogs without echocardiographic evidence of PH, and to determine the relationship between coagulation profiles and echocardiographic probability of PH. ANIMALS: 66 dogs with PH (cases) and 86 dogs without PH (controls). METHODS: Retrospective evaluation of records between 2013 and 2021 of dogs that had both an echocardiogram and a coagulation panel performed within 7 days. Dogs that received antithrombotics within 7 days of evaluation and dogs diagnosed with congenital or acquired coagulopathy or other severe systemic disease that could lead to coagulopathy were excluded. Dogs with a low echocardiographic probability of PH were also excluded. The dogs were divided into a PH group and non-PH group based on echocardiographic results. Demographic, clinicopathologic, and traditional coagulation parameters and VCM Vet (Entegrion) parameters were compared between the 2 groups. RESULTS: Dogs with PH were significantly older (median, 11 years vs 9.5 years, P = .02) and had a significantly lower body weight (median, 7.3 kg vs 19.3 kg, P < .001) than controls. Dogs with PH also had a significantly greater percent increase in prothrombin time (PT; P = .02), partial thromboplastin time (PTT; P < .0001), and fibrinogen (P = .045); however, their antithrombin concentration was lower (P = .005) compared to controls. Eight of 65 dogs (12.3%) in the PH group and 1/86 (1.2%) dogs in the non-PH group had an elevation of PT and/or PTT greater than 50% above the reference interval (P = .005). Dogs with PH had 11.9 times (95% CI, 1.5 to 97.9; P = .02) greater odds of being hypocoagulable than dogs without PH based on PT and PTT. CLINICAL RELEVANCE: This study demonstrated an association between a moderate to high echocardiographic probability of PH and a hypocoagulable state in dogs as determined by traditional coagulation assays. It underscores the importance of monitoring the coagulation status in canine patients with PH, particularly before initiating antithrombotic medications.

Mixing studies for lupus anticoagulant: does it matter how we mix?

Although clear and detailed recommendation regarding the lupus anticoagulant mixing test exist, various sources of NPP are used. We decided to inspect the possible differences in mixing studies depending on the mixing media. Four types of mixing media were prepared for 45 random remnant plasma samples: standard human plasma, control plasma N, previously analyzed patient with normal coagulation values, and home-made normal pool plasma (NPP). Samples were analyzed by using Siemens Dade Actin FSL Activated PTT Reagent on BCS XP analyzer. The median aPTT values of mixing studies with commercial lyophilized NPP, with commercial IQC, as well as with a patient did not differ (26.6, 26.3, and 26.8 s, respectively). Median value of a mixing study with home-made NPP was significantly higher from the rest of the group (27.9 s) ( P  < 0.05). According to the obtained results, we decided to employ the commercial lyophilized NPP for future lupus anticoagulant mixing studies.

Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors.

A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated excellent in-vitro potency (FXIa IC50: 15 nM, 2 x aPTT: 6.8 µM) and good in-vivo efficacy (prolonged in-vivo aPTT by more than 1-fold but not PT). Moreover, the pharmacokinetics property of 14c were evaluated following intravenous administration in rats, which indicated that 14c probably will be a clinical candidate for intravenous administration.

Adjusted Global Antiphospholipid Syndrome Score (aGAPSS) and PLT, APTT: Predictive Value of Thrombotic Risk Assessment in SLE Patients.

BACKGROUND: Risk assessment of vascular thrombosis in SLE patients with the presence of antiphospholipid antibodies (aPL) remains a challenge. The adjusted global antiphospholipid syndrome score (aGAPSS) has been validated and used to predict aPL-related thrombosis in SLE patients in some countries. Relevant data of aGAPSS in thrombotic evaluation in SLE population from China has not been reported. We aim to validate aGAPSS in thrombosis assessment in Chinese patients with SLE and to explore the correlations of aGAPSS with routine laboratory parameters and their clinical significance as well. METHODS: A total of 166 consecutive SLE patients were retrospectively analyzed. Multivariate logistic regression analysis was performed to examine the impact of multiple cardiovascular risk factors and laboratory parameters in recurrent thrombosis risk in SLE. ROC was conducted to explore the discriminative ability of aGAPSS and platelet (PLT), activated partial thromboplastin time (APTT), alone or in combination. RESULTS: Significantly higher value of aGAPSS was seen in SLE patients with vascular thrombosis. ROC curve indicated that aGAPSS of 3.5 or more had the best diagnostic accuracy for the prediction of aPL-related thrombosis in SLE patients. PLT with cutoff of 187.5 x 109/L and APTT with 37.5 seconds were predictors of aPL-related thrombosis as well. The combination of aGAPSS with PLT and APTT improved AUC compared to aGAPSS alone. CONCLUSIONS: The aGAPSS could predict the risk of aPL-related vascular thrombosis in SLE patients from China. The combination of aGAPSS with PLT and APTT was first time proved to have better predictive performance in thrombosis risk assessment in SLE.

Comparison of the Correlation Between Coagulation Indices and Rivaroxaban Concentrations.

BACKGROUND: Rivaroxaban has predictable pharmacokinetics and pharmacodynamics. However, monitoring rivaroxaban concentrations should be provided for special patients with hepatic insufficiency, high bleeding risk, and high thrombotic risk. OBJECTIVE: This study aimed to correlate chromogenic anti-Xa assay, prothrombin time (PT), activated partial thromboplastin time (APTT), thromboelastogram reaction time (TEG R-time), and rivaroxaban concentration measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) (MS-Riva). METHODS: Peripheral venous blood was collected from recruited patients 30 minutes before and 2 to 4 hours after drug administration. High-performance liquid chromatography-tandem mass spectrometry and chromogenic anti-Xa assay measured rivaroxaban concentration. Different assays were compared by Pearson correlation coefficient and Bland-Altman analysis. RESULTS: A total of 104 patients with 191 plasma were included in the study. Overall analysis shows that chromogenic anti-Xa assay, PT, APTT, and TEG R-time strongly correlated with MS-Riva (r = 0.986; r = 0.884; r = 0.741; r = 0.739; P < 0.001). Rivaroxaban peak concentration detected by HPLC-MS/MS (MS-peak) showed a very strong correlation with the chromogenic anti-Xa assay (r = 0.977, P < 0.001) and moderate correlation with PT, APTT, and TEG R-time (r = 0.670; r = 0.571; r = 0.481, P < 0.001). Rivaroxaban trough concentration detected by HPLC-MS/MS (MS-trough) correlated strongly with the chromogenic anti-Xa assay (r = 0.884, P < 0.001), weakly with APTT (r = 0.313; P = 0.043), and not significantly with PT and TEG R-time (P = 0.140; P = 0.341). CONCLUSION AND RELEVANCE: High-performance liquid chromatography-tandem mass spectrometry/MS is the preferred choice for monitoring peak and tough concentrations, followed by anti-Xa, while PT is only suitable for peak concentrations. This study can help the clinicians to better adjust the medication regimen and reduce the risk of recurrence of thrombosis as well as the risk of bleeding.

Implementation of a Heparin Infusion Calculator in the Electronic Health Record System as a Risk-Mitigation Strategy in a Community Teaching Hospital Emergency Department.

INTRODUCTION: According to the Institute for Safe Medication Practices, unfractionated heparin is a high-risk medication due to the potential for medication errors and adverse events. Unfractionated heparin is often started in the emergency department for patients with acute coronary syndromes or coagulopathies. Risk-mitigation strategies should be implemented to ensure appropriate initiation and monitoring of this high-risk medication. In 2019, an unfractionated heparin calculator was built into the electronic health record at a community medical center. The purpose of this study was to evaluate the impact of the calculator as a risk-mitigation strategy. METHODS: Patients ≥18 years old admitted between January 1, 2020, and December 31, 2020, were included if they were administered an unfractionated heparin infusion in the emergency department. Patient encounters were excluded if unfractionated heparin order was discontinued before administration. Patient encounters were classified into the unfractionated heparin calculator arm if the unfractionated heparin calculator was used to determine initial dosing, and the remaining patient encounters were classified into the unfractionated heparin no calculator arm. Unfractionated heparin orders were reviewed if a baseline activated partial thromboplastin time was collected and if the correct initial bolus dose and infusion rate were administered. The primary objective is to determine whether the use of unfractionated heparin initiation calculator reduced the rate of medication administration errors. Medication administration errors are defined as baseline activated partial thromboplastin time not collected or incorrectly collected or the administration of incorrect initial bolus dose and infusion rate. RESULTS: A total of 356 patient encounters with unfractionated heparin orders were included in the primary analysis. There were 13.9% errors (39 of 279) present when the calculator was used and 23.3% (18 of 77) when the calculator was not used (P = .046). There was 86% correct administration of heparin (240 of 279) when the calculator was used and 76% correct administrations (59 of 77) when the calculator was not used. DISCUSSION: The use of the unfractionated heparin infusion calculator in the emergency department led to decrease in medication administration errors. This is the first study to evaluate the integration of an unfractionated heparin calculator into the electronic health record.

Whole blood PT/aPTT assay based on non-contact drop-of-sample acoustic tweezing spectroscopy.

Most coagulation tests are photo-optical turbidimetric assays that require the removal of cellular components from whole blood for optical clearing. If the resulting blood plasma samples are hemolyzed, they may become unsuitable for turbidimetric analysis. To resolve this issue, whole-blood analogs to plasma turbidimetric assays need to be developed. Using samples collected from non-smokers (normal group), smokers (thrombotic group), and hemophilia A (bleeding group) patients, we demonstrate that the reaction time assessed from whole blood viscosity data of the drop-of-blood acoustic tweezing spectroscopy (ATS) technique strongly correlates (Rp ≥ 0.95) with PT/aPTT values obtained from plasma turbidimetric data. Linear correlation (Rp ≥ 0.88) was also obtained between the viscous and elastic outputs of the ATS technique and the fibrinogen concentration. The integration of ATS data enabled the assessment of the functional level of fibrin cross-linkers such as factor XIII. Overall, ATS allows comprehensive sample-sparing analysis of whole blood coagulation for reliable and safe diagnosis of bleeding/thrombosis risks.

Clot waveform analysis in acute promyelocytic leukemia.

The aim of this study was to evaluate the activated partial thromboplastin time (APTT) and prothrombin time (PT)-based clot waveform analysis (CWA) in patients diagnosed with acute promyelocytic leukemia (APL). APTT-based and PT-based CWA parameters of patients diagnosed with APL were analyzed and compared with healthy volunteers. Four APTT-CWA parameters were noted, maximum velocity corresponding to the first peak of the first derivative (max1), maximum acceleration corresponding to the first peak of the second derivative (max2) and the corresponding peak times of max1 and max2 (Tmax1, Tmax2). For the PT-CWA, two PT-CWA parameters were noted, maximum velocity (max1') and the corresponding timing (Tmax1'). The results were expressed in medians. Mann-Whitney U test was used to compare the CWA parameters. Correlations were examined using the Spearman correlation test. Tmax1 and Tmax2 were significantly prolonged in patients with APL in comparison with healthy volunteers. Although max1 and max2 were lower in APL patients compared with healthy volunteers, no significant difference was noted. There was a strong and significant correlation between the DIC score and the parameters max1, max2 and max1' and a very strong and significant correlation between fibrinogen levels and max1, max2 and max1'. When comparing DIC patients with hypofibrinogenemia and DIC without hypofibrinogenemia, a significant difference was noted in max1, max2, Tmax1 and Tmax2. The APTT and PT-based CWA analysis is a good tool to evaluate the bleeding tendency in APL, as it offers a novel approach for evaluating global hemostasis, predicting the bleeding risk and delivering improvements to APL patients management.

Interpreting coagulation mixing study results in the era of direct oral anticoagulants.

Interpretation of coagulation mixing studies is complicated by interference arising from direct oral anticoagulants (DOACs), which are increasingly prescribed. In this retrospective study, we reviewed 1035 consecutive coagulation mixing studies performed from 2017 to 2021. Three hundred and ninety-nine cases with normal prothrombin time (PT) and activated partial thromboplastin time (aPTT) were excluded. aPTT mixing studies were performed at time 0 and after 60 min of incubation. We confirmed the presence of interfering factors with additional laboratory testing, medication records, and medical history. Mixing corrected most prolonged PT samples (93%), but 32 cases showed incomplete correction. Of these 32 cases, 18 were confounded by DOAC use, and 3 by factor V (FV) inhibitor. We observed an unusual pattern of prolongation of aPTT after incubation, which was previously considered a characteristic of specific factor inhibitors, most commonly FVIII inhibitor. However, we found that lupus anticoagulant (28%) and DOAC (25%) contributed to this pattern similarly as specific factor inhibitors (28%). Coagulation laboratories should be aware of interference arising from DOACs and other factors in PT/aPTT mixing studies, especially in some unusual correction patterns.