Factor XIII Levels Research Articles

Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease

Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.

A comparative study on the haemostatic changes in kidney failure patients: Pre- and post- haemodialysis and haemodiafiltration

BackgroundIndividuals with kidney failure have a compromised haemostatic system making them susceptible to both thrombosis and bleeding. ObjectivesAssessment of primary haemostasis in patients treated with either haemodialysis (HD) or haemodiafiltration (HDF) was performed through the measurement of several coagulation-based tests, both pre- and post-dialysis. Patients/methods41 renal failure patients and 40 controls were recruited. Platelet aggregometry, Factor XIII (FXIII), Fibrinogen, Von Willebrand Factor (VWF) and Soluble P-Selectin (sP-Sel) levels were measured. ResultsMaximum platelet aggregation was diminished in renal patients irrespective of aspirin intake. Post-dialysis, platelet function was exacerbated. Pre-dialysis FXIII levels were similar to the healthy cohort and became elevated post-dialysis. This elevation could not be explained by the relative decrease of water by dialysis. Fibrinogen levels were already elevated pre-dialysis and further increased post-dialysis. This elevation was associated with the relative decrease of water by dialysis. VWF levels in males were similar to the healthy cohort and became elevated post-dialysis. This elevation was associated with dialysis-related water loss. VWF antigen and activity in female patients were already elevated pre-dialysis and further increased post-dialysis with the exception of VWF activity in HDF treated female patients. sP-Sel levels were lower than those of the healthy cohort and became similar to the healthy cohort post-dialysis. This elevation could not be explained by the relative decrease of water by dialysis. ConclusionsWhilst platelet aggregometry was diminished, we noted elevated clotting factors such as fibrinogen, FXIII and VWF with no significant differences between HD and HDF-treated patients.

Limited value of testing for factor XIII and α2-antiplasmin deficiency in patients with a bleeding disorder of unknown cause.

In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2-antiplasmin (α2AP) deficiency. To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC). A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured. We included 158 consecutive patients; mean ISTH-BAT scores were 8.2 (SD±3.7) in children, 6.2 (SD±2.1) in men and 10.6 (SD±3.3) in women. Median age was 37 (range 5-79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR=97-131) and median α2AP activity of 112% (IQR=103-119). Three (1.9%) patients had FXIII levels<50%, respectively 43%, 45% and 46%. Corresponding ISTH-BAT scores were 7, 12 and 14. No α2AP levels<60% was observed. No significant association was found between FXIII levels and ISTH-BAT scores. In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value.

Factor XIII in major burns coagulation

BackgroundIn the days following a burn injury, major burn patients (MBP) present a multifactorial coagulation disorder known as acute burn-induced coagulopathy. Several studies have investigated coagulation in MBPs; however, Factor XIII (FXIII), which converts fibrin monomers into a stable clot and promotes wound healing, has not yet been studied. ObjectiveTo determine the kinetics of FXIII and other coagulation factors and cofactors in MBPs in order to clarify coagulopathy in these patients and its potential relationship with surgical bleeding. MethodsProspective observational pilot study of the kinetics of FXIII and other coagulation factors and cofactors in MBPs during the first 30 days of burn injury. ResultsFXIII levels show a significant decline of 75.10% in the interval between the burn injury and surgery, and a decline of 87.70% in the 24 h following surgery. Patients undergo surgery with a median antigenic FXIII of 32%. Plasma levels of most factors decrease significantly 24 h after the burn injury. ConclusionMBPs experience a significant decrease in plasma levels of FXIII from the time of admission up to 24 h after surgery. Abnormally low levels were observed at the time of surgery that could not be detected by other coagulation tests. The decrease in most factors at 24 h seems to be associated with dilution due to intensive fluid resuscitation.

P146 A phase II, randomised, double-blind, placebo-controlled trial exploring pharmacokinetics, safety and efficacy of intravenous factor XIII treatment in adults with systemic sclerosis

Abstract Background/Aims Systemic sclerosis (SSc) is a multi-system autoimmune disease with significant morbidity and mortality, and an unmet therapeutic need. The pathogenesis of SSc involves dysfunctional immune signalling, fibroblast behaviour and vascular development. Factor XIII (FXIII) is an enzyme involved in coagulation, and in wound healing where it promotes angiogenesis via inhibition of thrombospondin-1 (TSP-1). Therapeutic administration of FXIII in SSc is proposed to increase angiogenesis via suppression of TSP-1, which is known to be dysregulated in SSc. Previous preclinical and clinical studies suggest that therapeutic administration of factor XIII could improve vascular function in SSc. Methods Two interlinked clinical trials were conducted at a single centre. First, a single-dose open-label study was performed to assess the safety and pharmacokinetics of FXIII treatment in SSc. Eight adult patients with limited or diffuse SSc received a single dose of intravenous purified human FXIII, followed by a 6-week monitoring period. Second, a phase II, double-blind, randomised, placebo-controlled study was performed to investigate the safety and efficacy of factor XIII treatment in SSc. 18 adult patients with limited or diffuse SSc were randomised 2:1 to receive study intervention (intravenous purified human FXIII) or placebo (intravenous 0.9% sodium chloride solution). Safety endpoints were assessment of the safety and tolerability of FXIII treatment via review of adverse events, physical examination and monitoring of physiological function. Efficacy was explored as change in skin severity by modified Rodnan skin score (mRSS) at week 24 compared to baseline, and change in severity of Raynaud’s phenomenon, assessed by review of the Raynaud’s Condition Score (RCS) at week 24, compared to baseline. The study is registered with ClinicalTrials.gov (number NCT02551042). Results The main objective of the clinical trial was met by demonstrating that FXIII is safe and well tolerated in SSc. Pharmacokinetic analysis showed a predictable rise and fall in FXIII level following therapeutic administration, with the mean time taken for the FXIII level to return to within 10 IU/dL of the endogenous level being 16.6 days (SD 8.7). Adverse event and safety monitoring did not reveal any concerning pattern. Study intervention-related adverse events were self-resolving and tolerable. There was no statistically significant change in mRSS or RCS during the trial, but there was a trend towards improvement in RCS in the FXIII group (mean change in RCS of -1.2 (95% CI -2.26 to -0.14) in the FXIII group versus -0.83 (95% CI -3.44 to 1.77) in the placebo group). Conclusion Our results suggest that therapeutic strategies to modulate links between coagulation and tissue repair using FXIII are safe and feasible. Further studies with different patient populations and FXIII doses could investigate the role of FXIII in SSc further. Disclosure A. Leslie: Other; A.L. is an employee of GSK. S. Vigneswaran: None. K. Khan: None. V. Ong: None. C.P. Denton: Consultancies; C. D. has received consulting fees from Roche, Janssen, GlaxoSmithKline, Sanofi, Galapagos, Boehringer Ingelheim, and CSL Behring, and Acceleron. Grants/research support; C. D. has received research funding from CSL Behring, Horizon, Abbvie, and GlaxoSmithKline.

Changes in coagulation factor XIII activity during resuscitation for hemorrhagic shock.

Little is known about the coagulation activity of factor XIII (FXIII) during resuscitation for hemorrhagic shock and the effects of plasma transfusions. We performed a single-center observational study to evaluate the changes in FXIII activity during resuscitation for hemorrhagic shock. Twenty-three adult patients with hemorrhagic shock were enrolled in this study. Blood samples were drawn upon arrival (T1), at the time of hemostasis completion (T2), and on day 2 (T3). Baseline and changes in FXIII activity and the proportion of patients with adequate levels of FXIII activity (FXIII activity >70%) were evaluated. The effects of plasma transfusion on these parameters were also investigated. At T1, the median (interquartile range) FXIII activity was 53% (47-85%), which did not increase (T1 vs. T3: 53% [47-85%] vs. 63% [52-70%], P=0.8766). The proportion of patients with adequate FXIII activity decreased throughout the resuscitation period (T1, T2, and T3: 30, 34, and 21%, respectively). Plasma transfusion did not affect FXIII activity (T1 vs. T2, 66.4% [23.4] vs. 70.0% [16.2%], P=0.3956; T2 vs. T3, 72.0% [19.5] vs. 63.5% [8.6%], P=0.1161) or the proportion of adequate levels of FXIII activity at 44% at T2 and 27% at T3. FXIII activity is low during the early phase of a hemorrhagic shock. Even with plasma transfusion, FXIII levels were not adequately maintained throughout resuscitation.

Low factor XIII levels and altered fibrinolysis in patients with multiple myeloma

BackgroundAcquired factor FXIII (FXIII) deficiency can be immune- or non-immune mediated and may cause severe bleeding symptoms. The incidence of acquired FXIII deficiency and its etiology in patients with multiple myeloma (MM) are poorly understood. ObjectivesTo assess FXIII levels and the balance of fibrinolysis in newly diagnosed, untreated MM and monoclonal gammopathy of undetermined significance (MGUS) patients. MethodsFXIII activity, mixing studies, FXIII-A2B2 antigen, total FXIII-B antigen were measured in platelet-poor plasma from 17 untreated MM patients, 33 untreated MGUS patients, and 30 age and sex-matched healthy controls. Besides routine laboratory measurements, the balance of coagulation and fibrinolysis was evaluated using quantitative fibrin monomer (FM) test, thrombin-antithrombin assay, α2-antiplasmin activity, plasmin-α2-antiplasmin (PAP) complex, D-dimer, plasmin generation assay, clot lysis assay, and ClotPro-TPA test. ResultsFXIII-A2B2 levels were significantly lower in MM patients compared to controls [median (IQR):14.6 (11.2–19.4) vs. 21.8 (17.1–26.4) mg/L, p = 0.0015], whereas total FXIII-B did not differ between groups. Decrease in FXIII activity was parallel to the decrease in FXIII-A2B2. An immune-mediated inhibitory mechanism was ruled out. Free/total FXIII-B was significantly higher in MM patients compared to MGUS and healthy controls, suggesting an etiology of FXIII-A consumption. In MM and MGUS patients, FM, D-dimer, and PAP complex were significantly elevated compared to controls, indicating hypercoagulability and ongoing fibrinolysis. ConclusionsLow FXIII levels due to consumption were observed in MM patients at diagnosis. Hypercoagulability and ongoing fibrinolysis were detected in MM and MGUS, indicating that a disturbed hemostasis balance is already present in the latter benign condition.

Histidine-rich glycoprotein attenuates catheter thrombosis.

Factor XII (FXII) knockdown attenuates catheter thrombosis in rabbits. Because histidine-rich glycoprotein (HRG) modulates FXIIa activity, we hypothesized that HRG depletion would promote catheter thrombosis. To test this, rabbits were given either antisense oligonucleotides (ASOs) against HRG or FXII, a control ASO, or saline. The activated partial thromboplastin time (aPTT), prothrombin time (PT), and catheter-induced thrombin generation were determined in blood collected before and after treatment. Compared with the controls, the HRG- and FXII-directed ASOs reduced hepatic messenger RNA and plasma levels of HRG and FXII, respectively, by >90%. Although HRG knockdown shortened the aPTT by 2.5 fold, FXII knockdown prolonged it by fourfold; neither of the ASOs affected the PT. Catheter segments shortened the lag time and increased peak thrombin in the plasma from control rabbits; effects were significantly enhanced and attenuated in the plasma from rabbits given the HRG- and FXII-directed ASOs, respectively. Catheters were then inserted into the right external jugular vein of the rabbits, and the time for catheter occlusion was determined. The catheter occlusion times with the control ASO or saline were 62± 8minutes and 60± 11minutes, respectively. The occlusion time was significantly reduced to 34± 9minutes, with HRG knockdown and significantly prolonged to 128± 19minutes with FXII knockdown. HRG levels are decreased with sepsis or cancer, and such patients are prone to catheter thrombosis. Because HRG modulates catheter thrombosis, our findings suggest that HRG supplementation may prevent this problem.

Fibrinogenolysis and fibrinolysis in vaccine-induced immune thrombocytopenia and thrombosis

BackgroundVaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia. ObjectivesTo investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT. MethodsPlasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen. ResultsVITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1β, IL-6, IL-8, TNFα, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors. ConclusionVITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

Differences in coagulation-relevant parameters: Comparing cryoprecipitate and a human fibrinogen concentrate.

Variable fibrinogen content within cryoprecipitate makes accurate dosing challenging in patients with coagulopathic bleeding, in addition to pathogen transmission risks associated with its administration. Purified and standardized human fibrinogen concentrates (HFCs) represent reliable alternatives. Full cryoprecipitate characterization is required to inform selection of an appropriate fibrinogen source for supplementation therapy. Extended biochemical comparison of pooled cryoprecipitate and HFC (Fibryga, Octapharma) was performed using commercially available assays to determine levels of variability in cryoprecipitate and HFC. In addition to standard procoagulant factors, measurements included activities of platelet-derived microparticles (PMPs) and plasminogen, and levels of fibrin degradation products. Cryoprecipitate contains lower fibrinogen levels than HFC (4.83 vs.19.73 g/L; p<0.001), translating to approximately half the amount of fibrinogen per standard cryoprecipitate dose (two pools, pre-pooled from five donations each) vs. HFC (2.14 vs. 3.95 g; p<0.001). Factor XIII (FXIII) levels were also lower in cryoprecipitate vs. HFC (192.17 vs. 328.33 IU/dL; p = 0.002). Levels of procoagulants in cryoprecipitate, such as von Willebrand Factor (VWF) and factor VIII (FVIII), were highly variable, as was PMP activity. A standard cryoprecipitate dose contains significantly higher levels of measured plasminogen and D-dimer fragments than a standard HFC dose. The tested HFC is a more reliable fibrinogen and FXIII source for accurate dosing compared with cryoprecipitate. Cryoprecipitate appears considerably less predictable for bleeding management due to wide variation in pro- and anticoagulation factors, the presence of PMPs, and the potential to elevate VWF and FVIII to prothrombotic levels.

Coagulation biomarkers and coronavirus disease 2019 phenotyping: a prospective cohort study

BackgroundBecause severe acute respiratory syndrome coronarivus 2 (SARS-CoV-2) leads to severe conditions and thrombus formation, evaluation of the coagulation markers is important in determining the prognosis and phenotyping of patients with COVID-19.MethodsIn a prospective study that included 213 COVID-19 patients admitted to the intensive care unit (ICU) the levels of antithrombin, C-reactive protein (CRP); factors XI, XII, XIII; prothrombin and D-dimer were measured. Spearman’s correlation coefficient was used to assess the pairwise correlations between the biomarkers. Hierarchical and non-hierarchical cluster analysis was performed using the levels of biomarkers to identify patients´ phenotypes. Multivariate binary regression was used to determine the association of the patient´s outcome with clinical variables and biomarker levels.ResultsThe levels of factors XI and XIII were significantly higher in patients with less severe COVID-19, while factor XIII and antithrombin levels were significantly associated with mortality. These coagulation biomarkers were associated with the in-hospital survival of COVID-19 patients over and above the core clinical factors on admission. Hierarchical cluster analysis showed a cluster between factor XIII and antithrombin, and this hierarchical cluster was extended to CRP in the next step. Furthermore, a non-hierarchical K-means cluster analysis was performed, and two phenotypes were identified based on the CRP and antithrombin levels independently of clinical variables and were associated with mortality.ConclusionCoagulation biomarkers were associated with in-hospital survival of COVID-19 patients. Lower levels of factors XI, XII and XIII and prothrombin were associated with disease severity, while higher levels of both CRP and antithrombin clustered with worse prognosis. These results suggest the role of coagulation abnormalities in the development of COVID-19 and open the perspective of identifying subgroups of patients who would benefit more from interventions focused on regulating coagulation.

Evaluation of the association of factor XIII at hospital arrival and outcomes in a cohort of severely injured patients

BackgroundSevere traumatic bleeding depletes coagulation factor XIII (FXIII) and fibrinogen. However, the role of FXIII level in bleeding-related outcomes is unknown. ObjectivesTo evaluate the association between FXIII levels at hospital arrival and critical administration threshold (≥3 red blood cell units in 1 hour within the first 24 hours), bleeding-related outcomes, death, and baseline characteristics. MethodsA retrospective cohort study was conducted in severely injured adult patients (Injury Severity Score of ≥22 or ≥2 red blood cell units transfused in 24 hours) admitted to a level 1 trauma center. Clinical and laboratory data were collected. Baseline FXIII antigen levels were measured in banked patient plasma. Multivariable logistic and linear regression models were used to estimate the association between FXIII levels, outcomes, and baseline characteristics. ResultsThree hundred sixty-four of 1730 subjects admitted during a 2-year period were analyzed. Median age was 44 years (IQR, 27-62 years), and median Injury Severity Score was 29 (IQR, 22-34). FXIII levels were not associated with critical administration threshold (odds ratio [OR], 1.06; 95% CI, 0.97-1.17) or death (OR, 0.98; 95% CI, 0.90-1.07). FXIII was associated with major bleeding (OR, 1.10; 95% CI, 1.02-1.2) and massive transfusion (OR, 1.25; 95% CI, 1.08-1.44). Lower baseline FXIII levels were associated with arrival from a referring hospital (FXIII level, −0.07 U/mL; 95% CI, −0.11 to −0.03), hemoglobin (FXIII level, −0.05 U/mL; 95% CI, −0.07 to −0.03), fibrinogen level (FXIII level, −0.05 U/mL; 95% CI, −0.08 to −0.02), and platelet count (FXIII level, −0.02 U/mL; 95% CI, −0.04 to −0.008). ConclusionsBaseline FXIII levels in severely injured patients were inconsistently associated with bleeding-related outcomes and mortality. However, their association with major bleeding warrants further investigation of the role of FXIII in massively transfused patients with trauma.

Whole-exome sequencing reveals a novel frameshift mutation in a consanguineous family with a hereditary coagulation factor XII deficiency

Background and aimsWe aimed to elucidate a hereditary mutation of coagulation factor XII (FXII) in a consanguineous Chinese family. MethodsMutations were investigated using Sanger and whole-exome sequencing. FXII (FXII:C) activity and FXII antigen (FXII:Ag) were assessed using clotting assays and ELISA, respectively. Gene variants were annotated and the likelihood that amino acid mutations would affect protein function was predicted using bioinformatics. ResultsActivated partial thromboplastin time was prolonged to > 170 s (reference range, 22.3–32.5 s), and FXII:C and FXII:Ag were decreased to 0.3% and 1%, respectively, (normal range for both, 72%–150%) in the proband. Sequencing revealed a homozygous frameshift mutation c.150delC (p.Phe51Serfs*44) site in the F12 gene exon 3. This mutation results in premature termination of the encoded protein translation and the protein is truncated. Bioinformatic findings indicated a novel pathogenic frameshift mutation. ConclusionThe c.150delC frameshift mutation p.Phe51Serfs*44 in the F12 gene likely explains the low FXII level and the molecular pathogenesis of an inherited FXII deficiency in a consanguineous family.

Combined oral contraceptives may activate the contact system in healthy women

BackgroundThe contact system (CAS) is part of the coagulation system, consisting of a group of plasma proteins stimulating inflammation, coagulation, and fibrinolysis when activated. CAS can be triggered by several activating surfaces, and CAS may play a potential role in thrombus formation. Combined oral contraceptives (COCs) are known to increase the risk of venous thromboembolism, and COCs induce various prothrombotic changes in the coagulation system, whereas the effect of COC on CAS has not been thoroughly investigated. ObjectivesTo investigate CAS in COC users compared with nonusers. MethodsBlood samples from 62 study subjects, 30 COC users, and 32 nonusers, were analyzed. Coagulation factor XII (FXII), prekallikrein (PK), H-Kininogen (HK), cleaved HK (cHK), C1-esterase inhibitor (C1-inh), and the endogenous kallikrein potential (EKP) were measured. ResultsCOC users had significantly higher FXII (median, 38.4 vs 28.9 mg/L) and lower C1-inh levels (0.20 vs 0.23 g/L) than nonusers. The levels of PK and HK were not significantly different. Measurement of EKP indicated an increased capacity of CAS in COC users (1860 vs 1500 nmol/L × min), and increased plasma levels of cHK (2.02 vs 1.07 μg/L) indicated an increased activity in vivo. ConclusionThis study demonstrates an increased CAS capacity in women using COC compared with nonusers and also an increased activity in vivo. The results indicate that increased contact activation may contribute to the increased thrombotic risk caused by COC.

Factor XIII levels, clot strength, and impact of fibrinogen concentrate in infants undergoing cardiopulmonary bypass: a mechanistic sub-study of the FIBCON trial

BackgroundAcquired factor XIII (FXIII) deficiency after major surgery can increase postoperative bleeding. We evaluated FXIII contribution to clot strength and the effect of fibrinogen concentrate administration on FXIII activity in infants undergoing cardiac surgery using cardiopulmonary bypass. MethodsWe conducted a prospectively planned, mechanistic sub-study, nested within the Fibrinogen Concentrate Supplementation in the Management of Bleeding During Paediatric Cardiopulmonary Bypass: A Phase 1B/2A, Open-Label Dose Escalation Study (FIBCON) trial, which investigated fibrinogen concentrate supplementation during cardiopulmonary bypass (ISRCTN: 50553029) in 111 infants (median age 6.4 months). The relationships between platelet number, fibrinogen concentration, and FXIII activity with rotational thromboelastometry clot strength (EXTEM-MCF) in blood taken immediately before cardiopulmonary bypass and after separation from bypass were estimated using multivariable linear regression. Changes in coagulation variables over time were quantified using a generalised linear model comparing three groups: fibrinogen concentrate-supplemented infants, placebo, and a third cohort with lower bleeding risk. ResultsOverall, 48% of the variability (multivariable R2) in EXTEM-MCF clot strength was explained by three factors: the largest contribution was from FXIII activity (partial R2=0.21), followed by platelet number (partial R2=0.14), and fibrinogen concentration (partial R2=0.095). During cardiopulmonary bypass, mean platelet count fell by a similar amount in the three groups (–36% to –41%; interaction P=0.98). Conversely, fibrinogen concentration increased in all three groups: 132% in the fibrinogen concentrate-supplemented group, 26% in the placebo group, and 51% in the low-risk group. A similar increase was observed for FXIII activity (61%, 23%, and 25%, respectively; interaction P<0.0001). ConclusionsFXIII contribution to clot strength is considerable in infants undergoing cardiac surgery. Fibrinogen concentrate supplementation also increased FXIII activity, and hence clot strength. Clinical trial registrationISRCTN: 50553029.

A comparison of the ClotPro system with rotational thromboelastometry in cardiac surgery: a prospective observational study

Viscoelastic coagulation tests have been increasingly used for hemostasis management in cardiac surgery. The ClotPro system is a novel viscoelastic device based on principles of rotational thromboelastometry. We aimed to compare ClotPro with ROTEM and plasma coagulation assays in cardiopulmonary bypass (CPB) patients. Blood samples were collected from 25 CPB patients at (1) baseline, (2) start of CPB, (3) end of CPB, and (4) end of surgery. The EX-test, IN-test, HI-test, FIB-test parameters on ClotPro were compared with corresponding ROTEM assay (EXTEM, INTEM, HEPTEM, and FIBTEM). Standard plasma coagulation assays and endogenous thrombin generation (TG) were simultaneously evaluated. Pearson correlation analyses showed moderate correlations between clotting times (CTs) (r = 0.63–0.67; p < 0.001, respectively), and strong correlations with maximal clot firmness (MCF) (r = 0.93–0.98; p < 0.001, respectively) between ClotPro and ROTEM. EX-test and IN-test MCF parameters were interchangeable with acceptable percentage errors (EX-test MCF: 7.3%, IN-test MCF: 8.3%), but FIB-test MCF (27.0%) and CT results were not (EX-test CT: 44.7%, IN-test CT: 31.4%). The correlations of PT/INR or peak TG with EX-test CTs were higher than with EXTEM CTs (PT/INR: r = 0.80 and 0.41, peak TG: 0.43 and 0.18, respectively). FIB-test MCF has strong correlation with plasma fibrinogen and factor XIII level (r = 0.84 and 0.66, respectively). ROC analyses showed that ClotPro was capable of emulating well-established ROTEM thresholds (area under curves: 0.83–1.00). ClotPro demonstrated strong correlations in MCF parameters of ROTEM in CPB patients. It may be reasonable to modify ROTEM-based transfusion algorithm pertaining to MCF parameters to establish cut-off values for ClotPro device.

Prevalence and determinants of atrial fibrillation progression in paroxysmal atrial fibrillation

ObjectiveAtrial fibrillation (AF) often progresses from paroxysmal AF (PAF) to more permanent forms. To improve personalised medicine, we aim to develop a new AF progression risk prediction model in patients...

Factor XIII Deficiency in a Mother-Baby Dyad

Background: Factor XIII deficiency is a rare autosomal recessive coagulation disorder with varied presentations including prolonged bleeding from the umbilical cord stump, defective wound healing, recurrent miscarriages, or life-threatening intracranial hemorrhage. Clinical Description: A male baby was born at term gestation to a fourth gravida mother with a history of two abortions in the past. He was born out of a third-degree consanguineous marriage, with smooth perinatal transition, but developed multiple episodes of seizures associated with poor feeding and lethargy after 24 h of life. Management: On evaluation, septic screen, metabolic screen (serum electrolytes, calcium, and blood sugar), and coagulation assays were normal. Ultrasonogram revealed a hyperechoic lesion restricted to the left cerebral hemisphere, suggestive of an intraparenchymal hemorrhage. Magnetic resonance imaging brain showed left intraparenchymal hemorrhage with significant mass effect and midline shift. In view of intracranial bleed with normal coagulation assay and other causes being ruled out, factor XIII clot solubility assay was sent and found to have undetectable levels. Factor XIII levels of the mother were also found low (5.5%) though the levels in the father were normal. The baby was managed conservatively with supportive measures in the form of anticonvulsant and anti-edema measures. He recovered successfully and is under close follow-up. Conclusion: A high index of suspicion of factor XIII deficiency should be kept in any neonate presenting with intraparenchymal hemorrhage and recurrent abortions in the mother. This case is being reported to highlight factor XIII deficiency in recurrent pregnancy loss and neonatal intracranial bleeding. Prenatal screening for factor XIII deficiency in these circumstances will help in effective management of future pregnancies.

Reduced fibrin clot lysis in Klinefelter syndrome associated with hypogonadism.

Objective Klinefelter syndrome (KS) is associated with increased risk of thrombosis. Hypogonadism and accumulating body fat in KS have a potential impact on fibrinolysis. In this study, we assessed the fibrinolytic system and the association with testosterone levels in KS.Design This study is a cross-sectional comparison of men with KS and age-matched male controls.Methods Fibrin clot lysis was evaluated by turbidity measurements and by measuring levels of individual fibrinolytic proteins in plasma samples. Fibrin clot structure was evaluated by scanning electron microscopy. Total testosterone was measured by liquid chromatography-tandem mass spectrometry. Body fat was evaluated by dual-energy X-ray absorptiometry.Results In this study, 45 men with KS and 45 age- and education-matched controls were included. Men with KS had a 24% reduction in fibrin clot lysis compared with controls (46.2 ± 17.1 vs 60.6 ± 18.8 %/h, P = 0.0003) and higher levels of fibrinogen, factor XIII (P ≤ 0.01), and plasminogen activator inhibitor type 1 (P = 0.04). Men with KS had lower total testosterone (P = 0.008) and higher body fat (P = 0.001). In KS, reduced fibrin clot lysability was associated with higher fibrinogen and body fat related to decreasing total testosterone and hypogonadism among men with KS. Fibrin clot structure was not different compared to KS and controls.Conclusions Fibrin clot lysis in KS was markedly reduced, potentially contributing to a prothrombotic state and increasing thrombotic risk. Hypogonadism in KS was associated with increased fibrinogen and total body fat, predicting reduced fibrin clot lysis.

The Efficacy of Fibrinogen Concentrates in Relation to Cryoprecipitate in Restoring Clot Integrity and Stability against Lysis.

Loss of fibrinogen is a feature of trauma-induced coagulopathy (TIC), and restoring this clotting factor is protective against hemorrhages. We compared the efficacy of cryoprecipitate, and of the fibrinogen concentrates RiaSTAP® and FibCLOT® in restoring the clot integrity in models of TIC. Cryoprecipitate and FibCLOT® produced clots with higher maximal absorbance and enhanced resistance to lysis relative to RiaSTAP®. The fibrin structure of clots, comprising cryoprecipitate and FibCLOT®, mirrored those of normal plasma, whereas those with RiaSTAP® showed stunted fibers and reduced porosity. The hemodilution of whole blood reduced the maximum clot firmness (MCF) as assessed by thromboelastography. MCF could be restored with the inclusion of 1 mg/mL of fibrinogen, but only FibCLOT® was effective at stabilizing against lysis. The overall clot strength, measured using the Quantra® hemostasis analyzer, was restored with both fibrinogen concentrates but not cryoprecipitate. α2antiplasmin and plasminogen activator inhibitor-1 (PAI-1) were constituents of cryoprecipitate but were negligible in RiaSTAP® and FibCLOT®. Interestingly, cryoprecipitate and FibCLOT® contained significantly higher factor XIII (FXIII) levels, approximately three-fold higher than RiaSTAP®. Our data show that 1 mg/mL fibrinogen, a clinically achievable concentration, can restore adequate clot integrity. However, FibCLOT®, which contained more FXIII, was superior in normalizing the clot structure and in stabilizing hemodiluted clots against mechanical and fibrinolytic degradation.