Hemostasis and complement in allogeneic hematopoietic stem cell transplantation: clinical significance of two interactive systems.

Hematopoietic stem cell transplantation (HCT) represents a curative treatment option for certain malignant and nonmalignant hematological diseases. Conditioning regimens before HCT, the development of graft-versus-host disease (GVHD) in the allogeneic setting, and delayed immune reconstitution contribute to early and late complications by inducing tissue damage or humoral alterations. Hemostasis and/or the complement system are biological regulatory defense systems involving humoral and cellular reactions and are variably involved in these complications after allogeneic HCT. The hemostasis and complement systems have multiple interactions, which have been described both under physiological and pathological conditions. They share common tissue targets, such as the endothelium, which suggests interactions in the pathogenesis of several serious complications in the early or late phase after HCT. Complications in which both systems interfere with each other and thus contribute to disease pathogenesis include transplant-associated thrombotic microangiopathy (HSCT-TMA), sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), and GVHD. Here, we review the current knowledge on changes in hemostasis and complement after allogeneic HCT and how these changes may define clinical impact

A finite element method for non-linear hyperelasticity applied for the simulation of octopus ARM motions

An implicit non-linear finite element (FE) numerical procedure for the simulation of biological muscular tissues is presented. The method has been developed for studying the motion of muscular hydrostats, such as squid and octopus arms and its general framework is applicable to other muscular tissues. The FE framework considered is suitable for the dynamic numerical simulations of three-dimensional non-linear nearly incompressible hyperelastic materials that undergo large displacements and deformations. Human and animal muscles, consisting of fibers and connective tissues, belong to this class of materials. The stress distribution inside the muscular FE model is considered as the superposition of stresses along the muscular fibers and the connective tissues. The stresses along the fibers are modeled as the sum of active and passive stresses, according to the muscular model of Van Leeuwen and Kier (1997) Philos. Trans. R. Soc. London, 352: 551-571. Passive stress distribution is an experimentally-defined function of fibers’ deformation; while active stress distribution is the product of an activation level time function, a force-stretch function and a force-stretch ratio function. The mechanical behavior of the surrounding tissues is determined adopting a Mooney-Rivlin constitutive model. The incompressibility criterion is met by enforcing large bulk modulus and by introducing modified deformation measures. Due to the non-linear nature of the problem, approximate determination of the Jacobian matrix is performed, in order to utilize the full Newton-Raphson iterative procedure within each time-step. In addition, time discretization is performed via the implicit Newmark method. We developed an open-source finite element code that is capable of simulating large deflection maneuvers of muscular hydrostats. The proposed methodology is validated by comparing the numerical results with existing measurements for the squid arm extension. The efficiency and robustness of the proposed numerical method is demonstrated through a series of octopus arm maneuvers, such as extension, compression and bending

Antiretroviral Therapy Reduces Markers of Endothelial and Coagulation Activation in Patients Infected with Human Immunodeficiency Virus Type 1

We investigated the effect of antiretroviral therapy on vascular activation in 41 human immunodeficiency (HIV)—infected patients receiving a regimen that included either at least 1 protease inhibitor (PI; n = 21) or a nonnucleoside reverse-transcriptase inhibitor (NNRTI; n = 20). Acontrol group of 21 healthy subjectswas included for comparison. Levels of endothelialmarkers (soluble vascular cell adhesion molecule [sVCAM]-1, soluble intercellular adhesionmolecule-1, and vonWillebrand factor) were higher in HIV-infected persons before treatment than in control subjects anddecreasedsignificantlyafter 5-13 months of treatment. Levels of sVCAM-1 and vonWillebrand factor correlated significantly with initial virus load. D-dimer concentrations also decreased significantly after initiation of treatment. PI- and NNRTI-containing regimens had similar effects. Therapy did not reduce levels of the soluble platelet (sP) activation markers sP-selectin and CD40 ligand. The inhibition of markers of vascular activation may counterbalance sequelae of therapy-induced dyslipidemia and potentially prevent development of atherosclerosis in HIVinfected patient

Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice

Repopulation of immunodeficient mice remains the primary method for functional assessment of human acute myeloid leukemia. Published data report engraftment in ~40-66% of cases, mostly of intermediate- or poor-risk subtypes. Here we report that extending follow-up beyond the standard analysis endpoints of 10 to 16 weeks after transplantation permitted leukemic engraftment from nearly every case of xenotransplanted acute myeloid leukemia (18/19, ~95%). Xenogeneic leukemic cells showed conserved immune pheno-types and genetic signatures when compared to corresponding pre-transplant cells and, furthermore, were able to induce leukemia in re-transplantation assays. Importantly, bone marrow biopsies taken at standardized time points failed to detect leukemic cells in 11/18 of cases that later showed robust engraftment (61%, termed "long-latency engrafters"), indicating that leukemic cells can persist over months at undetectable levels without losing disease-initiating properties. Cells from favorable-risk leukemia subtypes required longer to become detectable in NOD/SCID/IL2Rγ; null; mice (27.5±9.4 weeks) than did cells from intermediate-risk (21.9±9.4 weeks,; P; <0.01) or adverse-risk (17±7.6 weeks;; P; <0.0001) subtypes, explaining why the engraftment of the first was missed with previous protocols. Mechanistically, leukemic cells engrafting after a prolonged latency showed inferior homing to the bone marrow. Finally, we applied our model to favorable-risk acute myeloid leukemia with inv(16); here, we showed that CD34; +; (but not CD34; -; ) blasts induced robust, long-latency engraftment and expressed enhanced levels of stem cell genes. In conclusion, we provide a model that allows; in vivo; mouse studies with a wide range of molecular subtypes of acute myeloid leukemia subtypes which were previously considered not able to engraft, thus enabling novel insights into leukemogenesis

Variability between laboratories performing coagulation tests with identical platforms: a nationwide evaluation study.

BACKGROUND While the assessment of analytical precision within medical laboratories has received much attention in scientific enquiry, the degree of as well as the sources causing variation between them remains incompletely understood. In this study, we quantified the variance components when performing coagulation tests with identical analytical platforms in different laboratories and computed intraclass correlations coefficients (ICC) for each coagulation test. METHODS Data from eight laboratories measuring fibrinogen twice in twenty healthy subjects with one out of 3 different platforms and single measurements of prothrombin time (PT), and coagulation factors II, V, VII, VIII, IX, X, XI and XIII were analysed. By platform, the variance components of (i) the subjects, (ii) the laboratory and the technician and (iii) the total variance were obtained for fibrinogen as well as (i) and (iii) for the remaining factors using ANOVA. RESULTS The variability for fibrinogen measurements within a laboratory ranged from 0.02 to 0.04, the variability between laboratories ranged from 0.006 to 0.097. The ICC for fibrinogen ranged from 0.37 to 0.66 and from 0.19 to 0.80 for PT between the platforms. For the remaining factors the ICC's ranged from 0.04 (FII) to 0.93 (FVIII). CONCLUSIONS Variance components that could be attributed to technicians or laboratory procedures were substantial, led to disappointingly low intraclass correlation coefficients for several factors and were pronounced for some of the platforms. Our findings call for sustained efforts to raise the level of standardization of structures and procedures involved in the quantification of coagulation factors

Failure of recombinant factor VIIa in a patient with severe polymicrobial sepsis and postoperative uncontrolled intraabdominal bleeding

<p>Abstract</p> <p>Background</p> <p>This report discusses a case of unsuccessful treatment with recombinant factor VIIa (rFVIIa) in off-label use. The need for international guidelines concerning the off-label use of rFVIIa is outlined as well as the need for methods to control the efficacy of rFVIIa objectively.</p> <p>Case presentation</p> <p>54 year old male with severe polymicrobial sepsis due to a perforated diverticulitis of the sigmoid colon and consecutive overt disseminated intravascular coagulation. He suffered severe intraabdominal bleeding after abdominal surgery despite conventional haemostatic support. Repeated applications of factor VIIa temporarily improved coagulation essays but did not stop clinical bleeding. The patient died in multiorgan failure due to septic and haemorrhagic shock.</p> <p>Conclusion</p> <p>Off-label use of rFVIIa could result in more side effects than could be expected from literature because of a publication bias. However for most off-label applications large prospective, randomised and controlled trials to confirm the positive findings are missing. For the future, not only guidelines concerning the off-label use of rFVIIa are urgently needed but also guidelines for monitoring the efficacy of rFVIIa.</p

Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (Pinteraction=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT02866838

Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial

BACKGROUND: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (P$_{interaction}$=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio