-
Clinical Immunology (Orlando, Fla.) Dec 2023COVID-19-associated coagulopathy, shown to increase the risk for the occurrence of thromboses and microthromboses, displays phenotypic features of the antiphospholipid...
BACKGROUND AND OBJECTIVES
COVID-19-associated coagulopathy, shown to increase the risk for the occurrence of thromboses and microthromboses, displays phenotypic features of the antiphospholipid syndrome (APS), a prototype antibody-mediated autoimmune disease. Several groups have reported elevated levels of criteria and non-criteria antiphospholipid antibodies (aPL), assumed to cause APS, during acute or post-acute COVID-19. However, disease heterogeneity of COVID-19 is accompanied by heterogeneity in molecular signatures, including aberrant cytokine profiles and an increased occurrence of autoantibodies. Moreover, little is known about the association between autoantibodies and the clinical events. Here, we first aim to characterise the antiphospholipid antibody, anti-SARS-CoV-2 antibody, and the cytokine profiles in a diverse collective of COVID-19 patients (disease severity: asymptomatic to intensive care), using vaccinated individuals and influenza patients as comparisons. We then aim to assess whether the presence of aPL in COVID-19 is associated with an increased incidence of thrombotic events in COVID-19.
METHODS AND RESULTS
We conducted anti-SARS-CoV-2 IgG and IgA microELISA and IgG, IgA, and IgM antiphospholipid line immunoassay (LIA) against 10 criteria and non-criteria antigens in 155 plasma samples of 124 individuals, and we measured 16 cytokines and chemokines in 112 plasma samples. We additionally employed clinical and demographic parameters to conduct multivariable regression analyses within multiple paradigms. In line with recent results, we find that IgM autoantibodies against annexin V (AnV), β2-glycoprotein I (β2GPI), and prothrombin (PT) are enriched upon infection with SARS-CoV-2. There was no evidence for seroconversion from IgM to IgG or IgA. PT, β2GPI, and AnV IgM as well as cardiolipin (CL) IgG antiphospholipid levels were significantly elevated in the COVID-19 but not in the influenza or control groups. They were associated predominantly with the strength of the anti-SARS-CoV-2 antibody titres and the major correlate for thromboses was SARS-CoV-2 disease severity.
CONCLUSION
While we have recapitulated previous findings, we conclude that the presence of the aPL, most notably PT, β2GPI, AnV IgM, and CL IgG in COVID-19 are not associated with a higher incidence of thrombotic events.
Topics: Humans; Antibodies, Antiphospholipid; Influenza, Human; COVID-19; SARS-CoV-2; Antiphospholipid Syndrome; Antibodies, Anticardiolipin; Thrombosis; beta 2-Glycoprotein I; Immunoglobulin G; Prothrombin; Immunoglobulin A; Immunoglobulin M; Cytokines
PubMed: 37995947
DOI: 10.1016/j.clim.2023.109845 -
Critical Care (London, England) Nov 2023Trauma-induced coagulopathy (TIC) is common in trauma patients with major hemorrhage. Prothrombin complex concentrate (PCC) is used as a potential treatment for the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Trauma-induced coagulopathy (TIC) is common in trauma patients with major hemorrhage. Prothrombin complex concentrate (PCC) is used as a potential treatment for the correction of TIC, but the efficacy, timing, and evidence to support its use in injured patients with hemorrhage are unclear.
METHODS
A systematic search of published studies was performed on MEDLINE and EMBASE databases using standardized search equations. Ongoing studies were identified using clinicaltrials.gov. Studies investigating the use of PCC to treat TIC (on its own or in combination with other treatments) in adult major trauma patients were included. Studies involving pediatric patients, studies of only traumatic brain injury (TBI), and studies involving only anticoagulated patients were excluded. Primary outcomes were in-hospital mortality and venous thromboembolism (VTE). Pooled effects of PCC use were reported using random-effects model meta-analyses. Risk of bias was assessed for each study, and we used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence.
RESULTS
After removing duplicates, 1745 reports were screened and nine observational studies and one randomized controlled trial (RCT) were included, with a total of 1150 patients receiving PCC. Most studies used 4-factor-PCC with a dose of 20-30U/Kg. Among observational studies, co-interventions included whole blood (n = 1), fibrinogen concentrate (n = 2), or fresh frozen plasma (n = 4). Outcomes were inconsistently reported across studies with wide variation in both measurements and time points. The eight observational studies included reported mortality with a pooled odds ratio of 0.97 [95% CI 0.56-1.69], and five reported deep venous thrombosis (DVT) with a pooled OR of 0.83 [95% CI 0.44-1.57]. When pooling the observational studies and the RCT, the OR for mortality and DVT was 0.94 [95% CI 0.60-1.45] and 1.00 [95% CI 0.64-1.55] respectively.
CONCLUSIONS
Among published studies of TIC, PCCs did not significantly reduce mortality, nor did they increase the risk of VTE. However, the potential thrombotic risk remains a concern that should be addressed in future studies. Several RCTs are currently ongoing to further explore the efficacy and safety of PCC.
Topics: Adult; Humans; Child; Venous Thromboembolism; Blood Coagulation Factors; Blood Coagulation Disorders; Hemorrhage; Randomized Controlled Trials as Topic
PubMed: 37919775
DOI: 10.1186/s13054-023-04688-z -
Lupus Dec 2023Classification criteria for antiphospholipid syndrome (APS) require IgG or IgM isotypes of the anticardiolipin (aCL) antibodies, anti-β2 glycoprotein I (anti-β2GPI)...
Classification criteria for antiphospholipid syndrome (APS) require IgG or IgM isotypes of the anticardiolipin (aCL) antibodies, anti-β2 glycoprotein I (anti-β2GPI) antibodies, and/or the lupus anticoagulant (LA) to satisfy the laboratory disease definition. Over the past 20 years, non-criteria antiphospholipid antibodies (aPL) directed to other proteins of the coagulation cascade (i.e. prothrombin and/or phosphatidylserine-prothrombin complex) or to some domains of β2GPI have been proposed. This task force concentrated and reviewed the literature on data including aPS/PT, antibodies to domain 4/5 of β2GPI and the newly described antibodies to protein/HLA-DR complex. In addition, we discussed testing of LA in the 'new' oral anticoagulants' era and the value of triple positivity in the risk assessment of aPL. The conclusions were presented at a special session during the 16 International Congress on aPL, Manchester, UK, September 2019.
Topics: Humans; Antiphospholipid Syndrome; Prothrombin; Lupus Erythematosus, Systemic; Antibodies, Antiphospholipid; Lupus Coagulation Inhibitor; Antibodies, Anticardiolipin; beta 2-Glycoprotein I
PubMed: 37933818
DOI: 10.1177/09612033231211820 -
Journal of Veterinary Emergency and... Jun 2024To describe and compare prothrombin time (PT), activated partial thromboplastin time (aPTT), thromboelastography (TEG), HCT, and platelet count measurements in a...
Prothrombin and activated partial thromboplastin times, thromboelastography, hematocrit, and platelet count in a feline hemorrhage/over-resuscitation model using lactated Ringer's solution or 6% tetrastarch 130/0.4.
OBJECTIVE
To describe and compare prothrombin time (PT), activated partial thromboplastin time (aPTT), thromboelastography (TEG), HCT, and platelet count measurements in a hemorrhage/over-resuscitation model.
DESIGN
Randomized crossover study.
SETTING
University teaching hospital.
ANIMALS
Six cats.
INTERVENTIONS
Anesthetized cats underwent 3 treatments at 2-month intervals. The treatments were as follows: NHR-no controlled hemorrhage and sham resuscitation; LRS-controlled hemorrhage and lactated Ringer's solution (LRS) for resuscitation; and Voluven-controlled hemorrhage and 6% tetrastarch 130/0.4 for resuscitation. The LRS and Voluven were administered at 60 and 20 mL/kg/h, respectively, for 120 minutes. Blood samples were drawn for PT, aPTT, TEG, HCT, and platelet count measurements at a healthy check (T - 7d), after controlled hemorrhage (T0), at 60 and 120 minutes of resuscitation (T60 and T120), and at 24 hours after completion of resuscitation (T24h). Data were analyzed using a general linear mixed model approach (significance was P < 0.05).
MEASUREMENTS AND MAIN RESULTS
Total median blood loss (controlled hemorrhage and blood sampling from T0 to T120) at T120 was 11.4, 31.0, and 30.8 mL/kg for NHR, LRS, and Voluven, respectively. PT and aPTT during LRS and Voluven were prolonged at T60 and T120 compared to NHR (P < 0.001). On TEG, the reaction time, kinetic time, and alpha-angle were within reference intervals for cats at all time points in all treatments, while maximum amplitude was less than the reference interval (40 mm) at T0, T60, and T120 during Voluven and at T60 and T120 during LRS compared to NHR (both P < 0.001). The HCT and platelet count were significantly lower at T60 and T120 during LRS and Voluven compared to NHR (P < 0.001).
CONCLUSIONS
Hypocoagulopathy was observed during hemorrhage and liberal fluid resuscitation. Prolongation of PT and aPPT and decreased clot strength may have been caused by hemodilution and platelet loss.
PubMed: 38874122
DOI: 10.1111/vec.13376 -
British Journal of Anaesthesia Feb 2024This study in vitro comprehensively assessed reversal of the anticoagulant effects of rivaroxaban, an oral factor Xa inhibitor, using andexanet alfa and various...
This study in vitro comprehensively assessed reversal of the anticoagulant effects of rivaroxaban, an oral factor Xa inhibitor, using andexanet alfa and various prothrombin complex concentrate (PCC) products in a battery of tests. In static coagulation assays, andexanet alpha outperformed PCCs except for activated PCC being more effective in standard coagulation times. However, in a flow chamber model mimicking arterial shear, both andexanet alpha and high-concentration PCC restored fibrin formation, but not platelet adhesion. In the Russell's viper venom test and anti-Xa assay, only andexanet alpha could be tested for efficacy. The antidote effects of andexanet alpha and PCCs in restoring coagulation can be qualitatively or selectively demonstrated using in vitro coagulation tests.
Topics: Humans; Factor Xa Inhibitors; Antidotes; Blood Coagulation Factors; Rivaroxaban; Factor IX; Recombinant Proteins; Anticoagulants; Factor Xa
PubMed: 38071150
DOI: 10.1016/j.bja.2023.11.028 -
Clinical Immunology (Orlando, Fla.) Nov 2023Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy...
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy complications. Within the diverse range of aPLs, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have gained significance in clinical practice. The detection of aPS/PT has proven valuable in identifying APS patients and stratifying their risk, especially when combined with other aPL tests like lupus anticoagulant (LA) and anti-β-glycoprotein I (aβGPI). Multivariate analyses have confirmed aPS/PT as an independent risk factor for vascular thrombosis and obstetric complications, with its inclusion in the aPL score and the Global Anti-Phospholipid Syndrome Score (GAPSS) aiding in risk evaluation. However, challenges remain in the laboratory testing of aPS/PT, including the need for assay standardization and its lower sensitivity in certain patient populations. Further research is necessary to validate the clinical utility of aPS/PT antibodies in APS diagnosis, risk stratification, and management.
Topics: Female; Pregnancy; Humans; Antiphospholipid Syndrome; Prothrombin; Phosphatidylserines; Antibodies, Antiphospholipid; beta 2-Glycoprotein I; Thrombosis
PubMed: 37838215
DOI: 10.1016/j.clim.2023.109804 -
Journal of Thrombosis and Haemostasis :... May 2024Thrombin generation (TG) in the presence of thrombomodulin (TG-TM) in the plasma of patients with cirrhosis (PWC) is tilted toward a hypercoagulable phenotype. Low...
BACKGROUND
Thrombin generation (TG) in the presence of thrombomodulin (TG-TM) in the plasma of patients with cirrhosis (PWC) is tilted toward a hypercoagulable phenotype. Low protein C and elevated factor VIII levels play a role, but other determinants, such as the prothrombin/antithrombin pair, must also be studied.
OBJECTIVES
The objectives were (i) to quantitatively assess the subprocesses (prothrombin conversion and thrombin decay) and (ii) to understand the underlying mechanism by studying TG dynamics after prothrombin and antithrombin plasma level correction in PWC.
METHODS
We studied TG-TM in plasma samples of 36 healthy controls (HCs) and 41 PWC with prothrombin and antithrombin levels of <70% and after their correction. We initiated coagulation with an intermediate picomolar concentration of tissue factor. We determined the overall thrombin potential, prothrombin conversion, and thrombin decay.
RESULTS
TG-TM was increased in PWC compared with HC due to impaired thrombin inhibition. Indeed, thrombin decay capacity (min) decreased from 0.37 (0.35-0.40) in HC to 0.33 (0.30-0.37) in the Child-Turcotte-Pugh A (CTP-A; P = .09), 0.27 (0.26-0.30) in the CTP-B (P < .001), and 0.20 (0.19-0.20) in the CTP-C (P < .001) group. Concomitant correction of prothrombin and antithrombin increased endogenous thrombin potential with prothrombin conversion surpassing thrombin decay. By contrast, when we corrected only antithrombin, TG-TM was normalized and even consistent with a hypocoagulable phenotype in the CTP-C group.
CONCLUSION
Our results highlight that in PWC, hypercoagulability (evidenced in the presence of TM) is due to impaired thrombin decay, whereas low prothrombin levels do not translate into decreased prothrombin conversion, likely due to altered TM-activated protein C negative feedback.
Topics: Humans; Prothrombin; Thrombin; Male; Female; Middle Aged; Case-Control Studies; Blood Coagulation; Liver Cirrhosis; Aged; Thrombomodulin; Adult; Antithrombins; Blood Coagulation Tests; Phenotype; Thromboplastin
PubMed: 38309434
DOI: 10.1016/j.jtha.2024.01.016 -
Journal of Thrombosis and Haemostasis :... Nov 2023Most of the carriers/patients triple-positive for antiphospholipid antibodies (lupus anticoagulant [LAC], immunoglobulin G [IgG]/immunoglobulin M [IgM] anticardiolipin,...
Close link between antiphosphatidylserine/prothrombin antibodies, lupus anticoagulant, and activated protein C resistance in tetra antiphospholipid antibody-positive subjects.
BACKGROUND
Most of the carriers/patients triple-positive for antiphospholipid antibodies (lupus anticoagulant [LAC], immunoglobulin G [IgG]/immunoglobulin M [IgM] anticardiolipin, and anti-β2-glycoprotein I antibodies) are tetra-positive, being positive for antiphosphatidylserine/prothrombin (aPS/PT) antibodies. The relationship between aPS/PT titer, LAC potency, and resistance to activated protein C (aPC-R) has not been investigated.
OBJECTIVES
The aim of this study was to clarify the mutual interdependence of these parameters in tetra-positive subjects.
METHODS
Twenty-three carriers and 30 patients with antiphospholipid syndrome, none of whom were being treated with anticoagulants, and 30 age- and sex-matched controls were studied. Detection of aPS/PT, LAC, and aPC-R in each individual was performed with established methods in our laboratory. Carriers and patients were positive for IgG or IgM aPS/PT or for both isotypes without significant difference. Since both IgG and IgM aPS/PT have anticoagulant activity, we used the sum of their titers (total aPS/PT) for the correlation studies.
RESULTS
Total aPS/PT in all individuals studied exceeded that in controls. There was no difference in total aPS/PT titers (P = .72), LAC potency (P = .56), and aPC-R (P = .82) between antiphospholipid antibody-carriers and patients with antiphospholipid syndrome. There was a significant correlation between total aPS/PT and LAC potency (r = 0.78; P < .0001) and between total aPS/PT titers and aPC-R (r = 0.80; P < .0001). LAC potency also was correlated significantly with aPC-R (r = 0.72; P < .0001).
CONCLUSION
This study shows that there is interdependence between aPS/PT, LAC potency, and aPC-R.
Topics: Humans; Antiphospholipid Syndrome; Lupus Coagulation Inhibitor; Prothrombin; Activated Protein C Resistance; Phosphatidylserines; Antibodies, Antiphospholipid; Immunoglobulin G; Immunoglobulin M
PubMed: 37422199
DOI: 10.1016/j.jtha.2023.06.033 -
Cureus Jul 2023A state of "re-balanced haemostasis" describes complex coagulation changes that arise in patients with liver disease. Changes include alterations in procoagulant and... (Review)
Review
A state of "re-balanced haemostasis" describes complex coagulation changes that arise in patients with liver disease. Changes include alterations in procoagulant and anticoagulant proteins, platelets and von Willebrand factor, as well as the fibrinolytic system. Various circumstances including infection, trauma, or surgery may disrupt this balance and predispose an individual to bleeding or thrombosis. The prothrombin time, international normalised ratio, and activated partial thromboplastin time are conventional coagulation screening tests that are routinely employed by clinicians to investigate unexplained bleeding, monitor anticoagulation, and inform preoperative assessments of bleeding risk. These standard coagulation tests assess quantitative defects in procoagulant clotting factors and are insensitive to levels of natural anticoagulants, which together with procoagulant factors, are often perturbed in liver disease. Therefore, the prolongation of clotting times measured by these tests often does not reflect the multifaceted alterations of haemostasis in these patients. Viscoelastic testing (VET) provides a more encompassing assessment of clotting function by recording real-time viscoelastic changes in whole blood and includes parameters that provide information on coagulation factor function, platelet contribution to clot formation, as well as fibrinolysis. To date, VET has been employed to predict and inform transfusion support in obstetric, trauma, and cardiac surgical fields, and its use in patients undergoing liver transplantation is well established. The ability of VET to accurately predict bleeding risk and precisely guide transfusion algorithms for patients with liver disease undergoing other invasive procedures or experiencing bleeding complications has been the topic of research over the last decade. This review is a critical summary of this data and provides a detailed snapshot of the position of VET as a clinical tool in patients with liver disease.
PubMed: 37546051
DOI: 10.7759/cureus.41401 -
The International Journal of Lower... Oct 2023We aim to identify the factors associated with the failure of amputation of one to three toes (index toe amputation) in patients with diabetes and foot infection. We... (Review)
Review
We aim to identify the factors associated with the failure of amputation of one to three toes (index toe amputation) in patients with diabetes and foot infection. We conducted a retrospective cohort of 175 patients with diabetes who were hospitalized for moderate to severe foot infection and underwent amputation of one to three toes. A Poisson regression model was used to determine the prevalence ratio (PR) as a measure of association. The mean age was 63.3 ± 11.4 years. Fifty-three patients presented failure after undergoing toe amputation (30.3%). Multivariate analysis, adjusted for age and sex, showed the following significant variables: severe infection (PR: 1.78; 95% confidence interval [CI]: 1.14-2.78; 0.011), infection by (PR: 2.21; 95% CI: 1.42-3.43; < 0.001), infection by (PR: 2.11; 95% CI: 1.29-3.43; 0.003) and prothrombin time (PR: 1.13; 95% CI: 1.05-1.21; 0.001), obesity (PR: 0.58; 95% CI: 0.37-0.93; 0.024), and haemoglobin value (PR: 0.92; 95% CI: 0.86-0.99; 0.023). About one-third of patients who underwent amputation of one to three toes for diabetic foot infection presented a failure and required a more proximal surgery. Severe infections, isolation of and , and prolonged prothrombin time were associated with a higher prevalence of failure. However, obesity and an elevated haemoglobin level were associated with a lower prevalence of failure.
PubMed: 37885211
DOI: 10.1177/15347346231207679