Acquired autoimmune Haemophilia following SARS-CoV-2 vaccines: Dual drug effects on blood coagulation and the Scylla and Charybdis phenomenon

Vaccination against the SARS-CoV-2 may lead to immunologic reactions activating the haemostatic system and resulting in both venous and arterial thromboembolism. Aquired autoimmune Haemophilia following SARS-CoV-2 vaccines were now reported 15 to 19 days (or later) after vaccination and resolution of symptoms by adequate treatment of the immunologic reaction. From patients’ point of view, anticoagulants and SARS-CoV-2 vaccines share their capacity to induce thrombosis as well as bleeding and clinicians are subjected to Scylla and Charybdis when they treat patients not only with anticoagulants but also with SARS-CoV-2 vaccines. Careful analysis of coincidence and causality requires attention when reporting on acquired coagulation inhibitors regarding severity, treatments, duration and statistical risk.

Prothrombotic state in patients with stable COPD: an observational study

BackgroundCOPD patients have an increased risk of cardiovascular disease and venous thromboembolism.MethodsThis study aimed to investigate whether patients with stable COPD have a prothrombotic state compared to COPD-free smokers. We conducted an observational study comparing levels of: D-dimers, INR, aPTT, coagulation factors: fibrinogen, FII, FV, FVII, FVIII, FIX, FX and coagulation inhibitors: protein S, proteins C and antithrombin between stable COPD patients and control subjects.ResultsA total of 103 COPD patients and 42 controls with similar age, sex, current smoking status, comorbidity burden and cardiovascular risk met the inclusion criteria. Compared to controls, COPD patients had higher levels of: D-dimers [360 (230–600) ng·mL−1versus 240 (180–400) ng·mL−1, p=0.001], fibrinogen (399±82 mg·dL−1versus 346±65 mg·dL−1, p<0.001), FII (122±22% versus 109±19%, p=0.004), FV (131±25% versus 121±19%, p=0.015), FVIII (143±32% versus 122±20%, p<0.001), FX [111 (94–134)% versus 98 (88–107)%, p=0.002] and lower levels of: Protein S [95 (85–105)% versus 116 (98–121)%, p<0.001], and antithrombin (94.4±11.5% versus 102.3±13.2%, p=0.001). In the COPD group, patients with more severe airflow limitation and frequent exacerbations had significantly higher levels of FII, FV and FX, whereas patients with higher CAT score had significantly higher levels of FX and lower levels of protein S.ConclusionPatients with stable COPD exhibited increased levels of key coagulation factors and decreased levels of coagulation inhibitors, namely protein S and antithrombin, compared to COPD-free smokers. Among COPD patients, increased levels of FII, FV and FX and decreased levels of protein S were found in patients with more severe disease.

The risk of arterial thrombosis in carriers of natural coagulation inhibitors: a prospective family cohort study

Background Whether the carriership of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiency increases the risk of arterial thromboembolic events (ATE) is controversial. This information has the potential to inform the management of family members of probands with inherited deficiency of natural anticoagulants. Patients/methods We conducted a large prospective family cohort study in 640 subjects (of whom 341 carriers and 299 non-carriers) belonging to 86 families with inherited deficiency of AT, PC, or PS. Results A total of 4240 and 3810 patient-years were available for carriers and non-carriers, respectively. Risk factors for atherosclerosis were similarly distributed in the two groups. Of the 26 ATE that were recorded, 19 occurred in carriers (5.6%), as compared to 7 in non-carriers (2.3%) [p = 0.07]. After adjusting for confounders, the hazard ratio (HR) for ATE was 4.9 (95% CI 1.5–16.3) in carriers as compared to non-carriers. Conclusions Among family members of probands with an inherited deficiency of natural anticoagulants, carriers exhibit a risk of ATE that is almost five times higher than in non-carriers.

Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency

High levels of tissue factor pathway inhibitor (TFPI), caused by a longer TFPIα half-life after binding to a factor V splice variant and variants in the F5 gene, were recently identified in 2 families with an as-yet-unexplained bleeding tendency. This study aimed to investigate free TFPIα in a well-characterized cohort of 620 patients with mild to moderate bleeding tendencies and its association to genetic alterations in the F5 gene. TFPIα levels were higher in patients with bleeding compared with healthy controls (median [interquartile range], 8.2 [5.5-11.7] vs 7.8 [4.3-11.1]; P = .026). A higher proportion of patients had free TFPIα levels more than or equal to the 95th percentile compared with healthy controls (odds ratio [OR] [95% confidence interval (CI)], 2.82 [0.98-8.13]). This was pronounced in the subgroup of patients in whom no bleeding disorder could be identified (bleeding of unknown cause [BUC; n = 420]; OR [95% CI], 3.03 [1.02-8.98]) and in platelet function defects (PFDs) (n = 121; OR [95% CI], 3.47 [1.09-11.08]). An increase in free TFPIα was associated with a mild delay in thrombin generation (prolonged lag time and time to peak), but not with alterations in routinely used global clotting tests. We could neither identify new or known genetic variations in the F5 gene that are associated with free TFPIα levels, nor an influence of the single-nucleotide variant rs10800453 on free TFPIα levels in our patient cohort. An imbalance of natural coagulation inhibitors such as TFPIα could be an underlying cause or contributor for unexplained bleeding, which is most probably multifactorial in a majority of patients.

Vascular Endothelial Damage: The Role of Syndecan-1 and Hyaluronan as Severity Indicators in COVID-19

SARS-CoV-2 was firstly found in bronchoalveloar lavage (BAL) of three suspected COVID-19 patients at Jinyintan Hospital, Wuhan, Hubei Province, China. The cases are still raisingwith2,12% global mortality rate. Hypoxic respiratory failure due to acute respiratory distress syndrome (ARDS) is the main cause of COVID-19 death. Endothelial cell damage has an important role in the pathogenesis of ARDS and multi-organ dysfuntion of COVID-19 patients. The endothelium is protected by mural cells, which keep vascular integrity. Inflammation is prevented by these cells by inhibiting the interaction of immune cells and platelets with endothelial cells. These cells also prevent coagulation by producing glycocalyx, coagulation inhibitors, and blood-clotting enzyme. Vascular glycocalyx has an important role to maintain endothelial function and is disrupted systemically in elderly and patients with various comorbidities, which can be a probable mechanism for the serious complications of COVID-19. Glycocalyx disruption in severe and critical COVID-19 patients causes increased levels of its components such assyndecan-1 and hyaluronan in the serum. Previous studies showed the significant increase ofsyndecan-1 and hyaluronan levels in septic, and severe Kawasaki and dengue patients. These biomarkers are also markers of organ damage. Therefore, hyaluronan and syndecan-1can be significant prognostic factors for morbidity and survival in patients with COVID-19.

Thrombin Generation and Cirrhosis: State of the Art and Perspectives

Epidemiological and laboratory studies performed in the last decades have changed our understanding of coagulopathy in cirrhosis, from a condition at increased risk of hemorrhagic events to one at higher thrombotic risk. However, it is not clear whether the decrease in factors that promote (except factor [F] VIII) versus inhibit coagulation in patients with cirrhosis results in a rebalanced state or in a hypercoagulable phenotype. This issue can be partially addressed using thrombin generation assays (TGA), which unlike routine clotting tests (prothrombin time or activated partial thromboplastin time) are sensitive to both procoagulant factors and coagulation inhibitors. However, many preanalytical issues and variable analytical methodologies used in TGAs complicate data analysis and interlaboratory comparisons. The introduction of TGAs in which activators of the protein C pathway (particularly soluble forms of thrombomodulin [TM]) are added has allowed detection of a reduced anticoagulant effect of TM or even a hypercoagulable phenotype as judged by endogenous thrombin potential. However, inter- and intra-assay variability may be greater with this TGA variant compared with “standard” TGAs. TGAs also allowed identifying main determinants of the hypercoagulability phenotype in the presence of TM: acquired antithrombin and protein C deficiencies, and elevated FVIII levels. The aim of this narrative review is to summarize the preanalytical and methodological variables of TGAs and also the findings of the main studies that have evaluated TGAs in patients with cirrhosis. The review also provides some propositions for future studies and outlines some perspectives on the potential implementation of this promising tool in clinical practice for the study of coagulation in patients with cirrhosis.