The protective rather than prothrombotic fibrinogen in COVID-19 and other inflammatory states.

Hypercoagulability has been recognized as a common complication of COVID-19. Exact mechanisms for this extreme coagulation activation have not yet been elucidated. However, one of the consistent laboratory finding is the increase in fibrinogen, in some cases, marked elevation. High circulating levels of fibrinogen have been linked to thrombosis for years and for this reason, hyperfibrinogenemia is considered one of the mechanisms for COVID-19 coagulopathy. In this forum article, instead of the prothrombotic role, a protective function for fibrinogen is discussed. Fibrinogen, like the other well-known acute phase reactants, is increased in COVID-19 possibly to protect the host.

The D-dimer level predicts the postoperative prognosis in patients with non-small cell lung cancer.

BACKGROUND: Carcinoma cells often modulate coagulation and fibrinolysis among cancer patients. Plasma dimerized plasmin fragment D (D-dimer) has been reported as a prognostic marker of various types of malignancies, including non-small cell lung cancer (NSCLC). However, the associations between the plasma D-dimer level and peripheral small NSCLC remain unclear. METHODS: Three hundred and sixty-two patients with NSCLC who underwent radical surgery were retrospectively reviewed. Patients who received anticoagulation therapy before surgery or who lacked preoperative D-dimer data were excluded. The other 235 patients were divided into a high D-dimer (over 1.0 µg/mL) group (HDD group, n = 47) and a normal D-dimer group (NDD group, n = 188) and investigated for their clinical characteristics, computed tomography (CT) findings, pathological findings, and clinical outcomes. RESULTS: The mean D-dimer levels was 2.49±2.58 µg/ml in the HDD group and 0.42±0.23 µg/ml in the NDD group. The HDD group was characterized by a predominance of male gender, older age, pure solid appearance on chest CT, vascular invasion in pathology, and a large solid part of the tumor. The HDD group showed a worse overall survival, disease-free survival, and disease-specific survival than the NDD group (p<0.001, <0.001, <0.001, respectively). These survival features were also observed in p-Stage IA disease. There was no marked survival difference when tumors showed ground-glass opacity on CT. CONCLUSION: In NSCLC patients with a solid tumor appearance on CT, high D-dimer levels predict a poor survival and early recurrence.

Factor XI and recurrent venous thrombosis: an observational cohort study.

Essentials Factor XI is a potential target for anticoagulation. The association between factor XI and venous thrombosis recurrence was tested in a cohort study. Low factor XI was associated with reduced risk of recurrent venous thrombosis. A sex-and age-adjusted linear association between D-Dimer and factor XI was found. SUMMARY: Background and objectives Low factor XI activity (FXIa) reduces the risk of venous thromboembolism (VTE), and FXI is regarded as a potential target for anticoagulation. Patients/methods We studied the relationship between FXIa and VTE in 851 patients with unprovoked VTE in whom anticoagulation had been stopped. Results Recurrent VTE was recorded in 265 patients. The sex-adjusted and age-adjusted hazard ratio (HR) of recurrence was 0.94 (95% confidence interval [CI] 0.89-0.99) for each decrease of 10 IU dL-1 in FXIa. The HRs of recurrence were 0.73 (95% CI 0.54-0.99) for patients with FXIa below the 34th percentile, and 1.05 (95% CI 0.79-1.39) for patients with FXIa between the 34th and 67th percentiles, as compared with patients with higher FXIa. The probability of recurrence was lower among patients with FXIa below the 34th percentile than in patients with higher FXIa (P = 0.029). At 10 years, the probabilities of recurrence were 31%, 43% and 41% among patients with FXIa below the 34th percentile, with FXIa between the 34th and 67th percentiles, or with higher FXIa, respectively. We found a significant sex-adjusted and age-adjusted linear association between D-dimer levels, measured 3 weeks after anticoagulation, and FXIa. When patients' age and sex are taken into account, a patient with 10 IU dL-1 lower FXIa is expected to have a 2.79% (95% CI 0.95-4.59%) lower D-dimer value (P = 0.003). Conclusions Our findings of a lower thrombosis risk and less pronounced hemostatic system activation among patients with low FXIa is in line with the concept that FXI is a promising target for anticoagulation.

D-dimer: An Overview of Hemostasis and Fibrinolysis, Assays, and Clinical Applications.

D-dimer is the smallest fibrinolysis-specific degradation product found in the circulation. The origins, assays, and clinical use of D-dimer will be addressed. Hemostasis (platelet and vascular function, coagulation, fibrinolysis, hemostasis) is briefly reviewed. D-dimer assays are reviewed. The D-dimer is very sensitive to intravascular thrombus and may be markedly elevated in disseminated intravascular coagulation, acute aortic dissection, and pulmonary embolus. Because of its exquisite sensitivity, negative tests are useful in the exclusion venous thromboembolism. Elevations occur in normal pregnancy, rising two- to fourfold by delivery. D-dimer also rises with age, limiting its use in those >80 years old. There is a variable rise in D-dimer in active malignancy and indicates increased thrombosis risk in active disease. Elevated D-dimer following anticoagulation for a thrombotic event indicates increased risk of recurrent thrombosis. These and other issues are addressed.

The inflammatory actions of coagulant and fibrinolytic proteases in disease.

Aside from their role in hemostasis, coagulant and fibrinolytic proteases are important mediators of inflammation in diseases such as asthma, atherosclerosis, rheumatoid arthritis, and cancer. The blood circulating zymogens of these proteases enter damaged tissue as a consequence of vascular leak or rupture to become activated and contribute to extravascular coagulation or fibrinolysis. The coagulants, factor Xa (FXa), factor VIIa (FVIIa), tissue factor, and thrombin, also evoke cell-mediated actions on structural cells (e.g., fibroblasts and smooth muscle cells) or inflammatory cells (e.g., macrophages) via the proteolytic activation of protease-activated receptors (PARs). Plasmin, the principle enzymatic mediator of fibrinolysis, also forms toll-like receptor-4 (TLR-4) activating fibrin degradation products (FDPs) and can release latent-matrix bound growth factors such as transforming growth factor-ß (TGF-ß). Furthermore, the proteases that convert plasminogen into plasmin (e.g., urokinase plasminogen activator) evoke plasmin-independent proinflammatory actions involving coreceptor activation. Selectively targeting the receptor-mediated actions of hemostatic proteases is a strategy that may be used to treat inflammatory disease without the bleeding complications of conventional anticoagulant therapies. The mechanisms by which proteases of the coagulant and fibrinolytic systems contribute to extravascular inflammation in disease will be considered in this review.

Endothelial barrier dysfunction in septic shock.

The endothelium provides an essential and selective membrane barrier that regulates the movement of water, solutes, gases, macromolecules and the cellular elements of the blood from the tissue compartment in health and disease. Its structure and continuous function is essential for life for all vertebrate organisms. Recent evidence indicates that the endothelial surface does not have a passive role in systemic inflammatory states such as septic shock. In fact, endothelial cells are in dynamic equilibrium with a myriad of inflammatory mediators and elements of the innate immune and coagulation systems to orchestrate the host response in sepsis. The barrier function of the endothelial surface is almost uniformly impaired in septic shock, and it is likely that this contributes to adverse outcomes. In this review, we will highlight recent advances in the understanding of the signalling events that regulate endothelial function and molecular events that induce endothelial dysfunction in sepsis. Endothelial barrier repair strategies as a treatment for sepsis include modulation of C5a, high-mobility group box 1 and VEGF receptor 2; stimulation of angiopoietin-1, sphingosine 1 phosphate receptor 1 and Slit; and a number of other innovative approaches.

Colorectal cancer and hypercoagulability.

Since the first report of the spontaneous appearance of venous thrombophlebitis as a sign of visceral cancer by Trousseau in 1865, many other studies have documented the existence of cancer-associated coagulation disorders. In this review, we describe the hypercoagulable state associated with colorectal cancer, from three perspectives: first, the incidence, risk factors and prevention of clinically symptomatic thromboembolic conditions associated with cancer, such as venous thromboembolism and arterial thrombosis; second, the association between hypercoagulable conditions, such as thrombocytosis, hyperfibrinogenemia, or D-dimer elevation, and the clinical progression and poor prognosis of cancer patients; third, the experimental approach to elucidate the role of various coagulation-related factors in the process of cancer progression, focusing specifically on the role of platelets and tissue factors.

[Effect of fibrin monomer on spontaneous platelet aggregation].

Fibrin monomer (FM) was shown to cause a considerable increase in artificial shear-induced platelet aggregation. The aggregatory effect of FM was found to be tangibly higher than that in fibrinogen. The mechanism of action of FM on platelet aggregation is hypothesized.

Pro-inflammatory effect of fibrinogen and FDP on vascular smooth muscle cells by IL-6, TNF-α and iNOS.

AIMS: Atherosclerosis is a chronic inflammatory response of the arterial wall to multiple endothelial injuries. As one of the inflammatory markers, fibrinogen has been implicated in pathogenesis of atherosclerosis. But, it is not completely understood whether atherogenesis of fibrinogen is related to its pro-inflammatory effect on vascular smooth muscle cells (VSMCs). The purpose of the present study was to observe effects of fibrinogen and fibrin degradation products (FDP) on interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) generation in rat VSMCs. MAIN METHODS: Rat VSMCs were cultured, and fibrinogen and FDP were used as stimulants for IL-6, TNF-α, and iNOS. IL-6 and TNF-α level in the supernatant were measured by ELISA, mRNA expression of IL-6, TNF-α, and iNOS were assayed with RT-PCR, and protein expression of iNOS was detected with western blot and immunocytochemistry. KEY FINDINGS: Fibrinogen and FDP both significantly stimulated mRNA and protein expressions of IL-6, TNF-α and iNOS in VSMCs in time- and concentration-dependent ways. The pro-inflammatory potency of FDP is higher than fibrinogen, which seems to mean that smaller fragments of the protein have greater pro-inflammatory activity. Fibrinogen and FDP promote more protein expressions of IL-6 and TNF-α compared to iNOS, suggesting that fibrinogen and FDP produce a pro-inflammatory effect on VSMCs mainly by IL-6 and TNF-α. SIGNIFICANCE: These findings are helpful to better understand pro-inflammatory effect of fibrinogen on VSMCs involved in atherogenesis, and imply a therapeutic strategy targeting hyperfibrinogenemia in atherosclerosis.

Fibrinogen and D-dimer analysis of chronic subdural hematomas and computed tomography findings: a prospective study.

OBJECTIVE: We investigated the relationship between fibrinolytic factors and computed tomography (CT) findings in patients with chronic subdural hematomas (CSDHs). METHODS: Thirty-one patients with CSDHs were divided on the basis of CT findings into heterogeneous and homogeneous groups. A sample from the subdural hematoma was obtained at surgery to measure the concentrations of fibrinogen and D-dimer. RESULTS: The mean level of fibrinogen in the heterogeneous group, including the layering (n=4) and mixed (n=10) type, was 88.2±121.2 mg/dL, whereas in the homogeneous group, including high density (n=2), isodensity (n=9), and low density (n=6) types, it was <25 mg/dL. The concentration of fibrinogen was significantly higher in the heterogeneous group than in the homogeneous group (p=0.006). The mean level of D-dimer in the heterogeneous group was 35,407.9±16,325.5 µg/L, whereas for the homogeneous group it was 1476.4±2091.4 µg/L. The concentration of D-dimer was significantly higher in the heterogeneous group than in the homogeneous group (p<0.001). CONCLUSIONS: The layering and mixed types of CSDH exhibited higher concentrations of fibrinogen and D-dimer in subdural hematoma than the homogeneous types. These fibrinolytic factors appear to be associated with evolution in CSDHs with heterogeneous density.

Role of D-dimer testing in severe pelvic inflammatory disease: a new usable marker to assess the need for fertility-impairing surgery?

Pelvic inflammatory disease (PID), like many other inflammatory diseases, can be characterized by an inflammation-induced activation of the coagulation cascade, resulting in the production of D-dimers. In this study it is demonstrated how high levels of D-dimers, assayed at the time of hospitalization, are encountered in patients diagnosed with PID and how the levels of this parameter are significantly higher in patients, which due to the severity of the disease, needed surgical treatment. Therefore the d-dimer is shown to be an important parameter to be considered in the therapeutic counseling of severe forms of PID.

D-dimer as a possible prognostic marker of operable hormone receptor-negative breast cancer.

BACKGROUND: Breast cancer is the most common cause of death in women by neoplasia. The mechanisms related to recurrence are unclear, specially the hemostatic alterations that occur during the development of the disease. Plasma D-dimer is a hypercoagulability and fibrinolytic system marker and is increased in patients with various solid tumors. The purpose of this study was to evaluate the hemostatic status assessed by plasma D-dimer in operable breast cancer patients and to investigate its value as a prognostic marker. MATERIALS AND METHODS: The study comprised 32 patients with operable hormone receptor-negative breast cancer and a control group with 43 healthy women. Variables included presence and absence of breast cancer, clinical and histopathology findings, and overall survival. RESULTS: Plasma D-dimer level was normal in the control group and significantly higher in breast cancer patients (P = 0.001), as well as in nonsurvivors compared with survivors (P = 0.025). The results showed that plasma D-dimer levels were not correlated with clinical and histopathology findings (P > 0.213). CONCLUSIONS: The results taken together indicate the presence of a hypercoagulability state in women with operable hormone receptor-negative breast cancer given the increased levels of D-dimer in this group. Therefore, considering higher levels of D-dimer in patients with a poor outcome, its evaluation may be a promising tool for prognosis in women with operable hormone receptor-negative breast cancer.

The role of coagulation marker fibrin D-dimer in early diagnosis of catatonia.

Catatonia is a common but under-diagnosed neuropsychiatric syndrome characterized by the occurrence in a single patient of concomitant affective, motor and behavioral symptoms with a hazardous outcome (called lethal catatonia: LC). Deaths by thromboembolic disease have been previously reported in LC. A 2-year prospective study was carried out to examine D-dimer levels, an early and sensitive coagulation marker, in patients with catatonic disorders. Twenty-five acute catatonic patients and 50 psychiatric control patients - matched on age, gender, psychiatric diagnosis, general psychopathology and neuroleptic medication matched - were investigated and considered in relation to D-dimer blood levels and other biological variables (serum iron, creatine phosphokinase, leukocytosis). All catatonic patients had high D-dimer levels and mean levels were significantly higher in catatonics than in non-catatonic patients, independently of age, gender, immobility, comorbid diagnosis, general psychopathology and neuroleptic medication. No significant association was observed with other biological parameters investigated. These preliminary and exploratory results suggest that catatonia is associated with early coagulation activation.

Biology of the peritoneum in normal homeostasis and after surgical trauma.

The peritoneum is a serous membrane, which has a protective function for the contents of the abdominal cavity. It maintains homeostasis by allowing exchange of molecules and production of peritoneal fluid, thus providing an environment in which intra-abdominal organs can function properly. When traumatized, whether by surgery or due to inflammatory processes, a series of responses come into action to regenerate the injured part of the peritoneum. The inflammatory reaction causes influx of inflammatory cells but also activates resident mesothelial cells, ultimately leading to a fibrinous exudate. Depending on the severity of the trauma this exudate is transient due to fibrinolysis, or becomes more dense as a result of fibroblasts persisting, leading to fibrinous adhesions. A pivotal role is taken by the enzyme plasmin and its promotors and inhibitors; it is mainly the tissue-type plasminogen activator/plasminogen activator inhibitor ratio which determines the rate of fibrinolysis and therefore the rate of adhesion formation. The rate of injury determines the rate and extent of the inflammatory response to that injury; in its turn the inflammatory reaction determines the extent of adhesion formation. One should realize this when performing intra-abdominal surgery, which is in fact operating inside the peritoneal organ.

The chymotrypsin-like protease complex of Treponema denticola ATCC 35405 mediates fibrinogen adherence and degradation.

Treponema denticola is an anaerobic spirochete strongly associated with human periodontal disease. T. denticola bacteria interact with a range of host tissue proteins, including fibronectin, laminin, and fibrinogen. The latter localizes in the extracellular matrix where tissue damage has occurred, and interactions with fibrinogen may play a key role in T. denticola colonization of the damaged sites. T. denticola ATCC 35405 showed saturable binding of fluid-phase fibrinogen to the cell surface and saturable adherence to immobilized fibrinogen. Levels of fibrinogen binding were enhanced in the presence of the serine protease inhibitor phenylmethylsulfonyl fluoride. The Aalpha and Bbeta chains of fibrinogen, but not the gamma chains, were specifically recognized by T. denticola. Following fibrinogen affinity chromatography analysis of cell surface extracts, a major fibrinogen-binding component (polypeptide molecular mass, approximately 100 kDa), which also degraded fibrinogen, was purified. Upon heating at 100 degrees C, the polypeptide was dissociated into three components (apparent molecular masses, 80, 48, and 45 kDa) that did not individually bind or degrade fibrinogen. The native 100-kDa polypeptide complex was identified as chymotrypsin-like protease (CTLP), or dentilisin. In an isogenic CTLP(-) mutant strain, CKE, chymotrypsin-like activity was reduced >90% compared to that in the wild type and fibrinogen binding and hydrolysis were ablated. Isogenic mutant strain MHE, deficient in the production of Msp (major surface protein), showed levels of CTLP reduced 40% relative to those in the wild type and exhibited correspondingly reduced levels of fibrinogen binding and proteolysis. Thrombin clotting times in the presence of wild-type T. denticola cells, but not strain CKE (CTLP(-)) cells, were extended. These results suggest that interactions of T. denticola with fibrinogen, which may promote colonization and modulate hemostasis, are mediated principally by CTLP.

Incorporation of fibrin molecules containing fibrinopeptide A alters clot ultrastructure and decreases permeability.

Previous studies have shown that a heterozygous mutation in the fibrinogen Aalpha chain gene, which results in an Aalpha R16C substitution, causes fibrinolytic resistance in the fibrin clot. This mutation prevents thrombin cleavage of fibrinopeptide A from mutant Aalpha R16C chains, but not from wild-type Aalpha chains. However, the mechanism underlying the fibrinolytic resistance is unclear. Therefore, this study investigated the biophysical properties of the mutant fibrin that contribute to fibrinolytic resistance. Fibrin clots made from the mutant fibrinogen incorporated molecules containing fibrinopeptide A into the polymerised clot, which resulted in a 'spiky' clot ultrastructure with barbed fibrin strands. The clots were less stiff than normal fibrin and were cross-linked slower by activated FXIII, but had an increased average fiber diameter, were more dense, had smaller pores and were less permeable. Protein sequencing showed that unclottable fibrinogen remaining in the supernatant consisted entirely of homodimeric Aalpha R16C fibrinogen, whereas both cleaved wild-type alpha chains and uncleaved Aalpha R16C chains were in the fibrin clot. Therefore, fibrinolytic resistance of the mutant clots is probably a result of altered clot ultrastructure caused by the incorporation of fibrin molecules containing fibrinopeptide A, resulting in larger diameter fibers and decreased permeability to fibrinolytic enzymes.

[Process of complexation of prothrombine and fibrin E-fragment].

The study is devoted to research of the blood coagulation key proenzyme complexation process. It is prothrombin, and the E-fragment of fibrin can be a component in blood circulation. It is shown, that non-enzyme activation of prothrombin by the E-fragment proceeds as a result of formation of stable non-covalent prothrombin-E fragment complex. The cringle structures of prothrombin and the N-terminal site of beta-chain of E-fragment of fibrin are important for formation of the given complex. It has been defined, that other fragments of fibrin (D and DD) are not capable to induce amydolytic activity of prothrombin.

Fibrinogen fragment D is necessary and sufficient to anchor a surface plasminogen-activating complex in Streptococcus pyogenes.

In this study, the importance of different domains of the fibrinogen molecule in the binding and assembly of a surface plasminogen (plgn) activator has been analyzed. This was achieved using SELDI technology that enabled dissociation of bound fragments from intact bacteria and accurate distinction between fibrinogen fragments based on their molecular mass. These studies indicate that Streptococcus pyogenes binds directly to human fibrinogen fragment D but not fragment E. The predominant surface proteins binding to fragment D were associated with the mrp gene product. Surface-associated fibrinogen fragment D was capable of anchoring a functional surface plgn activator complex. Taken together, these data indicated that fragment D of fibrinogen is necessary and sufficient to anchor a plgn activator complex on the surface of Streptococcus pyogenes.

New risk factors for atherosclerosis in hypertension: focus on the prothrombotic state and lipoprotein(a).

Although adequate control of blood pressure is of basic importance in cardiovascular prevention in hypertensive patients, correction of additional risk factors is an integral part of their management. In addition to classical risk factors, epidemiological research has identified a number of other conditions that might significantly contribute to cardiovascular risk in the general population and might achieve specific relevance in patients with high blood pressure. In fact, more than 20% of patients with premature cardiovascular events do not have any of the traditional risk factors and, although effective intervention on blood pressure and additional risk factors has significantly reduced cardiovascular morbidity and mortality, the contribution to stroke, coronary artery disease and renal failure is still unacceptably high. Evaluation of new risk factors may further expand our capacity to predict atherothrombotic events when these factors are included along with the traditional ones in the assessment of global cardiovascular risk in hypertensive patients. Because it could be anticipated that the role of these novel factors will become increasingly evident in the future, researchers with an interest in hypertension and physicians dealing with problems related to cardiovascular prevention should give them appropriate consideration. This review summarizes the basic biology and clinical evidence of two emerging risk factors that are reciprocally related and contribute to the development and progression of organ damage in hypertension: the prothrombotic state and lipoprotein(a).