A relationship between microvascular disorders and sensorineural hearing loss (SNHL) has been widely proposed. The vascular hypothesis, theorized for the onset of sudden SNHL (SSNHL), is among the most acknowledged: a localized acute cochlear damage, of ischemic or haemorrhagic nature, could be considered a causative factor of SSNHL. The aim of this review is to assess (i) the effect on hearing in patients affected by blood coagulation disorders (prothrombotic or haemorrhagic) and (ii) the possible etiopathogenetic mechanisms of the related hearing loss. A PRISMA-compliant review was performed. Medline, Embase, and Cinahl databases were searched from inception to 31 January 2023, and a total of 14 studies have been included in the review. The available data suggest that it is possible to consider clotting disorders as a potential condition at risk for sensorineural hearing loss; in particular, coagulation tests and eventually the assessment of genetic and acquired prothrombotic factors should be recommended in patients with SSNHL. Also, an audiological evaluation should be recommended for patients with blood coagulation disorders presenting cochlear symptoms, especially in those suffering from clotting diseases.

No abstract available

Thrombosis and cardiovascular complications are common manifestations of a variety of pathological conditions, including infections and chronic inflammatory diseases. Hence, there is great interest in determining the hitherto unforeseen immune role of the main blood coagulation executor-the platelet. Platelets store and release a plethora of immunoactive molecules, generate microparticles, and interact with cells classically belonging to the immune system. The observed effects of platelet involvement in immune processes, especially in autoimmune diseases, are conflicting-from inciting inflammation to mediating its resolution. An in-depth understanding of the role of platelets in inflammation and immunity could open new therapeutic pathways for patients with autoimmune disorders. This review aims to summarize the current knowledge on the role of platelets in the patomechanisms of autoimmune disorders and suggests directions for future research.

Coagulation factors are essential for hemostasis. Here, we show that these factors also team up to degrade plasma proteins that are unrelated to hemostasis. Prolidase, SRC and amyloid β1-42 (Aβ1-42) are used as probes. Each probe, upon entering the blood circulation, binds and activates factor XII (FXII), triggering the intrinsic and common coagulation cascades, which in turn activate factor VII, a component of the extrinsic coagulation cascade. Activated factor VII (FVIIa) rapidly degrades the circulating probes. Therefore, FXII and FVIIa serve as the sensor/initiator and executioner, respectively, for the proteolysis pathway. Moreover, activation of this pathway by one probe leads to the degradation of all three probes. Significant activation of this pathway follows tissue injury and may also occur in other disorders, e.g., Alzheimer's disease, of which Aβ1-42 is a key driver. However, enoxaparin, a clinically used anticoagulant, inhibits the proteolysis pathway and elevates plasma levels of the probes. Enoxaparin may also mitigate potential impact of activators of the proteolysis pathway on coagulation. Our results suggest that the proteolysis pathway is important for maintaining low levels of various plasma proteins. Our finding that enoxaparin inhibits this pathway provides a means to control it. Inhibition of this pathway may facilitate the development of disease biomarkers and protein therapeutics, e.g., plasma Aβ1-42 as a biomarker of Alzheimer's disease or recombinant human prolidase as an antitumor agent.

Experimental animal studies as well as clinical trials have shown that interventions targeting the blood coagulation cascade inhibit cancer cell metastasis. These data support the hypothesis that congenital prothrombotic disorders, like factor V Leiden, facilitate metastasis whereas bleeding disorders, like haemophilia impede metastasis. To test this hypothesis, we subjected factor V Leiden and factor VIII deficient mice to a murine model of experimental lung metastasis. In this model, B16F10 murine melanoma cells are injected into the tail vein resulting in multiple lung metastases within 20 days. Both hemi- and homozygous factor VIII deficient mice were protected against lung metastasis compared to wild-type littermate controls. In contrast, homozygous factor V Leiden mice developed more metastases than wild-type littermates, whereas heterozygous carriers showed an intermediate number of pulmonary foci. Overall, these data show that a congenital susceptibility to either bleeding or thrombosis modifies the metastatic capacity of cancer cells in the bloodstream and suggest that procoagulant phenotypes are a risk factor for tumour metastasis.

Hemolytic disorders are characterized by hemolysis and are prone to thrombosis. It has previously been shown that the RNA released from damaged blood cells activates clotting. However, the nature of the RNA released from hemolysis is still elusive. We found that after hemolysis, red blood cells from both zebrafish and humans released RNA that contained mostly 5.8S ribosomal RNA (5.8S rRNA), This RNA activated coagulation in zebrafish and human plasmas. By using both natural and synthetic 5.8S rRNA and its truncated fragments, we found that the 3'-end 26-nucleotide-long RNA (3'-26 RNA) and its stem-loop secondary structure were necessary and sufficient for clotting activity. Corn trypsin inhibitor (CTI), a coagulation factor XII (FXII) inhibitor, blocked 3'-26 RNA-mediated coagulation activation in the plasma of both zebrafish and humans. CTI also inhibited zebrafish coagulation in vivo. 5.8S rRNA monoclonal antibody inhibited both 5.8S rRNA- and 3'-26 RNA-mediated zebrafish coagulation activity. Both 5.8S rRNA and 3'-26 RNA activated normal human plasma but did not activate FXII-deficient human plasma. Taken together, these results suggested that the activation of zebrafish plasma is via an FXII-like protein. Because zebrafish have no FXII and because hepatocyte growth factor activator (Hgfac) has sequence similarities to FXII, we knocked down the hgfac in adult zebrafish. We found that plasma from this knockdown fish does not respond to 3'-26 RNA. To summarize, we identified that an rRNA released in hemolysis activates clotting in human and zebrafish plasma. Furthermore, we showed that fish Hgfac plays a role in rRNA-mediated activation of coagulation.

Zika virus (ZIKV) has caused major concern globally due to its rapid dissemination and close association with microcephaly in children and Gullian-Barr syndrome in adults. In this study, we identified a patient returned from Cambodia who experienced high fever, chill and myalgia. Lab tests discovered sign of severe liver injury including significantly elevated serum transaminases' level, decreased serum albumin level, and markedly increased levels of lactic dehydrogenase, alpha-hydroxybutyric dehydrogenase and creatine kinase in serum. Moreover, severe thrombocytopenia and altered blood levels of fibrinogen and fibrinogen degradation product were also observed, indicating the existence of clotting disorders. A ZIKV strain clustered into the Asian lineage was isolated from the patient's serum. When inoculated into suckling mice, this virus significantly retarded mouse body-weight gain and caused 70% mortality. Our results demonstrate a close association between ZIKV and severe liver injury and coagulation disorders and suggest that clinicians should be aware of compatible symptoms in patients and manage them accordingly.

The purpose of this study was to investigate the relationship between heart rate variability (HRV), a non-invasive tool for evaluating autonomic function, and routine coagulation indices (RCIs) in patients with breast cancer (BC). Forty-six BC patients were enrolled in this study. Blood biochemistry tests were performed to extract RCIs, including prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). Five-minute electrocardiograms were collected for analysis of HRV parameters (SDNN, RMSSD, LF, HF, LF n.u., HF n.u., LF/HF). Multiple linear regression models examined the relationship of HRV parameters with RCIs. RMSSD, LF n.u., HF n.u., LF/HF were significantly associated with PT. Specifically, the value of PT increased by 0.192 ± 0.091 or 0.231 ± 0.088 s, respectively for each 1 standard deviation (SD) increase in RMSSD or HF n.u.; it increased by 0.230 ± 0.088 or 0.215 ± 0.088 s, respectively for each 1 - SD decrease in LF n.u. or ln (LF/HF) (all P < 0.05). RMSSD was significantly associated with APTT, i.e., the value of APTT increased by 1.032 ± 0.470 s for each 1 - SD increase in RMSSD (P < 0.05). HRV parameters were associated with RCIs in patients with BC. These observations suggest that the autonomic nervous system and coagulation indices in BC patients are linked, potentially explaining the reason that they are both associated with the prognosis.

Clinical studies have shown that all-trans retinoic acid (RA), which is often used in treatment of cancer patients, improves hemostatic parameters and bleeding complications such as disseminated intravascular coagulation (DIC). However, the mechanisms underlying this improvement have yet to be elucidated. In vitro studies have reported that RA upregulates thrombomodulin (TM) expression on the endothelial cell surface. The objective of this study was to investigate how and to what extent the TM concentration changes after RA treatment in cancer patients, and how this variation influences the blood coagulation cascade.

Coagulation activation has been demonstrated in two prototypic autoimmune skin diseases, chronic autoimmune urticaria and bullous pemphigoid, but only the latter is associated with increased thrombotic risk. Two markers of coagulation activation (prothrombin fragment F1+2 and fibrin fragment D-dimer) were measured by immunoenzymatic methods in plasma samples from 30 patients with active chronic autoimmune urticaria, positive for autologous serum skin test, 30 patients with active bullous pemphigoid and 30 healthy subjects. In skin biopsies, tissue factor expression was evaluated by both immunohistochemistry and in situ hybridization. F1+2 and D-dimer levels were higher in active chronic autoimmune urticaria (276.5±89.8 pmol/L and 5.56±4.40 nmol/L, respectively) than in controls (145.2±38.0 pmol/L and 1.06±0.25 nmol/L; P=0.029 and P=0.011) and were much higher in active bullous pemphigoid (691.7±318.7 pmol/L and 15.24±9.09 nmol/L, respectively) (P<0.0001). Tissue factor positivity was evident in skin biopsies of both disorders with higher intensity in bullous pemphigoid. F1+2 and D-dimer, during remission, were markedly reduced in both disorders. These findings support the involvement of coagulation activation in the pathophysiology of both diseases. The strong systemic activation of coagulation in bullous pemphigoid may contribute to increase the thrombotic risk and provides the rationale for clinical trials on anticoagulant treatments in this disease.

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.

Factor VIII (fVIII) is a procoagulant protein that binds to activated factor IX (fIXa) on platelet surfaces to form the intrinsic tenase complex. Due to the high immunogenicity of fVIII, generation of antibody inhibitors is a common occurrence in patients during hemophilia A treatment and spontaneously occurs in acquired hemophilia A patients. Non-classical antibody inhibitors, which block fVIII activation by thrombin and formation of the tenase complex, are the most common anti-C2 domain pathogenic inhibitors in hemophilia A murine models and have been identified in patient plasmas. In this study, we report on the X-ray crystal structure of a B domain-deleted bioengineered fVIII bound to the non-classical antibody inhibitor, G99. While binding to G99 does not disrupt the overall domain architecture of fVIII, the C2 domain undergoes an ~8 Å translocation that is concomitant with breaking multiple domain-domain interactions. Analysis of normalized B-factor values revealed several solvent-exposed loops in the C1 and C2 domains which experience a decrease in thermal motion in the presence of inhibitory antibodies. These results enhance our understanding on the structural nature of binding non-classical inhibitors and provide a structural dynamics-based rationale for cooperativity between anti-C1 and anti-C2 domain inhibitors.

Intestinal ischemia/reperfusion (I/R) injury often causes inflammatory responses and coagulation disorders, which is further promoting the deterioration of the disease. Hydrogen has anti-inflammatory, antioxidative, and antiapoptotic properties against various diseases. However, the effect of hydrogen on coagulation dysfunction after intestinal I/R and the underlying mechanism remains unclear. The purpose of this study was to explore whether hydrogen-rich solution (HRS) could attenuate coagulation disorders and inflammation to improve intestinal injury and poor survival following intestinal I/R. The rat model of intestinal I/R injury was established by clamping the superior mesenteric artery for 90 min and reperfusion for 2 h. HRS (10 or 20 mL/kg) or 20 mL/kg 0.9% normal saline was intravenously injected at 10 min before reperfusion, respectively. The samples were harvested at 2 h after reperfusion for further analyses. Moreover, the survival rate was observed for 24 h. The results showed that HRS improved the survival rate and alleviated serum diamine oxidase activities, intestinal injury, edema, and apoptosis. Interestingly, HRS markedly improved intestinal I/R-mediated coagulation disorders as evidenced by abnormal conventional indicators of coagulation and thromboelastography. Additionally, HRS attenuated inflammatory responses and the elevated tissue factor (TF) and inhibited nuclear factor kappa beta (NF-κB) and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in peripheral blood mononuclear cells. Moreover, inflammatory factors and myeloperoxidase were closely associated with TF level. This study thus emphasized upon the amelioration of coagulation disorders and inflammation by HRS as a mechanism to improve intestinal I/R-induced intestinal injury and poor survival, which might be partially related to inhibition of NF-κB/NLRP3 pathway.

The use of mouse models for the study of thrombotic disorders has gained increasing importance. Methods for measurement of coagulation activation in mice are, however, scarce. The primary aim of this study was to develop a specific mouse thrombin-antithrombin (TAT) ELISA for measurement of coagulation activation and to compare it with two commercially available assays for human TAT complexes. In addition, we aimed to improve methods for mouse plasma anticoagulation and preparation.

The discovery of TMEM173/STING-dependent innate immunity has recently provided guidance for the prevention and management of inflammatory disorders. Here, we show that myeloid TMEM173 occupies an essential role in regulating coagulation in bacterial infections through a mechanism independent of type I interferon response. Mechanistically, TMEM173 binding to ITPR1 controls calcium release from the endoplasmic reticulum in macrophages and monocytes. The TMEM173-dependent increase in cytosolic calcium drives Gasdermin D (GSDMD) cleavage and activation, which triggers the release of F3, the key initiator of blood coagulation. Genetic or pharmacological inhibition of the TMEM173-GSDMD-F3 pathway blocks systemic coagulation and improves animal survival in three models of sepsis (cecal ligation and puncture or bacteremia with Escherichia coli or Streptococcus pneumoniae infection). The upregulation of the TMEM173 pathway correlates with the severity of disseminated intravascular coagulation and mortality in patients with sepsis. Thus, TMEM173 is a key regulator of blood clotting during lethal bacterial infections.

Dynamic monitoring of coagulation is important to predict both haemorrhagic and thrombotic complications and to guide blood product administration. Reducing blood loss and tailoring blood product administration may improve patient outcome and reduce mortality associated with transfusion. The current literature lacks a systematic, critical appraisal of current best evidence on which clinical decisions may be based.

Hemostatic defects are treated using coagulation factors; however, clot formation also requires a procoagulant phospholipid (PL) surface. Here, we show that innate immune cell-derived enzymatically oxidized phospholipids (eoxPL) termed hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) restore hemostasis in human and murine conditions of pathological bleeding. HETE-PLs abolished blood loss in murine hemophilia A and enhanced coagulation in factor VIII- (FVIII-), FIX-, and FX-deficient human plasma . HETE-PLs were decreased in platelets from patients after cardiopulmonary bypass (CPB). To explore molecular mechanisms, the ability of eoxPL to stimulate individual isolated coagulation factor/cofactor complexes was tested in vitro. Extrinsic tenase (FVIIa/tissue factor [TF]), intrinsic tenase (FVIIIa/FIXa), and prothrombinase (FVa/FXa) all were enhanced by both HETE-PEs and HETE-PCs, suggesting a common mechanism involving the fatty acid moiety. In plasma, 9-, 15-, and 12-HETE-PLs were more effective than 5-, 11-, or 8-HETE-PLs, indicating positional isomer specificity. Coagulation was enhanced at lower lipid/factor ratios, consistent with a more concentrated area for protein binding. Surface plasmon resonance confirmed binding of FII and FX to HETE-PEs. HETE-PEs increased membrane curvature and thickness, but not surface charge or homogeneity, possibly suggesting increased accessibility to cations/factors. In summary, innate immune-derived eoxPL enhance calcium-dependent coagulation factor function, and their potential utility in bleeding disorders is proposed.

Brain metastases (BMs) are the most common malignancy of the central nervous system. Recently it has been demonstrated that plasminogen activator inhibitor serpins promote brain metastatic colonization, suggesting that mutations in serpins or other members of the coagulation cascade can provide critical advantages during BM formation. We performed whole-exome sequencing on matched samples of breast cancer and BMs and found mutations in the coagulation pathway genes in 5 out of 10 BM samples. We then investigated the mutational status of 33 genes belonging to the coagulation cascade in a panel of 29 BMs and we identified 56 Single Nucleotide Variants (SNVs). The frequency of gene mutations of the pathway was significantly higher in BMs than in primary tumours, and SERPINI1 was the most frequently mutated gene in BMs. These findings provide direction in the development of new strategies for the treatment of BMs.

The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the pheno- and genotypic associations of thrombin generation (TG) and ROTEM in CFD. We measured fibrinogen (Fg) activity and antigen, prothrombin fragments F1+2, and TG by ST Genesia® with both Bleed- and ThromboScreen in 22 patients. ROTEM was available for 11 patients. All patients were genotyped for fibrinogen mutations. Ten patients were diagnosed with hypofibrinogenemia, nine with dysfibrinogenemia, and three with hypodysfibrinogenemia. Among the 17 mutations, eight were affecting the Fg γ chain, four the Fg Bβ chain, and five the Fg Aα chain. No statistical difference according to the clinical phenotypes was observed among FGG and FGA mutations. Median F1+2 and TG levels were normal among the different groups. Fg levels correlated negatively with F1+2 and peak height, and positively with lag time and time to peak. The pheno- and genotypes of the patients did not associate with TG. FIBTEM by ROTEM detected hypofibrinogenemia. Our study suggests an inverse link between low fibrinogen activity levels and enhanced TG, which could modify the structure-function relationship of fibrin to support hemostasis.

Excessive bleeding after cardiopulmonary bypass (CPB) is risk factor for adverse outcomes after elective cardiac surgery (ECS). Although many different point-of-care devices to diagnose hemostatic disturbances after CPB are available, the best test is still unclear. The study aim was to compare the accuracy of hemostatic disorder detection between two point-of-care devices.