Seminars in thrombosis and hemostasis最新文献

Apical ballooning syndrome, commonly known as Takotsubo syndrome, is a distinct cardiomyopathy often resembling acute myocardial infarction in presentation. Takotsubo syndrome patients exhibit varied patterns of left ventricular wall motion abnormalities, most frequently apical dyskinesis with basal hyperkinesis, that are characteristically transient. Although emotional or physical stressors precipitate Takotsubo syndrome in most cases, a significant proportion presents without identifiable triggers, with a pronounced female predominance. Despite recovery of left ventricular function, Takotsubo syndrome may lead to serious complications akin to acute coronary syndromes. The pathophysiology remains incompletely understood, with catecholamine surge implicated in the genesis of myocardial injury, although direct causation remains debated. Diagnosis involves integrating clinical history, imaging modalities like echocardiography, and cardiac MRI. Psychiatric disorders, particularly anxiety and depression, are frequently associated with Takotsubo syndrome, suggesting a role of chronic stress in disease susceptibility. Management includes supportive care, with anticoagulation considered in cases of apical thrombus, alongside close monitoring for complications and recovery of left ventricular function. This article reviews the current understanding, challenges in diagnosis, and management strategies for Takotsubo syndrome.

The CD40-CD40L receptor ligand pair plays a fundamental role in the modulation of the innate as well as the adaptive immune response, regulating monocyte, T and B cell activation, and antibody isotype switching. Although the expression and function of the CD40-CD40L dyad is mainly attributed to the classical immune cells, the majority of CD40L is expressed by activated platelets, either in a membrane-bound form or shed as soluble molecules in the circulation. Platelet-derived CD40L is involved in the communication with different immune cell subpopulations and regulates their functions effectively. Thus, platelet CD40L contributes to the containment and clearance of bacterial and viral infections, and additionally guides leukocytes to sites of infection. However, platelet CD40L promotes inflammatory cellular responses also in a pathophysiological context. For example, in HIV infections, platelet CD40L is supportive of neuronal inflammation, damage, and finally HIV-related dementia. In sepsis, platelet CD40L can induce extensive endothelial and epithelial damage resulting in barrier dysfunction of the gut, whereby the translocation of microbiota into the circulation further aggravates the uncontrolled systemic inflammation. Nevertheless, a distinct platelet subpopulation expressing CD40L under septic conditions can attenuate systemic inflammation and reduce mortality in mice. This review focuses on recent findings in the field of platelet CD40L biology and its physiological and pathophysiological implications, and thereby highlights platelets as vital immune cells that are essential for a proper immune surveillance. In this context, platelet CD40L proves to be an interesting target for various inflammatory diseases. However, either an agonism or a blockade of CD40L needs to be well balanced since both the approaches can cause severe adverse events, ranging from hyperinflammation to immune deficiency. Thus, an interference in CD40L activities should be likely done in a context-dependent and timely restricted manner.

Intravenous direct thrombin inhibitors (DTIs) are used for thromboembolic disorders. This systematic review aims to characterize intravenous DTI agents, dosing, monitoring strategies (or use), bleeding, and mortality, in pediatric patients with acute venous thromboembolism (VTE) or heparin-induced thrombocytopenia with thrombosis (HITT). MEDLINE, Embase, and Cochrane's CENTRAL were searched from inception through July 2023. Case series, retrospective studies, and prospective studies providing per-patient or summary data for patients < 18 years of age with VTE or HITT treated with an intravenous DTI were included. Selection and data extraction were conducted independently by two reviewers. Sixteen studies (7 case reports, 1 case series, 5 retrospective studies, 3 prospective studies) with 85 patients were included. Target conditions included acute VTE in 54 (64%) and HITT in 31 (36%) patients. Bivalirudin, argatroban, and lepirudin were used in 52 (61%), 27 (32%), and 6 (7%) patients, respectively. Fifty-two (61%) patients received a bolus dose, and weighted mean infusion rates for bivalirudin, argatroban, and lepirudin were 0.2 mg/kg/hr, 1.2 mcg/kg/min, and 0.15 mg/kg/hr, respectively. The activated partial thromboplastin time was utilized for monitoring in 82 (96%) patients. Complete or partial thrombus resolution was reported in 53 (62%) patients, mortality in 6 (7%) patients, and bleeding complications in 14 (16%) patients. In this systematic review involving 85 pediatric patients treated with an intravenous DTI for acute VTE or HITT, bivalirudin was the most commonly utilized agent, with a rate of resolution over 60% despite a high acuity in the population studied. Prospective collaborative studies are warranted to establish optimal dosing and further characterize VTE and bleeding outcomes.

Antiphospholipid syndrome (APS) diagnosis hinges on identifying antiphospholipid antibodies (aPL). Currently, laboratory testing encompasses lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2-glycoprotein I antibodies (aβ2GPI) IgG or IgM, which are included in the APS classification criteria. All the assays needed to detect aPL antibodies have methodological concerns. LA testing remains challenging due to its complexity and susceptibility to interference from anticoagulant therapy. Solid phase assays for aCL and aβ2GPI exhibit discrepancies between different assays. Antibody profiles aid in identifying the patients at risk for thrombosis through integrated interpretation of all positive aPL tests. Antibodies targeting domain I of β2-glycoprotein and antiphosphatidylserine-prothrombin antibodies have been evaluated for their role in thrombotic APS but are not yet included in the APS criteria. Detecting these antibodies may help patients with incomplete antibody profiles and stratify the risk of APS patients. The added diagnostic value of other methodologies and measurements of other APS-associated antibodies are inconsistent. This manuscript describes laboratory parameters useful in the diagnosis of thrombotic APS and will concentrate on the laboratory aspects, clinical significance of assays, and interpretation of aPL results in the diagnosis of thrombotic APS.

The contact pathway of blood clotting has received intense interest in recent years as studies have linked it to thrombosis, inflammation, and innate immunity. Because the contact pathway plays little to no role in normal hemostasis, it has emerged as a potential target for safer thromboprotection, relative to currently approved antithrombotic drugs which all target the final common pathway of blood clotting. Research since the mid-2000s has identified polyphosphate, DNA, and RNA as important triggers of the contact pathway with roles in thrombosis, although these molecules also modulate blood clotting and inflammation via mechanisms other than the contact pathway of the clotting cascade. The most significant source of extracellular DNA in many disease settings is in the form of neutrophil extracellular traps (NETs), which have been shown to contribute to incidence and severity of thrombosis. This review summarizes known roles of extracellular polyphosphate and nucleic acids in thrombosis, with an emphasis on novel agents under current development that target the prothrombotic activities of polyphosphate and NETs.

Historically, heparin has had the longest historical use as an anticoagulant and continues this day to be the primary therapeutic option for preventing thrombosis and thromboembolism in critically ill hospitalized patients. Heparin is also used to treat sepsis and sepsis-associated disseminated intravascular coagulation (DIC) in various countries. However, the efficacy and safety of heparin for this indication remains controversial, as adequately powered randomized clinical studies have not demonstrated as yet a survival benefit in sepsis and sepsis-associated DIC, despite meta-analyses and propensity analyses reporting improved outcomes without increasing bleeding risk. Further, activated protein C and recombinant thrombomodulin showed greater improvements in outcomes compared with heparin, although these effects were inconclusive. In summary, further research is warranted, despite the ongoing clinical use of heparin for sepsis and sepsis-associated DIC. Based on Japanese guidelines, antithrombin or recombinant thrombomodulin may be a preferable choice if they are accessible.

Factor XII (FXII), the zymogen of the protease FXIIa, contributes to pathologic processes such as bradykinin-dependent angioedema and thrombosis through its capacity to convert the homologs prekallikrein and factor XI to the proteases plasma kallikrein and factor XIa. FXII activation and FXIIa activity are enhanced when the protein binds to a surface. Here, we review recent work on the structure and enzymology of FXII with an emphasis on how they relate to pathology. FXII is a homolog of pro-hepatocyte growth factor activator (pro-HGFA). We prepared a panel of FXII molecules in which individual domains were replaced with corresponding pro-HGFA domains and tested them in FXII activation and activity assays. When in fluid phase (not surface bound), FXII and prekallikrein undergo reciprocal activation. The FXII heavy chain restricts reciprocal activation, setting limits on the rate of this process. Pro-HGFA replacements for the FXII fibronectin type 2 or kringle domains markedly accelerate reciprocal activation, indicating disruption of the normal regulatory function of the heavy chain. Surface binding also enhances FXII activation and activity. This effect is lost if the FXII first epidermal growth factor (EGF1) domain is replaced with pro-HGFA EGF1. These results suggest that FXII circulates in blood in a "closed" form that is resistant to activation. Intramolecular interactions involving the fibronectin type 2 and kringle domains maintain the closed form. FXII binding to a surface through the EGF1 domain disrupts these interactions, resulting in an open conformation that facilitates FXII activation. These observations have implications for understanding FXII contributions to diseases such as hereditary angioedema and surface-triggered thrombosis, and for developing treatments for thrombo-inflammatory disorders.