Rare bleeding disorders (RBDs) represent 3 to 5% of congenital bleeding disorders and are primarily inherited in an autosomal recessive manner, with increased prevalence in consanguineous populations. Clinically, RBDs can be accompanied by mild to severe bleeding episodes, often assessed using bleeding assessment tools (BATs) such as the International Society on Thrombosis and Hemostasis (ISTH)-BAT. However, the correlation between bleeding severity and coagulation factor activity levels remains inconsistent. This systematic review investigates this relationship to enhance understanding and improve management strategies for patients with RBD. This review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered with the International Prospective Register for Systematic Reviews (PROSPERO) (CRD42024504537). Using the PICO (Population, Intervention, Comparator, and Outcomes) framework, the study focused on RBD patients to explore the correlation between coagulation factor activity levels and bleeding severity. A comprehensive search was conducted across PubMed, Scopus, and Web of Science until April 1, 2024, with data extracted on bleeding severity, phenotype, and coagulation factor activity levels. The analysis highlights complex and often inconsistent relationships between coagulation factor levels and the severity of bleeding. In cases of fibrinogen deficiency, three out of four studies ( = 73 of 111 cases, 66%) demonstrated a moderate to strong correlation between fibrinogen levels and bleeding severity. In prothrombin deficiency, one of two studies ( = 16 of 29 cases, 55%) found a strong correlation between FII levels and bleeding severity. Four of six studies ( = 106 of 139 cases, 76%) in FV deficiency found a weak or no correlation between factor activity and bleeding severity. In combined FV and FVIII deficiency, two of three studies ( = 26 of 60 cases, 43%) found a significant correlation between factor activity and bleeding severity. In FVII deficiency, four (of nine) studies with a study population of 325 patients (65%) found a weak correlation between factor activity and severity of bleeding. Almost all studies (five of six studies,  = 114 of 118 patients, 97%) in FX deficiency revealed a strong correlation between FX levels and bleeding severity. In FXI deficiency, most studies (five of seven studies,  = 254 patients, 93%) found a weak or no correlation between factor activity and bleeding severity or symptoms. For FXIII deficiency, there was a moderate to strong correlation between FXIII activity and bleeding severity in all three studies ( = 61 patients). In conclusion, despite current controversies, this review highlights a moderate or strong correlation between factor activity and bleeding severity in fibrinogen, FX, and FXIII deficiencies, but no correlation or weak correlation for FV, FVII, and FXI deficiencies. Further prospective studies with standardized BATs on a large number of patients are needed to better understand these relationships and optimize patient management.

The prevalence of factor XI (FXI) deficiency is 1 per 10 to 20,000 in the general population, much higher than that reported in most texts. The prevalence is higher in Ashkenazi Jews where it is about 1:20. Clinically, FXI deficiency presents as a mild bleeding disorder mostly associated with posttraumatic or postsurgical hemorrhages or unexplained minor bleeding. It is often discovered due to incidental finding of a prolonged activated partial thromboplastin time (aPTT) on routine laboratory screening. FXI deficiency is an autosomal recessive bleeding disorder with many causative gene defects. Diagnosis is based on FXI activity, antigen levels, and molecular diagnostics. As FXI levels do not correlate with bleeding symptoms, identification of pathogenic genetic variants may be a more accurate predictor of bleeding risk and therefore aid in the clinical management of the patient. Two variants in the gene account for most cases found in the Jewish and Arab populations. Patients with FXI deficiency can develop inhibitors to FXI although spontaneously acquired inhibitors are extremely rare. We will discuss laboratory and molecular assays used to diagnose FXI deficiency as well as interferences that can complicate diagnosis including new anticoagulants and acquired FXI inhibitors.

Deficiencies in coagulation factors I (FI), FII, FV, combined FV and FVIII (CF5F8) and vitamin K-dependent coagulation factors FVII, FX, FXI, and FXIII have been referred to as rare bleeding disorders (RBDs), rare coagulation factor deficiencies (RCFDs), or recessively inherited coagulation disorders. Fibrinogen was most likely the first member of this group to be identified, with reports of its discovery spanning from 1859 to 1966. If not, then the first coagulation factor to be identified was prothrombin in 1894, and the last coagulation factor to be found was FX in 1956, about 60 years later. The first patient to be diagnosed with an RBD was a 9-year-old boy with afibrinogenemia in 1920 and the vitamin K-dependent coagulation factors deficiency was the most recent RBD in this group to be identified in a 3-month-old child in 1966. The initial therapeutic option for nearly all patients with RBDs was whole blood transfusion; this was replaced in 1941 by fresh frozen plasma (FFP), and then in later years by cryoprecipitate and coagulation factor concentrates. Fibrinogen concentrate was the first coagulation factor concentrate produced in 1956. Coagulation factor concentrate is now available for FI, FVII, FX, FXI, and FXIII; however, FFP and/or platelet transfusion are the only treatments available for FV deficiency. The only recombinant concentrates available for RBDs are for FVII and FXIII, which date from 1988 and the 2000s, respectively. Even though the clinical presentations, diagnosis, and management of lesser-known bleeding disorders have improved significantly in recent decades, more studies are needed to reveal the hidden aspects of these disorders in order to overcome diagnostic and therapeutic challenges and ultimately improve the quality of life for those who are affected.

The human body has the ability to adapt to changing circumstances, and mobilizes various biological systems in order to do so. When exposed to stressful conditions, the endocrine, nervous, and immune systems come together to aid in maintaining homeostasis; however, during periods of chronic stress, these systems can become maladaptive and lead to long-term detrimental health outcomes. Amongst the lingering effects associated with chronic stress exposure, increasingly, studies are identifying a link to adverse pregnancy and neonatal outcomes. This review explores what has been uncovered in the field to date, and examines the effects of stress on fertility and gestation. Establishing additional factors which put women at risk for adverse pregnancy outcomes can aid in identifying a vulnerable population who could benefit from early stress-reducing interventions.

Atherosclerosis is a chronic, multifactorial inflammatory disorder of large and medium-size arteries, which is the leading cause of cardiovascular mortality and morbidity worldwide. Although platelets in cardiovascular disease have mainly been studied for their crucial role in the thrombotic event triggered by atherosclerotic plaque rupture, over the last two decades it has become clear that platelets participate also in the development of atherosclerosis, owing to their ability to interact with the damaged arterial wall and with leukocytes. Platelets participate in all phases of atherogenesis, from the initial functional damage to endothelial cells to plaque unstabilization. Platelets deposit at atherosclerosis predilection sites before the appearance of manifest lesions to the endothelium and contribute to induce endothelial dysfunction, thus supporting leukocyte adhesion to the vessel wall. In particular, platelets release matrix metalloproteinases, which interact with protease-activated receptor 1 on endothelial cells triggering adhesion molecule expression. Moreover, P-selectin and glycoprotein Ibα expressed on the surface of vessel wall-adhering platelets bind PSGL-1 and β2 integrins on leukocytes, favoring their arrest and transendothelial migration. Platelet-leukocyte interactions promote the formation of radical oxygen species which are strongly involved in the lipid peroxidation associated with atherosclerosis. Platelets themselves actively migrate through the endothelium toward the plaque core where they release chemokines that modify the microenvironment by modulating the function of other inflammatory cells, such as macrophages. While current antiplatelet agents seem unable to prevent the contribution of platelets to atherogenesis, the inhibition of platelet secretion, of the release of MMPs, and of some specific pathways of platelet adhesion to the vessel wall may represent promising future strategies for the prevention of atheroprogression.

Platelet-derived growth factor (PDGF) is a critical cytokine with substantial regulatory effects on hematopoiesis. Recent research highlights the essential role of PDGF in the modulation of hematopoietic stem/progenitor cells (HSPCs), megakaryocytes/platelets, and thrombopoietin (TPO) synthesis within the bone marrow microenvironment. PDGF directly stimulates the proliferation and differentiation of HSPCs while also inhibiting apoptosis. In addition, PDGF indirectly enhances the production of other growth factors, including granulocyte-macrophage colony-stimulating factors. Further, PDGF regulates TPO production and influences the bone marrow milieu, thus impacting hematopoiesis and platelet formation. Mechanistically, PDGF binds to its receptor, PDGF receptor (PDGFR), thus activating the PDGF/PDGFR signaling pathway. This pathway subsequently activates phosphoinositide 3-kinase/protein kinase B, leading to the activation of downstream cytokines, including c-Fos and NF-E2, while inhibiting caspase-3 activation. Collectively, these actions have prodifferentiation and antiapoptotic effects on megakaryocytes, thereby regulating platelet production. This review provides a comprehensive analysis of the regulatory role of the PDGF/PDGFR axis in hematopoiesis, with a particular focus on platelet production, by summarizing all studies on PDGF/PDGFR from our group and globally.

Historically, the aim of treatment for hemophilia, the congenital X-linked hemorrhagic disorder due to deficiencies of coagulation Factor (F) VIII (hemophilia A) or FIX (hemophilia B), has been the replacement through factor concentrates, whose regular administration (i.e., prophylaxis) has been shown to be highly effective in preventing bleeding complications and it is currently considered the gold standard of hemophilia treatment. However, continuous technological progress (i.e., plasma-derived factor concentrates, recombinant standard and extended half-life [EHL] products) has allowed clinicians operating at hemophilia treatment centers to individualize the management of persons with hemophilia, improving outcomes, adherence to therapy, and their quality of life. The achievement of normal hemostasis, the final goal that now seems possible with new-generation EHL products, non-replacement and gene therapies, will translate into normalization of life for persons with hemophilia, also addressing health equity (i.e., rendering them indistinguishable from their healthy peers). The evolution of hemophilia treatment and, in parallel, of therapeutic targets in the management of hemophilia patients over the last decades will be critically discussed in this narrative review.

Factor XIII-A (FXIII-A) deficiency is an ultra-rare bleeding disorder characterized by high rates of morbidity and mortality, primarily resulting from intracranial hemorrhage, umbilical cord bleeding, and miscarriage, whereas patients with severe FXIII-B deficiency present with a milder phenotype. Although the estimated incidence of severe FXIII-A deficiency is one per 2 million, a high prevalence ranging from 0.8 to 3.5% has been observed for heterozygous FXIII-A deficiency. Unlike most bleeding disorders, individuals with heterozygous FXIII-A deficiency, particularly women, are more likely to experience hemorrhagic complications during hemostatic challenges. About 200 Mutations have been observed in and genes, with most being missense mutations, while large deletions are the rarest. There is no correlation between genotype and phenotype, but a moderate to strong correlation between factor activity and clinical severity in FXIII-A deficiency difficult. Primary prophylaxis is mandatory for all patients with severe FXIII-A deficiency, while those with heterozygous deficiency are generally asymptomatic and may require on-demand therapy during hemostatic challenges, most commonly in women. On the other hand, patients with severe FXIII-B deficiency may only require on-demand therapy, while heterozygotes are generally asymptomatic. Although there are general recommended therapeutic regimens for prophylaxis or on-demand therapy in different situations, personalized pharmacokinetic-based replacement therapy represents the optimal approach that can optimize intervention efficacy. In such an approach, several factors may affect the effectiveness of treatment and determine the dose and type of intervention, including the classification of FXIII deficiency, residual plasma levels of FXIII, clinical situation requiring intervention, age, weight, and also gender.

Non-factor replacement therapies (NFTs) have been developed to address the limitations of conventional replacement therapies, aiming to improve hemostasis and provide enhanced protection against bleeding episodes and long-term joint damage for patients both with and without inhibitors. Factor VIII (FVIII)-mimetic agents, such as emicizumab, have transformed the management of hemophilia A with inhibitors, offering a lower treatment burden and an effective alternative for those without inhibitors as well. Rebalancing agents, including anti-tissular factor pathway inhibitor agents (concizumab and marstacimab) and serpin inhibitors like fitusiran, have shown promising efficacy for patients with hemophilia B with inhibitors and other hemophilia subtypes. Administered subcutaneously, NFTs generate stable thrombin levels and feature a long half-life, which can shift severe hemophilia toward a milder phenotype. These therapies are effective regardless of inhibitor status and hold potential for application in other bleeding disorders. Evaluating the potential thrombotic risk after implementing mitigation measures, along with the development of anti-drug antibodies (ADAs), remain critical areas for further analysis. NFTs pose additional challenges due to their complex mechanism of action and the absence of a standardized laboratory assessment method. Unresolved issues include optimal management strategies for major surgeries and tailored approaches for safe use in older populations. This review highlights the progress and future potential of NFTs in treating persons with hemophilia.

Vitamin K-dependent coagulation factors deficiency (VKCFD) is a rare autosomal recessive genetic disease characterized by impaired levels of multiple coagulation factors (II, VII, IX, and X) and natural anticoagulants (proteins C and S). VKCFD is part of familial multiple coagulation factor deficiencies, reporting overall 50 affected families thus far. Disease manifestations are quite heterogeneous, bleeding symptoms may vary, and even, although generally mild, some patients may succumb to fatal outcomes. VKCFD diagnosis may be delayed because the disease phenotype simulates the most frequently acquired deficiencies of vitamin K. First-line coagulation assays, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are both prolonged; mixing test typically normalizes the clotting times; and vitamin K-dependent coagulation factors will be variably decreased. Molecularly, VKCFD is associated with mutations in () or complex subunit 1 () genes. Vitamin K is involved not only in the biosynthesis of coagulation proteins but also in bone metabolism and cell proliferation. Therapeutic options are based on vitamin K supplementation, coagulation factors (prothrombin complex), and fresh frozen plasma, in case of severe bleeding episodes. Two case studies here illustrate the diagnostic challenges of VKCFD: case 1 depicts a woman with a history of bleeding episodes, diagnosed, only in her third decade of life with inherited homozygous gene mutation. Case 2 shows a man with an acquired vitamin K deficiency caused by Crohn's disease. Better understanding of and mutations aids in prognosis and treatment planning, with emerging insights suggesting potential limitations in the effectiveness of vitamin K supplementation in certain mutations.

The mainstay of treatment for persons with hemophilia A (PwHA) with severe bleeding phenotype is prophylaxis. The pharmacokinetic (PK) profile of native factor VIII (FVIII) imposes the need for rather frequent intravenous injections to ensure effective prophylaxis, but this represents a relevant treatment burden and is associated with suboptimal adherence to treatment. In this light, the advent of extended half-life (EHL) FVIII molecules has improved prophylaxis feasibility and outcomes by favoring treatment individualization and tailoring protection according to specific clinical and nonclinical needs. Different technologies have been used to enhance FVIII PK properties including Fc-fusion and conjugation with polyethylene glycol. Data from clinical development programs for such molecules, together with growing real-world experience, have shown numerous benefits related to the use of EHL FVIII in PwHA. Recently a new class of ultra-long-acting EHL FVIII has been developed to further improve protection against bleeding episodes and achieve the ambitious goal of providing PwHA with hemostatic protection in the nonhemophilia range over longer time periods, hence ensuring very low bleeding rates and improving joint health and quality of life. In this review, the achievements and perspectives of replacement therapies for PwHA are summarized and discussed.

Venous thromboembolism (VTE) after hospital discharge poses a serious health risk. Assessments of patient characteristics, prophylaxis, treatment, outcomes, and over time changes lack consistency. Data on 16,901 hospitalized patients in the Registro Informatizado Enfermedad TromboEmbolica registry (2003-2022) were analyzed to evaluate trends in baseline characteristics, prophylaxis, treatments, and 90-day outcomes among medical (6,218) and surgical (10,683) patient cohorts. Multivariable logistic regression was used to assess the risks of the composite of fatal pulmonary embolism (PE) or recurrent VTE and major bleeding. The proportion of patients who presented with PE increased among medical (from 54 to 72%) and surgical patients (from 55 to 58%). Prophylaxis use increased in medical patients (from 53 to 71%), while decreasing in surgical patients (from 67 to 58%). Notably, the 90-day composite of fatal PE or recurrent VTE decreased in medical (from 3.9 to 1.8%) and surgical patients (from 2.9 to 1.2%;  < 0.001 for both). Conversely, major bleeding increased (3.1 to 4.5%) in medical patients ( = 0.008), with no change in surgical patients (from 2.5 to 2.4%). Risk-adjusted analysis showed a yearly decrease in the risk for the composite outcome (subhazard ratio [sHR]: 0.95; 95% confidence interval [CI]: 0.93-0.98) in medical and surgical patients and an increase in the risk for major bleeding in medical patients only (sHR: 1.04; 95% CI: 1.01-1.07). Results were consistent after excluding coronavirus disease 2019 patients. Over 20 years, the composite of fatal PE or recurrent VTE within 90 days had significantly decreased in VTE patients after hospitalization for medical or surgical care. Medical patients, however, exhibited an increase in major bleeding.

D-dimer assessment has several established roles in venous thromboembolism (VTE) and disseminated intravascular coagulation diagnosis, and recently the risk stratification of coronavirus disease 2019 (COVID-19). D-dimer assays are neither standardized nor harmonized, use varying methodologies, and use different reporting units, all resulting in a lack of interchangeability and generalizability of assays. Using large multiyear datasets from an international laboratory quality assurance program, we assessed (1) common D-dimer assays in use worldwide, (2) differences in analytical performance between different methods, and (3) interlaboratory variability between positive samples. External proficiency testing results from laboratories participating in the External Quality Control for Assays and Tests (ECAT) Foundation were analyzed from 2017 to 2023. Annually, between 578 and 690 laboratories participated in the D-dimer sample surveys with response rates ranging from 88 to 97%. The three most common assays in use in 2023 were the Siemens Innovance D-dimer (42%), the IL HemosIL D-dimer HS 500 (20%), and the Diagnostica Stago (Stago) Liatest D-dimer Plus (10%)-all these are automated, quantitative, latex immunoassays expressed in fibrinogen equivalent units (FEU). The highest interlaboratory variability was observed around the typical VTE exclusion threshold of 0.5 mg/L FEU. Lower interlaboratory variability was observed at values above 0.8 mg/L FEU. Our study provides recent, international performance data on currently used D-dimer assays and describes the significant variability between assays and across D-dimer concentrations. We demonstrate that assays are not interchangeable and that using them interchangeably has the potential to result in clinically important errors. There is an urgent need to educate users about these issues and to work towards harmonizing D-dimer units and reporting.

C1-inhibitor deficiency-associated hereditary angioedema (C1INH-HAE) is a rare congenital swelling disorder caused by mutations in the gene. Despite evidence of a systemic procoagulant state in C1INH-HAE, dogma held that this disorder was not associated with thrombotic pathologies. Recent population scale epidemiological evidence has directly challenged this, with C1INH-HAE being associated with a significantly increased risk of venous thromboembolism (VTE). This review considers the growing body of evidence supporting associations between HAE and both a systemic procoagulant state and an increased risk of VTE. In the setting of C1INH-HAE, the relationship between the observed procoagulant and thrombotic phenotypes is a prime example of "where there's smoke, there's fire." This review also discusses the impact of C1INH-HAE disease modifying therapies on coagulation and VTE. Further, the utility of preclinical mouse models of C1-inhibitor deficiency is considered.

ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also called von Willebrand factor (VWF) cleaving protease, acts as a moderator of VWF activity. ADAMTS13 cleaves VWF multimers, thereby reducing VWF activity in blood. When ADAMTS13 is absent (e.g., in patients with TTP [thrombotic thrombocytopenia purpura]), accumulation of VWF in plasma can occur, particularly as "ultra-large" VWF multimers, with this leading to adverse outcomes such as thrombosis. Relative ADAMTS13 deficiencies also occur in several other conditions, including secondary thrombotic microangiopathies (TMA), cancer, and with severe infections such as in COVID-19 (coronavirus disease 2019). These situations might therefore be accompanied with relative loss of ADAMTS13, thereby potentially also leading to pathological VWF accumulation, with this then generating a prothrombotic milieu, thus contributing to enhance the risk of thrombosis. Laboratory testing for ADAMTS13 can aid in the diagnosis of such disorders (i.e., TTP, TMA), and help guide their management, with testing now accomplished using various assays. As most presentations of TTP reflect an acquired condition due to anti-ADAMTS13 antibodies, there may also be a need to test for these, as this will also influence clinical management. We herein provide an overview of TTP, note other conditions in which low levels of ADAMTS13 may be present, and then detail laboratory testing for both ADAMTS13 and associated inhibitors.