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Factor V deficiency is a congenital coagulation disorder characterized by the absence or malfunction of factor V (FV). The purpose of this study was to develop a viable FV-deficient mouse model using CRISPR/Cas9 technology. A viable pathological model of the disease was not available to develop new therapies. A previous in silico study was performed to select a mutation causing a mild disease phenotype in humans (Thr1898Met missense). Such mutation was replicated in mice by CRISPR-mediated homology directed repair. Following crossing, homozygous individuals were subjected to coagulometry assays, including FV levels, prothrombin time (PT), and activated partial thromboplastin time (aPTT). The in silico study suggested that the mutation destabilizes FV structure of both mouse and human variants, putatively producing a mild phenotype of the disease in mice. Mendelian inheritance was observed in the offspring. No spontaneous signs of blood clotting disturbances, premature deaths or gestational dysfunctions were observed. FV levels in homozygous animals were 24.5% ± 5.1; 39.7 sec ± 2.8; PT was 61.8% ± 6.3; 23.4 sec ± 1.6 (INR = 1.47 ± 0.12); and aPTT was 46.9 sec ± 3.2. A viable FV-deficient mouse model was generated by introducing a missense mutation in FV. The model exhibits a mild phenotype of the disease, akin to that observed in humans.

Factor V is an essential protein in the blood clotting process and plays a central role in secondary hemostasis. Its deficiency causes a rare inherited disorder characterized by episodes of severe bleeding, some of which can be life-threatening. Although previous studies have established that factor V is essential for normal embryonic development, its specific contribution to vascular maturation remains incompletely understood, factor V is believed to contribute to blood vessel stabilization and regulate angiogenesis through its interaction with thrombin. In a recent study, a CRISPR-engineered mouse model intended to produced a mild factor V deficiency disease, unexpectedly produced a frameshift mutation in the A3 domain, resulting in a truncated protein. Factor V levels in healthy embryonic mouse tissues were assessed to investigate its role at different developmental stages. The mutation markedly impaired viability, as homozygous mice exhibited a lethal phenotype with severe bleeding and perinatal death, along with impaired coagulation function. Histopathological and immunohistochemical analyses indicated a link between factor V deficiency, thrombin and α-smooth muscle actin, potentially affecting proangiogenic signaling and embryonic vascular formation. Factor V gene expression increased during late embryogenesis, underscoring its importance in vascular development and maturation. Overall, these findings are consistent with a role for factor V in stabilizing embryonic blood vessels and modulating thrombin-dependent angiogenesis, and add further detail on the developmental impact of its deficiency and the pathogenesis of congenital bleeding disorders.

Background Acquired factor V deficiency (AFVD) is a rare hemorrhagic disorder caused by autoantibodies against coagulation factor V. Clinical manifestations vary widely, ranging from asymptomatic cases to severe hemorrhage or even thrombosis, and diagnosis is often challenging due to its rarity and nonspecific presentation. Reported triggers include bovine thrombin, antibiotics, surgery, autoimmune diseases, infections, and malignancy, although up to 20% of cases are idiopathic. We report a case of AFVD in an elderly hemodialysis patient, in whom corticosteroid therapy was effective but ultimately complicated by fatal gastrointestinal bleeding. Case presentation An 87-year-old woman on hemodialysis for diabetic nephropathy was admitted with acute cholecystitis and treated with ceftriaxone. On day 16, she developed bleeding from a gastrostomy site with markedly prolonged prothrombin time (69.3 s) and activated partial thromboplastin time (260.4 s). Cross-mixing studies showed inhibitor patterns, and factor V activity was reduced to 1.3%, with an inhibitor titer of 33.3 Bethesda units/mL, confirming AFVD. Despite no bleeding from vascular access sites, she developed progressive anemia and gingival bleeding. Intravenous prednisolone (40 mg/day) was initiated, resulting in normalization of coagulation parameters and recovery of factor V activity to 111.7% within 30 days. However, on day 57, she developed massive melena. Endoscopy revealed hemorrhagic duodenal ulcers with exposed vessels, requiring endoscopic hemostasis. Recurrent gastrointestinal bleeding occurred on day 61, and she died of hemorrhagic shock. Conclusions This case illustrates the diagnostic process and therapeutic challenges of AFVD in a hemodialysis patient. Corticosteroid therapy was effective in eradicating the inhibitor and restoring factor V activity, but fatal gastrointestinal bleeding occurred as a severe treatment-related complication. Clinicians should be aware of AFVD as a rare but important cause of acquired coagulopathy, and careful monitoring for corticosteroid-associated adverse effects is crucial, especially in elderly and critically ill individuals.

Statins are powerful lipid-lowering drugs that inhibit cholesterol biosynthesis via downregulation of hydroxymethylglutaryl coenzyme-A reductase, which are largely used in patients with or at risk of cardiovascular disease. Available data on thromboembolic disease include primary and secondary prevention as well as bleeding and mortality rates in statin users during anticoagulation for VTE. Experimental studies indicate that statins alter blood clotting at various levels. Statins produce anticoagulant effects via downregulation of tissue factor expression and enhanced endothelial thrombomodulin expression resulting in reduced thrombin generation. Statins impair fibrinogen cleavage and reduce thrombin generation. A reduction of factor V and factor XIII activation has been observed in patients treated with statins. It is postulated that the mechanisms involved are downregulation of factor V and activated factor V, modulation of the protein C pathway and alteration of the tissue factor pathway inhibitor. Clinical and experimental studies have shown that statins exert antiplatelet effects through early and delayed inhibition of platelet activation, adhesion and aggregation. It has been postulated that statin-induced anticoagulant effects can explain, at least partially, a reduction in primary and secondary VTE and death. Evidence supporting the use of statins for prevention of arterial thrombosis-related cardiovascular events is robust, but their role in VTE remains to be further elucidated. In this review, we present biological evidence and experimental data supporting the ability of statins to directly interfere with the clotting system.

• Nitric oxide (NO) is known to modulate the action of several phytohormones. This includes the gaseous hormone ethylene, but the molecular mechanisms underlying the effect of NO on ethylene biosynthesis are unclear. • Here, we observed a decrease in endogenous NO abundance during apple (Malus domestica) fruit development and exogenous treatment of apple fruit with a NO donor suppressed ethylene production, suggesting that NO is a ripening suppressor. • Expression of the transcription factor MdERF5 was activated by NO donor treatment. NO induced the nucleocytoplasmic shuttling of MdERF5 by modulating its interaction with the protein phosphatase, MdPP2C57. MdPP2C57-induced dephosphorylation of MdERF5 at Ser260 is sufficient to promote nuclear export of MdERF5. As a consequence of this export, MdERF5 proteins in the cytoplasm interacted with and suppressed the activity of MdACO1, an enzyme that converts 1-aminocyclopropane-1-carboxylic acid (ACC) to ethylene. The NO-activated MdERF5 was observed to increase in abundance in the nucleus and bind to the promoter of the ACC synthase gene MdACS1 and directly suppress its transcription. • Together, these results suggest that NO-activated nucleocytoplasmic MdERF5 suppresses the action of ethylene biosynthetic genes, thereby suppressing ethylene biosynthesis and limiting fruit ripening.

Congenital factor V (FV) deficiency is a rare autosomal recessive bleeding disorder caused by pathogenic variants in F5 gene and characterized by heterogeneous clinical manifestations. The aim of this study was to define the mutational spectrum of F5 in Russian patients with congenital FV deficiency. We analyzed 16 unrelated patients with different disease severity and 9 relatives from five families. All functionally relevant regions of F5 were examined by Sanger sequencing. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions and duplications. Whole-genome sequencing and functional cDNA analysis were performed in selected cases. This study represents the first description of the F5 mutational spectrum in a Russian cohort. We identified 12 novel variants and demonstrated the functional effect of two previously unreported variants located outside canonical splice-site dinucleotides, leading to aberrant splicing. Notably, the proportion of variants undetectable by routine diagnostic approaches was higher than that reported in other populations. No clear genotype–phenotype correlation was observed. Despite the limited sample size, our findings expand current knowledge of the molecular basis of congenital FV deficiency and may improve genetic diagnostics in Russia.

Human gene F5, encoding coagulation factor V, was previously reported to be highly polymorphic. Apart from FV Leiden, several other rare variants have been detected in clinical practice and associated with thrombotic events, especially in cases when patient’s phenotype and FV Leiden genotype were not in agreement. In this study, the prevalence of 17 rare F5 variants has been studied on a sample of 130 healthy adult individuals from the general Bosnian-Herzegovinian population. DNA was isolated from buccal swab samples, while genotyping was performed using MALDI-TOF MS method. The results have shown that Asp2194Gly and Met2120Thr are polymorphic in the study population with minor allele frequencies of 0.077 and 0.073, respectively. Additionally, these two variants were mutually exclusive with FV Leiden and none of them was positively associated with participants’ family history of cardiovascular or cerebrovascular diseases. While the obtained results are in agreement with previously reported data for the general Caucasian populations, it is worth noting that only two rare F5 variants were detected in the study population, albeit at considerable frequencies. Still, scientific information on rare F5 variants is rather scarce and further studies aiming to assess functional importance of these variants, as well as their role as prothrombotic factors are necessary.

Proteostasis, i.e., the homeostasis of proteins, responsible for ensuring protein turnover, is regulated by proteases, which also participate in the etiopathogenesis of multiple conditions. The magic of proteases is such that, in blood coagulation, one same molecule, such as coagulation factor V, for example, can perform both a procoagulant and an anticoagulant function as a result of the activity of proteases. However, this magic has an insidious side to it, as it may also prevent the completion of the clinical value chain of factor V deficiency. This value chain encompasses the discovery of knowledge, the transfer of this knowledge, and its translation to clinical practice. In the case of rare and ultra-rare diseases like factor V deficiency, this value chain has not been completed as the knowledge acquisition phase has dragged out over time, holding up the transfer of knowledge to clinical practice. The reason for this is related to the small number of patients afflicted with these conditions. As a result, new indications must be found to make the therapies cost-effective. In the case of factor V, significant research efforts have been directed at developing a recombinant factor V capable of resisting the action of the proteases capable of inactivating this factor. This is where bioethics and health equity considerations come into the equation.

The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.

We present what appears to be the first documented case worldwide of bilateral avascular necrosis (AVN) of the femoral heads in a young adult with the rare co-occurrence of congenital factor V (FV) deficiency and heterozygous FV Leiden mutation.