scholarly journals Autoimmune Factor V Deficiency That Took 16 Years to Diagnose due to Pseudodeficiency of Multiple Coagulation Factors

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Takaaki Kato ◽  
Takaya Hanawa ◽  
Mea Asou ◽  
Tomohiko Asakawa ◽  
Hisashi Sakamaki ◽  
...  
Keyword(s):  
High Titer ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
International Normalized Ratio ◽  
University Hospital ◽  
Coagulation Cascade ◽  
Factor V ◽  
Normal Limits ◽  
Factor V Deficiency ◽  
The Right

A 70-year-old man presented to our hospital with intramuscular hemorrhage in the right thigh. He had exhibited a tendency to bleed for the last 16 years and had visited several medical institutions, but no diagnosis had been made. Since the risk of sudden bleeding was assumed to be high due to his age, we decided to examine him in our department. A coagulation abnormality with prothrombin time-international normalized ratio (PT-INR) of 4.5 and activated partial thromboplastin time (aPTT) of 99.6 seconds was observed, but the platelet count, fibrinogen, and PIVKAII were within normal limits. Coagulation activities of factor V, VII, VIII, IX, X, XI, XII, and XIII were all reduced. Anti-factor VIII and IX antibodies which were measured by the Bethesda method, lupus anti-coagulant (diluted Russell snake venom time method) and anti-cardiolipin antibody were also positive. The results of these tests were comparable to those undertaken 15 years ago when they were scrutinized at the university hospital. We suspected the presence of anti-factor V antibodies because there was a dissociation between the thrombotest values measured and those calculated from the PT-INR. Moreover, cross-mixing test showed an immediate inhibitor pattern. Subsequently, factor V antibodies were confirmed by the immunoblot method and the diagnosis of autoimmune factor V deficiency was made. When factor V, which is downstream of the coagulation cascade, is inhibited, coagulation test using the one-stage clotting method shows a pseudolow value. Therefore, extensive abnormalities of coagulation factor activity and inhibitor assay should be interpreted with caution, and the presence of a high titer of factor V inhibitor should be considered.

scholarly journals Cryo-EM structures of human coagulation factors V and Va

Blood ◽  
2021 ◽  
Author(s):  
Eliza A Ruben ◽  
Michael J Rau ◽  
James Fitzpatrick ◽  
Enrico Di Cera
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Proteolytic Processing ◽  
Coagulation Cascade ◽  
Factor V ◽  
Prothrombinase Complex ◽  
A2 Domain

Coagulation factor V is the precursor of factor Va that, together with factor Xa, Ca2+ and phospholipids, defines the prothrombinase complex and activates prothrombin in the penultimate step of the coagulation cascade. Here we present cryo-EM structures of human factors V and Va at atomic (3.3 Å) and near-atomic (4.4 Å) resolution, respectively. The structure of fV reveals the entire A1-A2-B-A3-C1-C2 assembly but with a surprisingly disordered B domain. The C1 and C2 domains provide a platform for interaction with phospholipid membranes and support the A1 and A3 domains, with the A2 domain sitting on top of them. The B domain is highly dynamic and visible only for short segments connecting to the A2 and A3 domains. The A2 domain reveals all sites of proteolytic processing by thrombin and activated protein C, a partially buried epitope for binding factor Xa and fully exposed epitopes for binding activated protein C and prothrombin. Removal of the B domain and activation to fVa exposes the sites of cleavage by activated protein C at R306 and R506 and produces increased disorder in the A1-A2-A3-C1-C2 assembly, especially in the C-terminal acidic portion of the A2 domain responsible for prothrombin binding. Ordering of this region and full exposure of the factor Xa epitope emerge as a necessary step for the assembly of the prothrombin-prothrombinase complex. These structures offer molecular context for the function of factors V and Va and pioneer the analysis of coagulation factors by cryo-EM.

scholarly journals High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies

2021 ◽  
Vol 22 (18) ◽  
pp. 9705
Author(s):  
Sara Bernal ◽  
Irene Pelaez ◽  
Laura Alias ◽  
Manel Baena ◽  
Juan A. De Pablo-Moreno ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Coagulation Disorder ◽  
Factor V ◽  
Factor V Deficiency ◽  
Advanced Therapies ◽  
Factor V Gene ◽  
V Gene

Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder.

The murine platelet and plasma factor V pools are biosynthetically distinct and sufficient for minimal hemostasis

Blood ◽  
2003 ◽  
Vol 102 (8) ◽  
pp. 2856-2861 ◽  
Author(s):  
Hongmin Sun ◽  
Tony L. Yang ◽  
Angela Yang ◽  
Xixi Wang ◽  
David Ginsburg
Keyword(s):  
Gene Expression ◽  
Bacterial Artificial Chromosome ◽  
Transgenic Mice ◽  
Coagulation Factor ◽  
Artificial Chromosome ◽  
Coagulation Cascade ◽  
Factor V ◽  
Wild Type ◽  
Plasma Factor ◽  
Coagulation Factor V

Abstract Coagulation factor V (FV) is a central regulator of the coagulation cascade. Circulating FV is found in plasma and within platelet α granules. The specific functions of these distinct FV pools are uncertain. We now report the generation of transgenic mice with FV gene expression restricted to either the liver or megakaryocyte/platelet lineage using bacterial artificial chromosome (BAC) constructs. Six of 6 independent albumin BAC transgenes rescue the neonatal lethal hemorrhage of FV deficiency. Rescued mice all exhibit liver-specific Fv expression at levels ranging from 6% to 46% of the endogenous Fv gene, with no detectable FV activity within the platelet pool. One of the 3 Pf4 BAC transgenes available for analysis also rescues the lethal FV null phenotype, with FV activity restricted to only the platelet pool (approximately 3% of the wild-type FV level). FV-null mice rescued by either the albumin or Pf4 BAC exhibit nearly normal tail bleeding times. These results demonstrate that Fv expression in either the platelet or plasma FV pool is sufficient for basal hemostasis. In addition, these findings indicate that the murine platelet and plasma FV pools are biosynthetically distinct, in contrast to a previous report demonstrating a plasma origin for platelet FV in humans.

scholarly journals Direct Determination of Coagulation Factor IIa and Plasmin Activities for Monitoring of Thrombotic State

2020 ◽  
Vol 5 (6) ◽  
pp. 1265-1276
Author(s):  
Junhua Zhang ◽  
Lihui Zou ◽  
Chengyang Liu ◽  
Chuanbao Li ◽  
Meng Wang ◽  
...  
Keyword(s):  
Direct Detection ◽  
Oral Anticoagulants ◽  
Direct Determination ◽  
Coagulation Factor ◽  
High Specificity ◽  
Coagulation Factors ◽  
Coagulation Cascade ◽  
Proteolytic Activation ◽  
Activated State

Abstract Background Current laboratory examinations for hypercoagulable diseases focus on the biomarker content of the activated coagulation cascade and fibrinolytic system. Direct detection of physiologically important protease activities in blood remains a challenge. This study aims to develop a general approach that enables the determination of activities of crucial coagulation factors and plasmin in blood. Methods This assay is based on the proteolytic activation of an engineered zymogen of l-phenylalanine oxidase (proPAO), for which the specific blood protease cleavage sites were engineered between the inhibitory and activity domains of proPAO. Specific cleavage of the recombinant proenzyme leads to the activation of proPAO, followed by oxidation and oxygenation of l-phenylalanine, resulting in an increase of chromogenic production when coupled with the Trinder reaction. Results We applied this method to determine the activities of both coagulation factor IIa and plasmin in their physiologically relevant basal state and fully activated state in sodium citrate–anticoagulated plasma respectively. Factor IIa and plasmin activities could be dynamically monitored in patients with thrombotic disease who were taking oral anticoagulants and used for assessing the hypercoagulable state in pregnant women. Conclusions The high specificity, sensitivity, and stability of this novel assay not only makes it useful for determining clinically important protease activities in human blood and diagnosing thrombotic diseases but also provides a new way to monitor the effectiveness and safety of anticoagulant drugs.

scholarly journals Profiling the mutational landscape of coagulation factor V deficiency

Haematologica ◽  
2019 ◽  
Vol 105 (4) ◽  
pp. e180-e185
Author(s):  
Elvezia Maria Paraboschi ◽  
Marzia Menegatti ◽  
Valeria Rimoldi ◽  
Munira Borhany ◽  
Magy Abdelwahab ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Factor V ◽  
Mutational Landscape ◽  
Factor V Deficiency ◽  
Coagulation Factor V

New Interactive Effects Involving Factor XIII Gene Polymorphisms in Venous Thrombotic Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2590-2590
Author(s):  
Maria C. Pintao ◽  
Dayse M. Lourenço ◽  
Francisco H.A. Maffei ◽  
Vania M. Morelli ◽  
Amelia G. Araujo ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Specific Activity ◽  
Interactive Effect ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Interactive Effects ◽  
Coagulation Cascade ◽  
Factor V ◽  
Thrombotic Risk ◽  
Increased Risk

Abstract Venous thrombosis (VT) is considered to be a multifactorial disorder in which several genetic and acquired risk factors interact dynamically. Coagulation factor XIII (FXIII) is an enzyme that participates in the final steps of the coagulation cascade. A number of gene variations have been described in both FXIII A and B subunits. FXIIIA Val34Leu, Tyr204Phe and Pro564Leu polymorphisms have been associated to increased specific activity of FXIII, and FXIIIA Val34Leu has been claimed to be protective against VT in several studies. In the FXIII B subunit, two common polymorphisms (His95Arg and G30899A) have been also reported, but its association with VT is uncertain. In addition, possible interactive effects between these polymorphisms and between these polymorphisms and the two most prevalent mutations associated with VT, factor V Leiden (FVL) and factor II (FII) G20210A mutations, have not been explored. In the present study, we determined the prevalence of the five above-mentioned FXIII polymorphisms in 418 consecutive patients with an objective diagnosis of VT and in 418 age-, gender- and race-matched controls in the BRATROS (Brazilian Thrombosis Study) case-control investigation. Genotyping for Val34Leu, Pro564Leu, His95Arg and G30899A was performed by PCR amplification followed by MseI, BstUI, NsiI and BspHI restriction digestion analysis, respectively. Genotyping for Tyr204Phe was performed by single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing of samples showing mobility shifts. Odds ratios (OR) as a measure of relative risks of VT, and 95% confidence intervals (CI95), were calculated. Stratified analyses were performed to search for interactions between the FXIII polymorphisms and between the FXIII polymorphisms, FVL and FII G20210A. Overall OR for VT linked to Val34Leu was 0,78 (CI95: 0,59–1,03); OR for heterozygotes (HT) was 0,85 (CI95: 0,64–1,13) and for homozygotes (HM) the OR was 0,33 (CI95: 0,15–0,71). Overall OR linked to G30899A was 1,06 (CI95: 0,81–1,39); OR for HT was 0,96 (CI95: 0,72–1,28) and for HM the OR was 1,58 (IC95: 1,00–2,49). No impacts over the risk of VT were observed, related to the other three polymorphisms investigated. When stratified analyses were performed to search for interactions, a trend towards increased risk of VT was detected when the Val34 allele was co-inherited with the Arg95 allele (OR 1,45; CI95: 0,97–2,18), and a trend towards decreased thrombotic risk was verified when the Leu34 and Leu564 alleles were co-inherited (OR 0,63; CI95: 0,40–1,00). Furthermore, increased risk for VT was observed when the mutant A30899 allele was co-inherited with FII G20210A, pointing to a notable interaction effect (OR 18,29; CI95: 2,41–138,87). The data confirm that homozygosity for FXIII Val34Leu is protective against the occurrence of VT in our population. In addition, the findings point to a previously unknown increased risk of VT related to homozygosity for FXIIIB G30899A of the order of 58%. Lastly, an impressive interactive effect (18-fold increased risk of VT) between FXIIIB G30899A and FII G20210A is reported for the first time. Taken together, the findings from the present investigation strengthen the clinical significance of FXIII in vascular thrombosis and reinforce the concept of VT as a multigenic disease.

scholarly journals Exosites expedite blood coagulation

2020 ◽  
Vol 295 (45) ◽  
pp. 15208-15209
Author(s):  
Maria Luiza Vilela Oliva ◽  
Ingrid Dreveny ◽  
Jonas Emsley
Keyword(s):  
Active Site ◽  
Serine Proteases ◽  
Critical Role ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation Cascade ◽  
Factor X ◽  
Inhibitor Development ◽  
Prothrombinase Complex ◽  
Factor X Activation

A careful balance between active-site and exosite contributions is critically important for the specificity of many proteases, but this balance is not yet defined for some of the serine proteases that serve as coagulation factors. Basavaraj and Krishnaswamy have closed an important gap in our knowledge of coagulation factor X activation by the intrinsic Xase complex by showing that exosite binding plays a critical role in this process, which they describe as a “dock and lock.” This finding not only significantly enhances our understanding of this step in the coagulation cascade and highlights parallels with the prothrombinase complex, but will also provide a novel rationale for inhibitor development in the future.

International Normalized Ratio Versus Plasma Levels of Coagulation Factors in Patients on Vitamin K Antagonist Therapy

2011 ◽  
Vol 135 (4) ◽  
pp. 490-494 ◽  
Author(s):  
Gene Gulati ◽  
Megan Hevelow ◽  
Melissa George ◽  
Eric Behling ◽  
Jamie Siegel
Keyword(s):  
Vitamin K ◽  
Warfarin Therapy ◽  
Clinical Laboratory ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
International Normalized Ratio ◽  
Activity Levels ◽  
Factor X ◽  
Life Threatening ◽  
Average Factor

Abstract Context.—The key question when managing patients on warfarin therapy who present with life-threatening bleeding is how to use the international normalized ratio (INR) to best direct corrective therapy. The corollary question for the clinical laboratory is at what level will the INR reflect a critical value that requires notifying the clinician. Objective.—To determine the levels of vitamin K–dependent factors over a range of INR values. Design.—Evaluation of the vitamin K–dependent coagulation factor levels on plasma remnants from patients in whom a prothrombin time and INR was ordered to monitor warfarin therapy. There were a total of 83 specimens evaluated with an INR range from 1.0 to 8.26. Results.—The mean activity levels of all 4 factors remained near or above 50% when the INR was less than 1.5. The average factor X level was 23% when the INR range was 1.6 to 2.5, but levels of factors II, VII, and IX did not drop below the hemostatic range until the INR was greater than 2.5. At an INR of 3.6 or more, the activity levels of all 4 factors were less than 30% in more than 90% of the specimens. Conclusion.—Levels of factors II, VII, IX, and X declined with increasing INR but not at the same rate and not to the same level at a given INR. However, most of the values were below the hemostatic value once the INR was 3.6 or more, the level that was also considered critical for physician notification.

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