Characterization of a novel autosomal dominant bleeding disorder in a large kindred from east Texas

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1549-1554 ◽  
Author(s):  
Shao-Qing Kuang ◽  
Sumera Hasham ◽  
Martin D. Phillips ◽  
David Wolf ◽  
Ying Wan ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Genetic Defect ◽  
Coagulation Factors ◽  
Polymorphic Marker ◽  
Bleeding Disorder ◽  
Coagulation Cascade ◽  
Factor V ◽  
Heparin Binding ◽  
East Texas ◽  
Coding Region

A large east Texas family with autosomal dominant inheritance of a novel bleeding disorder has been identified. The disorder is characterized clinically by easy bruising, life-threatening bleeding with trauma or surgery, and menorrhagia in affected women. Laboratory studies demonstrated prolongation of the prothrombin time and activated partial thromboplastin time in affected individuals. Paradoxically, assays of known coagulation factors are all within normal limits. To determine the molecular basis of this disease, a candidate gene linkage analysis in this kindred was done. Initially it was hypothesized that the cause of the disease in this family could be an antithrombin III (AT3) mutation that resulted in a constitutively active AT3 in the absence of heparin binding. Linkage studies using DNA from the family and an intragenic polymorphic marker within the AT3 gene showed that the disease mapped to this locus. The coding region and intron/exon junctions of AT3were sequenced using the proband's DNA, but this analysis failed to identify a mutation. Additional family members were recruited for the study, and 16 polymorphic markers around the AT3 gene were analyzed. Using 2 recombinants, the critical interval for the defective gene was narrowed to approximately 1.5 Mb, centromeric toAT3. The factor V (FV) gene was mapped into the disease interval and sequenced; there were no mutations found. Elucidation of the genetic defect causing the bleeding disorder in this family may reveal a novel protein involved in the coagulation cascade.

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 Studies of a Second Family With the Quebec Platelet Disorder: Evidence That the Degradation of the α-Granule Membrane and Its Soluble Contents Are Not Secondary to a Defect in Targeting Proteins to α-Granules

Blood ◽  
1997 ◽  
Vol 89 (4) ◽  
pp. 1243-1253 ◽  
Author(s):  
Catherine P.M. Hayward ◽  
Elisabeth M. Cramer ◽  
William H. Kane ◽  
Shilun Zheng ◽  
Madeleine Bouchard ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Autosomal Dominant ◽  
Degradation Products ◽  
Bleeding Disorder ◽  
Factor V ◽  
Platelet Counts ◽  
Normal Platelet ◽  
Platelet Disorder ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract We recently described a Quebec family with an autosomal dominant bleeding disorder characterized by mildly reduced-low normal platelet counts, an epinephrine aggregation defect, multimerin deficiency, and proteolytic degradation of several, soluble α-granular proteins. Similar clinical features led us to investigate a second family with an unexplained, autosomal dominant bleeding disorder. The affected individuals had reduced to normal platelet counts, absent platelet aggregation with epinephrine, and multimerin deficiency. Their platelet α-granular proteins factor V, thrombospondin, von Willebrand factor, fibrinogen, fibronectin, osteonectin, and P-selectin were proteolyzed and comigrated with the degradation products found in patients from the other family. However, their platelet albumin, IgG, external membrane glycoproteins, CD63 (a lysosomal and dense granular protein), calpain, and plasma von Willebrand factor were normal, indicating restriction in the proteins proteolyzed. Electron microscopy studies indicated preserved α-granular ultrastructure, despite degradation of soluble and membrane α-granular proteins. Immunoelectron microscopy studies of the patients' platelets indicated that fibrinogen, von Willebrand factor, P-selectin, multimerin, and factor V were within α-granules, with normal to reduced labeling for these proteins. Pathologic proteolysis of α-granular contents, rather than a defect in targeting proteins to α-granules, may be the cause of the protein degradation in the Quebec platelet disorder.

scholarly journals A novel mutation in the F5 gene (factor V Amsterdam) associated with bleeding independent of factor V procoagulant function

Blood ◽  
2015 ◽  
Vol 125 (11) ◽  
pp. 1822-1825 ◽  
Author(s):  
Marisa L. R. Cunha ◽  
Kamran Bakhtiari ◽  
Jorge Peter ◽  
J. Arnoud Marquart ◽  
Joost C. M. Meijers ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Bleeding Disorder ◽  
Factor V ◽  
East Texas ◽  
Gain Of Function ◽  
Whole Exome ◽  
Key Points

Key Points A novel gain-of-function mutation in factor V leading to increased levels of TFPI and bleeding was identified by whole exome sequencing. Factor V Amsterdam (F5 C2588G) resembles the mutation (F5 A2350G) leading to East Texas bleeding disorder.

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.

Antithrombin-mediated Inhibition of Factor Vlla-Tissue Factor Complex by the Synthetic Pentasaccharide Representing the Heparin Binding Site to Antithrombin

1996 ◽  
Vol 76 (01) ◽  
pp. 005-008 ◽  
Author(s):  
Jean Claude Lormeau ◽  
Jean Pascal Herault ◽  
Jean Marc Herbert
Keyword(s):  
Binding Site ◽  
Tissue Factor ◽  
Residual Activity ◽  
Coagulation Factors ◽  
Heparin Binding ◽  
Experimental Conditions ◽  
First Order ◽  
Heparin Binding Site ◽  
Coagulant Activity

SummaryWe examined the effect of the synthetic pentasaccharide representing the minimal binding site of heparin to antithrombin on the antithrombin-mediated inactivation of factor Vila bound to tissue factor. This effect was compared to the effect of unfractionated heparin. Using purified recombinant human coagulation factors and either a clotting or an amidolytic assay for the determination of the residual activity of factor Vila, we showed that the pentasaccharide was an efficient antithrombin-dependent inhibitor of the coagulant activity of tissue factor-factor Vila complex. In our experimental conditions, assuming a mean MW of 14,000 for heparin, the molar pseudo-first order rate constants for ATIII-mediated FVIIa inhibition by ATIII-binding heparin and by the synthetic pentasaccharide were found to be similar with respective values of 104,000 ± 10,500 min-1 and 112,000 ± 12,000 min-1 (mean ± s.e.m., n = 3)

Immunologic Assessment of Patients Treated with Bovine Fibrin as a Hemostatic Agent

1996 ◽  
Vol 76 (06) ◽  
pp. 0925-0931 ◽  
Author(s):  
John F Carroll ◽  
Keith A Moskowitz ◽  
Niloo M Edwards ◽  
Thomas J Hickey ◽  
Eric A Rose ◽  
...  
Keyword(s):  
Coagulation Factors ◽  
Allergic Reactions ◽  
Factor V ◽  
Normal Range ◽  
Serum Samples ◽  
Human Fibrinogen ◽  
Bovine Thrombin ◽  
Thrombotic Complications ◽  
The Mean ◽  
Clinically Significant

SummaryTwenty-one cardiothoracic surgical patients have been treated with fibrin as a topical hemostatic/sealing agent, prepared from bovine fibrinogen clotted with bovine thrombin. Serum samples have been collected before treatment with fibrin and postoperatively between 1 and 9 days, 3 and 12 weeks, and 6 and 8 months. The titers of anti-bovine fibrinogen antibodies, measured by ELISA specific for immunoglobulins IgG or IgM, increased to maximal values after about 8 or 6 weeks, respectively. After 8 months, IgG titers were on average 20-fold lower than the mean maximal value, while IgM titers returned to the normal range. IgG was the predominant anti-bovine fibrinogen immunoglobulin as documented by ELISA, affinity chromatography and electrophoresis. Anti-bovine fibrinogen antibodies present in patients reacted readily with bovine fibrinogen, but did not cross-react with human fibrinogen as measured by ELISA or by immunoelectrophoresis. A significant amount of antibodies against bovine thrombin and factor V has been found, many cross-reacting with the human counterparts. No hemorrhagic or thrombotic complications, or clinically significant allergic reactions, occurred in any patient, in spite of antibody presence against some bovine and human coagulation factors. The treatment of patients with bovine fibrin, without induction of immunologic response against human fibrinogen, appeared to be an effective topical hemostatic/sealing measure.

The Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

1993 ◽  
Vol 69 (02) ◽  
pp. 173-176 ◽  
Author(s):  
Anna M Randi ◽  
Elisabetta Sacchi ◽  
Gian Carlo Castaman ◽  
Francesco Rodeghiero ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Autosomal Dominant ◽  
Genetic Defect ◽  
Von Willebrand Disease ◽  
Type I ◽  
Bleeding Tendency ◽  
Factor Gene ◽  
Low Levels ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

Changes Occurring During Coagulation in Glass. I. Normal Human Blood

1960 ◽  
Vol 4 (01) ◽  
pp. 001-016
Author(s):  
Jessica H. Lewis ◽  
Paul Didisheim ◽  
John H. Ferguson ◽  
Kenichi Hattori
Keyword(s):  
Coagulation Factors ◽  
Factor Ix ◽  
Factor Vii ◽  
Sodium Oxalate ◽  
Factor V ◽  
Rapid Rise ◽  
Rapid Fall ◽  
Glass Tubes ◽  
Normal Human ◽  
The Individual

SummaryNormal whole blood was allowed to stand in glass tubes at 37° C, and the clotting process stopped at various intervals by the addition of sodium oxalate. During the first 15 minutes a marked acceleration of clotting activity was found. Study of the individual coagulation factors showed the following changes: a sustained and rapid fall in platelet count, a sustained and rapid rise in PTC (factor IX), a steady fall in fibrinogen, a more gradual fall in AHF (factor VIII), a rapid rise and subsequent fall in proaccelerin (factor V) activity, a somewhat lesser and slower rise and fall in proconvertin (factor VII) activity, and a slow fall in prothrombin concentration. No changes were noted in Hageman factor or PTA activities.

Coagulation Findings in Rats with Experimental Hypersplenism and Their Changes after Splenectomy and after Administration of Adrenaline

1970 ◽  
Vol 23 (03) ◽  
pp. 593-600
Author(s):  
P Pudlák ◽  
I Farská ◽  
V Brabec ◽  
V Pospíšilová
Keyword(s):  
Factor Viii ◽  
Normal Control ◽  
Normal Values ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Factor V ◽  
Thrombin Time ◽  
Factor Ii ◽  
Recalcification Time

Summary1. The following coagulation changes were found in rats with experimental hypersplenism: a mild prolongation of the recalcification time, shortened times in Quick’s test, a lowered activity in plasma thrombin time and shortened times in the partial thromboplastin test. Concentrations of factor II, V, VII (+X), VIII and X did not differ from those of normal control rats.2. The administration of adrenaline to hypersplenic rats induced the correction of the partial thromboplastin test, Quick’s test and plasma thrombin time to normal values. Concentrations of coagulation factors were not significantly changed. An increase was found in factor V.3. Splenectomy performed in hypersplenic rats was followed by a shortened recalcification time, a prolongation of the partial thromboplastin test and of the test with partial thromboplastin and kaolin. A prolongation was also observed in Quick’s test. Complete correction of plasma thrombin time was not observed. The concentration of factor VII increased.4. The administration of adrenaline to splenectomized rats with experimental hypersplenism did not induce any significant changes with the exception of a corrected plasma thrombin time and a decreased concentration of factor VIII.5. A different reaction of factor VIII to adrenaline in normal and hypersplenic rats is pointed out.

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