A Review of Coagulation Abnormalities of Autoimmune Acquired Factor V Deficiency with a Focus on Japan

2021 ◽  
Author(s):  
Akitada Ichinose ◽  
Tsukasa Osaki ◽  
Masayoshi Souri
Keyword(s):  
Coagulation Factor ◽  
Nationwide Survey ◽  
Autoimmune Disorder ◽  
Antibody Detection ◽  
Extensive Literature ◽  
Factor V ◽  
Bleeding Tendency ◽  
Factor X ◽  
Timely Initiation ◽  
Fv Antibody

AbstractCoagulation factor V (or FV for the purpose of medical safety) is an essential cofactor of coagulation factor X in the common pathway of coagulation; severe FV deficiency leads to a bleeding tendency. Although both congenital and acquired FV deficiencies are widely recognized, FV deficiency also presents as an autoimmune disorder. A nationwide survey on autoimmune coagulation factor deficiencies (AiCFDs) conducted in Japan by our Japanese Collaborative Research Group identified 24 new patients with autoimmune FV deficiency (AiFVD) in the past 5 years. Furthermore, our extensive literature search confirmed that 177 AiFVD cases have been reported in previous articles published from Japan. Patients with AiFVD in Japan were predominantly men, with age similar to those with other AiCFDs. AiFVD was confirmed as a relatively mild type of bleeding diathesis, associated with lower mortality rate than that for AiFVD and other AiCFDs reported in previous studies. Patients with AiFVD had variable FV inhibitor titers and both neutralizing anti-FV autoantibodies and nonneutralizing counterparts. Although spontaneous resolution occurs in some patients, timely initiation of hemostatic and immunosuppressive therapies helps arrest the bleeding and eliminate anti-FV antibodies, resulting in a high cumulative recovery rate. Immunological anti-FV antibody detection is recommended to avoid missing AiFVD cases for the presence of nonneutralizing anti-FV autoantibodies. Further investigation is necessary to clarify the long-term prognosis and optimal management of AiFVD.

scholarly journals Autoimmune Coagulation Factor X Deficiency as a Rare Acquired Hemorrhagic Disorder: A Literature Review

2021 ◽  
Author(s):  
Akitada Ichinose ◽  
Tsukasa Osaki ◽  
Masayoshi Souri
Keyword(s):  
Coagulation Factor ◽  
Nationwide Survey ◽  
Autoimmune Disorder ◽  
Coagulation Cascade ◽  
Antibody Detection ◽  
Extensive Literature ◽  
Bleeding Tendency ◽  
Factor X ◽  
Number Of Patients ◽  
Immunoglobulin Light Chain Amyloidosis

Coagulation factor X (F10) amplifies the clotting reaction in the middle of the coagulation cascade; and thus, F10 deficiency leads to a bleeding tendency. Isolated acquired F10 deficiency is widely recognized in patients with immunoglobulin light-chain amyloidosis or plasma cell dyscrasias. However, its occurrence as an autoimmune disorder is extremely rare. The Japanese Collaborative Research Group has been conducting a nationwide survey on autoimmune coagulation factor deficiencies (AiCFDs); we recently identified three patients with autoimmune F10 deficiency (AiF10D). Furthermore, an extensive literature search was performed, confirming 26 AiF10D and 28 possible cases. Our study revealed that AiF10D patients were younger than patients with other AiCFDs; AiF10D patients included children and were predominantly male. AiF10D was confirmed as a severe type of bleeding diathesis, although its mortality rate was not high. As AiF10D patients showed only low F10 inhibitor titers, they were considered to have non-neutralizing anti-F10 autoantibodies rather than their neutralizing counterparts. Accordingly, immunological anti-F10 antibody detection is highly recommended. Hemostatic and immunosuppressive therapies may help arrest bleeding and eliminate anti-F10 antibodies, leading to a high recovery rate. However, further investigation is necessary to understand the basic characteristics and proper management of AiF10D owing to the limited number of patients.

scholarly journals RASopathies and hemostatic abnormalities: key role of platelet dysfunction

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Francesca Di Candia ◽  
Valeria Marchetti ◽  
Ferdinando Cirillo ◽  
Alessandro Di Minno ◽  
Carmen Rosano ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Screening Tests ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Factor V ◽  
Bleeding Tendency ◽  
Factor X ◽  
Platelet Response ◽  
Platelet Dysfunction ◽  
Clotting Factors

Abstract Background Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. Patients and methods Forty-nine individuals (PTPN11, n = 27; SOS1, n = 7; RIT1, n = 3; SPRED1, n = 1; LZTR1, N = 3; RAF1, n = 2; BRAF, n = 4; MEK1, n = 1; MEK2, n = 1), and 49 age- and sex-matched controls were enrolled. The “Paediatric Bleeding Questionnaire Scoring Key” was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. Results Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11, 3 in SOS1, 2 in RIT1, 1 in BRAF, and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p = 0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV, p = 0.001), FVII (p = 0.003), FX (p = 0.0008) and FXIII (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with factor V (p = 0.002), factor VII (p = 0.003), factor X (p = 0.002) and factor XIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma (p = 0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with factor V levels (p = 0.03). Conclusions Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

Characterization of Recombinant Human Coagulation Factor XFriuli

1996 ◽  
Vol 75 (02) ◽  
pp. 313-317 ◽  
Author(s):  
D J Kim ◽  
A Girolami ◽  
H L James
Keyword(s):  
Catalytic Domain ◽  
Coagulation Factor ◽  
Molecular Size ◽  
Binding Pocket ◽  
Site Directed Mutagenesis ◽  
Bleeding Tendency ◽  
Factor X ◽  
Amino Terminal ◽  
Normal Plasma ◽  
Plasma Factor

SummaryNaturally occurring plasma factor XFriuli (pFXFr) is marginally activated by both the extrinsic and intrinsic coagulation pathways and has impaired catalytic potential. These studies were initiated to obtain confirmation that this molecule is multi-functionally defective due to the substitution of Ser for Pro at position 343 in the catalytic domain. By the Nelson-Long site-directed mutagenesis procedure a construct of cDNA in pRc/CMV was derived for recombinant factor XFriuli (rFXFr) produced in human embryonic (293) kidney cells. The rFXFr was purified and shown to have a molecular size identical to that of normal plasma factor X (pFX) by gel electrophoretic, and amino-terminal sequencing revealed normal processing cleavages. Using recombinant normal plasma factor X (rFXN) as a reference, the post-translational y-carboxy-glutamic acid (Gla) and (β-hydroxy aspartic acid (β-OH-Asp) content of rFXFr was over 85% and close to 100%, respectively, of expected levels. The specific activities of rFXFr in activation and catalytic assays were the same as those of pFXFr. Molecular modeling suggested the involvement of a new H-bond between the side-chains of Ser-343 and Thr-318 as they occur in anti-parallel (3-pleated sheets near the substrate-binding pocket of pFXFr. These results support the conclusion that the observed mutation in pFXFr is responsible for its dysfunctional activation and catalytic potentials, and that it accounts for the moderate bleeding tendency in the homozygous individuals who possess this variant procoagulant.

scholarly journals The Thrombogram in Rare Inherited Coagulation Disorders: Its Relation to Clinical Bleeding

2002 ◽  
Vol 88 (10) ◽  
pp. 576-582 ◽  
Author(s):  
Raed Al Dieri ◽  
Flora Peyvandi ◽  
Elena Santagostino ◽  
Muriel Giansily ◽  
Pier Mannuccio Mannucci ◽  
...  
Keyword(s):  
Lag Time ◽  
Peak Height ◽  
Factor Vii ◽  
Clotting Factor ◽  
Severe Bleeding ◽  
Factor V ◽  
Bleeding Tendency ◽  
Factor X ◽  
Factor Xi ◽  
Factor Concentration

SummaryWe investigated the relation between clotting factor concentration, the parameters of the thrombin generation curve (the thrombogram) and the severity of clinically observed bleeding in patients with congenital deficiency of prothrombin (n = 21), factor V (n = 22), factor VII (n = 22), factor X (n = 10), factor XI (n = 7) and factor XII (n = 6). The parameters used were: area under the curve (endogenous thrombin potential, ETP), peak concentration of thrombin attained and lag time before manifest formation.Peak height and ETP varied linearly with the concentration of prothrombin. For the other factors these parameters hyperbolically approached to the 100% limit with increasing clotting factor concentration. Half normal ETP was seen at about the following concentrations: prothrombin (50%), factor V (1%), factor VII (2%), factor X (5%) and factor XI (1%). As a rule, the peak height was somewhat more sensitive to clotting factor decrease than the ETP was.In all the patients with severe bleeding symptoms the ETP was less than 20% of normal. Bleeding tendency was absent or mild in patients with an ETP of 30% or higher. This value (except for prothrombin) is already obtained at concentrations of clotting factor of 1%-2%, which corroborates the clinical observation that a severe bleeding tendency is only seen in severe clotting factor deficiencies (less than 1%). The one exception was a patient with factor VII deficiency and severe bleeding, who showed a normal ETP value, albeit with a decreased peak height and a prolonged lag-time.

scholarly journals Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4014-4020 ◽  
Author(s):  
Elisabetta Castoldi ◽  
José W. P. Govers-Riemslag ◽  
Mirko Pinotti ◽  
Debora Bindini ◽  
Guido Tans ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Clinical Phenotype ◽  
Activated Protein C ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Factor V ◽  
Factor X ◽  
Fv Leiden ◽  
Fvii Deficiency ◽  
Thrombin Formation

Abstract We investigated the role of thrombophilic mutations as possible modifiers of the clinical phenotype in severe factor VII (FVII) deficiency. Among 7 patients homozygous for a cross-reacting material-negative (CRM-) FVII defect (9726+5G>A, FVII Lazio), the only asymptomatic individual carried FV Leiden. Differential modulation of FVII levels by intragenic polymorphisms was excluded by a FVII to factor X (FX) gene haplotype analysis. The coagulation efficiency in the FV Leiden carrier and a noncarrier was evaluated by measuring FXa, FVa, and thrombin generation after extrinsic activation of plasma in the absence and presence of activated protein C (APC). In both patients coagulation factor activation was much slower and resulted in significantly lower amounts of FXa and thrombin than in a normal control. However, more FXa and thrombin were formed in the plasma of the patient carrying FV Leiden than in the noncarrier, especially in the presence of APC. These results were confirmed in FV-FVII doubly deficient plasma reconstituted with purified normal FV or FV Leiden. The difference in thrombin generation between plasmas reconstituted with normal FV or FV Leiden gradually decreased at increasing FVII concentration. We conclude that coinheritance of FV Leiden increases thrombin formation and can improve the clinical phenotype in patients with severe FVII deficiency. (Blood. 2003;102:4014-4020)

The Severity of Bleeding Tendency in 5 Patients with Factor V Deficiency Due to Distinct Kinds of Factor V Mutations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1764-1764
Author(s):  
Keiko Shinozawa ◽  
Kagehiro Amano ◽  
Takashi Suzuki ◽  
Hiroshi Inaba ◽  
Katsuyuki Fukutake
Keyword(s):  
Coagulation Factor ◽  
Normal Subjects ◽  
Japanese Patients ◽  
The Other ◽  
Hek293 Cells ◽  
Poor Correlation ◽  
Factor V ◽  
Bleeding Tendency ◽  
Wild Type ◽  
Mammalian Expression

Abstract Coagulation factor V (FV) deficiency is a rare autosomal recessive bleeding disorder. It is poor correlation between FV levels in plasma and the severity of bleeding tendency. In the present study, we identified 5 mutations in the FV gene (F5) in 5 unrelated Japanese patients with reduced plasma FV activities associated with inherited FV deficiency. Their bleeding tendencies varied in severity from asymptomatic to severe. We hypothesized that the severity of bleeding symptoms with severe FV deficiency is correlated with FV levels in platelets, and performed recombinant mutant proteins expression experiments and analyzed of platelet FV. The data concerning 5 patient’s FV levels in plasma and the bleeding symptoms are given in Table. The F5 mutations in 5 Japanese patients were identified by direct sequencing. One of the 5 patients was a compound heterozygote for FV mutations and carried a 5-base pair (bp) deletion in exon 22 (del.ACCCT) and V1813M. The other 4 patients were homozygous for a D68H, N468S, V1813M, and R2174L mutations, respectively. Four mutations except V1813M are newly identified mutations. These mutations were introduced independently by site-directed mutagenesis into a pMT2/FV mammalian expression plasmid containing the full-length FV cDNA, and the wild-type and mutant FV proteins were expressed in HEK293 cells. In the conditioned media, FV specific activities of the FV-D68H, FV-N468S, FV-V1813M, FV-R2174L, and 5bp del. mutants were an approximately 22%, 81%, 28%, 40%, and 19% of wild-type, respectively. On the other hand, analysis of platelet from patient by using RT-PCR showed that platelet F5 mRNA of FV-R2174L and FV-N468S was equal amount to that of normal subjects, although the amount of FV-V1813M platelet F5 mRNA was reduced. Platelet FV protein from patients was analyzed by western blotting and ELISA. Although the amount of platelet FV-R2174L protein was equal to that of normal platelets, platelet FV-V1813M protein was considerably reduced. In addition, the amount of FV-N468S protein in platelet was observed between that of normal subjects and FV-V1813M. These results indicate that the fact that sufficient amounts of FV are stored in platelet is required for local hemostasis. The results of FV-R2174L suggest that both functionality and amount of FV-R2174L in platelet is enough to cope with local bleeding, resulting very mild bleeding tendency. On the basis of present findings, we conclude that the severity of bleeding due to severe FV deficiency is correlated with not only plasma FV level, but also platelet FV. Five patient’s FV levels in plasma and the bleeding symptoms Patient No. Mutation FV activity (%) FV antigen (%) Bleeding symptoms 1 D68H 4 4 asymptomatic 2 N468S 3 3 asymptomatic 3 V1813M & 5-bp deletion <1 9 severe 4 V1813M <1 4 moderate 5 R2174L 1 5 very mild

Severe coagulation factor V deficiency caused by 2 novel frameshift mutations: 2952delT in exon 13 and 5493insG in exon 16 of factor 5 gene

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 702-705 ◽  
Author(s):  
Éva Ajzner ◽  
István Balogh ◽  
Teréz Szabó ◽  
Anikó Marosi ◽  
Gizella Haramura ◽  
...  
Keyword(s):  
Light Chain ◽  
Weight Ratio ◽  
Coagulation Factor ◽  
Male Infant ◽  
Specific Protein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Severe Bleeding ◽  
Factor V ◽  
Bleeding Tendency ◽  
Protein Factor

Abstract A male infant with severe bleeding tendency had undetectable factor V activity. Sequence analysis of the proband's DNA revealed one base deletion in exon 13 (2952delT) and one base insertion in exon 16 (5493insG) in heterozygous form. Both mutations introduced a frameshift and a premature stop at codons 930 and 1776, respectively. The proband's father and mother were heterozygous for 2952delT and for 5493insG, respectively. Both mutations would result in the synthesis of truncated proteins lacking complete light chain or its C-terminal part. In the patient's plasma, no factor V light chain was detected by enzyme-linked immunosorbent assay. The N-terminal portion of factor V containing the heavy chain, and the connecting B domain was severely reduced but detectable (1.7%). A small amount of truncated factor V–specific protein with a molecular weight ratio of 236 kd could be immunoprecipitated from the plasma and detected by Western blotting. This protein, factor VDebrecen, corresponds to the translated product of exon 16 mutant allele.

scholarly journals RASopathies and Hemostatic Abnormalities: Key Role of Platelet Dysfunction

2021 ◽  
Author(s):  
Di Candia Francesca ◽  
Marchetti Valeria ◽  
Cirillo Ferdinando ◽  
Di Minno Alessandro ◽  
Rosano Carmen ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Screening Tests ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Bleeding Tendency ◽  
Factor X ◽  
Platelet Response ◽  
Platelet Dysfunction ◽  
Clotting Factors ◽  
Laboratory Findings

Abstract Background: Bleeding anomalies occur in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. Patients and methods: Forty-nine individuals (PTPN11, n=27; SOS1, n=7; RIT1, n=3; SPRED1, n=1; LZTR1, N=3; RAF1, n=2; BRAF, n=4; MEK1, n=1; MEK2, n=1), and 49 age- and sex-matched controls were enrolled in the study. The “Paediatric Bleeding Questionnaire Scoring Key” was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, prothrombin time, and partial thromboplastin time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. Results: Regardless the gene involved, pathological bleeding scores were recorded in 14 (28.5%) patients. Among these, 7 were mutated in PTPN11 (26% of total cases with PTPN11 mutations), 3 in SOS1 (43%), 2 in RIT1 (67%), 1 in BRAF (25%), and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p=0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV) (p = 0.001), factor VII (FVII) (p = 0.003), factor X (FX) (p = 0.0008) and factor XIII (FXIII) (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with FV (p = 0.002), FVII (p = 0.003), FX (p = 0.002) and FXIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with occurrence of hematoma (p=0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with FV levels (p = 0.03).Conclusions: Patients with RASopaties and a bleeding tendency exhibit multiple coagulation-related laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

Pathways of Blood Clotting Initiation by Cancer Cells

1979 ◽  
Author(s):  
N. Semeraro
Keyword(s):  
Cancer Cells ◽  
Blood Clotting ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Ehrlich Carcinoma ◽  
Factor V ◽  
Factor X ◽  
Experimental Tumors ◽  
Activate Coagulation Factor ◽  
Available Information

Although available information indicates that cancer cells may activate blood coagulation, the precise mechanism remains still uncertain. A procoagulant with characteristics of tissue thromboplastin has been found in human benign and malignant tissues and in some experimental tumors. On the other hand it has been reported that extracts from malignant tissues directly activate coagulation factor X, due to the presence of a serine protease. We have investigated the procoagulscitic fluid. Cells from Lewis lung carcinoma (primary and metastasis), Ehrlich carcinoma ascites and JW sarcoma ascites were able to shorten markedly the recalcification time of normal, factor VIII and factor VII-deficient, not of factor X-deficient human plasma. The same cells did generate thrombin when mixed with a source of prothrombin and factor X, absorbed bovine serum (as a source of factor V), phospholipid and CaCl2.Cells from Sarcoma ISO ascites were completely inactive in both test systems. It was a included that cells from some experimental tumors, similarly to normal platelets, possess the capacity to directly activate coagulation factor X. This suggests the existence of an alternative “cellular” pathway in blood clotting initiation distinct from both the intrin sic and extrinsic mechanisms.(Supported by Italian CNR and NIH, NCI, USA).

Sign in / Sign up

Export Citation Format

Share Document