scholarly journals Hemostasis Studies in Patients with Colon Cancer

1977 ◽  
Author(s):  
S.J. Scialla ◽  
D.B. Kimball
Keyword(s):  
Colon Cancer ◽  
Platelet Aggregation ◽  
Factor Viii ◽  
Coagulation Factor ◽  
Factor Analyses ◽  
Fibrin Monomer ◽  
Coagulant Activity ◽  
Spontaneous Platelet Aggregation ◽  
Extent Of Disease ◽  
Normal Controls

Coagulation and platelet function studies were evaluated in eighteen patients with colon cancer (all clinical stages) prior to treatment with chemotherapy. All patients were asymptomatic from bleeding or thrombosis and were not taking aspirin. The tests included general coagulation screening, coagulation factor analyses, platelet aggregation, fibrin split product concentration and a serial dilution protamine sulfate test for the presence of fibrin monomer. Average values compared to normal controls showed an elevated fibrinogen 400.5 mg.% (normal 300.0 mg.%), shorter activated partial thromboplastin time 29.4 seconds (normal 36.0), increased factor VIII coagulant activity 127-2% (normal 100%), and elevated fibrin split products 28.8 ug/ml.(normal less than l6 ug/ml.). Seven patients showed the presence of fibrin monomer. Eight patients showed enhanced aggregation reacting at or below 0.16 micromolar epinephrine. Six patients in the study showed more advanced cancer (five requiring intrahepatic artery infusion for extensive liver metastasis). Of this subgroup four patients demonstrated fibrin monomer and three patients showed spontaneous platelet aggregation. In this group, the fibrinogen was 484.22 mg.%, fibrin split products were 28.8 ug/ml., and factor VIII was 176%. A state of hypercoagulation with signs of a chronic process of intravascular coagulation was demonstrated in a group of colon cancer patients which corresponded to their extent of disease.

scholarly journals The role of the spleen in regulating the plasma levels of factor VIII-- von Willebrand's factor after DDAVP

Blood ◽  
1982 ◽  
Vol 60 (6) ◽  
pp. 1402-1406 ◽  
Author(s):  
VV Garcia ◽  
R Coppola ◽  
PM Mannucci
Keyword(s):  
Factor Viii ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
Storage Site ◽  
Inactive Form ◽  
Coagulant Activity ◽  
High Concentrations ◽  
Von Willebrand’S Factor ◽  
Normal Controls

Abstract Organ transplantation and perfusion studied indicate that the spleen plays an important role in the regulation of plasma levels of factor VIII-von Willebrand's factor (FVIII-vWF). To better understand the mechanisms that regulate the FVIII-vWF increases after infusion of 1- deamino-8-D-arginine vasopressin (DDAVP), we have measured factor VIII coagulant activity (FVIII:C) and antigen (FVIII:CAg) and von Willebrand's factor antigen (vWF:Ag) and ristocetin cofactor (vWF:RCof) in 9 asplenic subjects with normal baseline concentrations, in 7 asplenic subjects with high concentrations, and in 14 normal controls with intact spleens. In “normal” aasplenics, all the FVIII-vWF-related measurements increased significantly over baseline values, indicating that responsiveness to DDAVP is not abolished by splenectomy. The maximal vWF:Ag and vWF:RCof responses were no different from those of normal controls, suggesting that DDAVP releases vWF from storage sites other than the spleen. The FVIII:C response was significantly lower than in normal controls, but FVIII:CAg did not differ, making FVIII:CAg higher than FVIII:CAg in “normal” asplenics. These findings suggest that the spleen, rather than being a storage site for FVIII, is the organ in which a partially inactive form of FVIII acquires full coagulant activity. In “high” asplenics, all the FVIII-vWF-related measurements increased less than in “normal” splenics, indicating that long-term elevations of plasma concentrations of FVIII-vWF are accompanied by decreased release from those storage pool(s) mobilized by DDAVP.

Characterisation of an antibody specific for coagulation factor VIII that enhances factor VIII activity

2010 ◽  
Vol 103 (01) ◽  
pp. 94-102 ◽  
Author(s):  
Masahiro Takeyama ◽  
Keiji Nogami ◽  
Tomoko Matsumoto ◽  
Tetsuhiro Soeda ◽  
Tsukasa Suzuki ◽  
...  
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Neutralising Antibodies ◽  
Equal Degree ◽  
Fviii Activity ◽  
Coagulant Activity ◽  
The Common ◽  
Inhibitory Antibodies ◽  
A2 Domain ◽  
First Time

SummaryMany reports have identified factor (F)VIII inhibitory antibodies with epitopes located in all subunits of the FVIII molecule. Antibodies that promote FVIII activity do not appear to have been reported. We characterised, for the first time, a unique anti-FVIII monoclonal antibody, mAb216, that enhanced FVIII coagulant activity. The mAb216 shortened the activated partial thromboplastin time and specifically increased FVIII activity by ~1.5-fold dose-dependently. FXa generation and thrombin generation were similarly increased by ~1.4- and ~2.5-fold, respectively. An A2 epitope, not overlapping the common A2 epitope, was identified and the antibody was shown to enhance thrombin (and FXa)-catalysed activation of FVIII by modestly accelerating cleavage at Arg372. The presence of mAb216 mediated an ~1.5-fold decrease in Km for the FVIII-thrombin interaction. Enhanced FVIII activity was evident to an equal degree, even the presence of anti-FVIII neutralising antibodies with epitopes in each subunit. In addition, mAb216 depressed the rates of heat-denatured loss of FVIII activity and FVIIIa decay by 2 to ~2.5-fold. We have developed an anti-A2, FVIII mAb216 that augmented procoagulant activity. This enhancing effect could be attributed to an increase in thrombin-induced activation of FVIII, mediated by cleavage at Arg372 and a tighter interaction of thrombin with the A2 domain. The findings may cast new light on new principles for improving the treatment of haemophilia A patients.

Abnormal Ristocetin-Aggregation of Platelets in Uraemia and on Haemodialysis Therapy

1979 ◽  
Author(s):  
H. F. Woods ◽  
J. Turney ◽  
M. J. Weston
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Bleeding Time ◽  
Dialysis Patients ◽  
Normal Platelet ◽  
Crossover Studies ◽  
Coagulant Activity ◽  
Aggregation Of Platelets ◽  
Ristocetin Cofactor ◽  
Membrane Defect

Impaired platelet aggregation to ADP and collagen is recognised in uraemia and the loss of normal platelet function contributes to the prolonged capillary bleeding time observed in uraemia. in von Willebrand’s disease prolongation of capillary bleeding time is associated with impaired platelet aggregation to ristocetin because of a relative or absolute deficiency of the Factor VIII-Ristocetin Cofactor. We have studied platelet aggregation to ristocetin and Factor VIII coagulant activity (CA) and related antigen (RA) in 14 uraemic and 28 dialysed patients. Ristocetin aggregation (delta-0.D/min) was significantly less in uraemia (50 ± 21: m ± S.D) and in dialysis patients (38 ± 18) than in controls (78 ± 20). Factor VIII CA and RA were significantly higher in uraemic and dialysed patients than in controls.In crossover studies plasma from uraemic patients either enhanced or did not change ristocetin aggregation of normal platelets but plasma from dialysed patients impaired ristocetin aggregation of normal platelets. Plasma from dialysed patients was not contaminated by heparin. Thus in uraemia impaired platelet aggregation to ristocetin is unlikely to be due to a Factor VIII deficiency and may be due to a membrane defect as in Bernard-Soulier disease. in dialysed patients’ plasma there appears to be an additional circulating inhibitor of platelet-ristocetin interaction.

Abnormal Ristocetin-Aggregation of Platelets in Uraemia and on Haemodialysis Therapy

1979 ◽  
Author(s):  
H.F. Woods ◽  
J. Turney ◽  
M.J. Weston
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Bleeding Time ◽  
Dialysis Patients ◽  
Normal Platelet ◽  
Crossover Studies ◽  
Coagulant Activity ◽  
Aggregation Of Platelets ◽  
Ristocetin Cofactor ◽  
Membrane Defect

Impaired platelet aggregation to ADP and collagen is recognised in uraemia and the loss of normal platelet function contributes to the prolonged capillary bleeding time observed in uraemia. In von Willebrand’s disease prolongation of capillary bleeding time is associated with impaired platelet aggregation to ristocetin because of a relative or absolute deficiency of the Factor VIII-Ristocetin Cofactor. We have studied platelet aggregation to ristocetin and Factor VIII coagulant activity (CA) and related antigen (RA) in 14 uraemic and 28 dialysed patients. Ristocetin aggregation (delta-0.D/min) was significantly less in uraemia (50 ± 21: m ± S.D) and in dialysis patients (38 ± 18) than in controls (78 + 20). Factor VIII CA and RA were significantly higher in uraemic and dialysed patients than in controls.In crossover studies plasma from uraemic patients either enhanced or did not change ristocetin aggregation of normal platelets but plasma from dialysed patients impaired ristocetin aggregation of normal platelets. Plasma from dialysed patients was not contaminated by heparin. Thus in uraemia impaired platelet aggregation to ristocetin is unlikely to be due to a Factor VIII deficiency and may be due to a membrane defect as in Bernard-Soulier disease. In dialysed patients’ plasma there appears to be an additional circulating inhibitor of platelet-ristocetin interaction.

THE FUNCTIONAL DOMAINS OF COAGULATION FACTOR VIII

1987 ◽  
Author(s):  
Steven Rosenberg ◽  
Karin Hartog ◽  
Ole Nordfand ◽  
Mirella Ezban ◽  
Rae Lyn Burke
Keyword(s):  
Factor Viii ◽  
Heavy Chain ◽  
Coagulation Factor ◽  
Site Directed Mutagenesis ◽  
Expression Vectors ◽  
Functional Domains ◽  
Proteolytic Activation ◽  
Amino Terminal ◽  
Thrombin Cleavage ◽  
Coagulant Activity

The functional domains of Factor VIII have been investigated using site-directed mutagenesis to probe the effect of thrombin cleavage on pro-cofactor/cofactor activity. We have previously shown that clotting activity is obtained upon coexpression of the amino terminal (92 kDa) heavy chain and carboxyl terminal (80 kDa) light chain proteolytic cleavage products as individual, secreted proteins without the909 amino acid central region (Burke et.al., J. Biol. Chem. 261, 12574, 1986). In the present work the thrombin cleavage sites in the heavy and light chains previously characterized by others (D. Eaton et.al., Biochemistry 25, 505, 1986) have been modified to remove these sites and the mutagenized gene reassembled into separate expression vectors for the two chains. Coexpression of wild type and mutant proteins in COS-7 cells has been characterized by coagulant activity, immunological assays specific for each of the two chains, and radioimmuno-precipitations. Alteration of the thrombin cleavage site in the heavy chain (Arg-372→ΔArg-372) leads to loss of coagulant activity, whereas another mutant Arg-372→Lys-372 shows 20-fold reduced activity. Radioimmunoprecipitations and RIA data show that this is not a reflection of reduced synthesis or increased degradation of the mutant polypeptides. These results suggest that Arg-372 is required for the efficient folding, assembly, or proteolytic activation of Factor VIII.

Study of a Caucasian Family with von Willebrand’s Disease in Association with Vascular Telangiectasia and Hemoglobinopathy

1979 ◽  
Author(s):  
W. Hanna ◽  
C. McCarroll ◽  
J. Chen ◽  
T. McDonald ◽  
D. Lin ◽  
...  
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Factor Viii ◽  
Bleeding Time ◽  
Family Members ◽  
Inherited Disorders ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Normal Platelet ◽  
Coagulant Activity

This family carries multihematological inherited disorders; namely, von Wille-brand’s, vascular telangiectasia and hemoglobinopathy. Family members were studied by quantifying the following: Factor VIII pro-coagulant activity, Factor VIII related antigen, Factor VIII inhibitors, platelet adhesion, platelet aggregation (with ristocetin, collagen and ADP), bleeding time, platelet count, partial thromboplastin time, prothrombin time, hemoglobin electrophoresis, hemoglobin finger-printing, sickling preparation and the presence of telangiectasia.The affected members of this family with von Willebrand’s express their disease in a variable tendency to bleeding from almost clinically asymptomatic cases to cases with severe bleeding tendency.One member of this family had to have a hysterectomy at the age of 20 to control the abnormal uterine bleeding after conservative treatment failed. All affected members with von Willebrand’s disease had a normal platelet count, prolonged bleeding time, decreased Factor VIII pro-coagulant activity and related antigen, negative aggregation using the ristocetin co-factor for von Willebrand’s, defective platelet adhesiveness to glass beads, and normal platelet aggregation to collagen and ADP. Some members have vascular telangiectasia in the mucous membranes. An incidental finding was the presence of an abnormal hemoglobin S in some family members.Supported in part by the Cumberland Chapter of the National Hemophilia Foundation.

Platelet Aggregation Related to age in Diabetes Mellitus

1979 ◽  
Author(s):  
C. Lecrubier ◽  
P.Y. Scarabin ◽  
F. Grauso ◽  
H. Samama
Keyword(s):  
Diabetes Mellitus ◽  
Clinical Trial ◽  
Platelet Aggregation ◽  
Significant Relationship ◽  
Clinical Characteristics ◽  
Controlled Clinical Trial ◽  
Diabetic Patients ◽  
Background Retinopathy ◽  
Spontaneous Platelet Aggregation ◽  
Normal Controls

The relation between age and platelet sensitivity to various aggregating agents has been little explored until now. Previous studies have essentially concerned normal controls.Platelet aggregation induced by ADP and collagen was studied in 174 diabetic patients before entering a controlled clinical trial.The clinical characteristics have been precisely defined. The degree of retinal abnormality was assessed by fundus angiofluorography in every patient. Most patients had background retinopathy ; the remainder were normal. All results were computer analysed. The only significant relationship observed was between platelet sensitivity to ADP which increases in relation regularly to age in both insulin and non insulin treated diabetic patient with or without background retinopathy.Spontaneous platelet aggregation was observed in 13 subjects and was not correlated to the existence of a neuropathy or any other clinical characteristics.

Functional mapping of the A2 domain from human factor VIII

2012 ◽  
Vol 107 (02) ◽  
pp. 315-327 ◽  
Author(s):  
Didier Saboulard ◽  
Jean-Luc Pellequer ◽  
Jean-Luc Plantier ◽  
Claude Négrier ◽  
Marc Delcourt
Keyword(s):  
Amino Acids ◽  
Factor Viii ◽  
Human Factor ◽  
Coagulation Factor ◽  
Factor X ◽  
Structural Element ◽  
Human Factor Viii ◽  
Coagulant Activity ◽  
Factor X Activation ◽  
A2 Domain

SummaryCoagulation factor VIII (FVIII) is a multidomain glycoprotein in which the FVIII A2 domain is a key structural element. We aimed at identifying residues within FVIII A2 domain that are crucial for the maintenance of the cofactor function. A high number (n=206) of mutants were generated by substituting original residues with alanine. The mutants were expressed in COS-1 cells and their antigen levels and procoagulant activities were measured. The residues were classified in three categories: those with a non-detrimental alteration of their activities (activity >50 % of control FVIII; n=98), those with a moderate alteration (15 %<activity<50%; n=45) and those that were severely affected (activity<15%; n=63). The mutants sensitive to mutation were retrieved in the HAMSTeRS database with a higher percentage than those that were not affected (58.8% vs. 9.2%). The results revealed the existence of clusters of residues that are sensitive (Arg418-Phe436, Thr459-Ile475, Ser535-Gly549, Asn618-Ala635) or not (Leu398-Arg418, Pro485-Asp500, Gly506-Gly520, Pro596-Asp605) to mutations. The stretches of residues sensitive to mutations were buried within the molecule suggesting that these amino acids participate in the maintenance of the A2 domain structure. In contrast, residues resistant to mutations formed external loops without well- defined structures suggesting that these loops were not crucial for the process of factor X activation. This study provided a detailed map of the FVIII A2 domain between residues 371 and 649, identifying residues crucial for maintaining FVIII function and residues that can be mutated without jeopardising the coagulant activity.

scholarly journals The role of the spleen in regulating the plasma levels of factor VIII-- von Willebrand's factor after DDAVP

Blood ◽  
1982 ◽  
Vol 60 (6) ◽  
pp. 1402-1406 ◽  
Author(s):  
VV Garcia ◽  
R Coppola ◽  
PM Mannucci
Keyword(s):  
Factor Viii ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
Storage Site ◽  
Inactive Form ◽  
Coagulant Activity ◽  
High Concentrations ◽  
Von Willebrand’S Factor ◽  
Normal Controls

Organ transplantation and perfusion studied indicate that the spleen plays an important role in the regulation of plasma levels of factor VIII-von Willebrand's factor (FVIII-vWF). To better understand the mechanisms that regulate the FVIII-vWF increases after infusion of 1- deamino-8-D-arginine vasopressin (DDAVP), we have measured factor VIII coagulant activity (FVIII:C) and antigen (FVIII:CAg) and von Willebrand's factor antigen (vWF:Ag) and ristocetin cofactor (vWF:RCof) in 9 asplenic subjects with normal baseline concentrations, in 7 asplenic subjects with high concentrations, and in 14 normal controls with intact spleens. In “normal” aasplenics, all the FVIII-vWF-related measurements increased significantly over baseline values, indicating that responsiveness to DDAVP is not abolished by splenectomy. The maximal vWF:Ag and vWF:RCof responses were no different from those of normal controls, suggesting that DDAVP releases vWF from storage sites other than the spleen. The FVIII:C response was significantly lower than in normal controls, but FVIII:CAg did not differ, making FVIII:CAg higher than FVIII:CAg in “normal” asplenics. These findings suggest that the spleen, rather than being a storage site for FVIII, is the organ in which a partially inactive form of FVIII acquires full coagulant activity. In “high” asplenics, all the FVIII-vWF-related measurements increased less than in “normal” splenics, indicating that long-term elevations of plasma concentrations of FVIII-vWF are accompanied by decreased release from those storage pool(s) mobilized by DDAVP.

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