Effects of physiological concentrations of vasopressin on haemostatic function in man

1. Plasma concentrations of vasopressin (aVP) attained under conditions of stress were simulated by infusing four volunteers with 0.25, 0.5, 1.0 and 2.0 pressor units of aVP over 1 h (units/h). Three subjects had all four infusions and one received only 1.0 unit/h. 2. Blood samples were taken for assay of factor VIII coagulant activity (FVIIIC), factor VIII related antigen (FVIIIRAg), the ristocetin cofactor (FVIIIRiCof), euglobulin lysis time (ELT) and aVP concentrations before infusion (time 0) and every 20 min for 80 min. Fibrinopeptide A (FPA) generation time was measured at time 0, 60 and 80 min. 3. At infusion rates of 0.25 unit/h median aVP levels peaked at 6.5 pg/ml and there was no change in haemostatic function. At 0.5 unit/h aVP levels peaked at 16.0 pg/ml, there was no change in FVIII or FPA generation time, and plasminogen activator activity (106/ELT2) rose from 100 to 400 units. At 1.0 unit/h, aVP levels rose to 25.4 pg/ml, FVIIIC rose by 160% and activator activity from 87 to 360 units. At 2.0 units/h, aVP concentrations reached 83 pg/ml, there was an increase in all modalities of FVIII and activator activity rose from 251 to 452 units. FPA generation time shortened and circulating plasma levels of FPA were increased. 4. There was a highly significant correlation between the percentage increases in all three components of FVIII and plasma aVP levels (FVIIIC: r = 0.87, P < 0.0001; FVIIIRAg: r = 0.61, P < 0.0001; FVIIIRiCof: r = 0.80, P < 0.0001) and between the increase in plasminogen activator activity and aVP levels (r = 0.56, P < 0.0001). 5. The results indicate that plasma concentrations of aVP comparable with those attained during stress cause a rise in FVIII, an increase in plasma activator activity and effects on FPA generation consistent with low-level activation of the coagulation mechanism. Endogenous vasopressin could mediate alterations in haemostatic function known to accompany events such as surgical operations.

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Haemostatic responses and vasopressin release during colonoscopy in man

Clinical Science ◽

10.1042/cs0810257 ◽

1991 ◽

Vol 81 (2) ◽

pp. 257-260 ◽

Cited By ~ 19

Author(s):

K. K. Hampton ◽

P. J. Grant ◽

J. Primrose ◽

H. G. Dean ◽

J. A. Davies ◽

...

Keyword(s):

Factor Viii ◽

Plasminogen Activator ◽

Plasma Concentrations ◽

Tissue Type ◽

Tissue Type Plasminogen Activator ◽

Plasminogen Activator Activity ◽

Plasma Vasopressin ◽

Type Plasminogen Activator ◽

Coagulant Activity ◽

Von Willebrand

1. During major abdominal surgery there are increases in Factor VIII and plasminogen activator activity, associated with elevated plasma concentrations of vasopressin, of a magnitude shown to affect haemostasis. 2. To investigate the mechanisms involved in the haemostatic response to surgery, 12 patients undergoing fibre-optic colonoscopy were studied, of which six had a complete and six had an incomplete examination. 3. Venous blood samples were taken before, during and after the procedure for assay of plasma vasopressin, adrenaline and noradrenaline concentrations, Factor VIII coagulant activity, von Willebrand factor antigen level, euglobulin clot lysis time, tissue-type plasminogen activator activity and tissue-type plasminogen activator inhibition. 4. In the six patients who underwent a complete procedure the median plasma vasopressin concentration rose from 0.6 pg/ml to 153 pg/ml during colonoscopy. Factor VIII coagulant activity rose from 0.9 to 2.4 i.u./ml and von Willebrand factor antigen level rose from 139 to 224%. Plasminogen activator activity increased from 20 to 144 units and tissue-type plasminogen activator activity rose from 107 to 1338 m-i.u./ml, whereas tissue-type plasminogen activator inhibition fell from 4.8 to 1.0 i.u./ml. 5. In the six patients in whom a limited procedure was performed, there were no changes in haemostatic function or in plasma vasopressin concentration. Plasma concentrations of adrenaline and noradrenaline did not change in either group. 6. The results indicate that vasopressin regulates the intrinsic coagulation pathway and fibrinolytic system in the absence of adrenaline release.

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Vasopressin and catecholamine secretion during apomorphine-induced nausea mediate acute changes in haemostatic function in man

Clinical Science ◽

10.1042/cs0710621 ◽

1986 ◽

Vol 71 (5) ◽

pp. 621-624 ◽

Cited By ~ 14

Author(s):

P. J. Grant ◽

J. R. Hughes ◽

H. G. Dean ◽

J. A. Davies ◽

C. R. M. Prentice

Keyword(s):

Factor Viii ◽

Generation Time ◽

Clot Lysis ◽

Lysis Time ◽

Coagulant Activity ◽

Euglobulin Clot Lysis Time ◽

Acute Changes ◽

Von Willebrand ◽

Willebrand Factor ◽

Factor Antigen

1. Seven male volunteers were given apomorphine (14–20 μg/kg) subcutaneously on a total of ten occasions. Nausea was experienced on six occasions and on four occasions there was no effect. 2. Venous samples were taken before injection, at peak nausea and 20 min later for assay of factor VIII coagulant activity (FVIIIC), von Willebrand factor antigen (vWFAg), the ristocetin cofactor (FVIIIRiCof), euglobulin clot lysis time (ECLT), fibrinopeptide A (FPA), FPA generation time, activated partial thromboplastin time (APTT), vasopressin (aVP) and adrenaline. 3. During nausea plasma aVP concentrations rose from median values of 0.4 pg/ml (at time 0) to 76 pg/ml at peak nausea and fell to 32 pg/ml 20 min later. Adrenaline rose from 0.36 to 0.91 nmol/l (P < 0.05) before falling to 0.55 nmol/l. 4. During nausea, FVIIIC rose from 100% to 143% (P < 0.05) and to 214% (P < 0.05) 20 min later. FVIIIRiCof and vWFAg showed similar changes. Plasminogen activator activity (106/ECLT2) rose from 23 units at time 0 to 592 units during nausea and 1135 units (P < 0.05) after 20 min. 5. The APTT fell from 49 s to 44 s during the study, plasma FPA levels and the FPA generation time both remained unchanged. 6. On the four occasions nausea was not experienced, there were no changes in vasopressin and catecholamine concentrations nor in haemostatic function. 7. During the study, plasma aVP concentrations rose to levels previously shown to influence haemostatic function. This provides further support for the view that aVP has a secondary role as a mediator of acute changes in haemostasis, and during nausea contributes with adrenaline to an abrupt change in factor VIII and fibrinolytic activator activity.

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EFFECTS OF VASOPRESSIN AND ADRENALINE ON FIBRINOLYSIS: SYNERGISTIC OR ADDITIVE?

10.1055/s-0038-1644136 ◽

1987 ◽

Author(s):

P J Grant ◽

P G Wiles ◽

M Boothby ◽

J A Davies ◽

C R M Prentice

Keyword(s):

Factor Viii ◽

Plasminogen Activator ◽

Saline Infusion ◽

Low Doses ◽

Additive Effects ◽

Plasma Adrenaline ◽

Normal Volunteers ◽

Plasminogen Activator Activity ◽

Lysis Time

Vasopressin (aVP) andadrenalineboth enhance plasminogenactivator activity when infused at low doses in man and probably act asphysiological regulators of fibrinolysis under certain conditions. Therelative contributions of these hormones to changes in fibrinolysis are unknown. This study was carried out to investigate whether aVP and adrenaline act synergistically on plasminogen activator in man. Four normal volunteers were infused with (1) aVP (1. OU/h), (2) adrenaline (420 μg/h), (3) aVP and adrenaline and(4) 0.9% saline for 1h. Saline (0.9%) wasinfused for 30 min before and afterinfusion. There was a minimum of 2 weeks between infusions andthe subjects were not aware of the contentsof the infusate. Samples were takenafter 30 min saline infusion and every 30 min for 1 1/2h foreuglobulinclot lysis time (ECLT), factor VIII:C, aVP and adrenaline. During (1) and (3) plasma aVP rose from (median)0.9 pg/ml to 13.2 pg/ml after 1h. During (2) and (4) plasma aVP remained constant at 0.9 pg/ml. Plasma adrenaline rose from 0.21nmol/1 to 0.62 nmol/1 after 1h during (2) and (3) and remained unchanged at 0.20 nmol/1 during(1) and (4). Plasminogen activator activity (106 /ECLT2 ) rose (%) from 100 to 150% at 1h during adrenalineinfusion,(p < 0.05), 100 to 148% during aVP (p < 0.05), 100 to 252% (p < 0.05) when both wereinfused and from 100 to 123% (N. S) during saline infusion. Factor VIII remained unchanged. The results indicate that at low physiological concentrations, aVP and adrenaline have additive effects on fibrinolysis but are probably not synergistic. This is consistent with the view that aVP and adrenaline mediate this response by different receptors.

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Warfarin Induced Fibrinolysis: The Effect Of Recovery With And Without Vitamin K

10.1055/s-0038-1652291 ◽

1981 ◽

Author(s):

N A Marsh

Keyword(s):

Prothrombin Time ◽

Plasminogen Activator ◽

Vitamin K ◽

Dynamic Equilibrium ◽

Degradation Products ◽

Direct Action ◽

Plasma Fibrinogen ◽

Clotting Factors ◽

Lysis Time ◽

Euglobulin Lysis Time

We have previously shown that fibrinolysis in the rat is enhanced by levels of warfarin administration sufficient to produce moderate anticoagulation. This effect is mediated largely by an increase in plasma plasminogen activator. Plasminogen levels are decreased and fibrin(ogen) degradation products raised confirming the presence of a systemic hyperfibrinolytic state. In order to investigate this phenomenon further we have measured fibrinolytic components in rats recovering from warfarin administration. Groups of male Hooded rats received 14 yg warfarin/100 g body weight /day by mouth for one to two weeks. The animals were then allowed to recover without further treatment or following a single 50 μg dose of vitamin K1. Euglobulin lysis time, one stage prothrombin time, plasma plasminogen activator (fibrin plate method), plasma plasminogen (caseinolytic method), plasma fibrinogen (clot weight method) and plasma fibrinolytic inhibitors were measured at intervals after the end of the warfarin treatment. In animals recovering without vitamin K prothrombin time returned to normal within one week. However fibrinolysis remained elevated with plasma plasminogen activator concentrations of more than twice the control value. Plasma inhibitor levels were depressed and fibrinogen levels elevated. After two weeks all fibrinolytic components had returned to normal. Following vitamin Kj administration a different pattern emerged; prothrombin time returned to normal within 24 hours but fibrinolysis was diminished. The latter effect was due to a marked increase in plasma fibrinogen and moderate fall in plasma plasminogen activator both of which contributed to a prolonged euglobulin lysis time. These results indicate that fibrinolysis and coagulation in the rat are not linked in a 'dynamic equilibrium' like that proposed for man. The enhanced fibrinolysis rather than being a result of the fall in vitamin K dependant clotting factors may be due to the direct action of warfarin. The 'fibrinolytic shutdown' following vitamin K remains unexplained .

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

Blood ◽

10.1182/blood.v60.6.1402.1402 ◽

1982 ◽

Vol 60 (6) ◽

pp. 1402-1406 ◽

Cited By ~ 15

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.

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FACTOR XIII AND ITS NATURAL PLASMATIC TARGETS:FIBRINO-GEN,FIBRONECTIN AND ALPHA2-ANTIPLASMIN IN MALIGNANT DISEASE

10.1055/s-0038-1643208 ◽

1987 ◽

Author(s):

J Kioczko ◽

M Wojtukiewicz ◽

M Bielawiec ◽

E Pilecka

Keyword(s):

Malignant Disease ◽

Plasma Concentrations ◽

Subunit A ◽

Lysis Time ◽

At Iii ◽

Euglobulin Lysis Time ◽

Monospecific Antisera ◽

Melanoma Malignum ◽

Incorporation Method

The relevance of fibrin formation and its stabilization in tumour growth and metastasis formation seems to be important but it still remains unclear.The role of F.XIII in this process may emerge from a variety of mechanisms it is involved in,including crosslink of fibrin molecules,α2AP incorporation into fibrin and reciprocal crosslink of fibronectin,fibrin and collagen. We studied F.XIII and its natural targets such as fibrinogen , fibronectin and α2AP in 61 patients with various inoperable neoplasms (21 with Ca mammae,18 with Ca ventriculi and 22 with Melanoma malignum).F.XIII activity was measured by dansylcadaverine incorporation method acc.to Lorand et α2F.XIII subunit “a” and “b”, f ibronect in , α2AP , AT III, α22M , α2AT and C-I plasma concentrations were estimated by means of rocket immunoelectrophoresis acc.to Laurell using monospecific antisera (Behringwerke AG,Marburg).The following tests were performed in all cases:fibrinogen concentration, euglobulin lysis time and serum FDP.In comparison with healthy subjects the patients revealed statistically significant decrease in F.XIII activity and its subunit “a“ and “b“ concentrations concomitant with lowered fibronectin and α2AP levels.No statistically significant correlations were found between F.XIII and its natural plasmatic substrates.Furthermore,the malignant patients showed decreased AT III concentrations,whereas α2CiI and α2AT levels were elevated.Prolongation of ELT concomitant with an increase of FDP concentration were also found. Differences in F.XIII level and in other haemostasis parameters were stated between different tumour types. Our data indicate that the role of F.XIII in malignancy is not limited to fibrin stabilization but its interactions with fibronectin and α2AP should be taken into account.

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Serial studies in von Willebrand's disease: variability versus "variants"

Blood ◽

10.1182/blood.v56.4.712.bloodjournal564712 ◽

1980 ◽

Vol 56 (4) ◽

pp. 712-716 ◽

Cited By ~ 1

Author(s):

CF Abildgaard ◽

Z Suzuki ◽

J Harrison ◽

K Jefcoat ◽

TS Zimmerman

Keyword(s):

Factor Viii ◽

Repeated Testing ◽

Laboratory Findings ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Normal Individuals ◽

Coagulant Activity ◽

History Of ◽

Ristocetin Cofactor

The variability of laboratory findings in von Willebrand's disease (vWd) was evaluated by performing serial studies of bleeding time (BT), factor VIII coagulant activity (VIII:C), factor-VIII-related antigen (VIIIR:Ag) and ristocetin cofactor (VIIIR:Rcof) in 50 individuals from 25 families with this disorder. The types of results were characterized from 1 to 16 based on the possible combinations of findings using these four tests. The only patients observed to have consistently abnormal results of all four tests were three individuals with homozygous vWd. Individuals with autosomal dominant vWd were found to have a variety of results and all 16 possible types were observed. Although a consistent pattern was present within some families, others with equivalent history of bleeding demonstrated widely variable types of results. The results within some families, others with equivalent history of bleeding demonstrated widely variable types of results. The results of serial studies of the same tests in 10 normal individuals indicated relative stability, with nearly all values within the usual range of normal, but some independent variation of factor-VIII-related activities was observed. These studies indicate that: (1) the results of BT, VIII:C, VIIIR:Ag, and VIIIR:Rcof vary considerably from time to time in many individuals with vWd, (2) a classification of “variants” of vWd based solely on such studies may be inappropriate, particularly if the tests are not repeated, and (3) repeated testing may be required to establish the diagnosis of vWd in some individuals.

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Fibrinolytic, Factor VIII and Pulse Rate Responses to Repeated Adrenaline Infusion Followed by Haemorrhage

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649262 ◽

1977 ◽

Vol 37 (03) ◽

pp. 527-534 ◽

Cited By ~ 6

Author(s):

B. J Britton ◽

J. C Giddings ◽

Lynne Brooks ◽

A. L Bloom

Keyword(s):

Factor Viii ◽

Pulse Rate ◽

Control Series ◽

Lysis Time ◽

Euglobulin Lysis Time ◽

Adrenaline Infusion ◽

Activation Pathways ◽

Coagulation And Fibrinolysis ◽

Development Of Tolerance

SummaryThe role of catecholamines in the activation of coagulation and fibrinolysis following surgery remains controversial. In this study 5 dogs were infused with 1, 2, 3, 6, 9 and 12 μg kg–1 min–1 of adrenaline at twice weekly intervals and were then reexposed to 3 μg kg–1 min–1. Pulse rate and factor VIII increased after infusion of 1,2 and 3 μg kg–1 min–1 but thereafter there was a diminished response and no response on reexposure to 3 μg kg–1 min–1 although this was not significant in the case of pulse rate. Euglobulin lysis time shortened after each infusion of adrenaline and showed no development of tolerance. A control series of dogs infused with saline showed no similar changes.Both groups of animals were then bled to a blood pressure of 60 mm Hg for 60 minutes. Pulse rate and factor VIII did not change but euglobulin lysis time shortened in both groups. The results suggest that the activation pathways for changes in factor VIII and euglobulin lysis time induced by adrenaline are separate.

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In Vivo Interactions of Autoantibodies to Factor VIII with the Factor VIII Complex

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657243 ◽

1982 ◽

Vol 48 (02) ◽

pp. 142-145 ◽

Cited By ~ 2

Author(s):

J P Allain ◽

M P Croissant ◽

D Lerolle ◽

L Houbouyan ◽

M Zuzel ◽

...

Keyword(s):

Elderly Patients ◽

Factor Viii ◽

Immunosuppressive Therapy ◽

Immune Complexes ◽

Circulating Immune Complexes ◽

Factor Viii Related Antigen ◽

Coagulant Activity ◽

Ristocetin Cofactor ◽

Sequential Measurements

SummaryTwo non-haemophilic elderly patients who had developed autoantibodies to factor VIII were studied over a period of 9 months to 5 years. Sequential measurements of antibody to factor VIII (anti-VIII: C), factor VIII coagulant activity (VIII: C), factor VIII coagulant antigen (VIII: CAg), factor VIII-related antigen (VIIIR: Ag), and factor VIII ristocetin cofactor (VIII: WF) were performed. Before treatment, low VIII: C, norlnal or increased VIII: CAg and high VIIIR: Ag levels were found and were indicative of the presence of circulating immune complexes. Immunosuppressive therapy induced progressive correction of VIII: C and VIIIR: Ag values. High levels of VIII: CAg subsided in the patient who relapsed. It is suggested that antibodies to factor VIII bind and remove VIII: C from the circulation thereby inducing an increased synthesis of VIII: CAg which may be associated with an augmented release or production of VIIIR: Ag.

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

10.1055/s-0038-1665834 ◽

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.

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