No abstract

SummaryVasopressin infusions in normal volunteers that produce concentrations in plasma comparable to those seen during stress, cause an increase in plasma factor VIII and shortening of the euglobulin clot lysis time (ECLT). We have investigated the relationship between endogenous vasopressin (aVP) release and haemostatic function in 7 patients undergoing major abdominal surgery. Blood samples were taken at nine intervals during the operative procedure. Plasma aVP levels peaked at median values of 51 pg/ml during bowel manipulation and remained elevated on the first post-operative day. Following, and in close temporal relationship with the rise in aVP there were increases in factor VIII coagulant activity, the ristocetin co-factor, von Willebrand antigen, plasminogen activator activity (106/ECLT2) and fibrinopeptide A concentrations with shortening of the activated partial thromboplastin time. The relationship was similar to that seen following infusion of a VP in human volunteers. The results are consistent with the hypothesis that aVP is an important mediator of changes in haemostatic function which accompany stress and might contribute to the thrombotic risk associated with surgical operations.

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. 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. At infusion rates of 0.25 unit/h median aVP levels peaked at 6.5 pg/ml and there was no change in FVIII or FPA generation time, and plasminogen activator activity (10(6)/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. 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 less than 0.0001; FVIIIRAg: r = 0.61, P less than 0.0001; FVIIIRiCof: r = 0.80, P less than 0.0001) and between the increase in plasminogen activator activity and aVP levels (r = 0.56, P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

SummaryThrombotic diseases increase in incidence with advancing years and this might be partly due to an increased propensity for fibrin formation in older individuals. Accordingly we decided to investigate whether the time taken to generate 50% thrombin activity in vitro varied with the age of the plasma donor. Coagulation was initiated in defibrinated, diluted plasma by contact activation and thrombin activity measured using the chromogenic substrate, S2238. The rate of thrombin generation was assessed by measuring the time taken to reach 50% maximal activity (T50/s). There was a highly significant negative correlation between T50 and age, T50 declining from 93 s at 19 years to 71 s at 65 years (r = −0.637, p <0.0001). A strong negative correlation was demonstrated between T50 and FVII level (r = -0.415, p = 0.0007) and FVIII: C level (r = -0.465, p = 0.0001). Although FVII concentration correlated with age (r = 0.307, p = 0.014) no relationship was seen between age and FVIII :C. These data suggest that coagulation rates in plasma accelerate with age.

A number of workers have examined protein C in relation to other vitamin K dependent factors during warfarin therapy and successfully identified protein C deficient patients by ratio calculation. However, protein S deficiency has not been addressed in this manner. This study compares protein C and protein S by functional and antigenic determination with procoagulant factors of similar half life (Factors VII and II) in an attempt to identify protein C and protein S deficient patients whilst on oral anticoagulant therapy. Procoagulant and anticoagulant factors were compared by linear regression in a population of normal blood donors and patients on stabilized warfarin therapy to obtain expected values for protein C and protein S dependent upon FVII and FII levels, respectively. Observed over expected values for protein C and protein S were calculated for individual patients and normal ranges derived. Comparison of similarly calculated observed over expected protein C and protein S ratios with these normal ranges successfully identified known protein C and protein S deficient patients who were taking warfarin at time of testing.

Summary There is a discrepancy in the results of reported studies of levels of vitamin K dependent coagulation factors in patients on warfarin therapy. This may have arisen partly because of the problem of assuring compliance with therapy in outpatients. The plasma concentrations of the vitamin K dependent clotting factors II, VII, IX and X were studied in 23 outpatients whose adherence to prescribed warfarin therapy was determined using a pharmacological indicator of complicance. In these patients, who were shown to have consistently good compliance and stable anticoagulant control over a period of 3–6 months, the activities in plasma of the four coagulation factors were not equally suppressed. Factor IX levels were significantly greater than those of factor VII (P<0.0001) which in turn were significantly greater than the levels of factor II (P<0.0001) or factor X (P<0.0001). There was no significant difference between the levels of factors II and X which were depressed to a similar extent. The proportion of variability of the International Normalized Ratio (INR) explained by linear regression was 51–77% and a model was derived to predict the INR from the mean of the levels of the four clotting factors. The concentrations of the coagulation factors II, VII, IX and X are likely to be highly dependent on the degree of compliance with warfarin therapy which should be taken into account when investigating the behaviour of these factors.

The myelodysplastic syndromes (MDS) are characterised by dysplastic marrow and cytopenia. Clinically detectable bleeding is uncommon and usually attributed to thrombocytopenia. We have investigated some aspects of haemostatic function in 17 patient5 with MDS and compared the results with findings from 17 control patients matched for age and sex. No specific disorder of blood coagulation or fibrinolysis was identified. The main abnormalities observed in the patients were: prolongation of the bleeding time which was greater than could be explained on the basis of thrombocytopenia in 13 patients; absent, or severely impaired platelet aggregation in response to collagen in 7 patients; impaired platelet production of malondialydehyde when stimulated with collagen and abnormal release of I4C-5 hydroxytryptamine in 5 patients; and abnormalities of ultrastructure in all 5 patients whose platelets were viewed by electron microscopy. Accepred f o r publicalion September 7, 1984 ABREVIATIONS BT = bleeding time mg FDP l=PA ELT MDA MDS PPP PRP PT m Pm = fibrinogen = fibrinogen degradation products = fibrinogen peptide A = euglobulin clot lysis time = malondialdehyde = myelodysplastic syndrome = platelet poor plasma = platelet rich plasma = prothrombin time = partial thromboplastic time = ~thromboglobulin CLINICAL BEARINGThe myelodysplastic syndromes are now diagnosed with increasing frequency, particularly in the elderly. Throm-bocytopenia is common and we have demonstrated that serious defects in platelet function as judged by laboratory tests can co-exist in the absence of clinically apparent bleeding. These patients may suffer from haemorrhagic episodes, but routine tests for platelet function are apparently not much help in identifying those at greatest risk. Most likely, management of patients with myelodysplasia should include avoidance of drugs which inhibit platelet function. Whether or not platelet transfusions may be of any help in treating traumatic or spontaneous bleeding and covering surgical procedures remains to be shown.The myelodysplastic syndromes (MDS) are characterised by normo-or hypercellular bone marrow, varying degrees of cytopenia, and morphological evidence of dysplasia in the bone marrow

There is a discrepancy in the results of reported studies of levels of vitamin K dependent coagulation factors in patients on warfarin therapy. This may have arisen partly because of the problem of assuring compliance with therapy in outpatients. The plasma concentrations of the vitamin K dependent clotting factors II, VII, IX and X were studied in 23 outpatients whose adherence to prescribed warfarin therapy was determined using a pharmacological indicator of compliance. In these patients, who were shown to have consistently good compliance and stable anticoagulant control over a period of 3-6 months, the activities in plasma of the four coagulation factors were not equally suppressed. Factor IX levels were significantly greater than those of factor VII (P less than 0.0001) which in turn were significantly greater than the levels of factor II (P less than 0.0001) or factor X (P less than 0.0001). There was no significant difference between the levels of factors II and X which were depressed to a similar extent. The proportion of variability of the International Normalized Ratio (INR) explained by linear regression was 51-77% and a model was derived to predict the INR from the mean of the levels of the four clotting factors. The concentrations of the coagulation factors II, VII, IX and X are likely to be highly dependent on the degree of compliance with warfarin therapy which should be taken into account when investigating the behaviour of these factors.