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Plasma levels of FPA and FPB beta 15-42 in patients with Behçet's disease were examined. In the patients, the mean levels of FPA and FPB beta 15-42 were significantly higher than controls (p less than 0.001). Fibrinolysis subsequent to coagulation may be activated in the patients. The levels of both FPA and FPB beta 15-42 were higher during attack than in remission. The caution should be taken these levels to understand the disease activity.

Fibrinopeptide A (FPA) levels as an indicator of thrombin activity in the cerebrospinal fluid (CSF) and plasma of 25 patients with subarachnoid haemorrhage (SAH) were measured serially by radioimmunoassay (RIA). FPA levels in CSF were extremely high on days 0-1 (1253 +/- 269 ng/ml, mean +/- standard error) but decreased rapidly (11.3 +/- 3.9 ng/ml on days 2-4, 10.7 +/- 5.9 ng/ml on days 5-7, and 6.3 +/- 1.5 ng/ml on days 8-14). In the controls the FPA concentration in CSF was 1.2 +/- 0.9 ng/ml (mean +/- standard deviation). Plasma FPA levels in patients with SAH showed no statistically significant changes with time. The bradykinin (BK) concentration in CSF and plasma in 27 patients with SAH was measured serially by RIA. The concentrations in CSF were 122.7 +/- 22.7 pg/ml (mean +/- standard error) on day 0, 38.6 +/- 6.1 pg/ml on day 1, 22.7 +/- 6.3 pg/ml on day 2, and 17.1 +/- 3.0 pg/ml or less thereafter. Plasma BK levels in patients with SAH were higher than those in the control group, but there was no statistically significant change over time. From the measurement of FPA it was apparent that the coagulation system in the subarachnoid space is strongly activated in the early stage of SAH. The formation of BK in CSF after SAH is thought to be due to the contact activation of Hageman factor (intrinsic factor) in the subarachnoid space. Trabeculae as collagen bundles in the subarachnoid space were considered to have a possible role in activating the Hageman factor of the coagulation system in SAH.

The purpose of this study was to assess the predictive values of the assays of fibrinopeptide A (FPA), beta-thromboglobulin (BTG) and their combination in patients suspected of having acute deep venous thrombosis (DVT) or pulmonary embolism (PE). In 80 controls the mean (+/- SD) plasma concentrations of FPA and BTG were 0.72 +/- 0.47 and 28.2 +/- 10.1 ng/ml, respectively. In 26 patients in whom DVT was confirmed by phlebography and Doppler ultrasound, clearly raised mean FPA (5.62 ng/ml) and BTG (70.6 ng/ml) concentrations were measured compared to those in 13 patients in whom this disorder was excluded (1.00 and 33.6 ng/ml, respectively). Also in 25 patients, in whom PE was established by perfusion lung scanning, clearly increased mean FPA (6.28 ng/ml) and BTG (82.4 ng/ml) concentrations were measured compared to those in 12 patients without this disease (1.03 and 32.5 ng/ml, respectively). Raised FPA and BTG concentrations were also found in 20 patients with inflammatory disorders and in 10 with various types of malignancy. The mean FPA and BTG concentrations did not differ between patients with renal failure or diabetes mellitus and patients without these diseases. From the predictive values of these assays and their combination it can be concluded that raised FPA and BTG concentrations are not specific for thrombosis. However, when normal FPA and BTG concentrations are present, acute DVT or PE can safely be excluded in symptomatic patients. In the group with confirmed DVT/PE, anticoagulant treatment (heparin and phenprocoumon) brought down the mean FPA concentration to levels within the normal range in less than 1 hour while the mean BTG concentration remained elevated throughout the 10-day study period.

The intraperitoneal fibrin formation and its inhibition by intraperitoneal heparin (5000 U) was investigated in six patients on CAPD. The intraperitoneal heparin concentration decreased linearily from 1.78 U/ml to 1.13 U/ml during a 4-hour dwell time. The antithrombin III-concentration increased to 0.56 +/- 0.1 mg/dl, reaching 1.87% of normal plasma values. The antithrombin III-portion of total protein was 0.62% in plasma and 0.79% in dialysate. The fibrinopeptide A-concentration, a specific product of thrombin action on fibrinogen was 37.1 +/- 11.8 ng/ml in plasma (normal range: less than 2.5 ng/ml) and 153.4 +/- 16.8 ng/ml in dialysate during regular CAPD. After the addition of 5000 U heparin the fibrinopeptide A-concentration in dialysate decreased to 11.6 +/- 2.6 ng/ml during a 4-hour dwell time. In vitro experiments showed no remarkable inhibition of fibrin formation by heparin without antithrombin III in dialysate. We suggest that the fibrinopeptide A is produced intraperitoneally and the antithrombin III-concentration in dialysate is sufficient to inhibit the fibrin formation after acceleration by heparin.

Magnetically induced birefringence was used to monitor fibrin polymerization after the release of the small negatively charged A fibrinopeptides from human fibrinogen by the action of the snake-venom-derived enzymes reptilase and ancrod. A range of conditions was investigated. Fibrin polymerization in solutions of purified fibrinogen shows a distinct break near the gelation point. On addition of Ca2+ or albumin the lag period is shortened, fibre thickness is increased and the break in assembly almost vanishes, probably because both of these additives promote lateral aggregation. There are minor differences in the kinetics, depending on the venom enzyme used. The kinetics of fibrin assembly in model systems containing either Ca2+ or albumin and in human plasma with a largely dormant coagulation cascade are very similar. Therefore in the latter condition there is no significant alteration in the assembly process due to interaction between fibrin or the venom enzymes and any of the plasma proteins. When the cascade is activated, the polymerization progress curves have a character that resembles a combination of the reactions observed when the venom enzymes and endogenously generated thrombin separately induce coagulation, except for a region near gelation where, paradoxically, polymerization appears to be slower on activation. The low-angle neutron-diffraction patterns from oriented gels made with thrombin or reptilase are identical. Therefore at low resolution the packing of the monomers within fibres is the same when fibrinopeptide A only or both fibrinopeptides A and B are removed.

Ten patients participated in this study which evaluated the effect of two heparin dose regimes, a high dose regime (mean dose 6750 IU) and a low dose regime (mean dose 3750 IU), on the thrombin activity, achieved during a 4-hour-dialysis. The thrombin activity was measured by use of the FPA assay. Heparin was administered as bolus dose followed by a constant rate infusion which was discontinued 1.5-2 hours prior to the end of the dialysis. Both dose regimes inhibited thrombin activity equally effectively as long as heparin was administered. In the high dose regime, the FPA levels remained unchanged until the end of the dialyses in all patients. In the low dose regime, six patients had the same FPA values at the end of the heparin infusion and at the end of the dialysis. In the remaining four patients much higher FPA levels were achieved at the end of the dialysis. No serious bleeding or clotting complications occurred, and all dialyses were uneventful.

The clinical and metabolic effects of a short-term treatment with a combination contraceptive pill containing 0.150 mg desogestrel and 20 mcg ethinylestradiol were evaluated in a group of 17 healthy women. In spite of the low estrogen content, the pill exerted a good cycle control and the incidence of irregular bleedings was low. The minor side effects commonly associated with oral contraceptive (OC) use rarely occurred, and an improvement of premenstrual symptoms was reported during pill intake. As for the different biochemical parameters tested, the formulation induced a significant increase of fibrinopeptide A (FPA) plasma levels. However, the resulting increase of peptide was lower than that induced by pills containing 30 mcg ethinylestradiol. No significant modifications of plasma total cholesterol (T-CH) and low-density lipoprotein cholesterol (LDL-CH) were observed, while triglycerides (TG), high-density lipoprotein cholesterol (HDL-CH) concentrations and the HDL-CH/LDL-CH ratio significantly increased. A significant increase of apolipoproteins AI (Apo AI) and apolipoproteins AII (Apo AII) concentrations was also observed. Moreover, the pill did not alter fasting insulin and glucose levels and their response to an oral glucose tolerance test (OGTT). It may be concluded that this new formulation can be considered acceptable for clinical use, mainly in consideration of the minor or no changes in the biochemical parameters regarded as risk factors for venous and arterial diseases.

To assess whether the intense thrombotic state known to occur early after the onset of acute myocardial infarction is further exacerbated by impaired intrinsic fibrinolysis, we compared the intensity of fibrinolysis as measured by the level of crosslinked fibrin degradation products (XL-FDP) in plasma with the intensity of thrombosis as assessed by fibrinopeptide A (FPA) in 98 patients with transmural and 14 patients with non-Q wave infarction. Patients without complications of infarction such as shock, mural thrombi, or malignant arrhythmias requiring countershock generally had normal plasma levels of XL-FDP, less than or equal to 300 ng/ml (81% of those presenting less than 8 hours after onset and 66% of those presenting greater than 8 hours after onset) on admission despite elevated FPA indicative of ongoing thrombosis. In contrast, patients with complications generally had elevated levels of XL-FDP greater than 300 ng/ml (80% of those presenting early and 62.5% of those presenting late) and 50% of these patients had marked elevations to greater than 1000 ng/ml. FPA was markedly elevated in patients with complications whether they presented early or late after onset of infarction. Our direct measurements at the time of infarction support previous data indicating that intrinsic fibrinolysis is impaired in patients with acute infarction, despite marked thrombin activity, when complications are not present. However, when complications are present initially, a more exuberant fibrinolytic response is observed perhaps due to thrombosis associated with the complications themselves.

In 13 patients with effusions of varying etiology, considerably higher fibrinopeptide A (FPA) immunoreactivity were found in the effusions than in the corresponding plasmas. After instillation of heparin into the effusion the FPA concentration diminished significantly but very slowly. The difference in concentration between plasma and effusion therefore represents a relative FPA accumulation in the effusion. In view of its extremely short half-life in plasma, the FPA produced in the effusions is thought not to contribute to the increased plasma FPA levels. In addition, injection of amounts of FPA into the effusion such as to produce an acute increase of the local FPA level did not lead to a significant change in the FPA level in plasma.

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)

Plasma fibrinopeptide A (FPA), a dynamic measure of intravascular coagulation, was determined in 70 healthy Chinese women during normal pregnancy, labour, delivery and the early puerperium and compared to a group of healthy non-pregnant adult controls. In the normal controls the plasma FPA level (mean +/- SD) was 1.43 +/- 0.46 ng/ml. During pregnancy and labour, the FPA levels were 3.05 +/- 0.98 ng/ml and 11.47 +/- 4.43 ng/ml, respectively, and it reached a peak of 32.95 +/- 11.66 ng/ml at parturition, then falling to 6.15 +/- 2.52 ng/ml in the early puerperium. All these levels were significantly higher (p less than 0.001) compared to controls. Fifteen of the 21 mothers with blood sampling during parturition also had umbilical cord blood taken for determination of FPA level. There was no significant difference between the maternal (34.07 +/- 10.12 ng/ml) and cord (31.06 +/- 12.67 ng/ml) plasma FPA levels. It is concluded that the hypercoagulable state in women during pregnancy and the puerperium is associated with increased intravascular coagulation activity, and that increased intravascular coagulation activity also occurs in the fetus during parturition. This observation may account for the increased risk of thrombotic disorders observed in pregnant and parturient women as well as in the newborn.

Recurrent thrombocytopenia, thrombosis, or sudden death may develop in patients with heparin-induced thrombocytopenia who are reexposed to heparin. Three patients came to us in whom a diagnosis of heparin-induced thrombocytopenia had been made on the basis of clinical and serologic evidence; these patients required reexposure to heparin because of urgent cardiac surgery. Therefore, we evaluated the ability of iloprost (ZK36374), a new analogue of prostacyclin, to prevent heparin-dependent activation of platelets and thereby permit obligatory heparinization for safe extracorporeal circulation. Before operation, we demonstrated that iloprost prevented both heparin-dependent platelet aggregation and tritiated (3H)-serotonin release in vitro. Therefore a continuous infusion of iloprost was begun 1 hour before heparinization and was continued throughout cardiopulmonary bypass and for an additional 15 minutes after protamine administration. The mean platelet count of 130,000/microliters before operation remained stable, and no spontaneous platelet aggregation was observed in samples of platelet-rich plasma obtained before cardiopulmonary bypass but after heparin administration. Similarly, after heparin administration but before bypass, platelet responsiveness to adenosine diphosphate remained unchanged when compared with preoperative values. Plasma levels of platelet factor 4 increased from 26 +/- 1 ng/ml (mean +/- standard error) to 843 +/- 383 ng/ml after heparin administration but actually decreased throughout cardiopulmonary bypass to 52 +/- 25 ng/ml. Beta-thromboglobulin levels increased from 103 +/- 16 to 244 +/- 94 ng/ml with heparinization. The mean bleeding time was 10.5 minutes preoperatively and 13.3 minutes postoperatively. The mean amount of postoperative chest tube drainage (duration: 12 hours) was 432 +/- 67 ml. Thus, despite the confirmed presence of heparin-dependent platelet-activating factor in the plasma of these three patients, iloprost prevented heparin-induced platelet activation during cardiopulmonary bypass while preserving platelet function, as would be desired for postoperative hemostasis.

Increased thrombin generation is frequently associated with an increase in anginal activity. A cross-over, single-blind, completely randomized study was planned in order to evaluate whether the control of thrombin generation affected the increase in anginal activity. After discharge from the hospital, 24 patients (18 men and 6 women, aged 40 to 69 years) suffering from spontaneous angina were followed up to 12 months and were alternatively treated during two consecutive 6-month periods with calcium heparin, 12,500 IU by the subcutaneous route, or with placebo by the intramuscular route, in addition to the usual antianginal medications. Thrombin generation and clinical activity of angina were assessed every 15 days by measuring fibrinopeptide A (FPA) plasma levels and by grading in three classes (symptomless, mildly symptomatic, and severely symptomatic) the anginal activity on the basis of the number and the time concentration of the ischemic attacks and ECG changes. Low-dose heparin treatment significantly reduced both the FPA plasma level (from 4.1 +/- 3.7 to 2.3 +/- 1.8 ng/ml, p less than 0.001) and the clinical activity of angina. During heparin treatment, the frequency of the observations in the severely and mildly symptomatic classes decreased, respectively, by 53% and by 30%, whereas that in the symptomless class increased by 23% (p less than 0.001) in comparison with the period on placebo. Present results indicate that the control of thrombin generation obtained by low-dose heparin treatment favorably affects the degree of anginal activity in patients with spontaneous angina.

The assay of fibrinopeptide A (FPA) has stimulated particular interest because of its high sensitivity and unique specificity for the action of thrombin. It has proved to be an extremely useful tool in research studies concerning the pathophysiology of thrombotic disease. Use of FPA in the diagnosis and treatment of deep venous thrombosis and pulmonary embolism is reviewed, and the potential usefulness of measuring FPA in the monitoring of the effectiveness of anticoagulant therapy is discussed.

Fibrinopeptide A (FPA) concentrations were measured in blood taken by direct cardiac puncture from 31 patients who had died suddenly of ischaemic heart disease (IHD) and from 8 patients who had died suddenly of other causes. Mean FPA concentration in the IHD group was five times higher than that in the non-IHD group. This difference was almost entirely due to the high FPA level in the IHD subjects with a history of the disease. The FPA difference between the IHD and non-IHD groups is unlikely to have been due to differences in methods of resuscitation. A possible interpretation of the findings is that thrombin production causes or aggravates the course of events leading to sudden IHD death, particularly in subjects with a past history of IHD.

Strenuous physical exercise leads to a significant shortening of blood clotting in various test systems. Such short times are also characteristic of those observed in sedentary patients with thrombosis or disseminated intravascular coagulation, and of those observed in experimental animals after thrombin infusion. The patients exhibit an increase in circulating fibrinopeptide A, which is attributed to thrombin action on circulating fibrinogen, and to an increase of fibrinogen degradation products, which is thought to indicate reactive fibrinolysis. To check whether physical exercise leads to fibrinemia, 10 healthy male volunteers were subjected to strenuous exercise on a bicycle ergometer. Blood samples were taken immediately before and on completion of the exercise period. Despite a significant shortening of the activated partial thromboplastin time, the thrombin time, and the Reptilase time, no increase of fibrinopeptide A could be demonstrated and the ethanol gelation test remained consistently negative. Simultaneously, the euglobulin lysis time was significantly shortened, whereas the fibrin(ogen) degradation products did not increase. The results indicate that the shortening of the coagulation times associated with physical exercise must be explained by mechanisms other than thrombin-mediated conversion of fibrinogen to fibrin.

Elevated levels of fibrinopeptide A, a marker of thrombin activity associated with acute myocardial infarction, have been found to decrease after administration of streptokinase when reperfusion occurs. In contrast, in patients without reperfusion and those with reocclusion after streptokinase therapy, fibrinopeptide A remains elevated. In the present study early serial measurements of fibrinopeptide A were used to further characterize this paradoxic increase in thrombin activity after streptokinase and to characterize its response to heparin. In 19 patients with acute myocardial infarction fibrinopeptide A was elevated to 82.3 +/- 43.5 ng/ml (mean +/- SE) before therapy. Thirty minutes after the initiation of streptokinase, fibrinopeptide A increased to 300.1 +/- 117.4 ng/ml (p less than 0.01), consistent with extensive thrombin activity. Fibrinopeptide A remained elevated until 15 minutes after a heparin bolus injection when levels decreased to 15% of the poststreptokinase value (49.2 +/- 13.3 ng/ml) (p less than 0.001). These data document a prompt paradoxic increase in thrombin activity after administration of streptokinase that may be responsible for failure of therapy in some patients.

Urinary fpA excretion and fpA in plasma were studied in patients with peripheral artery disease, aortic aneurysm, severe coronary artery disease, acute myocardial infarction and in normal controls. Mean urinary fpA was significantly higher in all groups of patients than in normal controls whose excretion was 1.9 +/- 1.2 micrograms/24 hours (mean +/- SD). We found a good correlation between urinary fpA excretion and plasma fpA (r = 0.68, p less than 0.01, n = 81). The highest levels of urinary fpA were found in 9 patients with aortic aneurysm (11.9 +/- 6.1 micrograms/24 hours). The 10 patients with acute myocardial infarction had also abnormally elevated values (4.3 +/- 1.8 micrograms/24 hours) which were only slightly higher than the levels found in another 10 patients with myocardial infarction receiving subcutaneous heparin in a dosage of 2 X 5000 IU daily (2.9 +/- 1.7 micrograms/24 hours). The 13 patients with peripheral artery disease showed an increase in urinary fpA excretion from 4.0 +/- 1.7 to 10.5 +/- 2.3 micrograms/24 hours after percutaneous angioplasty (p less than 0.001). These data demonstrate that urinary fpA excretion may represent a valid means to detect the cumulative effect of thrombin action on fibrinogen in patients with atherosclerotic vascular disease and after therapeutic intervention.

The plasma concentrations of protein C, an anticoagulant protein, and fibrinopeptide A were measured in 37 patients with acute hemispheric stroke and in age-matched controls with nonvascular neurologic diseases. In 11 stroke patients who died within 15 days after the onset (nonsurvivors) protein C antigen concentration on admission was lower than in the control group (p less than 0.005), with a mean value of 63% of the concentrations found in the 26 survivors (p less than 0.001). The difference in protein C concentrations was not associated with different prothrombin time ratios and serum albumin concentration in survivors and nonsurvivors of stroke and was independent of the size of the cerebral lesion. Increased fibrinopeptide A concentration on admission was found in all stroke patients (p less than 0.001), but it was higher in nonsurvivors than in survivors (p less than 0.01), suggesting that lower protein C concentrations in nonsurvivors might be due to increased thrombin-dependent protein C activation. In survivors, protein C concentration was slightly but significantly higher than in controls (p less than 0.05) and was unchanged 2 months after stroke, a time when fibrinopeptide A concentrations had returned to normal. These results show that protein C is involved in the hemostatic derangement caused by stroke and provide a rationale for clinical trials evaluating the therapeutic supplementation with protein C of patients with acute ischemic stroke.

Thirty-seven patients affected by spontaneous angina and 15 comparable control subjects were enrolled in a 12-month prospective study to evaluate the relationship between blood clotting activation (assessed by fibrinopeptide A [FPA] plasma concentration) and the occurrence of myocardial ischemic attacks. FPA measurements and clinical examinations in patients were performed every 2 weeks. In control subjects blood sampling was performed every 4 weeks. Data from 28 patients who completed the study and from the 15 control subjects were analyzed. The clinical activity of angina was divided into three classes (asymptomatic, mildly symptomatic, and severely symptomatic) on the basis of the number and time-concentration of the ischemic attacks and ECG changes during the 15 days preceding each clinical examination. In all but one patient, a cyclic pattern of activity of coronary artery disease was observed. During follow-up studies, 624 FPA measurements were performed in patients and 173 in control subjects. Mean values were 4.68 +/- 4.53 and 1.32 +/- 0.60 ng/ml, respectively (p less than 0.001). FPA levels differed markedly in relation to the activity of angina. A relationship between FPA levels and activity of disease (r = 0.54, p less than 0.01) was found in time course. Bolus heparin administration (100 IU/kg) during the active phase of angina sharply but incompletely lowered FPA plasma levels, indicating thrombin formation both intravascularly and extravascularly. Present results indicate that a marked blood clotting activation occurs simultaneously with the outbursts of clinical activity of spontaneous angina.

Plasma fibrinopeptide A (FPA) levels were determined in 20 unselected adult patients with acute nonlymphocytic and lymphocytic leukemia. The mean FPA level in patients with active disease (15.0 ng/ml) was significantly higher than during clinical remission (2.4 ng/ml, p less than 0.01). Elevated FPA levels were observed in patients with all morphological forms of acute leukemia. In the group of patients in clinical remission, 20/47 FPA values remained elevated beyond the normal range, suggesting that low-grade intravascular coagulation was present even when no leukemic cells were observed. Sequential studies revealed reduction of FPA levels to the normal range in five patients who entered clinical remission after chemotherapy and rapid elevation of the levels in eight patients who entered relapse after clinical remission. FPA levels rose significantly in five patients studied during induction chemotherapy. Thus, subclinical activation of blood coagulation, as defined by elevation of plasma FPA level, may occur commonly in acute leukemia. Plasma FPA generation may relate to leukemic disease activity.

Fibrinopeptide A (FPA) was systematically investigated in 74 patients with acute leukaemia at different stages of the disease (50 with non-lymphocytic leukaemia, ANLL; 24 with lymphocytic leukaemia, ALL). At diagnosis, 75% of the cases had high FPA levels (86% in ANLL and 54% in ALL) with significantly higher levels in ANLL than in ALL (13.4 vs 4.4 ng/ml; p less than 0.001). Patients with DIC (20 cases in ANLL and 1 case in ALL) had significantly higher levels (p less than 0.001). FPA levels were neither correlated with fibrinogen or FDP levels nor with blast cell count. During chemotherapy, median FPA did not show significant changes whereas, at the end of therapy, a return toward normality was generally observed both in ALL and ANLL apart from the group of patients with acute promyelocytic leukaemia. Among the 24 patients who entered post-remission follow-up (13 ANLL and 11 ALL), 10 cases out of the 11 relapsing (6/6 with ANLL and 4/5 with ALL) had increased FPA 1 to 2 months before the ascertainment of the relapse. However, 16% and 9% of the samples obtained on different occasions, respectively from ANLL and ALL cases in maintained first remission, showed FPA above the normal limit. This study demonstrates that subclinical activation of blood coagulation, as indicated by high FPA level, is common both in lymphocytic and non-lymphocytic leukemia and suggests that this phenomenon is related to disease activity.

Both clinical and laboratory findings suggest that pregnancy constitutes a hypercoagulable condition; yet none of the observed laboratory changes are specific for thrombosis. An essential step involves thrombin-mediated fibrin generation. In the process, fibrinopeptide A (FPA) is cleaved from fibrinogen. Using a radioimmune assay, FPA was determined prospectively in a longitudinal and cross-sectional fashion. Fibrinopeptide A increased significantly over control by the end of the first trimester, from 1.3 ng/ml to 2.8 ng/ml. It continued to increase until 30 to 32 weeks' gestation and then plateaued at 4.3 to 4.7 ng/ml. In the immediate postpartum period, FPA remains elevated. In conclusion, thrombin generation as reflected in FPA production is increased throughout pregnancy, thus confirming a hypercoagulable milieu.

The plasma level of fibrinopeptide A (fpA) was used as an index of thrombin action on fibrinogen in order to investigate the rates of fibrin formation and the effect of heparin on thrombin in patients with acute myocardial infarction. The fpA levels measured on admission in 19 patients with acute myocardial infarction ranged from 1.7 to 12.4 ng/ml and were elevated (greater than 2.5 ng/ml) in 16 patients. A loading dose of 5000 IU of heparin resulted in a significant decrease within 20 min of the mean fpA level (from 5.1 to 2.2 ng/ml; p less than .001) and in an fpA normalization in five of 16 patients. During the following continuous infusion of 20,000 IU of heparin per day, the mean fpA levels measured on day 0, 1, and 2 were 3.0, 3.2, and 3.4 ng/ml, respectively, with 16 of 46 fpA values within the normal range. In 10 additional patients, the effect of higher concentrations of heparin and the consequences of stopping heparin infusion were studied. An additional 5000 IU of heparin injected intravenously during continuous infusion of 20,000 IU of heparin per day resulted in a substantial decrease of the plasma fpA level in three of 10 measurements. The stopping of heparin infusion led to an impressive increase of the mean fpA level (from 3.1 to 12.9 ng/ml; p less than .001) within 2 hr. These data demonstrate increased fibrin formation in patients with acute myocardial infarction and neutralization of thrombin in vivo by heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary fibrinopeptide A immunoreactivity was determined by radioimmunoassay using two anti-fibrinopeptide A sera with a different specificity in patients with venous thromboembolism, disseminated intravascular coagulation and rheumatoid arthritis. Elevated levels were frequently observed with both sera, and intravenous administration of heparin in patients with a thromboembolic disorder resulted in a decline of urinary fibrinopeptide A (FPA) concentrations to normal or nearly normal values. For both sera significant correlations with plasma levels were found although one of the sera reacted significantly better with the material in urine samples from these patients than the other (p less than 0.0001, n = 73). Analysis of urinary fibrinopeptide A immunoreactivity by high performance liquid chromatography (HPLC) provided evidence that A peptide material present in this body fluid was heterogeneous. In view of the characteristics of the antisera used in this study, data suggest that urinary FPA immunoreactivity consists to a large extent of carboxyterminally degraded FPA. Excretion of circulating FPA immunoreactive material through the kidneys apparently involves dephosphorylation and carboxyterminal breakdown of the A peptide. Since both synthetic and native phosphorylated or unphosphorylated fibrinopeptide A appeared to be stable in urine in vitro, an active role of the kidney in degrading the A peptide is likely.

Plasma fibrinopeptide B (Bbeta1-14 or FPB) immunoreactivity was studied by radioimmunoassay in patients who received intrauterine infusion of hypertonic saline to terminate pregnancy. FPB immunoreactivity increased with thrombin treatment (TIFPB) suggesting the presence of a larger FPB-containing peptide, since purified FPB is not altered by thrombin, whereas thrombin increases the immunoreactivity of Bbeta1-42 (which includes FPB) 10-fold. TIFPB immunoreactivity in plasma, drawn 4 h after hypertonic saline infusion eluted from Sephadex G-50 similarly to isolated Bbeta1-42. Streptokinase, incubated with normal plasma progressively generated TIFPB immunoreactivity, which showed a major component which eluted from Sephadex G-50 similarly to Bbeta1-42. Streptokinase generated TIFPB much more rapidly in reptilase-treated plasma that contains fibrin I, (which still includes FPB), indicating that fibrin I is preferred over fibrinogen as a substrate for plasmin cleavage of arginine (Bbeta42)-alanine (Bbeta43). Serial studies were then made in 10 patients receiving intrauterine hypertonic saline. Fibrinopeptide A (FPA) levels rose immediately, reached a peak between 1 and 2 h, were declining at 4 h, and were normal at 24 and 48 h. TIFPB levels rose slightly in the 1st h, reached a peak at 4 h, and had returned to base-line values at 24 h. Serum fibrinogen degradation product levels were unchanged at 1 h, reached their highest level at 4 h, and were still markedly elevated at 24 and 48 h. Fibrinogen levels dropped slightly being lowest at 4 and 24 h. Platelet counts declined in parallel with the fibrinogen levels over the first 4 h, but continued to decrease through 48 h. Beta thromboglobulin (betaTG) levels generally paralleled FPA levels whereas platelet factor 4 (PF4) levels showed only slight changes. The data indicate that immediately after intrauterine hypertonic saline infusion thrombin is formed that cleaves FPA from fibrinogen to produce fibrin I and releases betaTG and PF4 from platelets. Later plasmin cleaves Bbeta1-42 from fibrin I to produce fragment X, which is further degraded to form serum fibrinogen degradation products. This sequence of proteolysis indicates that plasmin action on fibrin I serves as a mechanism that regulates fibrin II formation by removing the Bbeta chain cleavage site, which is required for thrombin action in converting fibrin I to fibrin II.

Patients who underwent operations in which cardiopulmonary bypass was used had elevations of plasma fibrinopeptide A which did not return to normal during bypass despite conventional heparin anticoagulation, suggesting inadequate heparin dosage and continued thrombin activity during the operation. Patients who underwent aortocoronary artery grafting had high plasma thromboxane B2 levels and a rapid fall in platelet count at the onset of extracorporeal circulation. Thromboxane elevations were less marked in patients who underwent valve replacement. Platelet aggregation and coronary artery constriction secondary to thromboxane production may contribute to the morbidity of cardiopulmonary bypass.

In 124 patients with various types of malignancy, fpA and delta fpA were measured. In 35 of these patients the effect of heparin injection on fpA and delta fpA was studied. All patients were ambulant without clinical signs of venous thromboembolism or DIC and had not received cytostatic, anticoagulant, or radiotherapy recently. In about 75% of these patients, fpA was elevated, whereas in the blood of one third of the patients, both elevated fpA levels and accelerated delta fpA were detected. Eight of the 45 patients with accelerated delta fpA (and elevated fpA) presented laboratory signs of low-grade DIC. In the patients taken at random for heparin administration, delta fpA normalized upon heparin injection, whereas in the majority of patients, irrespective of the fpA-generation rate, fpA levels were not affected by "adequate" heparinization. These results indicate that (1) about 30% of the (selected) patients admitted to our cancer clinic present with evidence of intravascular thrombin activity and (2) in 70% of these patients fpA is generated, at least in part, at a site not accessible to heparin. In addition 95% of patients with active metastatic disease showed an elevated fpA, whereas 90% of cancer patients in remission and 80% of patients without metastasis had a normal fpA, indicating that fpA can potentially be used to estimate the spread and the activity of the malignant process.

The distribution, elimination, and metabolism of human fibrinopeptide A (FPA) were studied in normal and nephrectomized rabbits. The activity of 125-I-labeled desamino-tyrosyl human FPA (DAT-FPA) was followed over 4 hours after i.v. administration. Results show that in normal rabbits (n = 10) DAT-FPA is eliminated from plasma in four phases with half-lives of 30 sec, 3.5 min, 15 min, and 90 min. The distribution of 123-I-labeled DAT-FPA in plasma was determined in 15 control rabbits with scintigraphy over 2 hours. DAT-FPA was distributed primarily in the cardiovascular system, liver, and kidneys. In some animals minimal radioactivity was detected over the gall bladder. Radioactivity accumulated rapidly in the urinary bladder, approximately 50% being recorded after 15 min and 90% after 120 min. In the heart area radioactivity decreased with half-lives of 25 sec, 7.5 min, 25 min, and 180 min. Nephrectomized rabbits had similar initial fast distribution of DAT-FPA after administration of 125-I-labeled (n = 10) and 123-I-labeled peptide (n = 10). The estimated half-life of the slow component was in the order of several hours. The results of the scintigraphic and gel chromatographic studies show that FPA is primarily excreted in the urine. Previously reported half-lives of FPA reflect distribution rather than steady state conditions.

To determine the effect of improved, short-term glycemic control on various functions of hemostasis in insulin-dependent diabetes, we measured changes in plasma fibrinogen, fibrinopeptide A (FPA), functional antithrombin III (AT-III), factor VIII:ristocetin cofactor ( VIIIRCoF ), beta-thromboglobulin (BTG), platelet factor 4 (PF4), and platelet aggregation responses to ADP and collagen in 12 patients with low or undetectable stimulated (postprandial) serum C-peptide levels during 4-8 wk (median, 6 wk) of treatment with constant subcutaneous insulin infusion. Mean plasma fibrinogen, FPA, AT-III, VIIIRCoF , and BTG at baseline were elevated compared with normal. Three patients had heightened platelet responses to ADP that did not correlate to other indicators of a hypercoagulable state; the affected patients, in fact, had significantly lower plasma BTG (25.5 +/- 5.3 [SEM] versus 44.6 +/- 4.6 ng/ml, P less than 0.05) and FPA (1.1 +/- 0.1 versus 2.5 +/- 0.5 ng/ml, P less than 0.05) than the remaining patients. Patients with clinically evident vascular disease had higher baseline plasma BTG and FPA than those without vascular disease (44.6 +/- 5.4 versus 30.2 +/- 4.6, and 2.6 +/- 0.6 versus 1.3 +/- 0.2 ng/ml, P less than 0.05, respectively). During treatment, all patients had declining blood glucose (200 +/- 18 to 102 +/- 5 mg/dl, P less than 0.001) and HbA1 (11.8 +/- 0.6 to 10.2 +/- 0.4%, P less than 0.005). No statistically significant changes in hemostatic functions were noted. During treatment, one patient had an acute myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

FPA immunoreactivity was elevated in 14 out of 15 patients with disseminated neoplasia. Two of the patients showed signs of DIC, two had clinically evident thrombosis and one a positive 125I-fibrinogen uptake test suggesting thrombosis. Infusion of heparin produced a prompt fall in FPA levels. FPA immunoreactivity correlated well with the turnover of intravasal 125I-fibrinogen. The results confirm that the RIA of FPA provides a specific and quantitative index of the conversion of fibrinogen into fibrin and indirectly of the thrombin action in vivo.

Fibrinopeptide A (FPA) levels were measured in a group of 130 controls and patients with various types of primary hyperlipidemia to investigate whether an increased steady state level of thrombin activity is present in hyperlipidemic patients. In a subset of 56 subjects, levels of clotting factors II, VII, and X were measured as well. FPA levels in hyperlipidemic patients were not significantly different from those of control subjects. Furthermore, on multiple regression analysis, no significant relationships were found between FPA levels and the concentrations of serum cholesterol or triglyceride, or log triglyceride levels. Statistically significant relationships were found between all three clotting factor levels and triglyceride concentration. The correlation coefficients for these relationships, however, were low, so that the correlations are of questionable pathophysiological significance. A weak relationship also was found between the plasma levels of cholesterol and of factor II. Thus, although small increases in various clotting factors may be found in patients with hyperlipidemia, plasma FPA levels are normal. These data indicate that hyperlipidemia is not associated with a steady state of increased thrombin activity in vivo in humans.

The effect of bezafibrate (BZF) on plasma fibrinogen levels has been studied in 62 patients with atherosclerotic vasculopathy and hyperfibrinogenemia (643 +/- 15 (SEM) mg/dl). In a preliminary study, 15-30 days of BZF therapy (400-600 mg/day) normalized fibrinogen values in 16 subjects were compared to 16 controls. The effect was rapid and dose-dependent, and discontinuation in 6 patients who could not complete the study was followed by a rebound increase. A controlled study with 400 mg/day in the other 24 patients for 15 days showed that BZF lowered fibrinogen, PF4, blood filterability and platelet aggregating thresholds to the normal range. BTG and FpA decreased significantly compared to the placebo group (12 and 12 patients randomly distributed) without any variation in potentially biassing hematologic values (WBC, PLTS, Ht, lipids and plasma glucose). BZF may be of value in chronic treatment of hyperfibrinogenemia in atherosclerotic patients with a view to improving the haemorheologic pattern and, hence, reducing activation of the coagulation pathway.

The concentration of heparin in plasma was measured using a chromogenic substrate. It appeared that the measurement of heparin concentration in plasma was important in therapeutic control and evaluation of heparin. There was a correlation between the activated partial thromboplastin time (APTT) and heparin concentration in plasma, but since the gradients of regression line differed in each of the cases, measurement of APTT alone would give a different estimate of heparin concentration in each case. Fibrinopeptide A (FPA) is considered as the best indicator for evaluatin of therapeutic effects of heparin. Therapeutic heparin concentrations were defined as ranging from 0.2 to 1.2 IU/ml because the normalization of FPA was observed and there happened no hemorrhagic accidents in that range.