The role of hyperglycaemia-induced alterations of antithrombin III and factor X activation in the thrombin hyperactivity of diabetes mellitus

Factor X concentration and factor X activation, antithrombin III anti-Xa activity and plasma concentration, and fibrinopeptide A were measured in 20 diabetic patients and 20 normal subjects. Although factor X activation (81.3 +/- 2.2 vs 97.3 +/- 2.1%, p less than 0.01; mean +/- SE) and antithrombin III activity (76.5 +/- 2.2 vs 96.3 +/- 1.8%, p less than 0.01) were reduced in the diabetic patients, fibrinopeptide A concentration was increased (3.7 +/- 0.4 vs 1.7 +/- 0.2 ng ml-1, p less than 0.01). The ratio of factor X activation to antithrombin III anti-factor Xa activity was increased in the diabetic patients (1.10 +/- 0.01 vs 1.01 +/- 0.02, p less than 0.01). Induced hyperglycaemia was able to mimic all these abnormalities, without changing factor X or antithrombin III concentration. The results suggest that in vivo hyperglycaemia produces a decrease of factor X activation, but at the same time increases fibrinopeptide A formation due to a greater decrease of antithrombin III anti-Xa activity.     

Amyloid and Amyloidosis. The 2nd Romhányi Memorial Symposium April 24, 2004, Pécs,Hungary

Various pathogenic factors have been proposed to explain the abnormal hemostasis observed in AL amyloidosis. Since imbalance between clottingfactors and inhibitors could play a pathogenic role in both hemorrhagic and thrombotic manifestations, we investigated the thrombin-antithrombin pathway in 35 patients with AL amyloidosis. Ten patients suffered from bleeding while 3 patients experienced deep venous thrombosis. Thrombin time was prolonged in 29 subjects, the mean values of antithrombin III activity (ATIII Act) were significantly lower than those of antithrombin III antigen (ATIII Ag) with loss of relationship between these two direrent techniques of ATIII detection, normally observed in healthy controls. In 19 patients increased levels of thrombin-antithrombin (TAT) complexes were present. Crossed immunoelectrophoresis of ATIII, performed in presence of heparin, evidenced ATIII forms with reduced binding capacity to heparin and TAT complexes of various electrophoretic mobilities. In conclusion, the impairment of the thrombin-antithrombin pathway, in association with the low ATIII biological activity, mightplay a pathogenic role in the hypercoagulable state reported in AL amyloidosis, despite the higher frequency of bleeding manifestations.     

Thrombin-hirudin complex stability: a comparison with the thrombin-antithrombin III complex.

In the present in vitro study the stabilities of the thrombin-hirudin and the thrombin-antithrombin III complexes were investigated. After incubation of the complexes with free inhibitors the thrombin-antithrombin III levels were determined by ELISA. The thrombin-hirudin complex proved to be stable in the presence of antithrombin III or heparin. However, in the presence of heparin and plasma equivalent concentrations of antithrombin III, the thrombin-hirudin complex dissociated and hirudin was displaced. In contrast, both thrombin-antithrombin III and thrombin-antithrombin III/heparin complexes are very stable even in the presence of a large excess of hirudin.     

Effect of hirudin vs heparin on haemostatic activity in patients with acute coronary syndromes; the GUSTO-IIb haemostasis substudy.

AIMS: We compared the effects of hirudin and heparin on thrombin generation and activity among 350 patients with acute coronary syndromes enrolled in the GUSTO-IIb trial. METHODS AND RESULTS: We obtained blood at baseline; at 4, 8, and 24h into infusion; at drug termination; and 6 and 24h after termination. We assayed for thrombin activity (fibrinopeptide A, activated protein C, thrombin-antithrombin complex), thrombin generation (prothrombin fragment 1.2), and platelet activation (platelet factor 4). Median baseline fibrinopeptide A and platelet factor 4 levels were elevated. Thrombin formation tended to increase with hirudin and decrease with heparin; by 8h into infusion, thrombin formation was significantly less for heparin (P<0.01). Most patients showed reduced thrombin activity and platelet activation during infusion of either agent. Hirudin-assigned patients had significantly lower fibrinopeptide A levels during infusion. Six h post-termination, both groups had increased thrombin activity. Thrombin formation was increased in heparin patients (P<0.0001), significantly more than with hirudin (P=0.005). Higher values of haemostasis markers tended to be associated with poorer 30-day outcomes. CONCLUSION: Although hirudin did not prevent generation of new thrombin, it appeared to inhibit thrombin activity more than did heparin and produced slower increases in thrombin formation after discontinuation. The reelevation of thrombotic markers after stopping intravenous antithrombin therapy and the tendency toward increased thrombotic events with post-treatment increases in marker levels suggest an ongoing, clinically significant prothrombotic state. These results raise the possibility of improving on current antithrombotics by preventing thrombin generation and thrombin activity and by sustained suppression of the prothrombotic state.     

Failure of fixed dose intravenous heparin to suppress increases in thrombin activity after coronary thrombolysis with streptokinase

Objectives. This study was designed to define the extent of inhibition of thrombin activity achieved with conjunctive fixed dose intravenous sodium heparin compared with fixed dose subcutaneous calcium heparin in patients receiving intravenous streptokinase for acute myocardial infarction.Background. The role of heparin therapy during coronary thrombolysis with streptokinase is controversial, in part because the efficacy of different conjunctive heparin regimens in inhibiting early increases of thrombin activity is not known.Methods. Twenty-eight patients treated with 1.5 million U of streptokinase and 165 mg of aspirin for acute myocardial infarction were randomly assigned to receive fixed dose subcutaneous heparin therapy (12,500 U every 12 h delayed until 4 h after the end of streptokinase therapy [n = 14]) or fixed dose intravenous heparin (5,000-U bolus followed by 1,000-U/h infusion [n = 14]). Anticoagulation was assessed with serial measurements of activated partial thromboplastin time, and thrombin activity by measuring fibrinopeptide A and thrombin-antithrombin III complex levels. Plasma concentrations of creatine kinase (CK) MM isoforms were measured for 3 h to determine recanalization (increase la activity > 0.18%/min).Results. Recanalization occurred in 27%, 64% and 79% of patients given subcutaneous heparin versus 43%, 76% and 86% of those given intravenous heparin at 1, 2 and 3 h, respectively (p = 0.6). Concentrations of fibrinopeptide A (mean ± SEM) at 1 h were higher in patients without (n = 5) than in those with (n = 23) CK-MM isofona criteria for recanalization (76.4 ± 25.7 vs. 25.2 ± 52 nmol/liter, p = 0.02), and at 1, 2 and 3 h were significantly lower with fixed dose intravenous heparin (18.4 ± 4.8 vs. 46.7 ± 102 nmol/liter at 1 h, p = 0.004) than without heparin. After fixed dose subcutaneous heparin at 4 h, fibrinopeptide A levels were similar in both groups despite lower activated partial thromboplastin times in patients who received fixed dose subcutaneous heparin. However, fibrinopeptide A was not consistently suppressed in either group (fixed dose subcutaneous heparin 8.7 ± 1.8 nmol/liter vs. fixed dose intravenous heparin 11.8 ± 5.2 nmol/liter) at 48 h (p = 0.4). No significant changes in the concentration of thrombin-antithrombin III complexes were found between the two groups.Conclusions. Fixed dose intravenous heparin attenuates increases in fibrinopeptide A early after streptokinase. Subsequent fixed dose intravenous and subcutaneous heparin have similar effects but are relatively ineffective in suppressing thrombin activity, suggesting a role for more potent antithrombin agents during coronary thrombolysis with streptokinase.     

Choice of anticoagulant in a congenital antithrombin III (AT III)-deficient patient with chronic renal failure undergoing regular haemodialysis

Summary We describe a 43-year-old male patient with congenital antithrombin III deficiency requiring haemodialysis due to extension of venous thrombus from recurrent deep vein thrombosis. During dialysis with adequate heparinization, the patient often revealed clot formation in the extracorporeal circuit resulting in unexpected discontinuation of dialysis. When either a combination of antithrombin III concentrate plus heparin or the newly developed synthetic antithrombin preparation, MD805, was infused during dialysis, he could be uneventfully dialysed with either of the two regimens. The functional antithrombin III activity with MD805 increased to the same level as that obtained with antithrombin III concentrate, and it was possible to achieve an antithrombotic effect, as measured from the APTT and thrombin-antithrombin III complex with MD805 during and after dialysis. We thus found that MD805 could be used as an anticoagulant drug when an AT III-deficient patient required anticoagulation in the extracorporeal circulation.     

Coagulation activity is increased in the left atrium of patients with mitral stenosis

Objectives. This study investigated the hemostatic status of the right and left atria in patients with mitral stenosis.Background. Systemic thromboembolism is a serious major complication in patients with mitral stenosis. However, the pathogenesis of thromboembolism in mitral stenosis is not fully understood.Methods. We determined the plasma levels of biochemical markers for platelet activity (platelet factor 4 and beta-thromboglobulin) and status of thrombin generation (fibrinopeptide A and thrombin—antithrombin III complex) and fibrinolysis (D-dimer and plasmin—alpha₂-plasmin inhibitor complex) in specimens of blood obtained from the peripheral vein and right and left atria of 12 consecutive patients with mitral stenosis who were undergoing percutaneous mitral valvuloplasty.Results. Plasma levels of platelet factor 4, beta-thromboglobulin, D-dimer and plasmin—alpha₂-plasmin inhibitor complex in the patients did not differ significantly between the right and left atria, whereas levels of fibrinopeptide A and thrombin-antithrombin III complex in the left atrium were significantly higher than those in the right atrium (fibrinopeptide A in the left and right atria 19.35 ± 4.64 and 6.31 ± 0.75 ng/ml [mean ± SE], respectively, p < 0.02; thrombin-antithrombin III complex in the left and right atria 11.45 ± 2.29 and 3.98 ± 0.60 ng/ml, respectively, p < 0.01). Levels of fibrinopeptide A and thrombin-antithrombin III complex in the left atrium did not correlate with mean transmitral gradient, dimension of the left atrium or reciprocal of the mitral valve area. Peripheral blood plasma levels of von Willebrand factor antigen were significantly higher in the patients than in an age-matched control group of normal subjects (168 ± 25% and 99 ± 7%, respectively, p < 0.05) but showed no difference in the peripheral blood and right and left atria of the patients.Conclusions. The coagulation system is activated in the left atrium of patients with mitral stenosis even during anticoagulation.     

Abnormalities in thrombin-antithrombin pathway in AL amyloidosis.

Various pathogenic factors have been proposed to explain the abnormal hemostasis observed in AL amyloidosis. Since imbalance between clotting factors and inhibitors could play a pathogenic role in both hemorrhagic and thrombotic manifestations, we investigated the thrombin-antithrombin pathway in 35 patients with AL amyloidosis. Ten patients suffered from bleeding while 3 patients experienced deep venous thrombosis. Thrombin time was prolonged in 29 subjects, the mean values of antithrombin III activity (ATIII Act) were significantly lower than those of antithrombin III antigen (ATIII Ag) with loss of relationship between these two different techniques of ATIII detection, normally observed in healthy controls. In 19 patients increased levels of thrombin-antithrombin (TAT) complexes were present. Crossed immunoelectrophoresis of ATIII, performed in presence of heparin, evidenced ATIII forms with reduced binding capacity to heparin and TAT complexes of various electrophoretic mobilities. In conclusion, the impairment of the thrombin-antithrombin pathway, in association with the low ATIII biological activity, might play a pathogenic role in the hypercoagulable state reported in AL amyloidosis, despite the higher frequency of bleeding manifestations.     

The coagulation system is activated in idiopathic cardiomyopathy

Objectives. We investigated the plasma levels of molecular markers for platelet activity and the thrombotic and fibrinolytic status in patients with hypertrophic cardiomyopathy and dilated cardiomyopathy to determine the activating site of coagulation in these disorders.

Background. A thromboembolic event is a serious complication in patients with idiopathic cardiomyopathy. However, the activating site of the coagulation system in idiopathic cardiomyopathy has not been fully investigated.

Methods. We determined the plasma levels of molecular markers for platelet activity (platelet factor 4 and beta-thromboglobulin), thrombotic status (fibrinopeptide A and thrombin-antithrombin III complex) and fibrinolytic status (D-dimer and plasmin-alpha₂-plasmin inhibitor complex) in 13 patients with hypertrophic cardiomyopathy, 17 patients with dilated cardiomyopathy and 20 normal subjects.

Results. Plasma levels of platelet factor 4, beta-thromboglobulin and plasmin-alpha₂-plasmin inhibitor complex did not differ significantly among the three groups, whereas plasma levels of fibrinopeptide A and thrombin-antithrombin III complex in both patient groups were significantly higher than those in normal subjects. Plasma levels of D-dimer in patients with dilated cardiomyopathy were significantly higher than those in patients with hypertrophic cardiomyopathy and normal groups. In patients with hypertrophic cardiomyopathy, both fibrinopeptide A and thrombin-antithrombin III complex levels were significantly correlated with left atrial diameter. In patients with dilated cardiomyopathy, fibrinopeptide A and thrombin-antithrombin III complex levels showed a positive correlation with left ventricular end-diastolic volume and a negative correlation with fractional shortening of the left ventricle.

Conclusions. The activated coagulation system in patients with hypertrophic and dilated cardiomyopathy may be triggered by left atrial dilation in hypertrophic cardiomyopathy and left ventricular enlargement and dysfunction in dilated cardiomyopathy.     

Intraperitoneal heparin in peritoneal dialysis and its effect on fibrinopeptide A in plasma and dialysate

In 6 patients on continuous ambulatory peritoneal dialysis we investigated the inhibition of intraperitoneal fibrin formation by heparin. A continuous addition of 500 U of heparin per liter dialysate was used for 52 h. In plasma no heparin activity could be detected, even 52 h after intraperitoneal administration of heparin. The fibrin formation was determined by fibrinopeptide A, a thrombin-induced split product of fibrinogen. In patients under regular continuous ambulatory peritoneal dialysis we determined the fibrinopeptide A concentrations in plasma. The values were comparable with the fibrinopeptide A concentrations measured in disseminated intravascular coagulopathy. They decreased during intraperitoneal administration of heparin from 63.2 +/- 11.8 to 4.9 +/- 1.7 ng/ml. The fibrinopeptide A concentration in the 4-hour intraperitoneal dialysate (155.8 +/- 15.7 ng/ml) decreased after heparin administration to 8.5 +/- 2.0 ng/ml and was always higher than in plasma. We conclude that 500 U heparin per liter dialysate prevents the intraperitoneal fibrin formation. The low antithrombin III concentration (0.44 +/- 0.13 mg/dl) in protein-poor dialysate seems to be sufficient to inhibit the thrombin activity after acceleration by heparin.     

Fibrinopeptide A (FPA) levels in atrial fibrillation and the effects of heparin administration

It has been reported that a patient with atrial fibrillation (AF) is in the hypercoagulable state and that this state results in a high incidence of systemic thromboembolisms. In this paper, we have investigated plasma fibrinopeptide A (FPA) levels and the effects of subcutaneous administration of heparin on these levels in patients with AF. Forty-five patients with hypertension (HT) or mitral stenosis (MS) were classified into four groups according to whether they had AF complications; i.e. HT with normal sinus rhythm (NSR), HT with AF, MS with NSR and MS with AF. Patients with AF demonstrated significantly higher plasma FPA levels and lower plasma antithrombin III (AT III) activities than those with NSR. When low dose heparin was administered to patients with AF, plasma FPA levels were decreased to the near normal range, accompanied by an increase in heparin-AT III complex activity and heparin concentration 0.5-1.0 h after injection. These levels were maintained for 5 h. From these results it was concluded that patients with AF were in the hypercoagulable state and that the measurement of plasma FPA levels provided a possibility to detect the underlying activation of blood coagulation.     

Conformational states of vitronectin: preferential expression of an antigenic epitope when vitronectin is covalently and noncovalently complexed with thrombin-antithrombin III or treated with urea

A difference in recognition of the adhesive glycoprotein vitronectin (also called S-protein, serum spreading factor, and epibolin) by monoclonal antibody 8E6 (Hayman EG, et al, Proc Natl Acad Sci USA 80:4003, 1983) was investigated using a competitive enzyme- immunosorbent assay and immunoaffinity chromatography. Recognition of vitronectin in serum was approximately 50-fold greater than recognition of vitronectin in plasma. Recognition of vitronectin incubated with heparin, thrombin-antithrombin III complex, or heparin and thrombin- antithrombin III complex together was 2.5-, 7-, or 32-fold greater, respectively, than recognition of vitronectin alone. Thrombin or antithrombin III by itself did not induce the antigenic change. Factor Xa-antithrombin III was less effective than thrombin-antithrombin III in induction of the change. Dextran sulfate and fucoidan were more potent than heparin in induction of the antigenic change, whereas dermatan sulfate, hyaluronic acid, heparan sulfate, chondroitin sulfate, or keratan sulfate were less effective. Immunoblotting analysis of serum and of vitronectin incubated with thrombin and antithrombin III demonstrated the presence of complexes composed of vitronectin and thrombin-antithrombin III that could only be dissociated with reducing agent. N-ethylmaleimide completely blocked the formation of the presumably disulfide-bonded complexes and partially blocked the antigenic change. Both non-disulfide-bonded and disulfide-bonded vitronectin bound to antibody-Sepharose from a mixture of vitronectin and thrombin-antithrombin III. Treatment of vitronectin with 8 mol/L urea resulted in enhanced recognition by the monoclonal antibody. Thus, the 8E6 antibody reacts with an epitope that is preferentially expressed by noncovalently and covalently linked vitronectin/thrombin-antithrombin III complexes and by urea-treated vitronectin. The change in vitronectin induced by thrombin-antithrombin III, therefore, is a physiological correlate of urea treatment and of adsorption of vitronectin onto tissue culture plastic (as is done in cell adhesion assays). The change may be important for expression of vitronectin activity.     

Venous thrombosis in a family with defective release of vascular plasminogen activator and elevated plasma factor VIII/von Willebrand's factor

A family is described in which venous thrombosis developed in five members as early as 14 years of age. Routine coagulation studies, plasma antithrombin III, factor V, plasminogen, beta-thromboglobulin, fibrinopeptide A, prothrombin fragment F1+2, and thrombin-antithrombin III complex were all within normal limits. However, defective release of vascular plasminogen activator was observed on several occasions in all five subjects as compared with a control population of 125 persons (0.04 Committee on Thrombolytic Agents [CTA] units/ml plasma as compared with 0.21 CTS units/ml). In addition, levels of factor VII/von Willebrand's factor were significantly elevated above the normal range in this pedigree.     

Hereditary antithrombin III deficiency: case report and review of recent therapeutic advances

We report on a newly diagnosed family with hereditary antithrombin III deficiency, with thromboembolic complications in the propositus. Both the propositus and his asymptomatic sister had decreased plasma levels of antithrombin III antigen and activity (28-52% of normal with good agreement between functional and immunologic assays). The propositus developed deep venous thrombosis, followed by massive pulmonary emboli despite heparin therapy and was treated with streptokinase and heparin with excellent results. Shortly thereafter, small bowel obstruction required surgical intervention, and antithrombin III concentrate, recently available in the United States as an investigational new drug (I.N.D.), was administered with no postoperative thrombotic complications. He was subsequently asymptomatic while on warfarin prophylaxis but twice developed venous thrombosis when he failed to take warfarin. The addition of danazol therapy led to a sustained rise in the antithrombin III level. Each of these therapeutic approaches is discussed and the literature reviewed with emphasis on the newer agents--streptokinase, antithrombin III concentrate, and danazol.     

Acquired alpha-2-antiplasmin deficiency in acute promyelocytic leukaemia

We report a prospective study in nine consecutive adult patients with acute promyelocytic leukaemia (APL). The study objective was to assess the prevalence of activation of blood coagulation and/or activation of fibrinolysis in APL. Coagulation and fibrinolytic parameters relevant to the objective included antithrombin III, plasminogen, fibrin/fibrinogen degradation products and alpha-2 antiplasmin activity and antigen levels. The results of this study revealed consistently normal antithrombin III levels, both before and in the course of antileukaemic treatment. Plasminogen levels were slightly decreased or normal. However, a distinct alpha-2 antiplasmin activity deficiency in all patients was observed with levels even reaching zero in three patients, during chemotherapy. Alpha-2 antiplasmin activity levels were consistently lower than the alpha-2 antiplasmin antigen levels. The in vitro binding of alpha-2 antiplasmin activity to fibrin clots was severely reduced which appeared to be due to the reduced alpha-2 antiplasmin plasma levels. Upon crossed-immunoelectrophoresis against alpha-2 antiplasmin antiserum two alpha-2 antiplasmin antigen peaks were observed in the plasma of all nine patients. All abnormalities were reversible 4 d after completion of chemotherapy. In a second series of 12 consecutive APL patients we confirmed the consistency of the alpha-2 antiplasmin activity deficiency and normal antithrombin III plasma levels. In addition Protein C activity and antigen levels were normal or near normal in 10 and reduced in two patients. Thrombin-antithrombin III complexes were increased in 10 and normal in two patients. We conclude that some activation of blood coagulation is present in APL (increased thrombin-antithrombin III complex levels) but its contribution to the coagulopathy seems to be minor (normal antithrombin III and only slightly reduced protein C levels). The observed reduced alpha-2 antiplasmin content of the fibrin clot in vitro may result in vivo in a fibrin clot that is highly susceptible to fibrin degradation, thus aggravating the coagulopathy in APL.     

Hemostatic molecular markers in nephrotic syndrome

Quantitative changes of hemostatic molecular markers were studied in patients with nephrotic syndrome. The plasma levels of fibrinopeptide A (FPA), thrombin-antithrombin III complex (TAT), products of thrombin activation, and fragment F1 + 2 (F1 + 2), a product of prothrombin activation, were measured by enzyme immunoassay in 21 patients with nephrotic syndrome and in 16 normal controls. The mean value of FPA was 17.5 ± 7.5 ng/ml (mean ± SD) in nephrotic patients and 4.5 ± 0.3 ng/ml in normal controls (P < 0.02); F1 + 2 concentration was 1.4 ± 0.3 ng/ml in nephrotic patients and 0.5 ± 0.1 ng/ml in normal controls (P < 0.001); TAT level was 1.0 ± 0.3 μg/l in nephrotic patients and 0.2 ± 0.1 μg/l in normal controls (P < 0.05). These data indicated intravascular hemostasis activation. Based on these results, we propose that low antithrombin III level in nephrotic patients may be due to both urinary loss and intravascular consumption. © 1993 Wiley-Liss, Inc.     

An abnormal antithrombin III (AT III) with low heparin affinity: AT III Clichy

We have identified an inherited qualitative deficiency of antithrombin III (AT III) in a family with apparently no increased incidence of venous thrombosis. Plasma antithrombin and anti-Xa activities were normal, but the interaction with heparin, heparan sulphate and low molecular weight heparin was uniformly decreased. An immunoblotting technique performed in plasma showed normal complex formation with thrombin. By using heparin-Sepharose affinity chromatography and crossed immunoelectrophoresis, the variant could be separated: at least two fractions of low affinity AT III were obtained. A minor one had no antiprotease activity; the other one was further purified to homogeneity and found to have normal specific activity in absence of heparin and a 50% decreased activity in presence of heparin. We propose to call this new variant AT III Clichy.     

Biochemical markers of coagulation activation in mitral stenosis,atrial fibrillation,and cardiomyopathy

Advances in the understanding of the biochemistry of the mechanism of hemostasis have led to the development of sensitive methods for determining levels of markers which reflect thrombin activity (thrombin-antithrombin III complex, fibrinopeptide A, F1+2 fragment), active fibrinolysis (D-dimer, plasmin-α2-plasmin inhibitor complex), and platelet activity (platelet factor 4, ß-thromboglobulin) in vivo. Measurement of these markers may be useful in identifying patients with various cardiovascular disorders at high risk of thromboembolism.     

Coagulation inhibitor levels in pneumonia and stroke: changes due to consumption and acute phase reaction

The well-known coagulation inhibitors antithrombin and protein C, and the more recently described inhibitors, heparin cofactor II and extrinsic pathway inhibitor, were measured in plasma during a 7-day observation period, from patients with pneumonia (n = 13), and in stroke patients with infarction (n = 9) and haemorrhage (n = 9). In patients with pneumonia, elevated fibrinopeptide A levels and subnormal antithrombin and protein C levels suggested some degree of consumption of the inhibitors. Later, an increase was observed for all the inhibitors, but was most conspicuous for heparin cofactor II which reached high normal values. C-reactive protein, initially markedly elevated, decreased rapidly. This finding suggests that heparin cofactor II might act as a delayed acute phase reactant. In stroke patients only small, not statistically significant, changes occurred during the observation period, except for heparin cofactor II which increased in patients with haemorrhagic stroke.     

Effects of local heparin administration on coronary thrombin activity during percutaneous transluminal coronary angioplasty.

Simultaneously obtained blood samples from the coronary sinus and systemic arterial circulation were analyzed for antithrombin III (ATIII) activity and fibrinopeptide A (FpA) concentration in nine patients undergoing elective PTCA in order to determine the effects of locally delivered heparin. Samples were obtained at the following designated times: prior to the administration of systemic heparin (period I); 5 min following a loading dose of systemic heparin (period II); 5 min following the final balloon inflation but prior to local delivery (period III); and 5 min following the administration of 4,000 units of unfractionated heparin using a local delivery catheter system (period IV). We found consistent increases in both systemic arterial (P = 0.006) and coronary sinus (P = 0.0002) ATIII activity with systemic heparinization designed to prolong the activated clotting time to 300 sec. However, local delivery of heparin further increased coronary sinus ATIII activity (P = 0.003, period III vs. period IV). FpA concentration decreased in both systemic arterial (P < 0.0001) and coronary sinus (P < 0. 0001) samples following systemic heparinization. Moreover, local delivery of heparin further decreased coronary sinus FpA concentration (P = 0.04). Thus, on a background of intense anticoagulation during PTCA, the local delivery of 4,000 units of unfractionated heparin confers incremental antithrombotic activity. Cathet. Cardiovasc. Intervent. 48:84-88, 1999.