Hemostatic balance during the acute inflammatory reaction. (II). With special reference to plasma protein C.

While plasma fibrinogen level and clotting factor VIII activity obviously increased during the acute inflammatory reaction caused by intramuscular injections of turpentine in 10 rabbits, the activity of plasma protein C, with anticoagulant and antithrombotic effects, was found to display a slight yet significant (p < 0.02) decrease. When compared to protein C activity in humans, this vitamin K-dependent serine protease was found to be lower in rabbits (52, 7% +/- 3,63 of standard human plasma) and this activity decreased to 45,8% +/- 2,80 (mean +/- SEM), 48 hours after the injection of turpentine. This slight decrease should however be interpreted in the context of other disturbances of the hemostatic balance caused by inflammation and may contribute to the intravascular deposition of fibrin.

Plasma protein S-antigen (PS:Ag) in selected disease states.

Protein S is a vitamin K-dependent glycoprotein acting as a cofactor for activated protein C and thereby exerting an antithrombotic effect. When compared to values recorded in the 10 healthy normal weight normolipidemic control subjects (80.1% +/- 5.16; mean +/- SEM), plasma protein S-antigen (PS:Ag) level was found to be significantly (p < 0.01) decreased in the 11 patients with decompensated cirrhosis of the liver (54.72% +/- 4.89) and in the 12 surgical patients in critical condition (59.2 +/- 4.96), while obviously (p < 0.001) increased plasma levels were noted in the group including 20 overweight and hyperlipidemic subjects (113% +/- 3.1). Since the low PS:Ag level was associated with a decreased serum cholinesterase (CHE) activity, while both plasma PS:Ag and serum CHE activity were increased in overweight and hyperlipidemic subjects it is considered that impaired or respectively enhanced hepatic protein synthesis is at least partially responsible for changes affecting this antithrombotic plasma protein.

Plasma von Willebrand factor and antithrombin III in patients submitted to open heart surgery.

Cardiovascular surgery for valve replacement led to a significant (p < 0.001) increase of plasma von Willebrand factor antigen level from 227% +/- 30.9 (x +/- SEM) recorded before surgery, to 397% +/- 40.7 at the end of the surgical procedure and the levels of this endothelia-derived glycoprotein remained high (427% +/- 38.9) 48 hours later. On the other hand plasma antithrombin III activity decreased from 85.4% +/- 8 before surgery, to 67.0% +/- 6 at the end of the surgical intervention and rose to 81.3% +/- 7, two days later. Lethal outcome occurred in a patient with initial low antithrombin III level (62%). These observations stress the importance of a thorough investigation of hemostatic variables in patients submitted to cardiovascular surgery.

Clinical studies on plasma protein C. Correlation with serum cholinesterase.

When compared to 32 healthy normal weight normolipidemic control subjects, plasma protein C antigen and serum cholinesterase activity were significantly decreased in 17 patients with decompensated cirrhosis of the liver and in 29 critically-ill surgical patients displaying the acute phase reaction, most of them without evidence of consumption coagulopathy. The low levels of these variables are considered to be subsequent to impaired and dysregulated hepatic protein synthesis. On the contrary, plasma protein C and serum cholinesterase were increased in 20 nephrotic patients and in 20 overweight hypertriglyceridemic subjects, a finding highly suggestive of enhanced hepatic synthesis probably related to an accelerated turnover of triglycerides. A discrepancy between low serum cholinesterase activity and normal or even high plasma protein C antigen was noted in 15 patients with cholestasis. This was particularly evident in 7 subjects with extrahepatic cholestasis and an abnormal pattern of hepatic protein synthesis or impaired clearance of plasma protein C would appear to develop in such pathological conditions.

Plasma protein C and antithrombin III in patients with acute leukemia.

When compared to values recorded in the 32 healthy control subjects, plasma protein C activity was found to be significantly decreased in the 29 patients with acute leukemia and especially in those considered to be in a critical condition. On the other hand, plasma antithrombin III activity did not significantly differ from the values noted in control subjects. The concomitantly occurring high plasma fibrinogen levels and low serum cholinesterase activity were highly suggestive for a switch of hepatic protein synthesis towards the production of acute phase proteins. It is therefore considered that in the absence of a consumption coagulopathy, changes affecting plasma protein C and antithrombin III should be related to a modified pattern of hepatic protein synthesis.

Acute phase reaction and the hemostatic balance.

Data in the literature as well as authors own observations concerning a possible relationship between the acute phase reaction and changes of the hemostatic variables, which may favour or trigger a thrombotic event, are reviewed. Acute phase reaction is usually accompanied by increased plasma levels of fibrinogen, von Willebrand factor and clotting factor VIII, while endothelial cells in culture added proinflammatory cytokines were found to express tissue factor activity, to release von Willebrand factor and to increase the production of plasminogen activator inhibitor. Evidence is also provided that inflammation would lead to an increase of plasma antithrombin III while the protein C system is down regulated. It is also considered that the above-mentioned changes of hemostatic variables would favour the local deposition of fibrin and platelets while attempting to prevent an intravascular dissemination of fibrin formation.

Increased plasma factor VIII:c activity in patients with unstable angina pectoris.

Plasma factor VIII:c activity was found to be significantly (p < 0.01) higher in the 17 patients with unstable angina pectoris (201% +/- 121; x +/- SD) than in the 10 healthy control subjects (97% +/- 16). Plasma fibrinogen level was also significantly (p < 0.003) higher in patients (455 mg/dl +/- 188) than in controls (260 mg/dl +/- 35) but there was no significant correlation between these two variables within the group of patients with unstable angina. No difference could be noted between plasma antithrombin III activities in patients and in controls. It is considered that the increased factor VIII:c activity in patients with unstable angina pectoris could be subsequent to the acute phase reaction induced by cytokines and/or by an enhanced adrenergic stimulation, although the possible presence of genetically-conditioned hyperactive factor VIII:c molecules can not be excluded. Since the outcome of a ruptured plaque may also depend on the systemic thrombotic propensity at the time of rupture, the presently reported findings could be pathogenically relevant.