Common Coagulation Pathway Research Articles

Effect of Tumor Necrosis Factor in Normal Subjects

To the Editor: Considering that there is now a consensus on the central role of tumor necrosis factor in the pathogenesis of septic shock, the study by van der Poll et al. (June 7 issue),1 in which normal subjects were administered tumor necrosis factor, is both timely and important. I agree with their deduction — based on the increased levels of the activation peptide of factor X and prothrombin fragment F1+2 — that the common coagulation pathway is probably activated initially by tissue factor. However, their conclusion that the intrinsic pathway, particularly the contact system, was not activated is.

Activation of Coagulation after Administration of Tumor Necrosis Factor to Normal Subjects

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.

An Overview of Hemostasis

The normal hemostatic system is complex yet exquisitely well regulated. Interrelationships exist between responses of the vasculature, circulating platelets, coagulation proteins, and fibrinolytic mechanism. These relationships serve to limit blood loss, preserve tissue perfusion, and stimulate local repair processes. Natural inhibitors of coagulation and fibrinolysis modulate these systems to prevent uncontrolled thrombosis or hemorrhage following pathologic stimuli. Vascular endothelial cells play an important role in the maintenance of a thromboresistant luminal interface with circulating cells and proteins. Normal hemostasis also requires the synthetic, metabolic, and repair processes of the vascular endothelium. The initial vascular response to injury produces brief vasoconstriction and exposes subendothelial substances that attract circulating platelets and activate coagulation proteins. Platelets respond by adherence and aggregation at the site of injury, with subsequent release of substances that mitigate blood loss. Platelet adherence to collagen requires von Willebrand's factor, fibrinogen, fibronectin, and specific glycoprotein receptors on platelet surfaces. Platelet-to-platelet interactions (aggregation) recruit additional platelets to the primary hemostatic plug. Aggregation requires fibrinogen, energy, and calcium. Release of ADP, serotonin, and the contents of intracellular granules as well as generation of prostaglandins prepares platelet surfaces for reactions with the coagulation proteins. Activation of the intrinsic or extrinsic coagulation pathway, or of both, causes formation of fibrin from fibrinogen by means of an elaborate and intricate system that also entraps platelets and activated coagulation proteins. The intrinsic system is activated by the contact of factor XII with a negatively charged surface, most likely collagen. Through a series of reactions with prekallikrein, HMWK, and factors XI, IX, and VIII, the common coagulation pathway is propagated. The extrinsic, or tissue factor, system stimulates both the common pathway and factor IX the intrinsic pathway. Discovery of this stimulation of the intrinsic pathway by factor VII in the extrinsic pathway has stimulated reassessment of the biologic importance of the extrinsic system. The common pathway includes factors X and V and causes thrombin to convert fibrinogen to fibrin. Calcium and platelet phospholipids are substances that have important roles in steps in the coagulation scheme. Once fibrin is formed, factor XIII interacts with the substance, providing a stabilizing effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Extrinsic and common coagulation pathways in end-stage renal disease associated with spinal cord injury.

Data on the effects of combined long-standing spinal cord injury (SCI) and end-stage renal disease (ESRD) on blood coagulation system are limited. We studied the extrinsic and common pathways of blood coagulation system in 9 men with SCI-ESRD treated with maintenance hemodialysis. Plasma procoagulant activities of factors (F)VII, X and II were measured in a clotting assay using appropriate deficient plasmas as substrate. In addition, the antigen concentration of FII was measured using monospecific antibodies against human FII raised in goat in a gradient plate immunodiffusion system. Also measured were plasma fibrinogen concentration and platelet count. The results were compared with those obtained in a group of 10 ambulatory ESRD patients and 8 normal control volunteers. Plasma coagulant activity of FVII was markedly elevated and plasma fibrinogen concentration was moderately increased in SCI-ESRD patients. In contrast, plasma FII was mildly depressed while platelet count was within normal limits in SCI-ESRD patients. The data indicate that the combination of SCI and ESRD can lead to the alteration of the extrinsic and common coagulation pathways. Further studies are needed to elucidate the precise mechanism and the clinical significance of the observed abnormalities.

Blood coagulation parameters in clinically normal intensively farmed red deer(Cervus elaphus)and fallow deer(Dama dama)

Reference ranges for five parameters of blood coagulation were established in clinically normal farmed fallow deer (Dama dama) and red deer (Cervus elaphus). Storage of plasma at -15 degrees C resulted in small increases in activated partial thromboplastin time (APTT) for both species, and in the one stage prothrombin time (OSPT) of fallow deer, between days 1 and 30. These times were then stable between days 30 and 60. The fibrinogen levels of fallow deer plasma showed a small apparent increase over 60 days. These storage artefacts were not of sufficient magnitude to preclude the use of such plasma for diagnostic purposes although they could limit its use in research. Levels of fibrin/fibrinogen degradation products (FDP) were not affected by storage at -15 degrees C. Rabbit brain thromboplastin appeared adequate for OSPT determination in both species. The activated clotting time (ACT) is recommended as a field test for screening the intrinsic and common pathways of blood coagulation in deer.

Neurology and the lupus anticoagulant.

The lupus anticoagulant, an immunoglobulin of the IgG or IgM class, is one of a group of antiphospholipid antibodies. Although an anticoagulant in vitro, its action in vivo is that of a procoagulant. This procoagulant activity may involve many organ systems including the nervous system. Thus far cerebral thrombosis, spinal thrombosis, chorea and Guillain-Barré syndrome have been described in association with the lupus anticoagulant. Although the lupus anticoagulant is an uncommon cause of neurological disease, it must be considered, especially in a setting of a prolongation of the common pathway of coagulation, thrombosis and other autoimmune phenomena.

Effect of the polyene antibiotic filipin on the lipid-dependent intrinsic pathway of blood coagulation.

Clotting along the intrinsic pathway can be inhibited by the polyene antibiotic filipin. Besides inhibition of the prothrombinase complex (in the common pathway of intrinsic and extrinsic coagulation) a clot-delaying effect depending on the cholesterol content of the lipid for the formation of the factor VIII-IX lipid complex was found. The adsorption of factors VIII and IXa onto lipids is slightly enhanced by filipin. This phenomenon does not lead to an increase of factor X-converting activity.