Original Article
Activation of Coagulation after Administration of Tumor Necrosis Factor to Normal Subjects
N Engl J Med 1990; 322:1622-1627June 7, 1990
- Abstract
- Abstract
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 μg 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<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. (N Engl J Med 1990; 322:1622–7.)
Media in This Article
Figure 1
Mean (±SEM) Plasma Levels of Factor X Activation Peptide and the Prothrombin Fragment F1+2 and Serum Levels of Tumor Necrosis Factor after Intravenous Bolus Injections of Recombinant Human Tumor Necrosis Factor (50 μg per Square Meter; Solid Circles) or an Equivalent Volume of Isotonic Saline (Open Circles).Table 1
Indexes of Activation of the Intrinsic Pathway of Coagulation during the First 45 Minutes after the Administration of Recombinant Human Tumor Necrosis Factor.*Article Activity
- Article
SEPTICEMIA is frequently associated with disturbances of hemostatic balance. Disseminated intravascular coagulation, with widespread depositions of fibrin in the microvasculature, is commonly found in septic shock and is closely linked to the development of multiple organ failure.1 The mechanism by which the clotting cascade is activated during septicemia is incompletely understood.
Recently, it has become apparent that the cytokine known as tumor necrosis factor has a pivotal role in the initiation of the septic syndrome. Tumor necrosis factor is secreted by monocytes and macrophages in response to various stimuli, of which endotoxins, derived from gram-negative bacteria, are the most potent.2 , 3 Systemic release of tumor necrosis factor occurs soon after the injection of endotoxin in healthy volunteers,4 and high levels of the factor have been detected in patients with sepsis.5 , 6 In laboratory animals, recombinant tumor necrosis factor induces the septic syndrome,7 , 8 whereas passive immunization against tumor necrosis factor prevents death in experimental models of sepsis.9 , 10
In cultured endothelial cells, tumor necrosis factor exerts a net procoagulant effect by enhancing the expression of tissue factor11 12 13 and inhibiting the fibrinolytic response by suppressing the release of tissue-type plasminogen activator and inducing the secretion of plasminogen activator inhibitor Type I.14 15 16 Moreover, the activation of protein C becomes impaired by down-regulation of thrombomodulin.11 , 17 , 18 The infusion of high doses of recombinant tumor necrosis factor in dogs results in microvascular thrombosis.8 In patients with meningococcal sepsis, the plasma levels of tumor necrosis factor are proportional to the extent of intravascular coagulation.6 Hence, both in vitro and in vivo investigations have suggested that tumor necrosis factor is an important mediator of the activation of coagulation in septicemia.
In recent years tumor necrosis factor has been evaluated as an antineoplastic agent, given in low doses to patients with metastatic cancer. Bauer et al. confirmed the procoagulant effect of tumor necrosis factor in such patients by using highly sensitive and specific radioimmunoassays that permit the detection of in vivo activation of the hemostatic mechanism at the subnanomolar level (i.e., detection of the prothrombin fragment F1+2 and fibrinopeptide A).19 The early events of the coagulative response could not be determined, however, since the first coagulation studies were performed three hours after the start of a continuous infusion of tumor necrosis factor. Moreover, a procoagulant state already existed before treatment with tumor necrosis factor, as indicated by elevated plasma levels of F1+2 and fibrinopeptide A at base line.19 The aim of the present study was to investigate the early dynamics and route of coagulation activation after the administration of recombinant tumor necrosis factor. Therefore, we performed a controlled study in six healthy male subjects, sequentially measuring indexes of the activation of the common and intrinsic pathways of coagulation.
Methods
The study was approved by the institutional research and ethics committees of the Academic Medical Center, University of Amsterdam, and written informed consent was obtained from all subjects. All subjects were admitted to the Metabolic Research Ward.
Study Design
Six healthy men 27 to 33 years of age volunteered to participate in the study. None had abnormalities on physical examination or routine laboratory investigation. They did not use medications and had had no febrile illness in the month before the study. The study periods were 12 hours in length, starting at 7:30 a.m. The subjects fasted overnight until the end of each study period. Each subject was studied on two occasions at least three weeks apart. In one study period, a bolus intravenous injection of recombinant human tumor necrosis factor (50 μg per square meter of body-surface area) dissolved in 10 ml of isotonic saline was given; in the other period an equivalent volume of isotonic saline was administered. The order in which the two injections were given was determined randomly.
Mean arterial blood pressure and pulse rate were measured at 15-minute intervals with a Dinamap monitor (Critikon, Tampa). Temperature was recorded continuously by means of a rectal cannula (Hewlett—Packard, Boeblingen, Federal Republic of Germany).
Recombinant human tumor necrosis factor was kindly provided by Boehringer—Ingelheim (Ingelheim am Rhein, Federal Republic of Germany). It was more than 99 percent pure, as determined by sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and contained less than 10 ng of endotoxin per milligram of protein, as tested by the limulus amebocyte lysate test.
Blood Collection
Venous blood samples were obtained by separate venipunctures, with use of 19-gauge butterfly needles, directly before the injection of recombinant tumor necrosis factor or isotonic saline and 15, 30, and 45 minutes and 1, 2, 3, 4, 5, 6, and 12 hours thereafter.
Blood for the measurement of factor IX activation peptide, factor X activation peptide, and F1+2 was collected in plastic syringes loaded with the following anticoagulant: 38 mM citric acid, 75 mM sodium citrate, 136 mM dextrose, 6 mM EDTA, 6 mM adenosine, and 25 U of heparin per milliliter. The ratio of anticoagulant to blood was 0.2:1.0 (vol/vol). After collection of the blood samples, plasma was obtained by centrifugation at 4°C for 30 minutes at 1600×g and stored at —70°—C before measurement. Blood for the measurement of fibrinogen was collected in tubes loaded with 32 g of trisodium citrate dihydrate per liter (1 to 9 ml of blood) and centrifuged at 1600×g for 20 minutes at room temperature. The plasma samples were stored at —70°C until analyzed.
Blood for the determination of factor XII, prekallikrein, factor XIIa—C1 inhibitor complexes, and kallikrein—C1 inhibitor complexes was collected in siliconized Vacutainer tubes (Becton Dickinson, Plymouth, England), to which EDTA (10 mM) and Polybrene (0.05 percent, wt/vol) were added to prevent any in vitro activation of the contact system.20 The tubes were centrifuged at room temperature for 10 minutes at 1300×g, and the plasma was aliquoted and stored in polystyrene tubes at — 70°C until the tests were performed. Blood for the determination of platelet counts was collected in tubes loaded with EDTA tripotassium and analyzed immediately. Tumor necrosis factor was measured in serum samples obtained immediately before the injection of recombinant tumor necrosis factor and saline and 5, 10, 15, 30, 45, 60, 120, 180, and 240 minutes thereafter. The serum samples were frozen immediately and kept frozen until assayed.
Assays
The plasma levels of factor IX activation peptide, factor X activation peptide, F1+2, factor XII, prekallikrein, factor Xlla—C1 inhibitor complexes, and kallikrein—C1 inhibitor complexes were determined by radioimmunoassays as described elsewhere.21 22 23 24 25 Plasma fibrinogen concentrations were measured with a turbidimetric method (ChromoTimeSystem, Behringwerke, Marburg, Federal Republic of Germany).26 The plasma concentrations of factor IX activation peptide and factor X activation peptide are given in picomoles per liter, those of F1+2 in nanomoles per liter, and the plasma fibrinogen values in grams per liter. Plasma levels of factor XII and prekallikrein are expressed as units per milliliter of plasma, by reference to pooled plasma from healthy donors that contains one unit of both factor XII and prekallikrein per milliliter. The plasma values of factor XIIa—C1 inhibitor complexes and kallikrein—C1 inhibitor complexes are expressed as units per milliliter of plasma, by reference to dextran sulfate plasma, pooled from healthy donors, that contains one unit of both factor XIla—C1 inhibitor complexes and kallikrein—C1 inhibitor complexes per milliliter.25 The radioimmunoassays for these Cl-inhibitor complexes can detect the activation of 0.05 percent of plasma factor XII or prekallikrein.25 All samples obtained for measurement of the activation of the common and intrinsic pathway of coagulation were assayed in one to four runs. Each run contained both samples from the subjects given saline and samples from subjects given tumor necrosis factor, and care was taken that all the samples from one subject were assayed in the same run. The interassay coefficients of variation of the assays used were as follows: factor IX activation peptide, 12 percent21; factor X activation peptide, 12 percent22; F1+2, 8 percent19; factor XII and prekallikrein, <10 percent25; factor XIIa—C1 inhibitor complexes and kallikrein—C1 inhibitor complexes, <9 percent25; and fibrinogen, <9 percent.26
Platelet counts were determined with the use of a flow cytometer (Technicon HI system, Technicon Instruments, Tarrytown, N.Y.). Serum levels of tumor necrosis factor were determined by immunoradiometric assay (Medgenix, Fleurus, Belgium). Polypropylene tubes were coated with a combination of monoclonal antibodies to recombinant tumor necrosis factor that recognize distinct epitopes of tumor necrosis factor. These tubes were incubated overnight with a mixture of the sample to be tested and anti—tumor-necrosis-factor antibody labeled with iodine-125. After decantation, the bound fraction was counted in a gamma counter, and the level of tumor necrosis factor was expressed in picograms per milliliter in relation to a standard binding curve for recombinant human tumor necrosis factor.
Statistical Analysis
Values are given as means ±SEM. Differences in results between the tumor necrosis factor and saline experiments were tested by analysis of variance and Student's paired t-test, as indicated. A P value <0.05 was considered to represent a significant difference.
Results
Clinical Features
Tumor necrosis factor induced severe headache and nausea in all subjects, accompanied by vomiting in three subjects. The symptoms started as early as 10 minutes after the injection and lasted several hours. No significant changes in hemodynamic indexes were observed, and all subjects had recovered fully by the end of the experiment. Each subject had a rise in body temperature, preceded by chills. Peak temperatures (38.7±0.2°C) were reached after three hours. None of these changes were noted during the control period, in which saline was administered.
Common Pathway of Coagulation
The activation of the common pathway of coagulation was monitored by the determination of plasma levels of factor X activation peptide, the prothrombin fragment F1+2, and fibrinogen. The base-line values for these indexes of coagulation activation were similar in both study periods. The plasma levels of factor X activation peptide and F1+2 remained unchanged during the control period. As compared with saline, tumor necrosis factor induced an early and transient increase in plasma concentrations of factor X activation peptide (P = 0.015 by analysis of variance; Fig. 1Figure 1
Mean (±SEM) Plasma Levels of Factor X Activation Peptide and the Prothrombin Fragment F1+2 and Serum Levels of Tumor Necrosis Factor after Intravenous Bolus Injections of Recombinant Human Tumor Necrosis Factor (50 μg per Square Meter; Solid Circles) or an Equivalent Volume of Isotonic Saline (Open Circles).). Maximal plasma levels of factor X activation peptide were reached 30 to 45 minutes after the injection of tumor necrosis factor (from 67.6±8.1 pmol per liter at base line to 86.6±9.1 pmol per liter at 45 minutes; mean increase, 34.2±18.2 percent). The administration of tumor necrosis factor was also associated with a significant increase in levels of Fl+2, as compared with saline (P<0.0001 by analysis of variance) (Fig. 1). This more gradual increase became apparent after one hour. Peak plasma levels of F1+2 were observed after four to five hours (from 1.14±0.30 nmol per liter at base line to 3.66±0.77 nmol per liter at five hours; mean increase, 348.0± 144.8 percent). Thereafter, the plasma levels of F1+2 decreased gradually but were still elevated 6 to 12 hours after the injection of tumor necrosis factor. The plasma concentrations of fibrinogen did not change after the injection of either tumor necrosis factor or saline (data not shown).Intrinsic Pathway of Coagulation
During the entire observation period, the circulating levels of factor XIIa—C1 inhibitor complexes and kallikrein—C1 inhibitor complexes, both of which reflect activation of the contact system, as well as the plasma values of factor XII and prekallikrein, the zymogen proteins of the contact system, remained within the normal range after the administration of both tumor necrosis factor and saline. In addition, during the 12 hours of the study, plasma levels of factor IX activation peptide, a measure of in vivo activation of factor IX, were not significantly affected by tumor necrosis factor as compared with saline.
Table 1Table 1
Indexes of Activation of the Intrinsic Pathway of Coagulation during the First 45 Minutes after the Administration of Recombinant Human Tumor Necrosis Factor.* shows the results for the indexes of intrinsic-pathway activation during the first 45 minutes after the administration of tumor necrosis factor, in which factor X activation was maximal.Platelet Counts
The platelet counts showed no significant changes after the injection of either tumor necrosis factor or saline (data not shown).
Serum Levels of Tumor Necrosis Factor
Tumor necrosis factor was not detectable in serum obtained before the injections of tumor necrosis factor or saline or in the serum samples collected during the control period. After the injection of tumor necrosis factor, the highest serum level of this factor was measured in the first blood sample, taken after five minutes (4261 ±785 pg per milliliter). Thereafter, serum levels of tumor necrosis factor decreased rapidly (Fig. 1).
Discussion
Tumor necrosis factor is a polypeptide hormone with a wide range of biologic activities. Its role as a crucial mediator of septic shock has been well established. Several studies suggest that tumor necrosis factor may also be implicated in the induction of coagulation activation seen in septicemia. The recent development of a unique set of highly sensitive and specific radioimmunoassays that monitor the transitions of coagulation-system zymogens to serine proteinases allowed us to study the dynamics of the in vivo procoagulant effect of low-dose tumor necrosis factor (50 μg per square meter) at the subclinical level. It was demonstrated that a single intravenous bolus injection of recombinant tumor necrosis factor induced a rapid activation of the common pathway of the coagulation system in healthy subjects, as indicated by a brief increase in plasma levels of factor X activation peptide, peaking after 30 to 45 minutes, followed by a gradual increase in the plasma levels of the prothrombin fragment F1+2, which remained elevated for 6 to 12 hours.
Factor X activation peptide is liberated from factor X during the proteolytic cleavage of this zymogen by factor IXa or the factor Vila—tissue factor complex,22 representing activation by the intrinsic and extrinsic routes, respectively. The F1+2 fragment is released from prothrombin during its conversion to thrombin.23 , 24 Therefore, these peptides directly monitor the in vivo activation of factor X and prothrombin. Since tumor necrosis factor does not affect the metabolic behavior of F1+2,19 the elevation in the level of this fragment must have resulted from the excessive activity of factor Xa on prothrombin. Although the influence of tumor necrosis factor on the turnover of factor X activation peptide has not been examined, it is likely that the increase in this activation peptide was also caused by enhanced production.
Historically, common-pathway activation is supposed to proceed by either the intrinsic or extrinsic route. The intrinsic route is initiated by the activation of the contact system, during which the zymogens factor XII and prekallikrein are converted to factor XIla and kallikrein, respectively.27 These enzymes are rapidly inactivated by circulating proteinase inhibitors, of which C1 inhibitor is the most important. In patients with sepsis, decreased plasma levels of factor XII and prekallikrein25 , 27 and increased levels of factor XIIa—C1 inhibitor complexes and kallikrein—C1 inhibitor complexes25 have been reported, and they are interpreted to indicate contact activation. In the present study, the plasma levels of these zymogens and proteinase-inhibitor complexes remained within the normal range after the injection of tumor necrosis factor, indicating that the contact system was not stimulated. The absence of intrinsic-route activation was further supported by the observation that the plasma levels of factor IX activation peptide, a fragment formed during the conversion of factor IX to factor IXa and thus indicative of in vivo activation of factor IX,21 were not significantly affected by the administration of tumor necrosis factor. The noninvolvement of the contact system in the activation of coagulation after the low-dose injection of tumor necrosis factor may indicate that although there is evidence that the contact system is activated in the course of septicemia, it is not required for the initiation of the coagulative response.
Since the intrinsic pathway was not activated in our experiment, the generation of factor Xa that we observed must have been the result of activation of the extrinsic route or alternative pathways. The extrinsic route is initiated by the expression of tissue-factor activity. Evidence for the in vivo induction of the extrinsic route in septicemia has been provided by the observation of increased tissue-factor activity in the monocytes of patients with meningococcal infection.28 Under in vitro conditions, tumor necrosis factor can stimulate the synthesis of tissue factor in endothelial and mononuclear cells, but this effect becomes apparent only after several hours.11 12 13 , 29 However, recent immunohistochemical studies have detected substantial expression of tissue factor in the vascular tunica adventitia, which is anatomically sequestered from blood.30 The rapid generation of factor Xa observed in our study may have been the result of the exposure of this subendothelial tissue factor to plasma proteins, facilitated by increased vascular permeability induced by tumor necrosis factor.31 , 32 The activation of the common pathway, however, could be the result of direct proteolytic cleavage of factor X by an alternative mechanism. It has been demonstrated that factor X can be rapidly bound to the adhesive receptor Mac-1 (a component of the CD 11/18 complex) on stimulated monocytes and subsequently activated.33 Tumor necrosis factor elicits the expression of the CD11/18 complex,34 but whether this enables factor X to be activated is currently unknown.
Peak plasma levels of F1+2 were reached two to five hours after the maximal plasma concentrations of factor X activation peptide, indicating a delay between the maximal activation of factor X and that of prothrombin. Given that the plasma half-lives of factor X activation peptide and F1+2 are relatively short (15 and 90 minutes, respectively22 , 35), our results indicate that the activation of prothrombin continued even though the generation of factor Xa had already returned to the levels observed before the administration of tumor necrosis factor. Since the injected tumor necrosis factor was cleared from the circulation rapidly (Fig. 1) and no activation of the intrinsic route was observed throughout the experiment, the sustained activation of prothrombin must have resulted from the early activation of factor X. Apparently, the activity of factor Xa was neutralized only slowly — an observation that challenges our current understanding of the inhibitory regulation of coagulation proteinases in vivo and that may be relevant to the pathophysiologic features of thrombotic diseases. In particular, the repeated or prolonged release of tumor necrosis factor into the circulation, as has been observed in patients with sepsis, may exert a cumulative effect in the procoagulant state. The previous report that factor Xa sequestered on the surface of a platelet or phospholipid in vitro cannot be inhibited by the antithrombin III—heparin complex36 may explain this continuing formation of thrombin in the presence of the natural anticoagulant mechanisms.
Thrombocytopenia is a major feature of disseminated intravascular coagulation, believed to result from the increased consumption of platelets.1 In patients with cancer, a decline in platelet counts has been reported after the systemic administration of tumor necrosis factor.19 , 37 , 38 In contrast, we did not find significant changes in platelet counts after the injection of tumor necrosis factor. The reasons for this discrepancy are currently unknown, but they may be related to differences in the duration of the infusion of tumor necrosis factor or in the doses used, or to an altered susceptibility to tumor necrosis factor in patients with cancer.
This controlled study clearly shows that low-dose tumor necrosis factor induces a subclinical activation of the coagulation system, supporting the hypothesis that tumor necrosis factor is involved in the pathogenesis of hemostatic disorders associated with sepsis. Knowledge of the mechanisms responsible for the onset and maintenance of this activation may lead to the development of effective strategies for the treatment of patients with disseminated intravascular coagulation and multiple organ failure.
Supported in part by a grant (PO1 HL 33014) from the National Institutes of Health, a fellowship from the Royal Netherlands Academy of Art and Sciences to Dr. Büller, and a grant from the Netherlands Organization of Scientific Research and the Amstolstichting to Dr. H. ten Cate. Dr. Bauer is an Established Investigator of the American Heart Association.
We are indebted to Dr. Auguste Sturk, Rita van Wesep, Wil Morriën, Marianne van't Hullenaar, Marianne Schaap, Arie Prins, Han Levels, and the other members of the staff of the coagulation laboratory for their excellent technical support; to Dr. Frans Hoek for the determination of serum concentrations of tumor necrosis factor; to Marieke Kat for assistance in the preparation of the manuscript; and to Gerdie Wentink for preparing the illustration.
Source Information
From the Department of Internal Medicine (T.v.d.P., H.P.S.) and the Center for Hemostasis, Thrombosis and Atherosclerosis Research (H.R.B., C.H.W., S.J.H.v.D., J.W.t.C), Academic Medical Center, University of Amsterdam; the Division of Hematology and Oncology (H.t.C., K.A.B., R.D.R.), Beth Israel Hospital, Boston; and the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service (C.E.H.), Amsterdam. Address reprint requests to Dr. van der Poll at the Department of Internal Medicine, Academic Medical Center, F4–222, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
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