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Hemostatic-endothelial interactions: a potential anticoagulant role of the endothelium in the pulmonary circulation during cardiac surgery.

The use of extracorporeal circulation during cardiopulmonary bypass (CPB) procedures is associated with significant morbidity and mortality. Exposure of blood to the foreign surface of the extracorporeal circuit results in activation of complement, kinin, fibrinolytic and coagulation systems as well as cellular mediators of inflammation. Without the use of anticoagulants, the extracorporeal circuit would clot; high-dose heparin prevents coagulation, but activation of the coagulation system and consequent thrombin generation still occur. During CPB, the lungs are effectively removed from the circulation, and, hence, heparinized blood remains static within the pulmonary vasculature for this period. It was postulated that under these conditions, the hemostatic system may become activated and could contribute to pulmonary dysfunction in some patients after CPB. However, it appears that during CPB interactions among heparin, the hemostatic system, and the endothelium may exert a protective effect, at least against activation of the tissue factor coagulation pathway. In this article, the effect of CPB on the coagulation system, with particular reference to changes in coagulation proteins occurring in the pulmonary vasculature, are reviewed.

Anticoagulants↗

Waist circumference and VO2max are associated with metabolic and hemostatic risk in premenopausal nurses.

In 21 nurses (34.4+/-3.9 yr), VO2max physical activity, body composition and lifestyle parameters were measured to determine which of these characteristics are related to metabolic and hemostatic risk for cardiovascular disease. Physical activity was assessed with the 7-day recall interview. VO2max was measured in a progressive and continuous treadmill test to volitional fatigue. Fasting insulin, total cholesterol, HDL-C, triglycerides, fibrinogen, tPA-act, tPA-ag, and PAI-1-ag were determined from fasting blood samples. Contrary to our expectation, there was no association of physical activity with any of these risk indicators. High VO2max was associated with lower levels of insulin and fibrinogen. Regression analyses indicated that metabolic and hemostatic risk indicators, as measured in healthy premenopausal nurses, were mainly predicted by waist circumference and oral contraceptive use.

Adult↗

Counteracting effect of glycyrrhizin on the hemostatic abnormalities induced by Bothrops jararaca snake venom.

1. Envenomation by the snake Bothrops jararaca is typically associated with hemostatic abnormalities including pro- and anticoagulant disturbances. Glycyrrhizin (GL) is a plant-derived thrombin inhibitor that also exhibits in vivo antithrombotic properties. Here, we evaluated the ability of GL to counteract the hemostatic abnormalities promoted by B. jararaca venom. 2. GL inhibited the human fibrinogen clotting (IC50 = approximately 1.0 mg ml(-1); 1.2 mM), H-D-phenylalanyl-L-pipecolyl-L-arginine-p-nitroanilide dihydrochloride hydrolysis (IC50 = approximately 0.4 mg ml(-1); 0.47 mM) and platelet aggregation (IC50 = approximately 0.28 mg ml(-1); 0.33 mM) induced by B. jararaca venom, in vitro. 3. The in vivo effect of GL was tested in rats using a model of venous thrombosis in which intravenous (i.v.) administration of B. jararaca venom (100 microg kg(-1)) produced in all animals a thrombus with a mean weight of 10.6+/-1.7 mg. 4. Prior administration of GL (180 mg kg(-1)) or antibothropic serum (27 microl kg(-1)) inhibited thrombus formation by 86 and 67%, respectively. Remarkably, co-administration of ineffective doses of GL and antibothropic serum markedly decreased thrombus weight, suggesting a synergistic effect. 5. Co-administration of GL with antibothropic serum abolished venom-induced bleeding. Ex vivo clotting times showed that rat plasma was non-clotting after i.v. administration of B. jararaca venom. Treatment with GL, antibothropic serum or both before venom administration efficiently prevented this abnormality. 6. Altogether, we demonstrate here that GL prevents both in vitro and in vivo venom-induced changes in hemostasis, suggesting a potential antiophidic activity.

Animals↗

Changes in hemostatic parameters in hepatic veno-occlusive disease following bone marrow transplantation.

Hepatic veno-occlusive disease (VOD) is a major complication after bone marrow transplantation (BMT). Its prediction, diagnosis and treatment remain unclear. Examination was made of changes in hemostatic parameters in patients with or without VOD after BMT. Twenty-seven children were studied following BMT. Eight of them developed VOD. Tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), thrombomodulin (TM), von Willebrand factor (vWF), factor VII, fibrinogen (FBG), FDP, D-dimer (D-D), plasminogen (PLG), thrombin-antithrombin III (TAT), alpha 2-plasmin inhibitor/plasmin complex (PIC), antithrombin III (AT-III), protein C, N-terminal propeptide for type III procollagen (P-III-P), were measured weekly from pre-BMT to day 28 after BMT. In VOD patients, t-PA and PAI-1 significantly increased (P < 0.05) and FBG significantly fell during the post-transplant period (P < 0.05). Significantly low AT-III and PLG were also noted before VOD (P < 0.05). There were no changes in other hemostatic parameters. t-PA, PAI-1 and FBG would thus appear useful markers for the diagnosis of VOD, and AT-III and PLG, predictive markers for VOD. The coagulation-fibrinolysis system following endothelial cell damage may contribute to the onset of VOD.

Adolescent↗

Effects of oxypolygelatin and dextran 70 on hemostatic variables in dogs.

OBJECTIVE: To evaluate and compare coagulation variables following the administration of oxypolygelatin and dextran 70 to clinically healthy dogs. STUDY DESIGN: Randomized cross-over experimental study. ANIMALS: A total of eight healthy adult female Beagles aged 2-4 years old and weighing 11.8 +/- 2.7 kg. METHODS: The dogs received a 15-minute intravenous (IV) infusion of 5 mL kg-1 oxypolygelatin or 10 mL kg-1 6% dextran 70. Before (PRE) and at 2, 5, and 24 hours after administration, packed cell volume (PCV), total solids concentration (TS), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen concentration (FIB), platelet numbers (Plat), factor VIII coagulant activity (VIII:C), von Willebrand factor antigen concentration (vWf:Ag) and platelet function and buccal mucosal bleeding time (BMBT) were measured. Platelet function was assessed using aggregation and by measuring ATP release from aggregating platelets over 6 minutes, with 20, 10, and 5 micro m ADP and 5 and 10 micro g of collagen mL-1 as platelet activation agonists. RESULTS: All baseline values were within our normal ranges, except for one dog that had low vWf:Ag PRE values prior to both dextran and oxypolygelatin administration. Following dextran and oxypolygelatin administration, the PCV and TP were significantly (p < 0.05) decreased. Plat, FIB, and vWf:Ag decreased, while BMBT and VIII:C increased following dextran administration. Dextran also caused a significant decrease in platelet aggregation in response to ADP. Oxypolygelatin caused a significant decrease in vWf:Ag, Plat, and FIB compared to PRE values. The total amount of ATP released, standardized to platelet number, did not vary significantly for either group at any sampling time from PRE values. No significant changes from PRE values were noted at any time in either group for PT or APTT. CONCLUSION: At the doses administered, both dextran and oxypolygelatin can interfere with hemostatic variables in healthy dogs, but dextran's effect is more profound and prolonged when compared to oxypolygelatin. CLINICAL RELEVANCE: Oxypolygelatin causes fewer hemostatic abnormalities when compared to dextran, making it a superior colloid for administration at the doses tested.

Animals↗

Effect of angiotensin-converting enzyme inhibition on renal filtration surface area in hypertensive rats.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitor treatment leads to protective effects on the cellular structure of the glomerulus and the kidney. The aim of this study was to determine whether ACE inhibition increases renal filtration surface area in the spontaneously hypertensive rat (SHR). METHODS: SHR were treated with the ACE inhibitor perindopril at a high dose (3 mg/kg/day) or a low dose (0.1 mg/kg/day) during the period of hypertension development, from 7 to 14 weeks of age. Some animals were treated concomitantly with the bradykinin B2 receptor antagonist, S16118. Tail-cuff systolic blood pressure and body weights were measured twice weekly. At termination of treatment, glomerular number and volume, length, and surface area of glomerular capillaries and renal filtration surface area were estimated using unbiased stereological techniques. RESULTS: There were significant dose-related reductions in blood pressure with high- and low-dose perindopril treatment. Neither low- nor high-dose perindopril treatment had any effect on glomerular number or size or glomerular capillary length and surface area. Hence, there was no significant difference in total renal filtration surface area between any of the experimental groups (8721 +/- 610 mm2 in untreated SHR and 7879 +/- 338 mm2 and 8767 +/- 437 mm2 in the low and high dose perindopril-treated groups, respectively). Coadministration of the bradykinin antagonist did not affect any of the glomerular parameters. CONCLUSIONS: ACE inhibition during the period of hypertension development does not lead to an enhanced glomerular capillary growth or increases in total renal filtration surface area in this model.

Angiotensin-Converting Enzyme Inhibitors↗

The hemostatic effect of packed red cell transfusion in patients with anemia.

BACKGROUND: The hemostatic effect of platelets has been well established, but the possible role of red cells in hemostasis has not yet been well studied. An evaluation of the hemostatic effect of packed red cell transfusion in patients with chronic anemia was the purpose of this study. STUDY DESIGN AND METHODS: In a prospective study, bleeding time (BT), activated partial thromboplastin time (APTT), and prothrombin time (PT) were measured before and after the transfusion of allogeneic packed red cells in 42 patients with chronic anemia. The results were compared and analyzed. RESULTS: APTT and BT decreased significantly after transfusion, by a mean of 1.3 seconds (p = 0.01) and 2.6 minutes (p < 0.01), respectively. PT did not change significantly after transfusion (p = 0.65). Factors studied (patient's age, sex, and renal function measurements; pretransfusion and posttransfusion hemoglobin levels, platelet counts, and PTs; change in platelet count [delta platelet count] and PT [delta PT] after transfusion) did not independently affect the change in BT (delta BT) or in APTT (delta APTT). The delta BT was not affected by the pretransfusion or posttransfusion levels of APTT or by the delta APTT. The delta APTT was not affected by the pretransfusion or posttransfusion levels of BT or by the delta BT. Diagnosis of malignant or benign diseases was found to affect delta APTT, but not delta BT. Patients with pretransfusion hemoglobin < or = 60 g per L had a 4.07 times greater chance of posttranfusion increase in BT than the patients with hemoglobin > 60 g per L (p = 0.04). CONCLUSION: Red cell transfusion might decrease the APTT and BT in some anemic patients, though the actual cause of the decrease was not determined in the present study.

Aged↗

Effects of hemodilution, blood loss, and consumption on hemostatic factor levels during cardiopulmonary bypass.

OBJECTIVES: The purpose of this study was to determine quantitatively the effects of consumption, hemodilution, and blood loss on coagulation and fibrinolytic factor levels during cardiopulmonary bypass. DESIGN: A combination of measured levels of prothrombin, antithrombin, fibrinogen, plasminogen, and antiplasmin along with their activation markers F1.2, thrombin-antithrombin complex, fibrinopeptide A, plasmin-antiplasmin complex, and D-dimer were used with a computer model of each patient's vascular and hemostatic systems to estimate the cardiopulmonary bypass-associated loss of each factor because of hemodilution, blood loss, and consumption. SETTING: University hospital. PARTICIPANTS: Nine patients undergoing coronary artery bypass graft surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At baseline, it was estimated that on average 2%, 3%, and 25%, respectively, of the baseline liver secretion of plasminogen, prothrombin,and fibrinogen were consumed by activation of these proteins. During cardiopulmonary bypass, thrombin and plasmin generation were increased, whereas fibrin generation was decreased because of heparin. Compared with baseline, hemodilution during cardiopulmonary bypass resulted in an average 35% +/- 7% decrease in the concentration of coagulation and fibrinolytic proteins, whereas blood loss was responsible for an average 6% +/- 5% decrease in these proteins. Blood loss varied substantially among patients, resulting in <1% to 14% decreases in hemostatic protein levels. On average, consumption because of activation resulted in less than a 1% drop in the concentration of coagulation and fibrinolytic factors during cardiopulmonary bypass. CONCLUSIONS: Hemodilution is the primary cause of the drop in coagulation and fibrinolytic proteins during routine cardiopulmonary bypass, followed by blood loss, whereas consumption accounts for less than a 1% drop in most patients.

Aged↗

Novel hemostatic alternatives in reconstructive surgery.

Congenital vascular lesions are classed as hemangiomas, vascular malformations, or vascular tumors according to their histology and etiology. The majority of hemangiomas are benign and often involute before the child reaches the age of 12. Severe hemangiomas and vascular malformations were historically viewed as effectively inoperable due to the high risk of potentially catastrophic bleeding during surgery. An effective system of classification and increasing range of therapeutic options have improved the prognosis for many patients, but surgical resection of these lesions remains a serious undertaking. Topical hemostatic agents are widely used and effective in many cases for the control of intraoperative bleeding. The main limitations of these agents are their variability and lack of efficacy in severe bleeding, or in coagulopathic or anticoagulant-treated patients. This paper reviews recent developments in this field, including the possible placental origin of hemangiomas, and discusses current approaches to hemostasis during reconstructive surgery. We also discuss the recent introduction of recombinant activated factor VII (rFVIIa) as a systemic hemostatic agent, including our own experience using this treatment.

Arteriovenous Malformations↗

Molecular markers of hemostatic activation in atherosclerosis: a new concept in diagnostic profiling of endogenous pathophysiologic transition.

Molecular markers of hemostatic activation provide a reliable measure of the endogenous pathophysiologic state in atherosclerosis. Measurement of these markers before and after exercise provides a diagnostic probe for cellular-vascular interactions in patients with atherosclerosis. Molecular markers may possibly identify very early stages of atherosclerosis due to their inherent sensitivity. A high-risk cardiovascular population can be easily recognized by profiling molecular markers of hemostatic activation. Newly developed immunoassays can be used to quantitate these markers in routine laboratories. Additional clinical studies are needed to establish the diagnostic role of these molecular markers in patients with atherosclerosis and related disorders.

6-Ketoprostaglandin F1 alpha↗

Hemostatic molecular markers before onset of disseminated intravascular coagulation in leukemic patients.

The changes in various hemostatic parameters were examined within a period from 7 days before the onset of disseminated intravascular coagulation (DIC) in 114 patients (i.e. in their pre-DIC state). The changes in prothrombin time (PT) ratio and fibrinogen levels were not significant before the onset of DIC. Plasma fibrinogen and fibrin degradation products (FDP) levels before the onset of DIC were high, but these changes were already significant in 110 non-DIC patients examined. Plasma thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer and soluble fibrin monomer (SFM) levels were high before the onset of DIC. In the 110 leukemic DIC patients, the plasma SFM levels were significantly increased 5 days before, the plasma TAT levels were significantly increased 3 days before, and the D-dimer levels were significantly increased 1 day before the onset of DIC. The plasma tissue factor and plasminogen activator inhibitor-I levels were not significantly changed before the onset of DIC. The PT ratio, fibrinogen, FDP, platelet count, antithrombin, D-dimer, and PPIC levels at 7 days before the onset of DIC were not significantly different from the corresponding values in the non-DIC group, although the hemostatic molecular markers SFM, D-dimer, and TAT are useful for the diagnosis of pre-DIC. Plasma thrombomodulin levels were significantly increased in these patients who died, and plasma antithrombin and protein C activities markedly reduced in the patients who died. The outcome of the diseases underlying DIC is related to vascular endothelial cell injuries.

Biomarkers↗

Thrombin receptor-related hemostatic defect after cardiopulmonary bypass.

Platelet abnormalities have been blamed for the hemostatic defect that develops after cardiopulmonary bypass (CPB), but investigators have not been able to agree upon an intrinsic platelet abnormality responsible for the observed defect. To better define the blood components responsible for this post-operative hemostatic defect, we compared platelet function in whole blood (WB) to that in platelet-rich plasma (PRP) in 33 patients undergoing coronary artery bypass grafting. We measured platelet aggregation in response to various platelet agonists, including thrombin and TRAP-6 (a 6-amino acid peptide that activates the thrombin "tethered ligand" receptor site). In WB there was a lasting, diminished response to TRAP-6, but not to gamma-thrombin, after CPB. Control experiments showed that this diminished response to TRAP-6: (1) was not related to heparin or heparin-protamine complexes, (2) was not the result of hemodilution during CPB, (3) was not related to increased amounts of naturally occurring enzymes (aminopeptidases) that degrade TRAP, and (4) was not able to be reversed by the addition of as much as a 10-fold excess of the usual TRAP-6 aggregating dose to WB preparations. In contrast, no corresponding defect in platelet aggregation could be identified in PRP obtained from patients after CPB. These results show that, in post-operative blood samples, blood components present in WB and not in PRP (eg, red blood cells, activated white cells or platelets bound to white cells) diminish the ability of TRAP peptides to activate the thrombin receptor but do not decrease the ability of gamma-thrombin to induce platelet aggregation. This suggests that for circulating platelets after CPB: (1) interactions of platelets with other blood cell elements are the cause of altered postoperative platelet reactivity rather than any intrinsic CPB-induced platelet defect, (2) drugs, such as aprotinin, that limit activation of white cells and the fibrinolytic system may also have beneficial effects on platelet function after CPB, and (3) alternate mechanisms exist that allow thrombin, but not TRAP-6, to activate platelets normally after CPB (perhaps a second, as yet undefined, thrombin receptor).

Cardiopulmonary Bypass↗

Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.

BACKGROUND: Increased levels of certain hemostatic factors may play a part in the development of acute coronary syndromes and may be associated with an increased risk of coronary events in patients with angina pectoris. METHODS: We conducted a prospective multicenter study of 3043 patients with angina pectoris who underwent coronary angiography and were followed for two years. Base-line measurements included the concentrations of selected hemostatic factors indicative of a thrombophilic state or endothelial injury. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. RESULTS: After adjustment for the extent of coronary artery disease and other risk factors, an increased incidence of myocardial infarction or sudden death was associated with higher base-line concentrations of fibrinogen (mean +/- SD, 3.28 +/- 0.74 g per liter in patients who subsequently had coronary events, as compared with 3.00 +/- 0.71 g per liter in those who did not; P = 0.01), von Willebrand factor antigen (138 +/- 49 percent vs. 125 +/- 49 percent, P = 0.05), and tissue plasminogen activator (t-PA) antigen (11.9 +/- 4.7 ng per milliliter vs. 10.0 +/- 4.2 ng per milliliter, P = 0.02). The concentration of C-reactive protein was also directly correlated with the incidence of coronary events (P = 0.05), except when we adjusted for the fibrinogen concentration. In patients with high serum cholesterol levels, the risk of coronary events rose with increasing levels of fibrinogen and C-reactive protein, but the risk remained low even given high serum cholesterol levels in the presence of low fibrinogen concentrations. CONCLUSIONS: In patients with angina pectoris, the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent acute coronary syndromes. In addition, low fibrinogen concentrations characterize patients at low risk for coronary events despite increased serum cholesterol levels. Our data are consistent with a pathogenetic role of impaired fibrinolysis, endothelial-cell injury, and inflammatory activity in the progression of coronary artery disease.

Adult↗

Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice.

In multiple systems, impaired proteolysis associated with the loss of the hemostatic factor plasminogen (Plg) results in fibrin-dependent defects in tissue repair. However, repair within the liver is known to be defective in Plg-deficient (Plg(o)) mice independent of fibrin clearance and appears to be compromised in part by the poor clearance of necrotic cells. Based on these findings, we examined the hepatic transcriptome after injury in search of transcriptional programs that are sensitive to the Plg/fibrinogen system. To this end, we generated biotinylated cRNA pools from livers of Plg(o) mice and controls before and after a single dose of the hepatotoxin carbon tetrachloride and hybridized them against high-density oligonucleotide arrays. Analysis of the gene expression platform identified an unexpected transcriptional signature within challenged livers of Plg(o) mice for pancreatic gene products, including trypsinogen-2, amylase-2, elastase-1, elastase-2, and cholesteryl-ester lipase. Validation studies found that this transcriptional program also contained products of the endocrine pancreas (Reg-1 and insulin genes) and the expression of the pancreatic transcription factors p48 and PDX-1. By using a LacZ transgene to trace the cellular source of pancreatic gene expression, we found that PDX-1 was expressed in albumin-positive cells that were morphologically indistinguishable from hepatocytes, and in albumin-negative epithelioid cells within zones of pericentral injury. More detailed studies revealed that the mechanisms of heterotopic gene expression in Plg(o) mice required fibrin(ogen). Collectively, these data reveal a regulatory role for the hemostatic factors plasmin(ogen) and fibrin(ogen) in cellular plasticity within adult tissues of the digestive system.

Amylases↗

Hemostatic mechanisms, independent of platelet aggregation, arrest gastric mucosal bleeding.

Platelet adhesion, aggregation, and subsequent plug formation play a major role in the control of cutaneous and vascular hemostasis. Little is known, however, about the hemostatic processes in gastric mucosal tissue. A method for evaluating bleeding from a standard incision in the gastric mucosa of the rat, rabbit, and dog has therefore been developed. By using pharmacological agents that interfere with platelet aggregation and blood coagulation, the mechanism of gastric hemostasis has been compared to that in the vasculature, using the rat mesenteric artery. Intravenous infusion of prostacyclin (0.5 micrograms X kg-1 X min-1), which inhibits platelet aggregation directly, or administration of the thromboxane synthase inhibitor 1-benzylimidazole (50 mg X kg-1) significantly prolonged bleeding in the mesenteric artery yet failed to alter gastric mucosal bleeding. In contrast, a low dose of heparin (100 units X kg-1), which interferes with the clotting process, had no effect on mesenteric bleeding but substantially prolonged bleeding from the gastric mucosa. These findings suggest that, unlike in the skin or vasculature, platelet aggregation plays a minimal role in the initial hemostatic events in the gastric mucosa and that the arrest of gastric hemorrhage is brought about largely by processes primarily involving the coagulation system.

Animals↗

Circulating concentrations of hemostatic factors and two "steroid sensitive proteins" during oral hormone replacement therapy in women with coronary heart disease.

OBJECTIVE: To study a possible use of sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) as markers for changes in hemostatic factors during oral postmenopausal hormone replacement therapy (HRT). METHODS: Twenty-eight postmenopausal women were treated with oral conjugated equine estrogens+oral medroxyprogesterone acetate (CEE + MPA, n = 15) or with placebo (n = 13). Serum SHBG, CBG, testosterone, cortisol and plasma coagulation factors, coagulation inhibitors and markers of coagulation activation were measured before and after 6 and 12 months of treatment. RESULTS: Pretreatment plasminogen activator inhibitor 1 (PAI-1) levels correlated negatively to SHBG and antithrombin III (AT III) negatively to total and free cortisol. In the CEE + MPA group, CBG, SHBG and Factor VII increased, and PAI-1, AT III and free testosterone decreased during treatment. No significant changes were found in plasma von Willebrand factor antigen, thrombin-antithrombin complex, fibrin D-dimer and fibrinogen. A significant, negative correlation was found between changes in SHBG and PAI-1. No changes were found in the placebo group. CONCLUSION: The only correlation found between changes in "steroid sensitive" proteins and hemostatic factors was between increased SHBG and a possibly beneficial effect of estrogens, i.e. decreased PAI-1 values. SHBG or CBG could not be used as predictors of increased cardiovascular risk during postmenopausal oral HRT.

Administration, Oral↗

Chronic pulmonary hypertension--the monocrotaline model and involvement of the hemostatic system.

Monocrotaline (MCT) is a toxic pyrrolizidine alkaloid of plant origin. Administration of small doses of MCT or its active metabolite, monocrotaline pyrrole (MCTP), to rats causes delayed and progressive lung injury characterized by pulmonary vascular remodeling, pulmonary hypertension, and compensatory right heart hypertrophy. The lesions induced by MCT(P) administration in rats are similar to those observed in certain chronic pulmonary vascular diseases of people. This review begins with a synopsis of the hemostatic system, emphasizing the role of endothelium since endothelial cell dysfunction likely underlies the pathogenesis of MCT(P)-induced pneumotoxicity. MCT toxicology is discussed, focusing on morphologic, pulmonary mechanical, hemodynamic, and biochemical and molecular alterations that occur after toxicant exposure. Fibrin and platelet thrombosis of the pulmonary microvasculature occurs after administration of MCT(P) to rats, and several investigators have hypothesized that thrombi contribute to the lung injury and pulmonary hypertension. The evidence for involvement of the various components of the hemostatic system in MCT(P)-induced vascular injury and remodeling is reviewed. Current evidence is consistent with involvement of platelets and an altered fibrinolytic system, yet much remains to be learned about specific events and signals in the vascular pathogenesis.

Animals↗

Effects of two combined monophasic and triphasic ethinylestradiol/gestodene oral contraceptives on natural inhibitors and other hemostatic variables.

OBJECTIVE: To evaluate the effects of two preparations of combined oral contraceptives (COCs), the monophasic COC containing 30 micrograms ethinylestradiol and 75 micrograms gestodene and the triphasic COC containing 30/40/30 ethinylestradiol and 50/70/100 micrograms gestodene on seven natural inhibitors and hemostatic variables. METHOD: Forty-four healthy young women, randomly allocated into two groups (A and B) received the two preparations of COCs, respectively. The following variables were tested in a basic examination and at 1-, 3- and 6-month intervals to evaluate the role of the above preparations on the hemostatic balance of prothrombin time, fibrinogen, antithrombin III activity, protein C activity, total protein S antigen, plasminogen activity and lupus anticoagulant. RESULTS: Group A women presented shorter prothrombin time at 6 months, an increased fibrinogen level at 3 months, no influence on the anticoagulant factors, antithrombin III, protein C and total protein S and an increased plasminogen activity at the 1st and 3rd months of treatment. On the other hand, group B women presented shorter prothrombin time at 3 months, no increase in fibrinogen, a decrease in antithrombin III activity and total protein S activity at the 6th month, whereas protein C and plasminogen activities were found to be increased at the 3rd and 1st, 3rd and 6th month, respectively. CONCLUSIONS: The study did not find differences between the two treatment groups, for the evaluated parameters. This finding is clearly important in the light of the recent epidemiological reports on third-generation COCs. However, differences were found among the various periods of administration of both COCs.

Adolescent↗