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PubMed1973

Experimental hepatic necrosis: studies on coagulation abnormalities, plasma clearance, and organ distribution of 125I-labelled fibrinogen.

Studies in the rat with hepatic necrosis induced by carbon tetrachloride showed that the abnormalities in one-stage coagulation tests and the increased catabolism of fibrinogen were similar to those found in man with acute viral or drug-induced hepatic necrosis. Determination of the distribution of the radioactive label shows that excessive deposition was maximal in the liver but also occurred in the spleen. The appearance is delayed by heparin but accelerated by tranexamic acid.

Animals↗
PubMed2004

Normal complement C4 values do not exclude hereditary angioedema.

This report describes a patient with hereditary angioedema (HAE) in whom complement C4 values were consistently normal. There was a family history of HAE, for which the patient had previously been screened, but in view of her normal C4 values she was deemed unaffected. However, at 10 years of age she presented with an eight month history of episodes of swelling affecting her hands and recurrent episodes of abdominal pain over the previous few months. In view of the recent clinical history of swellings and the family history of HAE, C4 and C1 inhibitor (C1inh) were measured. The C4 concentration was found to be within the normal range but the C1inh value was low (0.07 g/litre; normal range, 0.18-0.37). The patient was started on tranexamic acid and at an outpatient review three months later her episodes of swelling were occurring less often and were less severe. Although recent papers have suggested that the diagnosis of HAE can be excluded if complement C4 concentrations are normal, this case highlights the fact that C4 concentrations can be normal in this condition, and it is recommended that both C4 and C1inh concentrations should be measured to exclude HAE.

Angioedema↗
PubMed1990

Gastric antral vascular ectasia (watermelon stomach)--therapeutic options.

We have encountered five cases of chronic iron deficiency anaemia due to bleeding from gastric antral vascular ectasia (watermelon stomach). Two cases were associated with a lymphoma and in three cases there was evidence of portal hypertension. Two patients were treated conservatively by blood transfusions. The other patients required either surgery or tranexamic acid or endoscopic laser therapy to control the chronic haemorrhage.

Aged↗
PubMed1987

CVF-induced decomplementation: effect on lung transvascular protein flux after thrombin.

We examined the effects of cobra venom factor (CVF) on the changes in pulmonary hemodynamics and transvascular fluid and protein exchange following thrombin-induced pulmonary microembolism. Studies were made in unanesthetized sheep prepared with lung lymph fistulas. The animals received tranexamic acid (100 mg) to suppress fibrinolysis and were then challenged with an intravenous infusion of alpha-thrombin (80 U/kg). Control-thrombin challenged sheep were compared with the CVF-treated sheep challenged with the same thrombin dosage. CVF treatment (187 U X kg-1 X day-1 for 4 days) decreased the total hemolytic complement activity by 45% of control. Thrombin infusion in control sheep increased the mean pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), and lymph protein clearance (pulmonary lymph flow X lymph-to-plasma protein concentration ratio, Clym). Thrombin infusion in CVF-treated sheep produced smaller increments in Ppa, PVR, and Clym. Pulmonary lymph obtained from control-thrombin and CVF-thrombin sheep induced migration of granulocytes obtained from normal unchallenged sheep. The granulocytes obtained from CVF-treated sheep responded relatively less to the migratory and O-2-generating stimuli (i.e., zymosan-treated serum, pulmonary lymph from sheep after thrombin challenge, and plasma from sheep after CVF treatment) compared with normal granulocytes. The attenuation of the thrombin-induced increases in Ppa, PVR, and lung transvascular fluid and protein exchange by CVF treatment may be the result of impaired function of granulocytes.

Animals↗
PubMed1999

Four cases of bleeding diathesis in children due to congenital plasminogen activator inhibitor-1 deficiency.

Congenital plasminogen activator inhibitor-1 (PAI-1) deficiency is an extremely rare disorder characterized by a bleeding diathesis that begins in childhood due to hyperfibrinolysis as a result of decreased PAI-1 activity. We now present 4 unrelated pediatric cases of congenital PAI-1 deficiency. All 4 patients had a history of recurrent episodes of subcutaneous bleeding beginning in early childhood. These episodes were characterized by abnormal prolonged bleeding after trauma, tooth extraction, and surgical procedures, as well as by rebleeding following initial hemostasis. The 2 female patients both had symptoms compatible with hypermenorrhea. The family history was positive in 2 of the 4 patients. Hemostatic screening studies in all 4 patients revealed no abnormalities. Testing for factor XIII antigen, von Willebrand factor antigen, ristocetin cofactor activity, alpha(2)-plasmin inhibitor (alpha2PI) activity, and plasminogen activity was normal. The euglobulin lysis times were shortened in all cases as compared with those in normal control subjects. None of the patients had elevated tissue plasminogen activator (tPA) antigen levels, but PAI activity was markedly decreased in all cases. Three of the patients also had reduced levels of PAI-1 antigen. There tended to be a reduction in tPA-PAI-1 complex in all cases. In addition, 2 patients had elevated PIC (plasmin-alpha2PI complex). Tourniquet tests were performed in 2 patients, with no appreciable rise in PAI-1 activity or PAI-1 antigen levels. The administration of tranexamic acid clearly improved hemorrhagic symptoms in these patients. We considered PAI-1 deficiency to be the likely etiology of the congenital bleeding diatheses in these 4 cases.

Adolescent↗
PubMedDate not supplied

Enhanced thrombolysis induced by argatroban or activated protein C in the presence or absence of staphylokinase, measured in an in vivo animal model using mesenteric arterioles.

Successful administration of thrombolytic agents is associated with vessel reocclusion in a high proportion of cases. We have previously established an animal model to investigate platelet-rich thrombolytic mechanisms in vivo and demonstrated that recombinant staphylokinase (rSAK)-induced thrombolysis was enhanced by the concomitant administration of the direct thrombin inhibitor argatroban. The present study expanded the use of this model by comparing arterial and venous thrombolysis using advanced image analysis software. Mural thrombi were formed by Helium-Neon laser irradiation in mesenteric arterioles and were shown to be lysed, dose-dependently, by smaller amounts of rSAK than those required in venules. Activated protein C (APC), as well as argatroban, enhanced the rSAK-induced thrombolysis. APC or argatroban also induced thrombolysis in the absence of rSAK, and the effect was inhibited by tranexamic acid. The enhanced thrombolysis induced by APC or argatroban in the presence or absence of rSAK may be due to increased endogenous thrombolysis mediated by the inhibition of thrombin activity or delayed thrombin generation.

Animals↗
PubMed2002

Mast cell-derived VEGF enhances the passage of IgE FE-3 through the rat aortic endothelial cell monolayer.

BACKGROUND: It is well known that the IgE-mediated allergic reaction in various extravascular tissues is induced by the mutual interaction of IgE, target cells (mast cells, MCs) and allergens. However, so far little has been known about the detailed mechanism whereby IgE in the circulating blood is transferred to the extravascular tissue. To examine whether or not MCs are involved in the permeability of IgE across rat aortic endothelial cells (RAECs) in vitro, we determined the permeability constant (PC) of dinitrophenyl-specific rat IgE (IgE FE-3) using a dual chamber system. METHODS: Isolated RAECs obtained by a primary explant technique were seeded on a collagen-coated membrane in the upper chamber. MCs were collected from the peritoneal cavity of Wistar rats and suspended in the lower chamber. The time-dependent changes in concentration of IgE FE-3 (IgE) in the upper and lower chambers were measured by IgE capture ELISA after addition of IgE (10 microg/ml) to the upper chamber. RESULTS: The cultured medium of IgE-stimulated MCs significantly increased the PC of IgE (9.86 +/- 0.46 x 10(-6) cm/s), as compared to the value to which calcium ionophore A 23187-stimulated MCs increased the PC of IgE (7.97 +/- 0.21 x 10(-6) cm/s). The increase of PC by IgE-stimulated MCs was most strongly inhibited by suramin (92.3% +/- 1.89), and was weakly inhibited by tranexamic acid, cimetidine and diphenhydramine. In addition, the PC of IgE was increased with the increase in the MC-derived vascular endothelial growth factor/permeability factor (VEGF). CONCLUSIONS: After IgE is transferred from the circulating blood to the extravascular tissue, it may bind to Fc epsilon RI of the MC and the other Fc epsilon RI-bearing cells. The MC is then activated through the interaction of IgE and Fc epsilon RI. Release of VEGF from the activated MC increases, and the VEGF enhances the permeability of IgE.

Animals↗
PubMed1981

Protective effect of angiotensin II inhibition on acute renal failure after intravascular coagulation in the rat.

Infusion of thrombin and the fibrinolysis inhibitor tranexamic acid during ether anaesthesia in the rat gives rise to fibrin deposition in the renal glomeruli. This resulted in renal insufficiency as indicated by an increase in the serum urea nitrogen, reduction in the renal blood flow and patchy cortical necrosis in the kidneys. The plasma renin activity was elevated initially probably due to the ether anaesthesia. Infusion of the angiotensin II antagonist saralasin prevented the renal insufficiency if it was given during the thrombin infusion but not if it was given afterwards. The deposition of fibrin in the kidneys was also reduced. The results indicate that angiotensin II is involved in the pathogenesis of the renal injury.

Acute Kidney Injury↗
PubMed1983

Studies in a case of Bernard-Soulier syndrome.

In two siblings, brother and sister, with a history of bleeding Bernard-Soulier syndrome was diagnosed: The stronger affected sister showed a high percentage of giant blood platelets, an abnormal platelet spreading test and a defect in ristocetin and bovine fibrinogen-induced platelet aggregation. In addition, the content of platelet ATP, ADP and AMP was increased. As leucocyte counts were consistently decreased in the more seriously affected anaemic sister, repeated cytochemical examinations of the haemopoietic cells were carried out, revealing maturational defects in the whole haemopoietic system. Therapy with tranexamic acid reduced bleeding in the sister and she has not been anaemic since.

Adenine Nucleotides↗
PubMed1992

Imbalance between thrombin and plasmin activity in disseminated intravascular coagulation. Assessment by the thrombin-antithrombin-III complex/plasmin-alpha-2-antiplasmin complex ratio.

We investigated the imbalance between thrombin and plasmin activity in vivo with various grades of severity of disseminated intravascular coagulation (DIC) in relation to the underlying diseases. Plasma thrombin-antithrombin-III complex (TAT) and plasmin-alpha 2-antiplasmin complex (PAP) levels were measured in 133 blood samples obtained from patients with DIC. The TAT/PAP ratio was higher in patients with sepsis or solid cancer than in those with hematologic malignancies. In acute promyelocytic leukemia (APL), the TAT levels were the highest, but the PAP levels were even higher and the TAT/PAP ratio was the lowest. As for the severity of DIC, in mild DIC, both thrombin and plasmin activities were increased. In moderate DIC, the TAT/PAP ratio increased, and thrombin activity was much more predominant. However, in severe DIC, the ratio decreased, and plasmin activity became excessive. In 3 patients with acute myeloblastic leukemia, APL and pancreatic cancer, respectively, the PAP level remained high during heparin therapy although the TAT level was decreased. When tranexamic acid was given, the PAP level was selectively reduced, and the TAT/PAP ratio was markedly decreased along with clinical improvement. These results indicate that monitoring of the TAT/PAP ratio may contribute to decisions regarding the institution and performance of combination therapy for DIC using anticoagulants and antifibrinolytic agents.

Adenocarcinoma↗
PubMed1989

[Recurrent herpes labialis infections: cellular immunity and immunomodulation].

The therapy with thymus extracts, oral and parenteral, reduced the frequency and the intensity of recurrences of herpes labialis infections. The duration of the effect was at least 6 month after interruption of the therapy. Indomethacin was effective and developed and intensive effect only during the therapy. The skin test with recall-antigens and the neopterin-elimination were altered at the first day of the menstruation during the recurrence. The normalisation succeeded during therapy. In patients with recurrences in the perimenstrual time we observed a reduced T-helper/T-suppressor index during the first day of menstruation. Normal data were registered out of the recurrence time and/or under therapy. Inhibitors of the lymphokine: leucocyte/migration inhibitory factor (LIF) with a molecular weight of 6-12 KD were obtained with the specific stimulation of mononuclear cells of patients with recurrent infections with herpes labialis using the herpes-virus-1 antigen. The inhibition of fibrinolysis/proteolysis with aprotinin, tranexamic acid, phenyl-methyl-sulphonyl-fluoride and di-isopropyl-fluorophosphate could prevent the appearance of inhibitors. Inhibitors could be produced by splitting the LIF-molecule with urokinase and plasminogen but not with trypsin. The production, but not the activity, of present LIF-inhibitors are blocked in vivo and in vitro by indomethacin and thymus peptides.

Adjuvants, Immunologic↗
PubMed1997

Autoimmune C1 inhibitor deficiency and angioedema.

C1 inhibitor (C1-INH) deficiency results in bouts of mucocutaneous edema and may be inherited (hereditary angioedema) or acquired (acquired angioedema). The syndrome of acquired angioedema, characterized by the adult onset of angioedema and by the lack of evidence of inheritance of the disease, may be associated with lymphoproliferative or other malignant diseases (type I) or with the presence of autoantibodies to C1-INH (type II); this is a rare variant form of C1-INH deficiency with angioedema. We report here a case of acquired C1-INH deficiency with angioedema, hypotension and abdominal discomfort observed in a 71-year-old man in whom complement abnormalities and autoantibodies against C1-INH have been observed and who was classified as having an autoimmune C1-INH deficiency. From the therapeutic point of view after resolution of the acute attacks, high doses of tranexamic acid have been able, at first, to decrease the frequency and the severity of the symptoms, and subsequently to provide a long symptom-free time.

Aged↗
PubMed1985

Acquired C1 inhibitor deficiency with angioedema symptoms in a patient infected with Echinococcus granulosus.

A patient with echinococcosis, acquired deficiency of the inhibitor of the activated first component of complement and angioedema symptoms has been studied. These symptoms started 7 months after the surgical removal of an echinococcus liver cyst. Eight years later, when the complement was investigated, a marked deficiency of the C1 inhibitor, C1, C4 and CH50 was present. The patient was therefore successfully treated with tranexamic acid. After 4 years, the woman needed another operation because of a relapse of echinococcosis; afterwards she was symptom-free without medications, while the complement profile remained unchanged. Circulating immune complexes were detected by the conglutinin method. The patient's serum was demonstrated to possess an anticomplementary activity without affecting the C1 inhibitor when incubated with normal human serum at 37 degrees C. At present, 16 years after the onset of the symptoms, there are no signs of lymphoproliferative disease.

Angioedema↗
PubMed1997

Basic fibroblast growth factor-induced angiogenic phenotype in mouse endothelium. A study of aortic and microvascular endothelial cell lines.

The mouse is the most commonly used species for in vivo studies on angiogenesis related to tumor development. Yet, to the best of our knowledge, very few reports on the in vitro interaction of the angiogenic basic fibroblast growth factor (bFGF) with mouse endothelial cells are available. Three mouse endothelial cell lines originated from aorta (MAECs), brain capillaries (MBECs), and heart capillaries (MHECs) were characterized for endothelial phenotypic markers, in vivo tumorigenic activity, and the capacity to respond in vitro to bFGF. These cells express angiotensin-converting enzyme, acetylated LDL receptor, constitutive endothelial nitric oxide synthase, and vascular cell adhesion molecule-1 and bind Griffonia simplicifolia-I lectin. When injected subcutaneously in nude mice, MAECs induced the appearance of slow-growing vascular lesions reminiscent of epithelioid hemangioendothelioma, whereas MBEC xenografts grew rapidly, showing Kaposi's sarcoma-like morphological features. No lesions were induced by injection of MHECs. MAECs, MBECs, and MHECs expressed both low-affinity heparan sulfate bFGF-binding sites and high-affinity tyrosine kinase receptors (FGFRs) on their surfaces. In particular, MAECs expressed FGFR-2/bek mRNA, whereas microvascular MBECs and MHECs expressed FGFR-1/flg mRNA. Accordingly, bFGF induced a mitogenic response and the phosphorylation of extracellular signal-regulated kinase-2 in all the cell lines. In contrast, upregulation of urokinase-type plasminogen activator expression was observed in bFGF-treated microvascular MBECs and MHECs but not in MAECs. Also, bFGF-treated MBECs and MHECs but not MAECs invaded a three-dimensional fibrin gel and formed hollow, capillary-like structures. The relevance of the modifications of the fibrinolytic balance of mouse microvascular endothelium in bFGF-induced angiogenesis was validated in vivo by a gelatin-sponge assay in which the plasmin inhibitors tranexamic acid and epsilon-aminocaproic acid given to mice in the drinking water inhibited neovascularization induced by the growth factor. In conclusion, differences in response to bFGF exist between large-vessel MAECs and microvascular MBECs and MHECs. Both in vitro and in vivo data point to a role of the profibrinolytic phenotype induced by bFGF in microvascular endothelial cells during mouse angiogenesis. Our observations make these endothelial cell lines suitable for further studies on mouse endothelium during angiogenesis and in angioproliferative diseases.

Animals↗
PubMed1997

Antibodies against the fibrin beta-chain amino-terminus detect active canine venous thrombi.

BACKGROUND: This study was performed to determine whether antibodies against the amino-terminus of the beta-chain of fibrin (anti-beta) could noninvasively distinguish actively enlarging thrombi from thrombi stabilized with anticoagulants. METHODS AND RESULTS: Dogs with unilateral femoral vein thrombi were allocated into three groups: (1) no anticoagulation, (2) intravenous heparin maintained in the "therapeutic" range (0.2 to 0.5 U/mL plasma), and (3) "excess" heparin, maintained at >1.0 U/mL plasma. Thrombolysis was suppressed with tranexamic acid. (111)In-labeled anti-beta was infused, and gamma scans of the legs were performed at regular intervals for 24 hours. Scans were interpreted in a blinded fashion. In addition, for each scan, the number of gamma counts from the femoral area on the thrombosed side was compared with the contralateral side. Clot/blood isotope density was determined postmortem. Leg thrombi in the no-anticoagulation group were 100% detectable, mean (+/-SD) relative count in the thrombosed femoral area was 186% (+/-30%) of the contralateral side, and clot/blood ratio was 14.7 (+/-2.0). Thrombi in the therapeutic heparin group were only 75% detectable, relative counts in the thrombosed femoral areas decreased to 125% (+/-20%), and clot/blood ratio declined to 11.3 (+/-3.5). In the "excess heparin" group, leg thrombi were only 50% detectable, the thrombosed femoral area had relative counts of 118%+/-17%, and the clot/blood ratio fell to 7.8+/-1.9. CONCLUSIONS: Radiolabeled anti-beta noninvasively distinguishes propagating thrombi from those stabilized by anticoagulants. They may be useful for detecting thrombosis clinically as well as for monitoring the efficacy of anticoagulation.

Animals↗
PubMed2006

Effects on coagulation and fibrinolysis induced by influenza in mice with a reduced capacity to generate activated protein C and a deficiency in plasminogen activator inhibitor type 1.

Influenza infections increase the risk of diseases associated with a prothrombotic state, such as venous thrombosis and atherothrombotic diseases. However, it is unclear whether influenza leads to a prothrombotic state in vivo. To determine whether influenza activates coagulation, we measured coagulation and fibrinolysis in influenza-infected C57BL/6 mice. We found that influenza increased thrombin generation, fibrin deposition, and fibrinolysis. In addition, we used various anti- and prothrombotic models to study pathways involved in the influenza-induced prothrombotic state. A reduced capacity to generate activated protein C in TM(pro/pro) mice increased thrombin generation and fibrinolysis, whereas treatment with heparin decreased thrombin generation in influenza-infected C57Bl/6 mice. Thrombin generation was not changed in hyperfibrinolytic mice, deficient in plasminogen activator inhibitor type-1 (PAI-1(-/-)); however, increased fibrin degradation was seen. Treatment with tranexamic acid reduced fibrinolysis, but thrombin generation was unchanged. We conclude that influenza infection generates thrombin, increased by reduced levels of protein C and decreased by heparin. The fibrinolytic system appears not to be important for thrombin generation. These findings suggest that influenza leads to a prothrombotic state by coagulation activation. Heparin treatment reduces the influenza induced prothrombotic state.

Animals↗
PubMed1988

Fibrin is a determinant of neutrophil sequestration in the lung.

We investigated the role of fibrin in the sequestration of neutrophils in lungs challenged with microembolism. Lungs of chronically prepared awake sheep were imaged after infusion of 111In-neutrophils and 131I-fibrinogen. Thrombin (80 units/kg) was administered to induce fibrin sequestration in the lung. One group received tranexamic acid (4 mg/kg i.v.) to inhibit fibrinolysis, and the control group received a saline infusion. Thrombin infusion increased both 131I-fibrinogen and 111In-neutrophils in the lung, but the increases were greater and more prolonged in the fibrinolysis-inhibited group. We examined the adherence of isolated neutrophils to fibrin matrix to investigate how neutrophil-fibrin interactions could mediate neutrophil sequestration. Unstimulated neutrophils showed a 37.5 +/- 3.1% adherence to fibrin in contrast to a 3.9 +/- 0.4% neutrophil adherence to endothelium and a 6.5 +/- 0.5% adherence to agarose. Neutrophil adherence to fibrin increased to 81.7 +/- 6.2% with activation by phorbol myristate acetate (10(-8) M) and was inhibited by a monoclonal antibody directed against the beta-chain of the CD18 leukocyte adhesion glycoprotein. The findings indicate that retention of pulmonary fibrin microthrombi is associated with increased lung uptake of neutrophils. Fibrin serves as a substrate for neutrophil adherence, and this adherence is mediated by expression of the CD18 glycoprotein complex on neutrophils. Fibrin sequestration in the lung may contribute to lung vascular injury by inducing pulmonary neutrophil uptake.

Animals↗
PubMed2005

Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia.

BACKGROUND AND PURPOSE: Thrombolytic therapy with tissue plasminogen activator (tPA) in ischemic stroke is limited by increased risks of cerebral hemorrhage and brain injury. In part, these phenomena may be related to neurovascular proteolysis mediated by matrix metalloproteinases (MMPs). Here, we used a combination of pharmacological and genetic approaches to show that tPA promotes MMP-9 levels in stroke in vivo. METHODS: In the first experiment, spontaneously hypertensive rats were subjected to 3 hours of transient focal cerebral ischemia. The effects of tPA (10 mg/kg IV) on ischemic brain MMP-9 levels were assessed by zymography. In the second experiment, wild-type (WT) and tPA knockout mice were subjected to 2 hours of transient focal cerebral ischemia, and MMP-9 levels and brain edema during reperfusion were assessed. Phenotype rescue was performed by administering tPA to the tPA knockout mice. RESULTS: In the first experiment, exogenous tPA did not change infarct size but amplified MMP-9 levels in ischemic rat brain at 24 hours. Coinfusion of the plasmin inhibitor tranexamic acid (300 mg/kg) did not ameliorate this effect, suggesting that it was independent of plasmin. In the second experiment, ischemic MMP-9 levels, infarct size, and brain edema in tPA knockouts were significantly lower than WT mice. Administration of exogenous tPA (10 mg/kg IV) did not alter infarction but reinstated the ischemic MMP-9 response back up to WT levels and correspondingly worsened edema. CONCLUSIONS: These data demonstrate that tPA upregulates brain MMP-9 levels in stroke in vivo, and suggest that combination therapies targeting MMPs may improve tPA therapy.

Animals↗