Endothelium, thrombosis and fibrinolysis

Vascular endothelium is involved in the control of thrombosis by influencing among other things, platelet functions, coagulation and fibrinolysis. Fibrinolysis is due to plasminogen conversion into plasmin by activators, which are efficiently and rapidly controlled by a specific inhibitor. Endothelium plays a pivotal role in these associations. It is a constitutive and inducible source of activators and inhibitor. It provides a favorable microenvironment for plasmin generation at the vessel surface. Furthermore, the fibrinolytic system participating in angiogenesis is implicated in plaque survival. Subjected to a pathological environment, endothelial activation leads to change in endothelial properties especially by increasing the production of inhibitor of plasminogen activators. These modifications could combine to create locally or distantly, a state predisposing to thrombosis.     

Fibrinolysis or angioplasty in acute myocardial infarction?

Early reperfusion during myocardial infarction limits myocardial injury and reduces mortality. Fibrinolysis (with streptokinase, or tissue or recombinant plasminogen activators) is today an established method for the treatment of myocardial infarction patients manifesting ST-segment elevation or left bundle branch block at ECG (electrocardiography), effective reperfusion being obtained in fifty per cent of cases. Extensive developments are under way, both of fibrinolytic substances and of various adjuvant treatments. A satisfactory alternative treatment to fibrinolysis is percutaneous transluminal coronary angioplasty (PTCA), a method which can be used when fibrinolysis is contraindicated or during cardiogenic shock, or when there is no sign of reperfusion in response to fibrinolytic treatment. Provided the facilities and competence are available, PTCA can even be used as primary treatment instead of fibrinolysis.     

Bleeding in portal hypertensive gastropathy evaluated in terms of gastric mucosal microcirculation and coagulation-fibrinolysis system

Gastric intramucosal bleeding in portal hypertensive gastropathy was investigated in terms of gastric mucosal microcirculation, coagulation-fibrinolysis factors, and local fibrinolysis in patients with liver cirrhosis. The gastric mucosa was examined by endoscopy, and the patients were classified into two groups with or without bleeding. Gastric mucosal blood flow was measured simultaneously with coagulation-fibrinolysis factors or local fibrinolysis in both groups. As gastric mucosal blood flow, the gastric mucosal blood volume (IHb) and the oxygenated hemoglobin concentration (ISO2) were determined by the organ reflection spectrum method. Coagulation-fibrinolysis factors were measured in the blood. For evaluation of local fibrinolysis, gastric biopsy specimens were placed on a standard fibrin plate, and the fibrinolysis area was measured. Compared with the non-bleeding group, the bleeding group showed increased IHb and decreased ISO2 (p < 0.05), suggesting marked congestion of blood flow. Gastric intramucosal bleeding was frequently observed in patients with marked congestion of blood flow and markedly abnormal values of coagulation-fibrinolysis factors. Gastric local fibrinolysis was also significantly enhanced in the bleeding group (p < 0.05). In addition, local fibrinolysis was correlated positively with the gastric mucosal blood volume (r = 0.68, p < 0.05) and negatively with the oxygenated hemoglobin concentration (r = -0.58, p < 0.05). These results suggest the following mechanism of gastric mucosal bleeding in liver cirrhosis and portal hypertension. Congestion of gastric mucosal blood flow is present in liver cirrhosis and portal hypertension. An increase in the microvascular pressure and hypoxia cause release of tissue plasminogen activators from gastric mucosal cells and vascular endothelial cells. As a result, gastric local fibrinolysis is enhanced, causing gastric mucosal bleeding.     

The mast cell as site of tissue-type plasminogen activator expression and fibrinolysis

Recent data suggest that mast cells (MC) and their products (heparin, proteases) are involved in the regulation of coagulation and fibrino(geno)lysis. The key enzyme of fibrinolysis, plasmin, derives from its inactive progenitor, plasminogen, through catalytic action of plasminogen activators (PAs). In most cell systems, however, PAs are neutralized by plasminogen activator inhibitors (PAIs). We report that human tissue MC as well as the MC line HMC-1 constitutively produce, express, and release tissue-type plasminogen activator (tPA) without producing inhibitory PAIs. As assessed by Northern blotting, highly enriched lung MC (>98% pure) as well as HMC-1 expressed tPA mRNA, but did not express mRNA for PAI-1, PAI-2, or PAI-3. The tPA protein was detectable in MC-conditioned medium by Western blotting and immunoassay, and the MC agonist stem cell factor (c-Kit ligand) was found to promote the release of tPA from MC. In addition, MC-conditioned medium induced fibrin-independent plasmin generation as well as clot lysis in vitro. These observations raise the possibility that MC play an important role in endogenous fibrinolysis.     

New insights into the pathogenesis of coagulation dysfunction in acute promyelocytic leukemia

Patients with acute promyelocytic leukemia (APL) are at high risk for the development of life-threatening thrombotic and hemorrhagic complications, particularly during induction chemotherapy. This propensity has been attributed to the release of tissue factor (TF)-like procoagulants from the leukemic cells leading to disseminated intravascular coagulation (DIC). However, recent data suggest that the pathogenesis of the coagulopathy is more complicated and may involve activation of the generalized proteolytic cascade resulting in either clotting and/or excessive fibrinolysis. Furthermore, controversy exists regarding the mechanism(s) responsible for the activation of either clotting or fibrinolysis. The malignant promyelocyte may act directly to activate coagulation and/or fibrinolysis. Alternatively, reactive inflammatory cells, which express procoagulant and/or profibrinolytic activities may play an essential role. A third possibility may involve endothelial cell expression of mediators with procoagulant/profibrinolytic properties. Putative profibrinolytic mechanisms include the release of urokinase-type and tissue-type plasminogen activators, decreases in plasminogen activator inhibitor-1 and 2, and decreases in alpha-2 plasmin inhibitor. Putative procoagulant mechanisms include the release of tissue factor, Cancer Procoagulant, or cytokines such as interleukin-1, tumor necrosis factor and vascular permeability factor. Putative anticoagulant mediators include annexins, a group of proteins in human tissue which bind phospholipids and have anticoagulant activity, which have been reported in patients with APL. The current treatment of APL is rapidly evolving because of the efficacy of all-trans retinoic acid (ATRA). All-trans retinoic acid promotes terminal differentiation of leukemic promyelocytes leading to complete remission in the majority of patients with APL with rapid resolution of the coagulopathy. Although the mechanism by which this occurs has not been established, preliminary data suggest that ATRA blocks the downregulation of the thrombomodulin gene and the up-regulation of the tissue factor gene induced by tumor necrosis factor. Since APL is a relatively uncommon disorder, the collaboration of cooperative oncology groups will be important to study patients receiving ATRA or conventional chemotherapy to further elucidate the mechanism(s) of the coagulopathy.     

The role of the endothelia in hemostasis

Unless associated with endothelial lesions or dysfunction, the increased plasma levels of fibrinogen, clotting factors VII and X as well as of fibrin stabilizing factor XIII and of the inhibitors of fibrinolysis, displayed by hyperlipidemic patients, could explain neither the localization nor the mechanisms triggering thrombotic events. Actually, endothelia are provided with both prohemostatic factors (tissue factor, von Willebrand factor, platelet activating factor) and antithrombotic mechanisms (tissue factor pathway inhibitor, proteoglycans activating antithrombin III, thrombodulin activating the protein C system as well as prostacyclin inhibiting platelet aggregation). Endothelia also modulate fibrinolytic activity by producing both activators and inhibitors of plasminogen activation. Evidence was provided that proinflammatory cytokines, anion superoxide and oxidized LDL would cause an upregulation of prohemostatic mechanisms, while down regulating the antithrombotic ones. Attempts made to detect endothelial dysfunction by methods available to the clinical laboratory and author's own observations concerning the behaviour of endothelia-derived plasma von Willebrand factor in various pathological conditions are briefly presented.     

The effects of ginseng radix rubra on human vascular endothelial cells

The effect of Ginseng Radix Rubra (Red ginseng) on human vascular endothelial cells was examined. Red ginseng was found to promote the proliferation of vascular endothelial cells, inhibit the production but promote the decomposition of endothelin, which is known to constrict blood vessels and raise blood pressure as well as accelerated the synthesis of nitric oxide, which is known to have an angio-tonic effect. Furthermore, Red ginseng was observed to increase the production of Interleukin 1 beta, which is known to play important roles in the homeostatic activities of the human body such as immunity and inflammation as well as increasing the production of tissue plasminogen activators, which suppress the formation of thrombin in the blood coagulation and fibrinolysis mechanisms. It is suggested that Red ginseng has the effect of accelerating endothelial cells proliferation and of promoting physiological activities.     

Human renal microvascular endothelial cells as a potential target in the development of the hemolytic uremic syndrome as related to fibrinolysis factor expression, in vitro

Renal glomerular microvascular endothelial cell damage is characteristic of Shiga toxin-associated hemolytic uremic syndrome (HUS). An impaired renal fibrinolysis may be responsible for renal microvascular fibrin accumulation during the course of HUS disease. This study examined the effect of Shiga toxin, bacterial lipopolysaccharide (LPS, endotoxin), and tumor necrosis factor (TNF) on the expression of fibrinolysis factors by human renal glomerular microvascular endothelial cells (HRMEC) in vitro. The results were compared to a previously better-characterized endothelial cell type, human umbilical vein endothelial cells (HUVEC). In HUVEC, the ratio of fibrinolysis antigens was antifibrinolytic, consisting of 55-fold more plasminogen activator inhibitor type 1 (PAI-1) than tissue-type plasminogen activator (tPA). Treatment of HUVEC with LPS or TNF accentuated this ratio by decreasing tPA and increasing PAI-1 expression. In contrast, HRMEC produced urokinase-type plasminogen activator (uPA) in a 24-fold excess to PAI-1 and were thereby profibrinolytic with regard to fibrinolysis antigen expression. LPS and TNF further decreased PAI-1 antigen expression by HRMEC. These results argue against a role for LPS or TNF in decreasing renal fibrinolysis at the level of fibrinolysis factor expression by renal endothelial cells. Nevertheless, HUVEC and HRMEC were responsive to the same LPS analogs in the same order of potency. Shiga toxin decreased fibrinolysis factor expression to a greater extent in HRMEC than in HUVEC. Since HRMEC fibrinolysis antigen expression was profibrinolytic, the Shiga toxin-mediated decrease in renal endothelial uPA synthesis may predispose renal microvasculature to thrombosis and may have implications for the development of HUS.     

Production of plasminogen activator inhibitor-1 by human saphenous vein endothelial cells seeded onto endarterectomy surfaces in vitro

PURPOSE: Endothelial cells produce many biologically important factors that may be used as functional markers, including plasminogen activators and their inhibitors (PAI). PAI-1 is a common peptide with a central role in the balance of thrombosis and fibrinolysis in vivo, and its production by vascular endothelial cells has been demonstrated for many in vitro cell lines. METHODS: The basal rate of PAI-1 release from cultured human adult endothelial cells was studied in both a well-plate-seeding model and after seeding onto human endarterectomy specimens. The effect of nonspecific stimulation with thrombin on PAI-1 release was examined in well-plate cultures. PAI-1 was measured by enzyme-linked immunosorbent assay. RESULTS: Cultured human saphenous endothelial cells release PAI-1 constitutively at a steady rate, which can be increased in the short term by the addition of thrombin. CONCLUSION: After seeding onto endarterectomy specimens, seeded endothelial cells release significant amounts of PAI-1, which suggests that they retain functional integrity and may potentially influence thrombosis in vivo after seeding.     

A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor

TAFI (thrombin-activable fibrinolysis inhibitor) is a recently described plasma zymogen that, when exposed to the thrombin-thrombomodulin complex, is converted by proteolysis at Arg92 to a basic carboxypeptidase that inhibits fibrinolysis (TAFIa). The studies described here were undertaken to elucidate the molecular basis for the inhibition of fibrinolysis. When TAFIa is included in a clot undergoing fibrinolysis induced by tissue plasminogen activator and plasminogen, the time to achieve lysis is prolonged, and free arginine and lysine are released over time. In addition, TAFIa prevents a 2.5-fold increase in the rate constant for plasminogen activation which occurs when fibrin is modified by plasmin in the early course of fibrin degradation. The effect is specific for the Glu- form of plasminogen. TAFIa prevents or at least attenuates positive feedback expressed through Lys-plasminogen formation during the process of fibrinolysis initiated by tissue plasminogen activator and plasminogen. TAFIa also inhibits plasmin activity in a clot and prolongs fibrinolysis initiated with plasmin. We conclude that TAFIa suppresses fibrinolysis by removing COOH-terminal lysine and arginine residues from fibrin, thereby reducing its cofactor functions in both plasminogen activation and the positive feedback conversion of Glu-plasminogen to Lys-plasminogen. At relatively elevated concentrations, it also directly inhibits plasmin.     

Interleukin-6 stimulates coagulation, not fibrinolysis, in humans

The role of IL-6 as a mediator of haemostatic changes during severe inflammation is controversial. To assess the effect of IL-6 on haemostasis we conducted a controlled cross-over study in eight patients with metastatic renal cell cancer. In all subjects coagulation and fibrinolysis were monitored during and after a 4-h infusion of either 150 micrograms recombinant human (rh) IL-6, or during infusion of saline (control study). Mean maximum IL-6 concentrations were 1418.0 +/- 755.8 pg/ml. Compared to the control study, rhIL-6 induced activation of coagulation as reflected by a 190 +/- 55% increase in the plasma levels of thrombin-antithrombin III complexes (p < 0.001) and by a 24 +/- 11% increase in the plasma levels of in the prothrombin activation fragment F1 + 2 (p < 0.001). In contrast, fibrinolysis was not affected. We conclude that in severe inflammation IL-6 may contribute to the activation of coagulation, whereas other factors mediate changes in fibrinolysis.     

Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene

Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue- and urokinase-type plasminogen activators, is considered a critical regulator of the fibrinolytic system. We previously reported a child with abnormal bleeding and complete PAI-1 deficiency caused by a frame-shift mutation in exon 4 of the PAI-1 gene. The purpose of this study was to provide genetic and clinical data on the extended pedigree of the original proband to better define the phenotype associated with PAI-1 deficiency. Allele-specific oligonucleotide hybridization was used to genotype individuals, and serum PAI-1 antigen was measured by enzyme-linked immunosorbent assay. By this approach we have identified 19 individuals who are heterozygous for the PAI-1 null allele and 7 homozygous individuals with complete PAI-1 deficiency. Clinical manifestations of PAI-1 deficiency were restricted to abnormal bleeding, which was observed only after trauma or surgery in homozygous affected individuals. A spectrum of bleeding patterns was observed, including intracranial and joint bleeding after mild trauma, delayed surgical bleeding, severe menstrual bleeding, and frequent bruising. Fibrinolysis inhibitors, including epsilon-aminocaproic acid and tranexamic acid, were effective in treating and preventing bleeding episodes. Other than abnormal bleeding, no significant developmental or other abnormalities were observed in homozygous PAI-1-deficient individuals. Heterozygous PAI-1 deficiency was not associated with abnormal bleeding, even after trauma or surgery. These observations define the clinical spectrum of PAI-1 deficiency and provide additional evidence to support the hypothesis that the primary function of plasminogen activator inhibitor-1 in vivo is to regulate vascular fibrinolysis.     

Spinal reflexes in the determination of brain death

Tranexamic acid (TA) is a synthetic drug that inhibits fibrinolysis. It has been administered to decrease the use of blood products during cardiac surgery and orthotopic liver transplantation when infused in larger doses. A small-dose infusion of aprotinin causes a reduction in fibrinolysis and blood product requirement during orthotopic liver transplantation without apparent risk of intravascular thrombosis. This prospective study was designed to investigate whether a small-dose infusion of TA would be equally effective in reducing fibrinolysis and blood product transfusions during orthotopic liver transplantation. A double-blind, controlled study was undertaken to compare the efficacy of a small-dose TA infusion with that of a placebo. Thirty-two consecutive patients were randomized either to the TA group (n = 16), which received an intravenous infusion of 2 mg x kg(-1) x h(-1), or to the control group (n = 16), which received an identical volume of normal saline. Coagulation values were measured, a field rating was made by the surgeon, and a thromboelastogram was produced at four predetermined intervals throughout the case-before TA infusion was started, after portal vein ligation, 10 min after reperfusion, and at the end of surgery. Intraoperative transfusion requirements were recorded during the procedure and for the first 24 h postoperatively. A record was kept of any intraoperative epsilon-aminocaproic acid administered for uncontrolled fibrinolysis. The thromboelastogram clot lysis index was significant for lysis in the control group during both the anhepatic and the neohepatic phases (P < 0.01 and P < 0.05, respectively) when compared with the TA group. Fibrin degradation products were significantly increased (>20 microg/mL) in the control group at reperfusion (P < 0.03) and at the end of surgery (P < 0.01). D-dimers were also significantly increased (>1 mg/L) in the control group at the end of surgery (P < 0.04). Nine of the 16 control patients versus 3 of the 16 TA patients required epsilon-aminocaproic acid rescue for fibrinolysis. There were no other significant differences between groups. Transfusion requirements during surgery and for the first 24 h postoperatively did not differ significantly between the two groups. We conclude that the use of small-dose TA reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation.     

Assembly and activation of the intrinsic fibrinolytic pathway on the surface of human endothelial cells in culture

Factor XII has long been implicated in the intrinsic pathway of fibrinolysis, but the mechanism by which it triggers plasminogen activation and targets fibrinolysis has not been established. In the present study, the assembly and function of activated Factor XII (F.XIIa), prourokinase (pro-u-PA), high molecular weight kininogen (H-kininogen), and prekallikrein on human umbilical vein endothelial cells (HUVEC) was investigated. 125I-prekallikrein was shown to bind to HUVEC via receptor-bound H-kininogen in the presence of 50 microM ZnCl2. After the addition of F.XIIa, 78% of the 125I-prekallikrein initially bound to HUVEC was converted to 125I-kallikrein. However, only 6% of the HUVEC-bound 125I-pro-u-PA was thereby activated. This discrepancy was shown to be related to rapid dissociation (> 50% within 15 min) of prekallikrein/kallikrein, but not pro-u-PA, from HUVEC. Increasing the level of cell-bound kallikrein increased the portion of cell-bound pro-u-PA activated, indicating that their co-localization was important for this pathway. Finally, F.XIIa was shown to trigger plasminogen activation on HUVEC via this pathway. This assembly of reactants on the endothelium suggests a mechanism whereby local fibrinolysis may be triggered by blood coagulation.     

Effects of heparin therapy on fibrinolysis in patients with pulmonary embolism

Previous investigations suggested that heparin administration to humans enhances the tissue type plasminogen activator (tPA) levels in blood, but it remains uncertain whether this effect induces fibrinolysis. We studied the effect of therapeutic levels of heparinization on plasma markers for fibrinolysis in patients suspected of pulmonary embolism (PE). Blood samples were taken from 49 consecutive patients; 28 had confirmed PE, 21 had PE excluded. On admission, the plasma levels of plasmin-alpha 2antiplasmin complexes and D-dimer were significantly higher in the patient group with PE compared to those in whom PE was excluded. After heparinization the tPA levels increased in both groups, showing that this effect was not dependent on the initial level of activity of fibrinolysis. In spite of this increment in tPA levels, the concentrations of plasmin-alpha 2antiplasmin complexes and D-dimer decreased. In conclusion, although heparinization in patients with or without pulmonary embolism does lead to elevated tPA:Ag levels, this is not accompanied by enhanced fibrinolysis.     

Both cellular and soluble forms of thrombomodulin inhibit fibrinolysis by potentiating the activation of thrombin-activable fibrinolysis inhibitor

Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described plasma zymogen that can be activated by thrombin to an enzyme with carboxypeptidase B-like activity. The enzyme, TAFIa, potently attentuates fibrinolysis. TAFI activation, like protein C activation, is augmented about 1250-fold by thrombomodulin (TM). In this work, the effects of both soluble and cellular forms of TM on TAFI activation-dependent suppression of fibrinolysis were investigated. Soluble TM included in clots formed from purified components, barium citrate-adsorbed plasma, or normal human plasma maximally increased the tissue plasminogen activator-induced lysis time 2-3-fold, with saturation occurring at 5, 10, and 1 nM TM in the three respective systems. Soluble TM did not effect lysis in the system of purified components lacking TAFI or in plasmas immunodepleted of TAFI. In addition, the antifibrinolytic effect of TM was negated by monoclonal antibodies against either TAFI or TM. The inhibition of fibrinolysis by cellular TM was assessed by forming clots in dialyzed, barium citrate-adsorbed, or normal plasma over cultured human umbilical vein endothelial cells (HUVECs). Tissue plasminogen activator-induced lysis time was increased 2-fold, with both plasmas, in the presence of HUVECs. The antifibrinolytic effect of HUVECs was abolished 66% by specific anti-TAFI or anti-TM monoclonal antibodies. A newly developed functional assay demonstrated that HUVECs potentiate the thrombin-catalyzed, TM-dependent formation of activated TAFI. Thus, endothelial cell TM, in vitro at least, appears to participate in the regulation of not only coagulation but also fibrinolysis.     

Risk factors for atherosclerosis in offspring of parents with primary hypertriglyceridemia

High triglycerides and low fibrinolysis activity are considered as a significant predictors for atherosclerosis. The aim of our study was: 1-to compare these risk factors levels in children with positive family history of hypertriglyceridemia (HTG) with children from healthy families and 2-to assess the association between triglyceride and fibrinolysis activity in offspring (y) and parental risk factors (xl ... xn) for atherosclerosis. The study population consisted of: I Group 15 children 7-12 years old and their parents from HTG families and II Group 26 control children 5-12 years old from healthy families. Triglyceride (TG), total cholesterol, cholesterol esters, LDL-Ch, HDL-Ch, HDL2Ch, apolipoprotein AI and BII, fibrinogen plasma level were determined. Plasminogen activator inhibitor (PAI-1) and fibrinolysis activity and (ELT) were determined. We found significant differences in clinical examinations (higher blood pressure and ECG disturbances more frequently), HDL-Ch and HDL2-Ch plasma level was lower in children with positive family history than in control children. Multiple regression analysis of parental variables demonstrated, that children's TG and ELT are strongly determined by parental lipids and haemostasis parameters in children with positive family history of HTG.     

Enhancement of fibrinolysis with 40-kHz ultrasound

BACKGROUND: Ultrasound at frequencies of 0.5 to 1 MHz and intensities of > or =0.5 W/cm2 accelerates enzymatic fibrinolysis in vitro and in some animal models, but unacceptable tissue heating can occur, and limited penetration would restrict application to superficial vessels. Tissue heating is less and penetration better at lower frequencies, but little information is available regarding the effect of lower-frequency ultrasound on enzymatic fibrinolysis. We therefore examined the effect of 40-kHz ultrasound on fibrinolysis, tissue penetration, and heating. METHODS AND RESULTS: 125I-fibrin-radiolabeled plasma clots in thin-walled tubes were overlaid with plasma containing tissue plasminogen activator (tPA) and exposed to ultrasound. Enzymatic fibrinolysis was measured as solubilization of radiolabel. Tissue attenuation and heating were examined in samples of porcine rib cage. Fibrinolysis was increased significantly in the presence of 40-kHz ultrasound at 0.25 W/cm2, reaching 39+/-7% and 93+/-11% at 60 minutes and 120 minutes, compared with 13+/-8% and 37+/-4% in the absence of ultrasound (P<0.0001). The acceleration of fibrinolysis increased at higher intensities. Attenuation of the ultrasound field was only 1.7+/-0.5 dB/cm through the intercostal space and 3.4+/-0.9 dB/cm through rib. Temperature increments in rib were <1 C/(W/cm2). CONCLUSIONS: These findings indicate that 40-kHz ultrasound significantly accelerates enzymatic fibrinolysis at intensities of > or =0.25 W/cm2 with excellent tissue penetration and minimal heating. Externally applied 40-kHz ultrasound at low intensities is a potentially useful therapeutic adjunct to enzymatic fibrinolysis with sufficient tissue penetration for both peripheral vascular and coronary applications.     

Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction

Plasminogen (Plg)-deficient mice were generated to define the physiological roles of this key fibrinolytic protein and its proteolytic derivatives, plasmin and angiostatin, in development, hemostasis, and reproduction. Plg-/- mice complete embryonic development, survive to adulthood, and are fertile. There is no evidence of fetal loss of Plg-/- mice based on the Mendelian pattern of transmission of the mutant Plg allele. Furthermore, embryonic development continues to term in the absence of endogenous, sibling-derived, or maternal Plg. However, Plg-/- mice are predisposed to severe thrombosis, and young animals developed multiple spontaneous thrombotic lesions in liver, stomach, colon, rectum, lung, pancreas, and other tissues. Fibrin deposition in the liver was a uniform finding in 5- to 21-week-old mice, and ulcerated lesions in the gastrointestinal tract and rectal tissue were common. A remarkable finding, considering the well-established linkage between plasmin and the proteolytic activation of plasminogen activators, was that the level of active urokinase-type plasminogen activator in urine was unaffected in Plg-/- mice. Therefore, Plg plays a pivotal role in fibrinolysis and hemostasis but is not essential for urokinase proenzyme activation, development, or growth to sexual maturity.     

Self-reported health and function status of elderly Turkish immigrants in Copenhagen, Denmark

Tissue damage by extracorporeal shock wave lithotripsy (ESWL) is assumed to be attributable to ischemic changes in the treated region surrounding the particular vessel which is first ruptured by shock waves. Such changes cannot take place without being accompanied by acceleration of coagulation and fibrinolysis. In the literature on renal damage by ESWL, no parameters of the coagulation and fibrinolysis of blood were used. The present study was designed to investigate renal damage by shock waves through the quantification of sequential changes in the following parameters between before and after ESWL: thrombin antithrombin III complex (TAT), alpha 2-plasmin inhibitor-plasmin complex (PIC), fibrin and fibrinogen degradation products (FDP) and D-dimer (D-D). In ESWL for renal stones, a significant acceleration of TAT occurred on the 1st postoperative day, followed by acceleration of PIC on the 3rd postoperative day. A transient acceleration was observed for FDP and D-D after operation. The levels of these parameters, however, returned to normal by the 1st postoperative week. In ESWL for ureteral stones, unlike for renal stones, none of the parameters showed statistically significant acceleration. In the construction of percutaneous nephrostomy (PNS) cases for ureteral stones before ESWL, none of the parameters showed significant acceleration either. Changes in these parameters of coagulation and fibrinolysis due to ESWL for renal stones were greater than those of construction of PNS or ESWL for ureteral stones. The reason for the difference of the alteration in these parameters between renal stones and ureteral stones were more abundant vessels in the kidney than the ureter. All these changes in the parameters, however, disappeared within almost 1 week.