人血清白蛋白修饰的尿激酶与天然尿激酶的家兔体内过程比较

家兔静注人血清白蛋白修饰的尿激酶(MUK)和天然尿激酶(NUK)40000IU后,MUK 的体内过程符合零级速率过程,NUK 则符合一级速率过程,血纤溶活性 MUK 持续100min,而 NUK 仅20～25min。在“功能性”去除肝肾的家兔,NUK 血浓度半衰期延长3～4倍,而 MUK 血浓度下降与正常家兔相似。MUK 及 NUK 在去除纤溶抑制物的优球蛋白成份中纤溶活性相似,但在血浆中 NUK 仅存24～35%的纤溶活性,MUK 则保留了64～85%的纤溶活性。提示肝肾的摄取、代谢和消除能力降低及对血浆纤溶抑制物抵抗力增强,是 MUK 血纤溶活性长时间维持高水平的主要原因。     

Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease

BACKGROUND: Aspirin increases fibrin clot porosity and susceptibility to lysis. It is unknown whether other drugs, in combination with aspirin, used in the treatment of coronary artery disease (CAD) might affect clot structure and resistance to lysis. AIM: The aim of the study was to assess the effects of statins, fibrates, or angiotensin-converting enzyme inhibitors (ACEIs) on fibrin clot properties. PATIENTS AND METHODS: In a randomized double-blind study, men with advanced CAD taking low-dose aspirin were assigned to receive one of the four drugs: simvastatin 40 mg day(-1) (n = 13), atorvastatin 40 mg day(-1) (n = 12), fenofibrate 160 mg day(-1) (n = 12), and quinapril 10 mg day(-1) (n = 11) for 28 +/- 2 days. Moreover, CAD patients (n = 13) taking aspirin (75 mg day(-1)) for 8 weeks were studied after additional 4 weeks on an open-label basis. Thirty men served as healthy controls. Plasma clot permeability and tissue plasminogen activator-induced fibrinolysis were evaluated at baseline and after drug administration. RESULTS: Permeability increased following the administration of simvastatin (by 20%; P = 0.01), atorvastatin (by 22%; P = 0.001), fenofibrate (by 16%; P = 0.02), and quinapril (by 13%; P = 0.04) like for aspirin (P < 0.001). Turbidity analysis showed that administration of any of the drugs was associated with higher maximum absorbancy, suggesting thicker fibers, and shorter fibrinolysis time (P < 0.001). Post-treatment reduction in lysis time correlated with an increase in clot porosity in all the groups (r from 0.42 to 0.61; P from 0.01 to 0.001). CONCLUSIONS: Statins, fibrates, and ACEIs may increase plasma clot permeability and susceptibility to fibrinolysis in CAD patients receiving aspirin. This novel antithrombotic mechanism might contribute to clinical benefits of the drugs tested.     

Targeted Thrombolytic Therapy

Venous and arterial thrombosis are closely related to many severe diseases, especially to cardiovascular and cerebrovasular disorders. Thrombolytic therapy has been proven to be an effective method to treat such disease, which decreased the mortality and morbidity greatly.     

Tissue plasminogen activator genetic polymorphisms do not influence tissue plasminogen activator release in patients with coronary heart disease

OBJECTIVES: To determine if polymorphisms of the tissue plasminogen activator (t-PA) gene influence acute endogenous t-PA release in patients with coronary heart disease (CHD). METHODS: Forearm blood flow and plasma t-PA concentrations were measured in response to intra-brachial infusion of substance P and sodium nitroprusside in 96 patients with stable CHD. Genotyping was performed using a Taqman polymerase chain reaction assay specifically designed to detect the polymorphisms of interest: (i) Alu-repeat insertion/deletion sequence; (ii) C-->T substitution in an upstream enhancer region (-7351 C/T); (iii) T-->C in exon 6 (20 099 T/C); and (iv) T-->A (27 445 T/A) in intron 10. RESULTS: Substance P and sodium nitroprusside caused dose-dependent increases in forearm blood flow in all patients (P < 0.001 for all) that were independent of the four genetic polymorphisms. Similarly, there were no differences in basal plasma t-PA antigen concentrations or net t-PA release between genotypes. Compared to non-smokers, smokers exhibited impaired substance P-induced vasodilatation (P < 0.001) and t-PA release (P = 0.05). CONCLUSIONS: Despite confirming our previous findings in cigarette smokers, we have found no effect of polymorphisms of the t-PA gene on two complementary aspects of endothelial function. We conclude that genetic variation of the t-PA locus is unlikely to have a major influence on acute t-PA release in subjects with established CHD.     

Local fibrinolysis for superior mesenteric artery thromboembolism

A 66-year-old man with atrial fibrillation was referred soon after developing left lower limb and abdominal pain with rectal bleeding. An immediate flush aortogram showed embolic occlusion of the left distal superficial femoral artery and superior mesenteric artery (SMA), 3 cm from its ostium. Recombinant tissue plasminogen activitor (rtPA) 40 mg was selectively in stilled in the SMA in two boluses. Abdominal symptoms resolved within 48 h, and complete recanalization of the SMA was shown on angiography. Exploratory laparotomy after 72 h showed a normal small bowel and right colon, and was completed by femoropopliteal embolectomy. Six months later, the patient remained asymptomatic.     

The profibrinolytic effect of plasma thrombomodulin in factor XI deficiency and its implications in hemostasis

Bleeding tendency in factor (F)XI deficiency may result from premature clot lysis due to insufficient thrombin activatable fibrinolysis inhibitor (TAFI) activation. Thrombomodulin (TM), upon binding to thrombin, is capable of modulating TAFI activation. In this study, we investigated the effects of plasma TM on fibrinolysis in FXI-deficient patients. A clot lysis assay showed the defective down-regulation of fibrinolysis in FXI-deficient patients as compared with normal controls. To evaluate the effects of plasma TM on fibrinolysis, a monoclonal anti-TM IgG was preincubated with plasma for 30 min. The presence of anti-TM IgG significantly prolonged the clot lysis times both in the FXI-deficient and normal plasma, indicating that plasma TM stimulated fibrinolysis. Furthermore, the presence of anti-TM IgG not only reduced protein C activation, but also increased thrombin generation and TAFI activation. The profibrinolytic effect of plasma TM was inhibited in the assay by including either a monoclonal anti-TAFI IgG or a specific TAFI inhibitor--carboxypeptidase inhibitor (CPI). Our results indicate that the impaired thrombin generation in FXI-deficient patients leads to the defective down-regulation of fibrinolysis, and that plasma TM stimulates fibrinolysis through APC pathway which inhibits TAFI activation. The profibrinolytic effect of plasma TM may contribute to the bleeding tendency observed in some FXI-deficient patients.     

Tumour cell u-PA as a cause of fibrinolytic bleeding in metastatic disease

Tumour cells may express urokinase type plasminogen activator (u-PA). This may influence the invasive properties of the cells but has seldom been implicated in production of a systemic bleeding state. Two patients are described in whom severe bleeding occurred in association with disseminated malignancies. Thrombin generation was little disturbed and platelet numbers were insufficient to account for the bleeding. Florid plasmin generation was evident in the circulation and the fibrinolytic inhibitor tranexamic acid controlled the bleeding well. Free active u-PA was demonstrated in the circulation and u-PA antigen on the malignant cells which invaded the marrow of one of the patients. Tumour cell u-PA may occasionally be responsible for a bleeding state.     

High resolution real-time B-mode echotomography in the diagnosis of extracranial carotid lesions. Comparison with traditional angiography

Summary Tumour growth essentially requires fibrin formation and fibrinopeptide A (FPA) is liberated into the circulation on fibrin formation. In the present study, a possible elevation of serum FPA level was examined in patients with metastatic brain tumour. A significant elevation of serum FPA level was shown in all 6 patients with metastatic brain tumour, when blood was drawn from the internal jugular vein. It was extremely high in 2 patients with rapidly growing tumour. However, such a significant elevation was not shown in 3 cancer patients without brain metastasis or in 1 patient with a huge meningioma. This suggests the possibility that the presence of metastatic brain tumour could be detected by measuring FPA in blood drawn form the internal jugular vein. This also suggests the tendency that elevation of serum FPA is higher in patients with more rapidly growing tumour.Infusion of urokinase into the internal carotid artery resulted in an elevation of serum fibrinopeptide B (1)15–42 (FPB) in 5 patients with metastatic brain tumour, when blood was drawn from the internal jugular vein. This suggests that urokinase could induce fibrinolysis in the tumour tissue, though this remains in conclusive because of the lack of complete controls.