(1/149) Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding.
alpha2-antiplasmin (alpha2-AP) is the main physiologic plasmin inhibitor in mammalian plasma. Inactivation of the murine alpha2-AP gene was achieved by replacing, through homologous recombination in embryonic stem cells, a 7-kb genomic sequence encoding the entire murine protein (exon 2 through part of exon 10, including the stop codon) with the neomycin resistance expression cassette. Germline transmission of the mutated allele was confirmed by Southern blot analysis. Mendelian inheritance of the inactivated alpha2-AP allele was observed, and homozygous deficient (alpha2-AP-/-) mice displayed normal fertility, viability, and development. Reverse transcription-polymerase chain reaction confirmed the absence of alpha2-AP mRNA in kidney and liver from alpha2-AP-/- mice, in contrast to wild-type (alpha2-AP+/+) mice. Immunologic and functional alpha2-AP levels were undetectable in plasma of alpha2-AP-/- mice, and were about half of wild-type in heterozygous littermates (alpha2-AP+/-). Other hemostasis parameters, including plasminogen activator inhibitor-1, plasminogen, fibrinogen, hemoglobin, hematocrit, and blood cell counts were comparable for alpha2-AP+/+, alpha2-AP+/-, and alpha2-AP-/- mice. After amputation of tail or toe tips, bleeding stopped spontaneously in alpha2-AP+/+, as well as in alpha2-AP+/- and alpha2-AP-/- mice. Spontaneous lysis after 4 hours of intravenously injected 125I-fibrin-labeled plasma clots was significantly higher in alpha2-AP-/- than in alpha2-AP+/+ mice when injecting clots prepared from alpha2-AP+/+ plasma (78% +/- 5% v 46% +/- 9%; mean +/- SEM, n = 6 to 7; P =.02) or from alpha2-AP-/- plasma (81% +/- 5% v 46% +/- 5%; mean +/- SEM, n = 5; P =.008). Four to 8 hours after endotoxin injection, fibrin deposition in the kidneys was significantly reduced in alpha2-AP-/- mice, as compared with alpha2-AP+/+ mice (P =.005). Thus, alpha2-AP-/- mice develop and reproduce normally; they have an enhanced endogenous fibrinolytic capacity without overt bleeding. (+info)
(2/149) Annexin II and bleeding in acute promyelocytic leukemia.
BACKGROUND: Acute promyelocytic leukemia (APL) is associated with a hemorrhagic disorder of unknown cause that responds to treatment with all-trans-retinoic acid. METHODS: We studied a newly described receptor for fibrinolytic proteins, annexin II, in cells from patients with APL or other leukemias. We examined initial rates of in vitro generation of plasmin by tissue plasminogen activator (t-PA) in the presence of APL cells that did or did not have the characteristic translocation of APL, t(15;17). We also determined the effect of all-trans-retinoic acid on the expression of annexin II and the generation of cell-surface plasmin. RESULTS: The expression of annexin II, as detected by a fluorescein-tagged antibody, was greater on leukemic cells from patients with APL than on other types of leukemic cells (mean fluorescence intensity, 6.9 and 2.9, respectively; P<0.01). The t(15;17)-positive APL cells stimulated the generation of cell-surface, t-PA-dependent plasmin twice as efficiently as the t(15;17)-negative cells. This increase in plasmin was blocked by an anti-annexin II antibody and was induced by transfection of t(15;17)-negative cells with annexin II complementary DNA. The t(15;17)-positive APL cells contained abundant messenger RNA for annexin II, which disappeared through a transcriptional mechanism after treatment with all-trans-retinoic acid. CONCLUSIONS: Abnormally high levels of expression of annexin II on APL cells increase the production of plasmin, a fibrinolytic protein. Overexpression of annexin II may be a mechanism for the hemorrhagic complications of APL. (+info)
(3/149) Coagulation and bleeding disorders: review and update.
Hemostasis is initiated by injury to the vascular wall, leading to the deposition of platelets adhering to components of the subendothelium. Platelet adhesion requires the presence of von Willebrand factor and platelet receptors (IIb/IIIa and Ib/IX). Additional platelets are recruited to the site of injury by release of platelet granular contents, including ADP. The "platelet plug" is stabilized by interaction with fibrinogen. In this review, I consider laboratory tests used to evaluate coagulation, including prothrombin time, activated partial thromboplastin time, thrombin time, and platelet count. I discuss hereditary disorders of platelets and/or coagulation proteins that lead to clinical bleeding as well as acquired disorders, including disseminated intravascular coagulation and acquired circulating anticoagulants. (+info)
(4/149) Reduced oxidative-stress response in red blood cells from p45NFE2-deficient mice.
p45NF-E2 is a member of the cap 'n' collar (CNC)-basic leucine zipper family of transcriptional activators that is expressed at high levels in various types of blood cells. Mice deficient in p45NF-E2 that were generated by gene targeting have high mortality from bleeding resulting from severe thrombocytopenia. Surviving p45nf-e2(-/-) adults have mild anemia characterized by hypochromic red blood cells (RBCs), reticulocytosis, and splenomegaly. Erythroid abnormalities in p45nf-e2(-/-) animals were previously attributed to stress erythropoiesis caused by chronic bleeding and, possibly, ineffective erythropoiesis. Previous studies suggested that CNC factors might play essential roles in regulating expression of genes that protect cells against oxidative stress. In this study, we found that p45NF-E2-deficient RBCs have increased levels of reactive oxygen species and an increased susceptibility to oxidative-stress-induced damage. Deformability of p45NF-E2-deficient RBCs was markedly reduced with oxidative stress, and mutant cells had a reduced life span. One possible reason for increased sensitivity to oxidative stress is that catalase levels were reduced in mutant RBCs. These findings suggest a role for p45NF-E2 in the oxidative-stress response in RBCs and indicate that p45NF-E2 deficiency contributes to the anemia in p45nf-e2(-/-) mice. (Blood. 2001;97:2151-2158) (+info)
(5/149) Comparison of hemostatic disturbances between patients on CAPD and patients on hemodialysis.
OBJECTIVE: Disturbances in hemostasis are common findings in uremic patients. Both bleeding diathesis and thrombosis are observed. The purpose of this study was to assess whether renal replacement therapy in the form of hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) affects coagulation and fibrinolysis in patients with end-stage renal failure. DESIGN: Comparison of hemostatic measures in patients on CAPD, HD, and matched healthy controls. SETTING: Department of Nephrology and Internal Medicine, Bialystok University School of Medicine. PATIENTS AND METHODS: Twenty-four HD patients and 23 CAPD patients were evaluated with respect to platelet aggregation, hemostatic parameters, serum lipids, lipoprotein(a), and cytokines [tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1)]. INTERVENTIONS: Four exchanges of CAPD per day, using 2.0 L dialysate over a period of 25 +/- 31 months; or 4-5 hours of HD 3 times per week for a period of 31 +/- 22 months. RESULTS: Platelet aggregation in whole blood and platelet-rich plasma was significantly impaired in both groups of dialyzed patients compared to healthy volunteers. Markers of endothelial cell injury (thrombomodulin and von Willebrand factor) were significantly higher in HD and CAPD patients compared to the control group. A similar pattern of changes was observed for lipoprotein(a), fibrinogen, tissue factor pathway activity, and factor VII activity. Activity of factor X was significantly enhanced in CAPD compared to HD patients and controls. Euglobulin clot lysis time was significantly prolonged in HD and CAPD patients over controls, being more prolonged in CAPD patients. Markers of ongoing coagulation (thrombin-antithrombin complexes and prothrombin fragments 1+2) were higher in uremic patients, significantly higher in CAPD than in HD. A marker of ongoing fibrinolysis (plasmin-antiplasmin complexes) was higher in uremic patients but was lower in CAPD than in HD patients. Concentrations of TNFalpha and IL-1 were higher in HD than in CAPD patients. CONCLUSION: Patients on CAPD showed evidence of a higher degree of hypercoagulation than HD patients.Thus, hemostatic abnormalities in end-stage renal failure may be affected to some extent by the choice of renal replacement therapy. (+info)
(6/149) Failure of methylhistidines to inhibit platelet aggregation at concentrations found in uremic plasma.
Methylhistidines are among the amino acids which are present in increased concentrations in the plasma of severely uremic patients who may have a hemorrhagic diathesis. Histidine contains an imidazole ring, and our previous work has shown inhibition of collagen-induced platelet aggregation by imidazole in concentrations as low as 0.5 mM. Collagen-induced, adenosine diphosphate-induced, and norepinephrine-induced platelet aggregation were tested in platelet-rich plasma by a turbidimetric technique after incubation of the plasma with varying concentrations of the methylhistidines for 1 hour. Platelet aggregation was unaffected by methylhistidine concentrations up to 0.6 mM. Only norepinephrine-induced platelet aggregation was slightly inhibited at a concentration of 4.7 (mM far higher than found in uremic patients). The imidazole ring as a portion of the methylhistidine molecule appears to have lost much of its effect on platelet aggregation. (+info)
(7/149) Disseminated intravascular clotting in kwashiorkor.
The role of disseminated intravascular clotting (DIC) in the pathogenesis of the bleeding diathesis kwashiorkor was investigated in 22 patients. According to the severity of the clinical and haematological findings, two grades of DIC were observed. A severe grade of DIC was shown in 6 cases (5 fatal) presenting with thrombocytopenia, hypofibinogenaemia, and multiple coagulation defects, and with abnormally prolonged partial thromboplastin,prothombin, and thrombin times]. A second goups of 16 patients (7 fatal) showed a less severe grade of DIC manifested by thrombocytopenia, low fibringoen level, and a clotting factor defect shown by rpolonged prothrombin and thrombin times. (+info)
(8/149) Orthodontic treatment of patients with medical disorders.
This article will highlight some of the problems encountered when orthodontic treatment is provided for patients who have serious medical conditions. The way in which various disease processes might influence treatment decisions will be described, as well as recommended methods of avoiding potential problems. (+info)