Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019087 (hemorrhagic diathesis)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The precipitous increase in the number of structurally defined fibrinogen defects in recent years has resulted from application of high performance liquid chromatography in combination with peptide mapping and sequencing procedures. More recently, application of DNA sequence of polymerase chain reaction products has accelerated the pace of identification of mutations. Highly frequent defects are Arg substitutions, accounting for eight mutation sites substituted by Cys or His and less frequently by Ser. Amino acid substitutions at different positions on all three chains have pointed to possible structures with polymerization-related functions. Also, substitutions yielding consensus sequences resulted in extra glycosylations of the appropriate Asn in four different mutation sites; the impaired polymerization was reported associated with undue bleeding in two of these. Among informative defects have been those of homozygous probands with A alpha 16Arg----His and A alpha 16Arg----Cys in that failure of release of peptide A (but not of B), as shown with A alpha 16Arg----Cys, resulted in markedly delayed polymerization of such fibrin monomers, in general agreement with conclusions reached in studies of normal fibrin. This dysfunction, as well as the slow rate of release of A shown with A alpha 16Arg----His, was associated with clinically significant hemorrhagic diathesis (in the homozygous probands), consistent with the known physiologic importance of peptide A cleavage in normal hemostasis. Also, defects on the A alpha 17-19 sequence resulting in impaired polymerization are consistent with the known role of this segment in polymerization. Of similar interest have been defects within a B beta chain span encoded its exon 2. Two defects resulting in impaired polymerization and thrombin binding were associated with clinical thrombosis commencing in early life, and this lends strong support to other evidence suggesting a role in polymerization and in noncatalytic thrombin binding by this B beta chain segment. Thrombosis associated with A alpha 554Arg----Cys in a heterozygous proband with impaired tPA interaction is unique and may shed light on this poorly understood but important interaction among fibrin, plasminogen, and tPA. A group of different defects within the gamma 275-375 sequence have pointed to a polymerization role, evidenced by delayed gelation and impaired binding of mutant D to normal fibrin E. An unusual example is a 15 residue insertion between gamma 350 and 351 resulting in impaired polymerization, gamma chain crosslinking, and platelet aggregation support and is associated with hemorrhagic diathesis and poor healing.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fibrinogen anomalies and disease. A clinical update. 140 80

After a bite by the aglyphous red-necked keelback snake Rhabdophis subminiatus a complete defibrinogenation syndrome with severe hemorrhagic diathesis developed in a 25-year-old man. In vitro studies showed that the venom gland extract of the snake contains a very active prothrombin (Factor II) activator. The thrombin generated is inhibited neither by antithrombin III nor the antithrombin-III-heparin complex. The venom gland extract stimulated also the tissue plasminogen activator; however, it did not cause direct activation of plasminogen, protein C, Factor X or direct degradation of fibrinogen.
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PMID:Hemostatic changes due to the venom gland extract of the red-necked keelback snake (Rhabdophis subminiatus). 180 26

Three of 13 patients with intracranial meningiomas showed the pre- and postoperative elevation of tissue-type plasminogen activator (t-PA) related fibrinolytic activity in euglobulin fractions (EFA). During operation, two of these three patients showed a significant elevation of the level of fibrin(ogen) degradation products and oozing in the operating field. However, oozing was not observed in the third patient who had been given tranexamic acid preoperatively. Fibrin autography revealed that a broad lytic band of mol wt 50-60 kDa, probably free t-PA, appeared in the plasma obtained from two of the three patients after operation when EFA elevated significantly. In all patients studied, the t-PA antigen levels were normal preoperatively but increased both during and after operation, and correlated mainly with the intensities of a lytic band of mol wt 110 kDa, probably t-PA complexed with its major inhibitor (PAI-1). These results suggest that the excessive fibrinolysis can induce the local hemorrhagic diathesis during operation and may be related to t-PA function in plasma.
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PMID:Tissue-type plasminogen activator in patients with intracranial meningiomas. 314 49

Haemorrhagic diathesis is a serious complication of uraemia. Desmopressin is known to shorten prolonged bleeding time in uraemia but mechanism of the haemostatic action of this drug remains still unknown. The aim of the work was to study the effect of desmopressin on some haemostatic parameters in relation to plasma and platelet serotonin. Desmopressin was administered i.v. to 33 haemodialysed patients (age range 27-66 years) in a dose of 0.4 microgram/kg b.w., 90 minutes after desmopressin infusion bleeding time became significantly shorter (p < 0.001) and correlated with the shortening of the euglobulin clot lysis time (r = -0.43, p < 0.05). Tissue plasminogen activator activity increased (p < 0.01) and its inhibitor (PAI) activity decreased (p < 0.001) after desmopressin infusion. A correlation between the fall in platelet serotonin content and changes in tissue plasminogen activator and PAI activities was found (r = 0.55, p < 0.01 respectively). A rise in plasma serotonin concentration was observed. In vitro desmopressin inhibited 14C serotonin uptake in a dose-dependent manner. After 2 hours of platelet incubation with desmopressin in a concentration of 4 ng/ml 16% of 14C serotonin was released. A possibility of serotoninergic mechanism in the haemostatic action of desmopressin is suggested.
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PMID:[Possible role of serotonin in hemostatic the mechanism of action of desmopressin (DDAVP) in patients with uremia]. 824 43

The history of the antithrombotic agents--aspirin, heparin, warfarin, and the thrombolytics--is a rich and lively odyssey of serendipity, perseverance, vision, and conflict involving a number of striking personalities. The history of aspirin spans ages and continents from Hippocrates' analgesic for women in labor to the rediscovery of the white willow bark by English country scholar Reverend Edward Stone. Bayer chemist Felix Hoffmann reinvented aspirin for his ailing father; suburban physician L.L. Craven pioneered the prophylactic antithrombotic uses of aspirin; and Sir John Vane elucidated aspirin's mechanism of action as the inhibition of prostaglandin synthetase. Heparin was discovered by McLean, working as a medical student in 1915 in search of a pure procoagulant in dog liver. His original impure material differed somewhat from today's heparin, but purified heparin was rapidly accepted for a myriad of clinical uses; to this day, diverse new properties of this complex glycosaminoglycan continue to be elucidated. The oral anticoagulants emerged from veterinary research in the 1920s on a hemorrhagic disorder afflicting cattle that consumed spoiled sweet clover hay. Several chance encounters led Karl Link and his University of Wisconsin team to the identification of dicumarol as the offending agent in 1939 and its widespread therapeutic use by Wright and others in the 1940s. Link later developed warfarin as a rodenticide, but its use in humans soon followed in the 1950s. Vitamin K was discovered in the 1930s; its involvement in the mechanism of the anticoagulant agents was not delineated until the 1970s. The intrinsic ability of clotted blood to liquify and the fibrinolytic properties of normal urine were noted in the 1800s. Tillett and Sherry's group stumbled on the fibrinolytic properties of streptokinase in the 1930s and pioneered the therapeutic use of streptokinase in the 1940s and of urokinase in the 1960s. Several teams found tissue-type plasminogen activator in various body sites beginning in the 1940s, leading to its cloning and widespread use in the 1980s; anisoylated plasminogen-streptokinase activator complex is an example of rational drug design. The discoverers of these diverse agents have not only provided physicians with a potent armamentarium of antithrombotic drugs but also helped elucidate much basic science and vividly demonstrated the merits of perseverance, independent thought, and adherance to the scientific method.
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PMID:History of drugs for thrombotic disease. Discovery, development, and directions for the future. 828 78

A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms.
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PMID:Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding. 848 16

Hemostasis abnormalities in cardiovascular and aortic surgery remain a major source of morbidity and mortality in patients undergoing such complex procedures. The need for frequent transfusions of red cell and other blood products increases risks and costs to patients and institutions providing patient care. Specifically in cardiovascular and aortic surgery, the nature of the surgery is, at best, semi-elective, and careful preparation to preserve the hemostatic mechanisms of the body is essential. Contact of blood with the extracorporeal circuit induces a hemorrhagic diathesis through a variety of different mechanisms. Dilution of the patient's blood volume by the extracorporeal circuit prime causes depletion of platelets and coagulation factor levels. Aorto intimal disease initiates fibrinolysis by the release of tissue plasminogen activator. Due to the numerous etiologies of bleeding, a combination of blood conservation strategies is suggested. The ideal combination of interventions has yet to be determined and is currently dependent on patient variables, physician and institutional practices, and economic pressures.
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PMID:Hemostasis in aortic and cardiothoracic surgery. 927 51

Vascular intimal carcinomatosis refers to a characteristic tumor proliferation on vascular intima that replaces normal endothelium. This pathological event of unknown cause is quite different from tumor thrombotic microangiopathy due to the absence of thrombi on the tumor cell surfaces. We analyzed renal transitional cell carcinoma cases with metastasis to the main pulmonary arteries and marked hyperfibrino(geno)lysis. The fibrinogen-derived products from patients' plasma were identified as D1A/gamma, D1/gamma, and D1/beta by immunoblotting with the NH2-terminus of the fragment D specific antibody JIF-23. In all cases, the neoplastic cells with vascular intimal carcinomatosis were stained positive for anti-human annexin 2, which is a unique cell surface co-receptor for plasminogen and tissue-type plasminogen activator. In contrast, normal renal pelvic mucosa or renal transitional cell carcinoma without vascular intimal carcinomatosis did not express any annexin 2. The isolated transitional cell carcinoma cells contained annexin 2 mRNA and expressed its protein. Anti-annexin 2 antibody and transfection of annexin 2 small interfering RNA into these carcinoma cells significantly inhibited tissue-type plasminogen activator dependent plasmin generation. These findings suggest that annexin 2 mediated fibrinolysis on the transitional cell carcinoma cells may play a role in inducing hemorrhagic disorder in vascular intimal carcinomatosis.
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PMID:Annexin 2 and hemorrhagic disorder in vascular intimal carcinomatosis. 1652 21

Reported evidence of a role in fibrinolysis by fibrinopeptide (Fp)B-dependent intermolecular fibrin polymerization contacts and of reversed FpA/FpB release sequence from fibrinogen Kingsport led us to investigate the fibrinolytic properties of Kingsport clots. Clot lysis was induced by either plasmin (pH 7.4) or by a mixture of plasminogen and recombinant tissue plasminogen activator and measured by lysis time and by turbidity (350 nm) time course. Clots were formed by thrombin from plasminogen-free fibrinogen (pH 7.4, 8 mmol/l CaCl2), with or without 40 nmol/l factor XIII or 20% afibrinogenemic plasma. Displaying no differences from corresponding normal controls were (a) lysis of repolymerized fibrin clots, and (b) chromogenic measurements of fibrin-stimulated Glu-plasminogen activation by recombinant tissue plasminogen activator. By contrast, thrombin-induced fine and coarse network clots (n = 7) displayed faster turbidity loss than corresponding normal controls and shorter lysis times ranging 31-55% of controls. Comparison of clots of fibrinogen fractions lacking approximately 90% of their alpha chain carboxyl terminal regions, n = 2, also displayed faster plasmin-induced lysis than corresponding controls. To assess the role of FpB release-dependent intermolecular polymerization contacts, clots were prepared in the presence of three molar excess antibeta 15-42 immunoglobulin G, n = 2, and displayed no differences in plasmin-induced lysis from nonimmune immunoglobulin G controls. The reversed FpA/FpB release sequence from Kingsport fibrinogen resulted in clots with decreased resistance to plasmin. We suggest that both markedly slow polymerization and decreased plasmin resistance played causative roles in the hemorrhagic diathesis associated with this dysfibrinogen.
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PMID:Decreased plasmin resistance by clots of a homophenotypic Aalpha R 16H fibrinogen (Kingsport, slower fibrinopeptide A than fibrinopeptide B release). 2001 99