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PubMed1977

Disseminated intravascular coagulation induced by progesterone in the pregnant rat. Prevention by estogens.

Fatal disseminated intravascular coagulation (DIC) was induced in female rats by administration of progesterone in late pregnacy. This prevented parturition, with intrauterine fetal death 2 to 4 days past term and subsequent retention of dead fetuses. Concomitantly with or closely following the intrauterine death of their litters, a large proportion of pregnant rats died with histologically evident DIC. Administration of cortisone, heparin, or disoumarin did not prevent DIC, and xi-aminocaproic acid, acetylsalicylic acid, or an onion-rich diet tended to increase its incidence. Antibiotic regimens gave variable results, with significant decrease in DIC only with a combination of two wide-spectrum penicillins. Neomycin and polymyxin had little effect on susceptible Sprague-dawley derived rats, but polymxin caused a significant increase in DIC in a resistant strain of hooded rats. Fatal maternal DIC was completely prevented only by use of natural or synthetic estrogens concurrently with progesterone, although this did not alter the sequence of abnormally prolonged pregnacy with intrauterine fetal death and retention of dead fetuses. Potencies of estrogens varied greatly, but all compounds tested prevented DIC at adequate dosage levels. Diethylstilbestrol, the most potent drug tested, was completely protective at 1 mug daily given subcutaneously. beta-Estradiol was the most effective natural estrogen, giving complete protection with a 10-mug daily subcutaneous injection. Estrogens were much more potent by subcutaneous injection than by oral ingestion, and toxic side effects were sometimes noted with higher levels of the latter. For estrogen therapy to be effective, it was necessary to begin its use before the expected onset of DIC, and in no instance was there evidence of reversal of this process after signs of illness were observed.

Animals↗
PubMed1983

Fibrin-associated plasminogen activation in alpha 2-plasmin inhibitor deficiency.

The clot formed from the plasma of a patient with congenital deficiency of alpha 2-plasmin inhibitor underwent a spontaneous extensive fibrinolysis. Radiolabeled fibrinogen was added to the plasma before clotting, and the whole process of the fibrinolysis was followed by measuring the release of radiolabels. Plasminogen activation was also followed by measuring the amidolytic activity that developed. There was an initial latent period, followed by an exponential increase of fibrinolytic activity. During the latent period, there was little or no release of radiolabels and no development of amidolytic activity. During the latent period, the clot was washed thoroughly to remove unbound proteins from fibrin and was incubated in buffered saline. The washed clot still underwent fibrinolysis, similar to the original plasma clot, suggesting that the plasminogen/plasminogen activators bound to fibrin during the initial latent period are responsible for fibrinolysis. The amount of plasminogen bound to fibrin during the latent period was close to the amount of plasminogen activated during the whole process of fibrinolysis. When the amount of plasminogen bound to fibrin was decreased by epsilon aminocaproic acid, the extent of fibrinolysis was decreased in parallel with the decrease of the amount of the bound plasminogen. This suggests that the amount of plasminogen bound to fibrin is one of the determinants of the rate of the fibrinolytic process.

Enzyme Activation↗
PubMed1983

Unexplained hematuria.

In 270 consecutive patients who presented with hematuria over a 12-month period, complete visualization of the urinary tract by urography and cystoscopy indicated a causative lesion in over 90%. Where a cause could not be found on the first presentation, the initial evaluation was repeated within 4 months, revealing the previously missed diagnoses in four patients. Of patients who bled while receiving anticoagulants, 17% were found to have an important underlying cause other than anticoagulant therapy. Despite repeated evaluation, and in many instances more elaborate investigation with angiography, computerized tomography and ultrasonography, no reasonable diagnosis could be made in 6% (12% of those with microscopic hematuria, 4% with gross hematuria). One hundred and fifty-nine patients with unexplained hematuria, seen between 1975 and 1983, were studied. The triad of "gross, total and painless" was present in 15%. Patients who bled heavily from one kidney without any apparent cause benefited from orally administered epsilon aminocaproic acid.

Anticoagulants↗
PubMed1983

[Mechanism of development of fatal pulmonary artery thromboembolism during the treatment of kidney and bladder cancer].

Retrospective evaluation of the state of hemostasis in 20 patients dying with pulmonary artery thromboembolism (PATE) after combined treatment of renal carcinoma (10) and urinary bladder carcinoma (10) was performed. The signs of intravascular blood coagulation (IVBC) in the initial condition were determined in all the patients. After a course of pre-operation actin therapy with large fractions (totally 20 g) activation of IVBC was observed both in renal and urinary bladder carcinoma. In the postoperation period, on the day of PATE development in patients with renal carcinoma the state of hemostasis corresponded to stage I of disseminated intravascular coagulation syndrome. In patients with urinary bladder carcinoma after operation the state of hemostasis corresponded to stage II of DIVC-syndrome with signs of local hemorrhage of the urinary bladder wound. The therapy of this condition with fibrinolysis inhibitors (aminocaproic acid) with hemotransfusion without heparin facilitated thrombus formation in these patients in deep pelvic veins followed by PATE.

Adult↗
PubMed1981

Influence of omega-aminoacids on the activation of the first component of complement at low ionic strength.

Cl, is the first component of human complement, was activated to Cls by diluting human plasma in a solution of low ionic strength. The addition of lysine and its related aminoacids to plasma resulted in inhibition of Cl activation, alpha, omega-diaminoacids such as lysine and ornithine were most effective and omega-aminoacids such as 6 aminohexanoic acid were far less effective. Tranexamic acid which is most potent in inhibition of fibrinolysis among those aminoacids was least effective in the inhibition of Cl activation. omega-aminoacids or their analogues hardly inhibited Cls which had already been activated.

Amino Acids↗
PubMed1980

Induction of cytotoxic factors by immunization of mice with Freund's adjuvant components.

Antiidiotypic antibody (AIA) was raised in mice by immunization with MOPC 315 immunoglobulin A emulsified in Freund's adjuvant (FA). The antibody content of mouse serum was assessed by (a) its ability to inhibit rosetting of 2,4,6-trinitro-phenyl-sheep red blood cells around MOPC 315 myeloma cells, and (b) by a solid phase antigen-binding plate assay based on reactivity with 125I-Protein A and inhibition in the presence of dinitrophenyl aminocaproic acid. FA was necessary for the production of AIA to MOPC 315 immunoglobulin A. Some of the AIA-containing mouse sera were cytotoxic for MOPC 315 cells in the presence of guinea pig complement. However, cytotoxicity was not correlated with amount of AIA, as assessed by inhibition of rosette formation, nor was it specific for myeloma cells bearing the MOPC 315 idiotype. Furthermore, cytotoxicity could also be generated by immunization of mice with complete Freund's adjuvant, incomplete Freund's adjuvant, or the muramyl dipeptide portion of mycobacteria, all in the absence of MOPC 315 immunoglobulin A. Therefore, the complement-dependent cytotoxic antibodies in the AIA-containing antisera, which belonged to the immunoglobulin G and M classes, were likely directed against some component of FA. Myeloma cells which were not killed by anti-FA antiserum, as assessed by dye exclusion, were inhibited in their ability to secrete immunoglobulin and to form clones in agar.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Pregnancy complicated by the Kasabach-Merritt syndrome.

The Kasabach-Merritt syndrome is the association of cavernous hemangiomas and consumption coagulopathy marked by anemia, thrombocytopenia, and hypofibronigenemia. Exacerbation of the consumption coagulopathy has been described in the 2 previous reports of this syndrome when associated with pregnancy. The authors report a third patient whose delivery and postopartum course were marked by increased coagulation abnormalities and subsequent hemorrhage. This patient's 32-day hospital course and need for multiple blood transfusions, clotting factors, platelets, heparin, and finally epsilon-aminocaproic acid underscore the need for patients with this syndrome to deliver in a referral center hospital where replacement therapy and hematologic consultation are readily available.

Adult↗
PubMed1981

A monoclonal antiidiotypic antibody to MOPC 315 IgA inhibits the growth of MOPC 315 myeloma cells in vitro.

Spleen cells from BALB/c mice immunized with MOPC 315 IgA were fused with P3X63/Ag8 myeloma cells. Hybrid clones were screened for antibody production by a plate-binding radioimmunoassay in which MOPC 315 IgA was reacted with culture supernatants and 125I-protein A. One antibody-producing hybridoma clone (D10) was selected and injected i.p. into BALB/c mice. Ascitic fluid of tum or-bearing animals reacted specifically with MOPC 315 IgA and the reaction was inhibited by DNP- aminocaproic acid, indicating that the monoclonal antibody was directed against the hapten-binding site of MOPC 315 IgA. The monoclonal antiidiotypic antibody was of the complement (C)-binding IgG2a subclass and inhibited IgA production and growth of MOPC 315 cells in vitro in the presence of guinea pig C, as assessed by inhibition of formation of plaques and colonies by MOPC 315 cells in agar.

Animals↗
PubMed1995

Limiting excessive postoperative blood transfusion after cardiac procedures. A review.

Analysis of blood product use after cardiac operations reveals that a few patients (< or = 20%) consume the majority of blood products (> 80%). The risk factors that predispose a minority of patients to excessive blood use include patient-related factors, transfusion practices, drug-related causes, and procedure-related factors. Multivariate studies suggest that patient age and red blood cell volume are independent patient-related variables that predict excessive blood product transfusion after cardiac procedures. Other factors include preoperative aspirin ingestion, type of operation, over- or underutilization of heparin during cardiopulmonary bypass, failure to correct hypothermia after cardiopulmonary bypass, and physician overtransfusion. A survey of the currently available blood conservation techniques reveals 5 that stand out as reliable methods: 1) high-dose aprotinin therapy, 2) preoperative erythropoietin therapy when time permits adequate dosage before operation, 3) hemodilution by harvest of whole blood immediately before cardiopulmonary bypass, 4) autologous predonation of blood, and 5) salvage of oxygenator blood after cardiopulmonary bypass. Other methods, such as the use of epsilon-aminocaproic acid or desmopressin, cell saving devices, reinfusion of shed mediastinal blood, and hemofiltration have been reported to be less reliable and may even be harmful in some high-risk patients. Consideration of the available data allows formulation of a 4-pronged plan for limiting excessive blood transfusion after surgery: 1) recognize the causes of excessive transfusion, including the importance of red blood cell volume, type of procedure being performed, preoperative aspirin ingestion, etc.; 2) establish a quality management program, including a survey of transfusion practices that emphasizes physician education and availability of real-time laboratory testing to guide transfusion therapy; 3) adopt a multimodal approach using institution-proven techniques; and 4) continually reassess blood product use and analyze the cost-benefits of blood conservation interventions.

Aspirin↗
PubMed1975

Purification and partial characterization of human and porcine C3a anaphylatoxin.

C3a anaphylatoxin is a protein fragment generated enzymatically in serum during activation of the third component of complement (C3). A four-step procedure is described for the purification of human and porcine C3a anaphylatoxins from their respective sera after activation with inulin. Because serum carboxypeptidase rapidly inactivates C3a, the inhibitor epsilon-aminocaproic acid (EACA) was added during C3 activation, thus permitting isolation of fully active C3a anaphylatoxins directly from serum. A 2000-fold purification of C3a was achieved with an average 30% recovery assuming total conversion of C3 during treatment of serum with inulin. Human C3a anaphylatoxin obtained through the action of the C3 activating enzyme of the "alternate" pathway appeared nearly identical with the C3a obtained from isolated C3 after treatment with the C4,2 enzyme of the "classical" pathway or with trypsin. Comparisons were made between various properties of human and porcine C3a anaphylatoxins. The molecular weights differed only slightly. Electrophoresis on a cellulose acetate strip at pH 8.6 indicated a difference of approximately one net charge between human and porcine C3a, with the human anaphylatoxin exhibiting the more basic behavior. Although the amino acid compositions are similar, significant differences exist. The most marked difference was the total absence of threonine residues in porcine C3a. The NH2-terminal sequences of 20 amino acid residues were examined; homology existed for 16 of the 20 positions. Although partial analysis of the primary structure of human and porcine C3a indicates approximately 80% homology, no immunological cross-reactivity between the anaphylatoxins could be detected with antisera produced to either human or porcine C3a. In spite of the structural differences, the biological activities of porcine and human C3a were essentially identical. Smooth muscle contraction, increase in vascular permeability, and release of histamine from mast cells were similarly induced by equal amounts of anaphylatoxin from either human or porcine origin. Porcine C3a, like human C3a, was shown to contain a COOH-terminal arginyl residue essential for smooth muscle contraction and for induction of histamine release from mast cells. The sequence adjacent to the COOH-terminal arginine was Leu-Ala-Arg-COOH for both humans and porcine C3a. Current evidence suggests common mechanisms exist for the generation of C3a in various animal species and that the two known C3 activating enzymes in serum exhibit trypsin-like specificity.

Amino Acid Sequence↗
PubMed1994

An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA). II. Annexin II-mediated enhancement of t-PA-dependent plasminogen activation.

In the preceding paper (Hajjar, K. A., Jacovina, A. T., and Chacko, J. (1994) J. Biol. Chem. 269, 21191-21197), we identified a M(r) = 40,000 endothelial cell receptor for tissue plasminogen activator (t-PA) and plasminogen (PLG) as the calcium- and phospholipid-binding protein, annexin II (Ann-II). Here, we examined the effect of Ann-II on t-PA-dependent plasminogen activation in a purified system. Purified native Ann-II bound t-PA, plasminogen, and plasmin with high affinity (Kd = 25 nM, 161 nM, and 75 nM, respectively). At fixed plasminogen concentrations, preincubation with purified native Ann-II was associated with an approximately 21-fold increase in the rate of Glu-PLG activation and an approximately 14-fold increase in activation of Lys-PLG. Three irrelevant proteins had no effect on plasmin formation, while fibrinogen increased the rate of Glu-PLG activation by approximately 4-fold. Annexin-II-mediated enhancement of t-PA-dependent plasminogen activation was 90-95% inhibited by epsilon-aminocaproic acid or by pretreatment of Ann-II with carboxypeptidase B, indicating a carboxyl-terminal lysine-dependent interaction. Kinetic analyses revealed that Ann-II conferred an approximately 60-fold increase in catalytic efficiency upon t-PA-dependent activation of either Glu-PLG or Lys-PLG. Thus, Ann-II-mediated assembly of plasminogen and t-PA may promote and localize constitutive plasmin generation on the surface of the blood vessel wall.

Amino Acid Sequence↗
PubMed1994

Cloning, expression, and characterization of human apolipoprotein(a) kringle IV37.

A portion of kringle IV37 (KIV37) of apolipoprotein (a), (apo(a)), was polymerase chain reaction-cloned from human liver cDNA. The protein product of this clone was expressed in Escherichia coli as a poly histidine fusion protein. Based on recovery of purified fusion apo(a) KIV37 protein expression levels were estimated to be 10 mg/g of E. coli cell paste. Mass spectral analysis showed the molecular mass of fusion apo(a) KIV37 to be 12,260 +/- 1 daltons. Almost all fusion apo(a) KIV37 was expressed as inclusion bodies and had to be refolded. Fusion apo(a) KIV37 was isolated from the inclusion bodies and purified by lysine-Sepharose affinity chromatography by eluting with 0.2 M epsilon-aminocaproic acid. The fusion protein was treated with thrombin to yield a homogeneous, functional apo(a) KIV37 domain composed of 92 amino acids having a molecular mass of 10,510 +/- 1 daltons. N-terminal protein sequencing and amino acid analysis have confirmed the sequence and composition of apo(a) KIV37. The molar extinction coefficient, epsilon, for apo(a) KIV37 was determined to be 3.1 x 10(4) M-1 cm-1, and the pI was measured to be 6.7 +/- 0.1. In addition, the dissociation constants, Kd, for a series of 11 lysine analogs have been determined by measuring the change in intrinsic fluorescence of apo(a) KIV37 upon saturable binding with these compounds. Kd values ranged from 4.2 +/- 0.9 microM for trans-4-(aminomethyl)cyclohexanecarboxylic acid to 4.6 +/- 0.4 mM for L-arginine. Apo(a) KIV37 binds to plasmin-treated fibrinogen with an EC50 value of 14 +/- 1.2 microM and prevents the binding of Lp(a) to plasmin-treated fibrinogen with an IC50 value of 16 +/- 6 microM. Lp(a) binds to the plasmin-treated fibrinogen surface with an EC50 value of approximately 1.0 +/- 0.3 nM. These studies demonstrate that apo(a) KIV37 can be expressed at high levels, refolded properly, and used as a fully functional lysine-binding domain. In addition, these results also demonstrate that apo(a) KIV37 provides the major interaction of Lp(a) with fibrinogen. One additional weak binding site in Lp(a) is adequate to describe overall Lp(a) binding to fibrinogen.

Apolipoproteins A↗
PubMed1994

Enzymatically stable renin inhibitors containing statine and 6 aminohexanoic acid. Part IV.

Eight new peptide renin inhibitors: Boc-Phe/4-OMe/His-Sta-epsilonAhx-Iaa(13), Boc-Phe/4-OMe/-His-Sta-episilonAhx-OMe,(21),Boc-Phe/4-OMe/-MePhe-S ta-epsilonAhx-Iaa(27),Boc-Phe/4-OMe/-MePhe-Sta-epsilonAhx-++ +epsilonAhx-Iaa(32),Boc-Phe/4-OMe/-MePhe-Sta-Val-epsilonAhx- OMe (38),Boc-Phe/4-OMe/-MeVal-Sta-Val-Iaa(48),Boc-Phe/4-OMe/-Me Val-Sta-Iaa(51), Boc-Phe/4-OMe/-MeLeu-Sta-epsilonAhx-Iaa (57) have been synthesized in search after compounds of improved biological properties. All peptides were obtained by carbodimide method in solution by stepwise elongation of the peptide chain or by fragment condensation. Their potency was assayed in vitro by a spectrofluorometric method/assay of Leu-Val-Tyr-Ser released from N-acetyltetradecapeptide substrate by renin in the presence of an inhibitor/. Their resistance to enzymatic degradation was assayed by determination of stability to chymotrypsin activity. The most potent inhibitor was (13):IC50 = 7 x 10(-8)M/1. All inhibitors were stable to chymotrypsin.

Amino Acid Sequence↗
PubMed1994

[Therapeutic possibilities in the management of gastrointestinal bleeding in thrombocytopenic patients].

Gastrointestinal bleeding is often fatal in elderly. The danger could be multiplied by thrombocytopenia or by other disorder of the coagulation system. In a thrombocytopenic patient with myelodysplastic syndrome life threatening gastrointestinal bleeding occurred which could not be controlled by conventional methods (cimetidine, antacids, aminocaproic acid, platelet transfusions, blood transfusion 400-1200 ml/day). Continuous i.v. infusion of somatostatin [250 micrograms/hour Stilamin (Serono)] and per os omeprazole [2 x 1 capsule Losec (Astra)] resulted in the cessation of bleeding in 24 hours. Adverse effect was not observed.

Aged↗
PubMed1993

Hyphema.

Hyphema is a potentially sight-threatening sequela of blunt trauma. Delayed healing time, poor visual outcome, and complications such as corneal blood staining, anterior and posterior synechiae, increased intraocular pressure, and glaucomatous optic atrophy are most often associated with hemorrhage filling more than one half of the anterior chamber. Rebleeds are most likely 3 to 5 days following injury, in children, in blacks (particularly if they have sickle cell disease), and in persons who have ingested aspirin or other antiplatelet compounds. Treatment of hyphema is controversial, and medical therapy (antibiotics, cycloplegics, steroids, aminocaproic acid) should be tailored to suit the needs of each case. Intraocular pressure-reducing medications may be required if there is significant elevation of IOP. The affected eye should be protected with a shield, and follow-up examinations should be conducted as necessary. Both the anterior and posterior eye should receive careful assessment.

Eye Injuries↗
PubMed1994

Conformational and biological studies of neuropeptide Y analogs containing structural alterations.

We evaluated the alpha-helix content, the biological activities and the affinities of a series of neuropeptide Y (NPY) analogs containing structural alterations, mainly in the central portion of the molecule for which a putative alpha-helix arrangement has been proposed. First, we investigated the conformational and pharmacological characteristics of derivatives containing the N-terminal tetrapeptide linked to C-terminal peptide-amide segments of various lengths. In some of these, the missing portion was replaced with epsilon-aminocaproic acid, a flexible arm-linker. Data revealed that (1-4)-Aca-(18-36)NPY is a discontinuous analog almost as potent as the native peptide in a pharmacological preparation enriched in Y2 receptors (rat vas deferens), whereas it is about 5 times less potent in a Y1 bioassay (rabbit saphenous vein). This analog showed a similar profile in [125I]PYY binding assays performed in rat frontoparietal cortex (Y1) and hippocampus (Y2) membrane preparations. In a series of truncated derivatives obtained with the successive removal of the 5-13 to 5-17 segments of the NPY molecule, no apparent correlation was observed between the affinity or potency in bioassays and the alpha-helix content, as measured by circular dichroism spectroscopy. Other truncated analogs, obtained by linking the C-terminal 31-36 fragment to various N-terminal tetrapeptides were also investigated. None showed any affinity in brain membrane preparations (frontoparietal cortex and hippocampus) or activity in the rat vas deferens bioassay. However, a weak short-lasting contraction was measured with some of these analogs in the rabbit saphenous vein, thus suggesting that the 1-4 and 31-36 segments of the molecule contains pharmacophores recognized by the Y1 receptor subtype. The contribution of the arginine residues also was evaluated in relation with the alpha-helix. Their successive substitution with lysine, an excellent helix-promoter, showed that the replacement of Arg-19 or Arg-25, two residues found in the putative alpha-helix, gave active analogs. Furthermore, the substitution of Arg-19 with lysine increased the activity in the rat vas deferens as well as the affinity in the brain membrane binding assays. On the other hand, the substitution of Arg-33 produced a weak agonist, whereas the replacement of Arg-35 generated an inactive analog in the Y2-pharmacological preparation and a very weak competitor in the CNS binding assays. Interestingly, this latter analog was still active in the rabbit saphenous vein, thus identifying the position 35 as an additional potential target for the development of Y1 versus Y2 specific molecules.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMedDate not supplied

Renin inhibitors containing statine and 6-aminohexanoic acid. Part III.

Five peptide renin inhibitors containing the sequence: Phe-His-Sta-epsilon Ahx (Sta = 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid, epsilon Ahx = 6-aminohexanoic acid) were synthesized and their potency was assayed in vitro by a spectrofluorometric method (assay of Leu-Val-Tyr-Ser released from N-acetyltetradecapeptide substrate by renin in the presence of an inhibitor). Their stability was tested by assay of Phe and Pro-Phe released after incubation with chymotrypsin. The most potent inhibitor was Boc-Phe-His-Sta-epsilon Ahx-OMe (IC50 = 5 x 10(-9) M/l), the most stable--Boc-Pro-Phe-His-Sta-epsilon Ahx-OMe (resistant to incubation with chymotrypsin for 4 h).

Amino Acids↗