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PubMed1981

[A study of coagulation contact factors in hereditary angioneurotic oedema (author's transl)].

Coagulation contact factors were studied in 9 patients with hereditary angioneurotic oedema. After storage of the plasma at O degrees C for 20 hours, activation of prekallikrein and factor VII, together with prekallikrein consumption, were observed. The cold activation, due to deficiency of C1 esterase inhibitor, was not suppressed by polybren in vitro (factor XII activation inhibitor) but was prevented by aprotinins (kallikrein inhibitors). These findings would suggest that patients with hereditary angioneurotic oedema should be investigated for prekallikrein consumption and should be treated with aprotinin as soon as the attack begins.

Angioedema↗
PubMed1987

Quantitation and characterization of glomerular procoagulant activity in experimental glomerulonephritis.

Glomerular procoagulant activity (PCA) was studied in four different models of experimental glomerulonephritis (GN) in rabbits. These models included 3 macrophage-dependent models: active autologous phase anti-glomerular basement membrane (GBM) antibody induced GN (active anti-GBMGN); passively induced autologous phase anti-GBMGN, and acute serum sickness; and a macrophage independent model of injury, heterologous phase anti-GBMGN was included also. PCA in glomerular lysates was significantly augmented in the three macrophage-dependent models, but not elevated significantly in heterologous anti-GBMGN when compared to glomerular lysates from normal rabbits. The greatest augmentation of PCA was found in glomeruli from rabbits with active anti-GBMGN which also contained the greatest numbers of macrophages. The functional characteristics of the glomerular PCA were similar in each of the models studied. Initiation of coagulation in vitro by these lysates was shown to be dependent on the presence of coagulation Factors VII and V, and largely independent of Factors XII and VIII, suggesting that glomerular PCA activates the extrinsic coagulation pathway. Inhibition studies using concanavalin A and phospholipase C demonstrated that glycoside residues and phospholipids are important chemical moieties for the coagulant activity of PCA. After sonication and ultracentrifugation PCA was found in the cell membrane fraction but not in the cell cytosol of glomerular lysates. These studies provide further evidence that glomerular PCA is markedly augmented in the presence of infiltrating glomerular macrophages and demonstrate that glomerular PCA has the functional characteristics of 'tissue factor', the procoagulant expressed by macrophages on their cell surface membrane. The quantitative association of glomerular PCA with glomerular macrophages, together with the shared functional characteristics of glomerular PCA and macrophage PCA, together suggests that the augmented glomerular PCA in experimental GN is due to tissue factor from infiltrating macrophages (macrophage PCA).

Animals↗
PubMed1982

Isolation and functional properties of the heavy and light chains of human plasma kallikrein.

Human plasma kallikrein was prepared by proteolytic activation of prekallikrein with beta-Factor XIIa (Mr = 28,000). Two forms of kallikrein were generated that were each composed of two disulfide-linked polypeptide chains: a heavy chain of apparent Mr = 43,000 and a light chain of apparent Mr = either 36,000 or 33,000. Following reduction and alkylation, the heavy and light chains of kallikrein were isolated by affinity chromatography using insolubilized high molecular weight kininogen. The alkylated light chain of kallikrein did not bind to high molecular weight kininogen-Sepharose while the heavy chain did bind with high affinity and was subsequently eluted. The light chain retained the specific amidolytic activity of native kallikrein. The Km and kcat values for the hydrolysis of H-D-Pro-Phe-Arg-p-nitroanilide by kallikrein or its light chain were identical. Activation of Factor XII in solution was equally well catalyzed by kallikrein and its light chain. However, in kaolin-dependent coagulation, kallikrein was 180 times more effective than the light chain in correcting the clotting defect of prekallikrein-deficient plasma. Furthermore, the light chain was 3.5 times less potent than kallikrein in cleaving high molecular weight kininogen in solution. These observations indicate that the light chain region contains the enzymatic active site and adequately accounts for the enzymatic properties of kallikrein in solution on the protein substrate, Factor XIII, and on oligopeptide substrates. However, the heavy chain region of kallikrein is required for binding to high molecular weight kininogen, for surface-dependent activation of coagulation, and for optimal cleavage of high molecular weight kininogen.

Humans↗
PubMed2001

Certain autoantibodies to phosphatidylethanolamine (aPE) recognize factor XI and prekallikrein independently or in addition to the kininogens.

Recent evidence shows that many antiphospholipid antibodies (aPL) to negatively-charged phospholipid (PL) do not target anionic PL per se, but are specific for anionic PL-binding plasma proteins, for example, beta(2)-glycoprotein I (beta(2)-GPI) and prothrombin. We also reported that certain antiphosphatidylethanolamine antibodies (aPE) are not specific for phosphatidylethanolamine (PE) per se, but are directed to PE-binding plasma proteins, high molecular weight kininogen (HK), and low molecular weight kininogen (LK). Additional studies have shown that certain aPE failed to recognize purified kininogens but continued to produce aPE ELISA reactivity in the presence of semipurified HK preparations containing the HK binding proteins, factor XI (FXI) and prekallikrein (PK). We therefore investigated if certain of these aPE recognized FXI and/or PK. In this study we observed that aPE can recognize contact proteins FXI and PK independently or in combination with HK. Since contact proteins such as HK, PK and factor XII (FXII) have anti-coagulant and profibrinolytic functions, the pathophysiological role of aPE has yet to be elucidated. We propose that aPE of different specificities may initiate or promote characteristics pathological conditions in patients with thrombosis or recurrent pregnancy losses.

Animals↗
PubMedDate not supplied

Thromboembolic diseases in neonates and children.

Acquired and inherited prothrombotic risk factors increase the risk of thrombosis in neonates, infants and children. After suffering thrombosis white paediatric patients should be screened for common gene mutations, i.e. the factor V G1691A, factor II G20210A and MTHFR C677T genotypes, rare inherited prothromboticrisk factors, i.e. deficiencies of protein C,protein S, and antithrombin, plasminogen, probably inherited risk factors, i.e. fibrinogen, factor VIIIC, factor XII, new candidates, i.e. elevation of lipoprotein (a),and fasting homocysteine concentrations (3-6 months after thrombotic onset). Data interpretation is based on age-dependent reference ranges or the identification of causative gene mutations/polymorphisms with respect to individual ethnic backgrounds.

Child↗
PubMed1973

Experimental hypercalcaemia and whole blood clotting.

Experimental hypercalcaemia was induced in rats by (1) transplantation of the solid Walker 256 tumour, and (2) intraperitoneal injections of calcium gluconate. Whole blood clotting was studied by means of thromboelastography and whole blood clotting times in polystyrene and glass test tubes. At serum calcium levels between 10.3 and 11.5 m-equiv/l a slight delay in clot formation was found which was reversible by the addition of EDTA to whole blood. Acute, calcium-gluconate-induced hypercalcaemia, however, leads to a significant shortening of the clotting time in the polystyrene tube and to a lesser degree in the glass tube. Maximal factor XII activation in vitro with ellagic acid levels the difference of clotting times again. From these experiments it is concluded that acute hypercalcaemia induces a hypercoagulable state, possibly by partial contact activation, and thus may favour thrombus formation in vivo.

Animals↗
PubMed1990

Coagulation abnormalities in chronic peritoneal dialysis.

To determine whether children treated with chronic peritoneal dialysis have a hypercoagulable state, various coagulation and fibrinolytic factor concentrations or activities were measured in 17 children undergoing chronic peritoneal dialysis. The patients had significantly increased activities of factors VII and VIII, and increased concentrations of von Willebrand factor (vWF), fibrinogen, factor XIIIA and factor XIIIS compared to reference values (P less than 0.001 in each case). The activated partial thromboplastin time was prolonged (P less than 0.001) and the thrombin clotting time was decreased (P less than 0.05) in these children. The prothrombin time and activities of factors XII, XI, IX, X, V and II were not significantly different from control values. Protein C concentrations were similar to normal, but antithrombin III concentrations were increased (P less than 0.05). Within the fibrinolytic pathway, decreased concentrations of plasminogen were found (P less than 0.001) and the concentrations of alpha-2-antiplasmin were increased (P less than 0.001). The plasma albumin concentration was below 33 g/l in 13 of the 17 children. The duration of treatment with peritoneal dialysis was directly correlated with vWF concentrations (P less than 0.001) and inversely correlated with factor VII concentrations (P less than 0.01). Of these patients 2 have since had clinical thrombotic episodes. The coagulation abnormalities found may have a role in the occurrence of thrombosis complicating renal transplantation.

Adolescent↗
PubMed2002

Thromboembolism in children.

Acquired and inherited prothrombotic risk factors increase the risk of thrombosis in children. This review is based on "milestone" pediatric reports and new literature data (January 2001-February 2002) on the presence of acquired and inherited prothrombotic risk factors, imaging methods, and treatment modalities in pediatric thromboembolism. After confirming clinically suspected thromboembolism with suitable imaging methods, pediatric patients should be screened for common gene mutations (factor V G1691A, prothrombin G20210A and MTHFR C677T genotypes), rare genetic deficiencies (protein C, protein S, antithrombin, and plasminogen), and new candidates for genetic thrombophilia causing elevated levels of lipoprotein(a), and homocysteine, and probable genetic risk factors (elevations in fibrinogen, factor IX, and factor VIIIC, and decreases in factor XII). Data interpretation is based on age-dependent reference ranges or the identification of causative gene mutations/polymorphisms with respect to individual ethnic backgrounds. Pediatric treatment protocols for acute thromboembolism, including thrombolytic and anticoagulant therapy, are mainly adapted from adult patient protocols.

Child↗
PubMed1986

Immunotoxicology of brown recluse spider (Loxosceles reclusa) venom.

A purified toxic protein from Loxosceles reclusa venom was assayed for its in vitro effects on the human immunological and blood clotting systems. The toxin caused inhibition of neutrophil chemotaxis, depletion of serum hemolytic complement, prolongation of the activated partial thromboplastin time and depletion of clotting factors XII, XI, IX and VIII by an average of 44% in human plasma. The prothrombin time of human plasma was also prolonged by 1.5-2.0 sec. No effect of the purified toxin was observed on microbicidal ability of neutrophils, the release of enzymes from neutrophils or the adherence of neutrophils to glass beads.

Arthropod Venoms↗
PubMed1986

Coagulation abnormalities associated with acute Angiostrongylus vasorum infection in dogs.

Ten dogs were experimentally infected with 150 3rd-stage larvae of the lungworm Angiostrongylus vasorum (Baillet, 1866). Blood samples obtained once a week for 5 weeks after infection was induced were examined for coagulation alterations. Thrombocytopenia developed in infected dogs before and after parasitic patency, which occurred 6 weeks after infection was induced. Prolongation of activated partial thromboplastin time and thrombocytopenia initially were associated with periods of larval migration and, later, at patency, with pulmonary egg embolism and hatching of 1st-stage larvae in the lung. Decreased factor-V activity, significantly shortened values for the prothrombin time, and increased factor-VIII activity were evident during postpatent periods of parasitic infection. Significant changes were not found in factors-XII and -IX activities throughout the course of infection. Coagulation abnormalities were attributed to excessive intravascular coagulation. Immature adults and first stages of the parasite seemed to have initiated the coagulopathy in the prepatent phase of infection, with subsequent coagulation abnormalities occurring at the time of patency.

Acute Disease↗
PubMedDate not supplied

Light scattering detection of microemboli in an extracorporeal LVAD bovine model.

Thromboembolization studies were performed on two calves supported by extracorporeal left ventricular assist devices (LVAD) using a light scattering (He Ne Laser) microemboli detector (LSMD). The LSMD system was placed on the outflow cannula of the LVAD in the extracorporeal loop of each animal. The measurements included the size, number, and rate of production of circulating microemboli in the range 20 microns less than microemboli diameter less than 1,000 microns. These data were compared to independently and concurrently obtained measurements of emboli shear rate (CPF), platelet count, red blood count (RBC), leukocyte count (WBC), plasma free hemoglobin, factors XIII, X, and V, and sorbitol dehydrogenase. Embolic number and volume were seen to be most dynamic in the very early phases of acute thromboembolization (0-40 minutes) with a peak embolic response within the first 30 minutes. The dynamics of reduced emboli volume, rather than number, may be implicated in the later stages of the thromboembolic passivation of these ventricles. The LSMD results generally showed an inverse correlation of microemboli volume rate with CPF measurements for each ventricle. LSMD, CPF, and leukocyte and platelet counts, showed a direct correlation with reduced counts for each additional ventricle for both calves. Factor XII was seen to have a more direct correlation in time with LSMD measurements for each ventricle than other parameters under investigation. This study represents the first time laser scattering and filtration methods have been applied simultaneously with hematologic assays in order to study the dynamics of device associated thrombogenesis.

Animals↗
PubMed1982

Acute acalculous cholecystitis. An increasing entity.

Acute acalculous cholecystitis was observed to increase in frequency between 1950 and 1979, an increase that was statistically significant. The greatest part of this increase occurred between 1965 and 1979. Acute acalculous cholecystitis was also found to be associated with a higher mortality rate, more than twice that of acute calculous cholecystitis. Acute acalculous cholecystitis occurred in a variety of clinical settings including bacterial sepsis, severe trauma including surgical trauma and burns, multiple transfusions, and severe debilitation. The lesion in the gallbladder consists of intense injury of blood vessels in the muscularis and serosa similar to those induced experimentally by in vivo activation of factor XII dependent pathways. Possibly because of the intensity of vascular injury, acute acalculous cholecystitis with minimal clinical manifestations may rapidly progress to gangrene with perforation. Undelayed surgical treatment, which has become more widely accepted over the past 50 years, is essential. It may have also contributed to the increased recognition of this clinical entity.

Adult↗
PubMed1994

Activation of the plasma clotting, fibrinolytic, and kinin-kallikrein system in preterm infants with severe idiopathic respiratory distress syndrome.

We studied the activation pattern of clotting, fibrinolysis, and kinin-kallikrein during the first 5 d of life in 10 preterm infants with signs of severe idiopathic respiratory distress syndrome (IRDS) after birth (IRDS group) and in 12 healthy preterm infants (reference group). We found systemic activation of clotting, fibrinolysis, and kinin-kallikrein in the IRDS infants within 12 to 24 h of birth, represented by increased median thrombin-antithrombin III complex formation (90 ng/mL versus 10 ng/mL in the reference group, p < 0.05), increased mean tissue-type plasminogen activator plasma concentrations (11.8 ng/mL versus 3.5 ng/mL in the reference group, p < 0.05), and increased mean plasma kallikrein activity (182.6% versus 162.0% of maximal activated human plasma in the reference group, p < 0.05), respectively. Clotting activation was accompanied by a significant decrease of the platelet count. Clotting and fibrinolytic activity decreased in the IRDS group during the first 2 to 3 d of life. Kinin-kallikrein activation was accompanied by decreased plasma kallikrein inhibitor activity values and did not change throughout the study period. Plasma factor XII activity was not significantly increased in the IRDS infants during the first 2 d of life but did significantly increase thereafter. The cause of simultaneous activation of clotting, fibrinolysis, and kinin-kallikrein in our IRDS infants has not yet been clarified. However, this activation process may contribute to lung injury such as that described in the adult respiratory distress syndrome.

Antithrombin III↗
PubMed1997

Effect of oral contraceptives on haemostasis variables.

Combined oral contraceptives (COCs) have effects on a large number of haemostasis variables. We have summarised literature data on effects of COCs containing 30-35 micrograms ethinyl estradiol for the third generation of progestogens (PGs): desogestrel, gestodene and norgestimate. It is concluded that about 15 variables show a shift in distribution of the order of magnitude of their interindividual variation coefficient. When comparing the third generation of PGs with the second one (norgestrel, levonorgestrel) stronger increases are noted for the former for some haemostatic variables. Also differences between desogestrel and gestodene for factor VII were apparent. It indicates that the role of PGs in the effects of COCs is significant and their design may in addition to reduction of oestrogen dosage be important in reducing haemostatic complications. The survey on molecular and cellular mechanisms by which the sex steroids might operate showed a great lack of knowledge. Only for factor XII has a functional oestrogen response element in the DNA definitely been identified. The study of molecular markers of coagulation and fibrinolysis have shown a distinct increased activation of coagulation (F 1 + 2, FPA) and fibrinolysis (PAP), and an increased fibrin turn-over (increased FDPs); platelet products are not found increased (beta TG, PF-4). The increase in fibrinolysis represent a counterforce, but individual changes in variables in coagulation and fibrinolysis do not correlate indicating independent effects and no evidence for a individually regulated balance. A first step in further research might be in understanding the increase in coagulation activation (F 1 + 2) which has so far not been satisfactorily related to changes in blood concentrations of haemostatic factors and possibly local factors.

Biomarkers↗
PubMed1975

Platelet hypersensitivity and intravascular coagulation in paroxysmal nocturnal hemoglobinuria.

The patient described had paroxysmal nocturnal hemoglobinuria associated with recurrent arterial as well as venous thrombosis. Study of platelet function revealed hypersensitivity to epinephrine, adenosine 5'phosphate (ADP) and collagen as judged by their ability to aggregate platelets as well as to release 14C serotonin. The release of total nucleotides was also markedly increased over normal with all aggregating agents. The abnormality was localized to the platelet since aggregation occurred when the patient's platelets were resuspended in normal plasma but not when normal platelets were incubated in the patient's plasma. Presumptive evidence for ongoing intravascular coagulation was an increase in fibrinogen derivatives of heavier molecular weight than the native protein presumably a result of thrombin action. However, factor XII was not activated and fibrinolysis was not increased. Complement component levels and antithrombin concentrations were also normal. The findings in this case suggest that hypersensitive platelets may contribute to the intravascular coagulation that is manifested by the increased incidence of thrombosis in patients with paroxysmal nocturnal hemoglobinuria.

Adenosine Diphosphate↗
PubMed2005

Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism.

PURPOSE: Oral estrogens were an effective treatment for prostate cancer but were abandoned because of an increased risk of cardiovascular toxicity and particularly thromboembolism. We have recently shown that transdermal estradiol produces an effective tumor response and negligible cardiovascular toxicity. Here we report the influence of transdermal estradiol therapy on the coagulation profile of men with advanced prostate cancer. MATERIALS AND METHODS: A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated using transdermal estradiol patches and the coagulation profile was assessed before and during 12 months therapy. Activation of coagulation was assessed by assaying the levels of activated factor VII (VIIa), activated factor XII (XIIa), prothrombin fragments 1 and 2 (F1 + 2), thrombin-antithrombin III (TAT III) complex and fibrinogen. Inhibition of the coagulation cascade was assayed by protein C, protein S and activated protein C resistance (APC-R). Fibrinolytic activity was determined by assaying tissue plasminogen activator (TPA) and plasminogen activation inhibitor type 1 (PAI-1). D-Dimer levels assessed both coagulation and fibrinolytic (thrombophilic) activity. Venous Duplex, color Doppler ultrasound and photoplethysmography were used to assess for thrombosis. RESULTS: Levels of VIIa and XIIa were unaffected by transdermal estradiol therapy. Although levels of TAT III were increased in some patients at 12 months, the increase was markedly less than that observed historically with equivalent doses of oral estrogens. Levels of the inhibitory and fibrinolytic factors including protein C, protein S, APC-R, TPA and PAI-1 remained stable. Reductions in F1+F2, fibrinogen and D-Dimer levels represented a normalization from increased levels to the physiological range. CONCLUSIONS: These results suggest that transdermal estradiol reduces thrombophilic activation in men with advanced prostate cancer, and protects against the risk of thrombosis.

Administration, Cutaneous↗
PubMed2001

Filtration of methylene blue-photooxidized plasma: influence on coagulation and cellular contamination.

BACKGROUND: Virus inactivation of plasma can be achieved by photodynamic methods in the presence of phenothiazine dyes such as methylene blue (MB). Subsequent filtration may increase the efficacy of virus inactivation and reduce adverse effects of WBC contamination and MB. STUDY DESIGN AND METHODS: This study examined the effect of filtration with three different filters (MBF1, MBF2, and MBF3) on MB concentration, residual cells, coagulation factors, and activation measures of coagulation, fibrinolysis, and complement in MB-treated (1 microM/L) plasma units. RESULTS: Filtration reduced the concentration of MB by > or = 89 percent. WBCs were depleted by 92 percent (MBF1) and >99.9 percent (MBF2 and MBF3). Treatment with MB significantly decreased the coagulation potency from levels in untreated plasma, as measured by thromboplastin time ratio (112 +/- 18% vs. 95 +/- 11%), activated partial thromboplastin time (40 +/- 3 sec vs. 44 +/- 3 sec), thrombin time (16.9 +/- 1.1 sec vs. 18.6 +/- 1.5 sec), factor VIII (1.09 +/- 0.21 U/mL vs. 0.85 +/- 0.13 U/mL), and vWF (0.94 +/- 0.65 U/mL vs. 0.65 +/- 0.24 U/mL). Filtration did not further decrease these values, while factor XI (0.75 +/- 0.22 U/mL vs. 0.37 +/- 0.20 U/mL) and prekallikrein values decreased in MB plasma units filtered with the MBF3. In addition, activated factor XII (0.7 +/- 0.5 microg/L vs. 4.5 +/- 1.0 microg/L) increased. CONCLUSION: WBCs and MB can be eliminated from MB-treated plasma units by filtration. Differences in biocompatibility of the different filters, especially the influence on the contact phase of coagulation, must be taken into consideration.

Blood Coagulation↗
PubMed1992

Changes in coagulation and anticoagulation in women taking low-dose triphasic oral contraceptives: a controlled comparative 12-month clinical trial.

OBJECTIVE: The effects of two triphasic oral contraceptives on coagulation and anticoagulation factors were compared in a 12-month open-label study. STUDY DESIGN: Fifty-two women (mean age 26 years) were enrolled in and completed the study; 20 had been randomly assigned to receive levonorgestrel plus ethinyl estradiol, 24 had been randomly assigned to receive norethindrone plus ethinyl estradiol, and eight surgically sterile women acted as untreated controls. Coagulation and anticoagulation factors were measured at baseline and during the sixth and twelfth months. RESULTS: Both oral contraceptives produced significant decreases from baseline in prothrombin time and partial thromboplastin time; there were also significant changes in laboratory control times. Factor XII was significantly increased in both oral contraceptive groups after 6 and 12 months. Fibrinogen antigen was significantly increased for norethindrone plus ethinyl estradiol after 6 and 12 months and for levonorgestrel plus ethinyl estradiol after 12 months. Platelet counts were unchanged. There was a significant increase in antithrombin III activity with norethindrone plus ethinyl estradiol at 12 months. Antithrombin III antigen was unchanged with the oral contraceptives; however, significant increases existed for alpha 1-antitrypsin antigen and plasminogen antigen and activity after 6 and 12 months and for alpha 2-macroglobulin antigen after 12 months for both oral contraceptives. alpha 2-Antiplasmin antigen was significantly increased for norethindrone plus ethinyl estradiol at the 12-month evaluation. There were no significant differences between the oral contraceptives for any coagulation or anticoagulation factor, and mean values generally remained within reference ranges. CONCLUSIONS: Levonorgestrel plus ethinyl estradiol and norethindrone plus ethinyl estradiol had equivalent, minimal effects on hemostasis, and changes in coagulation factors appeared to be balanced by changes in anticoagulation factors.

Adult↗