PubMed Health⌕ Search

Biomedical subjects

P C Comp

Publications and source records attributed to P C Comp.

At least 37 records · Page 2Linked to original sources
PubMed1993

Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation.

Although the majority of factor VII (FVII) circulates in the zymogen form, low levels of activated factor VII (FVIIa) have been postulated to exist in plasma and to serve a priming function for triggering of the clotting cascade. However, direct measurement of plasma FVIIa has not previously been possible. We have quantified plasma FVIIa levels using a novel, highly sensitive assay that is free from interference by FVII. Specificity of this clot-based assay results from the use of a mutant tissue factor that is selectively deficient in promoting FVII activation, but retains FVIIa cofactor function. In normal adults, FVIIa was found to be present in plasma (mean: 3.6 ng/mL) with considerable variation between individuals (range: 0.5 to 8.4 ng/mL). FVIIa levels were only loosely correlated with FVII coagulant activity, but were elevated in pregnancy and reduced with oral anticoagulant therapy. Incubation of plasma on ice in glass containers (cold activation) resulted in substantial FVIIa generation. Measurement of plasma forms of factor VII is of potential clinical importance because elevated FVII coagulant activity has been implicated as a significant risk predictor for ischemic heart disease. Clinically, this new assay will now permit direct assessment of the role of plasma FVIIa in thrombotic disorders.

Adult↗
PubMed1993

Contraceptive choices in women with coagulation disorders.

When compared with older reports on the thromboembolic effects of high-dose oral contraceptives, new studies with low-dose oral contraceptives have a significantly reduced risk of thromboembolism. In the absence of risk factors such as smoking or inherited disorders predisposing to thrombosis, the modern low-dose oral contraceptive (< 50 micrograms of estrogen) is a safe and effective choice for contraception in women without symptoms who have family histories of sporadic thromboembolism. An intrauterine device or some form of barrier method is recommended for women who have a personal history of venous thrombus disease. The low-dose oral contraceptive may be a good choice in women taking oral anticoagulants because of the risk of teratogenic effects of anticoagulants and the risks of intraperitoneal bleeding associated with ovulation. In addition, oral contraceptives help diminish the excessive menstrual bleeding often seen in these women.

Blood Coagulation Disorders↗
PubMed1993

Coumarin-induced skin necrosis. Incidence, mechanisms, management and avoidance.

Coumarin-induced tissue necrosis is a complication of oral anticoagulant therapy characterised by necrosis of the skin and underlying tissue. This occurrence of microvascular thrombosis associated with the administration of an anticoagulant has perplexed the medical and pharmaceutical community since the condition was first recognised in 1943. While the condition is rarely seen, it is of major clinical interest and raises a number of questions concerning pathological mechanisms and patient management. Although some cases occur in patients with hereditary disorders predisposing to thrombosis, the condition remains a mystery in terms of which patients will develop the condition, why the skin and underlying fatty tissues are the target of the microvascular thrombosis, and what the proper approach to a patient with coumarin-induced necrosis should be both in terms of acute management and long term anticoagulant therapy.

Coumarins↗
PubMed1992

Blockade of protein C activation reduces microvascular surgical blood loss.

Protein C is a natural anticoagulant glycoprotein which prevents intravascular clot formation. Protein C functions as an anticoagulant when converted to an active serine protease (activated protein C). Activated protein C is formed at the site of the endothelial injury in response to blood clotting and helps limit the size of blood clots. We tested the hypothesis that by temporarily blocking the activation of intrinsic protein C, we could reduce subsequent surgical blood loss from a microvascular surgical wound. The formation of activated protein C was blocked systemically by intravenous administration of a monoclonal antibody (HPC4) which binds to circulating protein C and prevents its conversion to activated protein C. Domestic pigs were blindly pretreated with intravenous HPC4 or saline then underwent partial-thickness skin graft harvesting to create a reproducible microvascular wound. Blood loss was measured from each wound and the hemostatic effect of protein C blockade was compared to intravenous saline alone as well as to topical thrombin or thromboplastin. We found that blocking the activation of protein C significantly (P = 0.005) reduces surgical blood loss in this model by 27% compared to saline control animals. Intravenous HPC4 performed equally as well as topical thrombin or tissue thromboplastin. In addition, topical thrombin acted synergistically with HPC4 to reduce blood loss an additional 44% (P = 0.01) as compared to intravenous HPC4 or topical thromboplastin alone. Autopsies performed 1 week after HPC4 treatment showed no evidence of systemic thrombosis resulting from the protein C blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Recent advances in understanding clotting and evaluating patients with recurrent thrombosis.

Significant advances have been made in defining the regulatory mechanisms that control blood clotting. These are reviewed, with special attention to the functions of the natural inhibitors antithrombin III, protein C, and protein S. Congenital deficiencies of these inhibitors as well as acquired abnormalities, such as defective fibrinolysis, and their role in promoting thrombosis are also discussed, as are thrombotic complications of pregnancy. Pregnancy decreases levels of protein S to 40% to 50% of normal levels. The decrease occurs early in pregnancy and persists into the postpartum period; it appears to be a hormonal rather than a dilutional effect. It is not known whether the thrombotic risk associated with pregnancy is increased in women who are congenitally deficient in protein S. Oral contraceptives decrease levels of protein S by about 20%. Women with a personal or family history of thrombosis should be evaluated for predisposing conditions before they start an oral contraceptive, as should women taking oral contraceptives who develop deep venous thrombosis.

Antithrombin III↗
PubMed1991

A 5.3-kb deletion including exon XIII of the protein S alpha gene occurs in two protein S-deficient families.

Genomic DNA samples from 12 protein S-deficient families with hereditary thrombophilia were analyzed by Southern hybridization using protein S cDNA probes. Protein S-deficient members of families A and B possessed identical restriction fragment length polymorphisms, which suggest the absence of 5.3 kb from one of their protein S alpha alleles. The abnormal alleles from individuals A7 and B1 were amplified by the polymerase chain reaction using a forward primer in intron K and a reverse primer in exon XIV. The amplified DNA was cloned and sequenced. Sequence comparison with the normal protein S alpha gene showed that most of intron L (roughly 4.7 kb), the entire exon XIII (151 bp), and about a quarter of intron M (407 bp) were missing from both the A7 and B1 clones. Exon XIII contains all three potential N-glycosylation sites in human protein S. This deletion may result in RNA transcripts in which exon XII is spliced to exon XIV. Such an arrangement would generate a stop codon at position 463 and consequently produce a nonglycosylated protein S molecule truncated by 173 amino acids.

Alleles↗
PubMed1991

The natural anticoagulant protein S is decreased in male smokers.

Protein S is a natural anticoagulant plasma protein; familial deficiency is associated with thrombotic complications. Since smoking carries an increased risk of myocardial infarction and stroke, we investigated the protein S system of men who smoke. In plasma, free protein S is functionally active and protein S bound to C4b binding protein is inactive. Male smokers (n = 24) have lower total protein S than nonsmokers (n = 24) (16.8 +/- 4.3 micrograms/ml versus 19.8 +/- 5.1 micrograms/ml, p less than 0.02). C4b binding protein levels are higher (p less than 0.05) in smokers (212 +/- 47 micrograms/ml versus 186 +/- 52 micrograms/ml). Free protein S is significantly lower in smokers (6.9 +/- 2.3 micrograms/ml versus 8.0 +/- 1.9 micrograms/ml, p = 0.02). These alterations in protein S may contribute to the thrombotic complications associated with smoking.

Adult↗
PubMed1991

Decrease in endothelial cell-dependent protein C activation induced by thrombomodulin by treatment with cyclosporine.

The use of cyclosporine has been associated with an increased incidence of thrombosis and endothelial cell perturbation. To explore possible mechanisms involved, we examined the effects of CSA on the activation of protein C by thrombomodulin. Cultured bovine aortic endothelial cell monolayers were incubated for 24 hr with a wide range of CSA concentrations. After removal of CSA and incubation with thrombin and purified protein C, thrombomodulin-dependent protein C activation was measured with an S-2238-based kinetic chromogenic assay. As compared to control, a significant fall in thrombomodulin activity occurred after 24-hr incubation with 100 (70.8 +/- 15.8%, P less than 0.05), 1000 (64.9 +/- 16.6%, P less than 0.05), or 10,000 (28.9 +/- 12.3%, P less than 0.05) ng/ml of CSA. A comparable inhibition of thrombomodulin activity was also observed in cultured renal artery endothelial cells (67.5 +/- 12.6%, P less than 0.05), after 24-hr incubation with 5000 ng/ml CSA. In cells incubated with 5000 ng/ml of CSA for 4 hr, thrombomodulin activity fell by almost 15% (85.6 +/- 8.3%, P less than 0.05) and tended to plateau between 7 hr (73.8 +/- 12.7%, P less than 0.05), and 24 hr of incubation (72.7 +/- 8.9%, P less than 0.05). These results indicate that CSA produces a time- and dose-dependent reduction in thrombomodulin activity of cultured endothelial cells, downregulating the protein C anticoagulant pathway, thereby increasing the risk of thrombosis.

Animals↗
PubMed1991

Afibrinogenemia and hypobetalipoproteinemia in a kindred.

A 3-year-old boy with minor bleeding problems had no plasma fibrinogen measured by both clottable assay and immuno-precipitation. Low normal fibrinogen levels were present in the mother and father. Markedly decreased plasma cholesterol and apolipoprotein B levels were found in the father, proband's brother, and the paternal side of the kindred. The proband and his mother had normal plasma total cholesterol and apolipoprotein B levels. These findings are compatible with autosomal dominant transmission of hypobetalipoproteinemia and autosomal recessive transmission of afibrinogenemia. Two members of the father's family had plasma cholesterol levels below the fifth percentile but elevated levels of fibrinogen (6.0 and 4.4 g/L). Both have symptomatic coronary heart disease. Finding coronary heart disease with very low cholesterol but elevated fibrinogen levels is consistent with fibrinogen levels being an independent risk factor for coronary heart disease.

Adult↗
PubMed1990

Free protein S levels are elevated in familial C4b-binding protein deficiency.

In plasma, 40% of the protein S is free and functions as a cofactor for the anticoagulant effects of activated protein C. The remaining 60% of protein S is complexed to C4b-binding protein and is functionally inactive. A family with hereditary C4b binding protein deficiency has been identified with C4b-binding protein levels in an affected father and daughter of 37 micrograms/mL and 23 micrograms/mL, respectively; these values are significantly below the normal range for this protein of 180 micrograms/mL +/- 44 micrograms/mL (mean +/- 2 SD). The total protein S (free + bound) is normal in these individuals (23.2 micrograms/mL and 17.8 micrograms/mL, respectively; normal 19.1 micrograms/mL +/- 6.0 micrograms/mL). The free protein S levels are markedly increased at 22.5 micrograms/mL and 17.4 micrograms/mL, respectively (normal 5.9 micrograms/mL +/- 2.4 micrograms/mL). This experiment of nature shows that total protein S levels in plasma are not affected by the absence of C4b-binding protein and that chronic elevation of free protein S is not associated with increased hemorrhagic tendencies.

Adult↗
PubMed1990

In vitro studies with the platelet-reactive antibody 50H.19 and its fragments.

The platelet-reactive monoclonal antibody 50H.19, its F(ab')2 fragments, and 99m-technetium (99m-Tc)-labeled fragments used in thrombus imaging were evaluated for their ability to cause platelet aggregation. The intact antibody caused a dose-dependent platelet aggregation in either platelet-rich plasma (PRP) or defined buffer solutions. The F(ab')2 fragments did not cause platelet aggregation except at high calcium concentrations. Neither stannous-ion-treated antibody fragments nor 99m-Tc-labeled antibody fragments caused platelet aggregation. The antibody-induced platelet aggregation was completely inhibited by 8-bromo-cAMP, caffeine, theophylline diltiazem, and staurosporin; partially inhibited by EDTA, EGTA, cytochalasin B, colchicine, aspirin, or indomethacin. Treatment of platelets with the intact 50H.19 antibody resulted in phosphorylation of a 40K dalton platelet protein, similar to that caused by treatment with phorbol myristate acetate (PMA). Phosphorylization of the 40K protein was not observed after treatment with either the 50H.19 F(ab')2 fragments or the calcium ionophore A23187.

Antibodies, Monoclonal↗
PubMed1990

Superior sagittal sinus thrombosis in a patient with protein S deficiency.

A 30-year-old man presented with sagittal sinus thrombosis. He had a history of multiple thrombotic events since adolescence, and his father had had a similar history. Laboratory studies revealed the complete absence of free protein S in his plasma. Protein S deficiency, an autosomal dominant disorder, is an identifiable cause of cerebral thrombosis. The literature and our experience with this case suggest that long-term anticoagulant therapy may prevent thrombotic episodes in patients with this disorder.

Adult↗
PubMed1988

Acquired deficiencies of protein S. Protein S activity during oral anticoagulation, in liver disease, and in disseminated intravascular coagulation.

Protein S is a vitamin K-dependent plasma protein which serves as the cofactor for activated protein C. Protein S circulates in both an active, free form and in an inactive complex with C4b-binding protein. To elucidate the role of protein S in disease states and during oral anticoagulation, we developed a functional assay for protein S that permits evaluation of the distribution of protein S between free and bound forms and permits determination of the specific activity of the free protein S. In liver disease, free protein S antigen is moderately reduced and the free protein S has significantly reduced specific activity. In disseminated intravascular coagulation, reduced protein S activity occurs due to a redistribution of protein S to the inactive bound form. During warfarin anticoagulation, reduction of free protein S antigen and the appearance of forms with abnormal electrophoretic mobility significantly decrease protein S activity. After the initiation of warfarin, the apparent half-life of protein S is 42.5 h. In patients with thromboembolic disease, transient protein S deficiency occurs due to redistribution to the complexed form. Caution should be exercised in diagnosing protein S deficiency in such patients by use of functional assays.

Adult↗
PubMed1987

Anticoagulation proteins C and S.

Proteins C and S are two vitamin K-dependent plasma proteins that work in concert as a natural anticoagulant system. Activated protein C is the proteolytic component of the complex and protein S serves as an activated protein C binding protein that is essential for assembly of the anticoagulant complex on cell surfaces. The anticoagulant activity is expressed through the selective inactivation of Factors Va and VIIIa. Many patients deficient in proteins C and S have been described and have an associated thrombotic tendency, but not all heterozygous protein C and S deficient individuals experience thrombotic complications. Multiple mechanisms and/or drugs can lead to acquired deficiencies of these proteins: oral anticoagulation, liver disease, DIC and in the case of protein S, lupus erythematosus, nephrotic syndrome, pregnancy and certain hormones. The anticoagulant activity of protein C decreases rapidly after administration of warfarin (i.e., with a time course similar to Factor VII). This rapid decrease may lead to a transient imbalance and contribute to coumarin induced skin necrosis. Protein S antigen levels do not decrease as rapidly, but protein S functional levels are often low in patients with an acute thrombus. The discrepancy between antigen and function results from elevations in C4b-binding protein, which complexes reversibly with protein S. Unlike free protein S, the complex does not function in the anticoagulant pathway. The available information all suggest that deficiency of protein C and protein S should be considered a risk factor contributing to recurrent thrombotic disease and that the function of these proteins is altered by many common clinical conditions which have associated an increased risk of thrombosis.

Anticoagulants↗