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PubMed1998

Tissue factor.

Tissue factor is the primary cellular initiator of blood coagulation via interaction with coagulation factor VII. Aberrant expression of tissue factor is responsible for thrombosis during septic shock, atherosclerosis and cancer. However, recent evidence has accumulated that tissue factor may have functions beyond controlling fibrin-dependent hemostasis. It is expressed as an immediate early gene by growth factors and cytokines, it transduces intracellular signals via its cytosolic domain, triggers production of growth factors and has been implicated in immune function, smooth muscle migration and metastasis, the latter via mechanisms requiring intracellular signaling as well as the proteolytic activity of the tissue factor-factor VIIa complex. Further evidence for a possible alternative role of tissue factor has been provided from tissue factor gene inactivation studies, indicating that tissue factor controls vascular integrity by affecting the maturation of the muscular wall around endothelial cell lined channels. Surprisingly, however, deficiency of factor VII does not affect vascular integrity and tissue factor may act independently of fibrin formation during embryogenesis. Elucidation of the mechanism of its action may provide insights for selective interference with the hemostatic versus morphogenic properties of tissue factor.

Animals↗
PubMed2006

Long-term FVII substitution in a preterm infant with severe gastrointestinal bleeding and FVII deficiency due to a homozygous donor splice mutation IVS4+1G-->A.

Congenital FVII deficiency is a rare bleeding disorder. Clinical complications are similar to those seen in hemophilia A, and an increased incidence of intracerebral hemorrhage related to birth trauma has been reported. The authors report on an infant who presented at the second day of life with melaena and hematemesis caused by congenital FVII deficiency with minimal activity of 4%. A homozygous mutation IVS4+G-->A, formerly described in 2 siblings, who died of brain hemorrhage within the first month of life, was identified. Severe bleeding events were prevented with prophylactic treatment. Early identification of the underlying mutation helps to assess the risk of hemorrhage and prevent severe bleeding by prophylactic FVII therapy.

Alternative Splicing↗
PubMed2002

Thrombophilic markers in patients with congenital bleeding disorders.

We have studied the presence or absence of thrombophilic markers in 59 patients with congenital bleeding disorders. Theoretically, the coexistence of coagulation factor deficiency and thrombophilia in patients with haemophilia may cause the bleeding tendency to decline. In 8 cases we have found thrombophilic marker positivity, in 7 patients APC resistance and in 1 patient protein S deficiency has been revealed. The presence of thrombophilic markers did not affect the frequency of bleeding episodes or the development of haemophilic arthropathy. The factor concentrate utilization, however, was lower in the group carrying thrombophilic markers, which indicates that the bleeding episodes were less severe. Relying on the strength of these findings, the medicinal influencing of inhibitor mechanisms may present itself as a potential therapy.

Activated Protein C Resistance↗
PubMed1988

Endotoxin-induced procoagulant activity in equine peripheral blood monocytes.

Increasing evidence has demonstrated the importance of monocyte procoagulant activity (PCA) in the pathogenesis of coagulopathies in a variety of diseases. Because endotoxin precipitated coagulopathies are common sequelae to intestinal ischemia/endotoxemia in the equine species, we investigated the ability of equine peripheral blood monocytes to express PCA. Monocytes isolated from five healthy adult horses were incubated in vitro with Escherichia coli endotoxin (10 micrograms), and the PCA was measured by the ability of cellular lysates to accelerate the clotting times of equine plasma in a modified one-stage recalcification assay. Equine monocyte PCA was identified as thromboplastin based on lack of clot formation in factor VII-deficient plasma. The induction of PCA occurred as early as 2 hr after endotoxin exposure, peaked at 6 hr (396% increase), and then gradually declined. The amount of PCA was proportional to the dose of endotoxin (0.01 to 100 micrograms) and the number of monocytes. Neither platelets nor neutrophils produced PCA, either in the absence or presence of endotoxin (1 microgram). Lymphocytes at a concentration of 4 x 10(6)/ml RPMI did produce a significant amount of PCA, compared to the time-matched controls. Co-incubation of neutrophils or lymphocytes with monocytes did not alter the PCA, whereas coincubation of platelets and monocytes significantly enhanced the expression of PCA. This effect was further augmented by the addition of endotoxin (1 microgram).

Animals↗
PubMed1997

Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity.

Interleukin (IL)-6 and IL-8 are important regulators of inflammatory responses in myocardial infarction. Induction of monocyte procoagulant activity (PCA) by these cytokines could present a mechanism that links inflammatory responses to thrombotic events. We therefore investigated the effect of IL-6 and IL-8 on monocyte tissue factor (TF) expression. Recombinant human IL-6 and IL-8 caused a time- and dose-dependent increase in PCA (recalcification time) of monocytic U937 cells and of mononuclear leukocytes. Using blocking anti-TF monoclonal antibodies and factor VII-deficient control plasma, this PCA was shown to be TF dependent. Compared with unstimulated cells, mononuclear cell PCA increased by 4.5-fold to 17 +/- 2 mU/5x10(5) cells after exposure to 100 ng/L IL-6 for 4 hours and by 6.6-fold to 27 +/- 4 mU/5x10(5) cells after exposure to IL-8 under the same conditions. Northern blot analysis showed an increase in TF mRNA after stimulation with IL-6 or IL-8 for 2 hours, and after 4 hours an increase in cellular TF protein content was found by immunoassay. Flow cytometry demonstrated that IL-6 and IL-8 induced an increase in TF surface expression on monocytes. Thus, IL-6 and IL-8 induce monocyte PCA by increasing mRNA, protein content, and surface expression of TF.

Blood Coagulation Factors↗
PubMed1975

Alteration of factor VII activity by activated Fletcher factor (a plasma kallikrein): a potential link between the intrinsic and extrinsic blood-clotting systems.

Although surface contact is known to accelerate the one-stage prothrombin time of human plasma through the participation of Hageman factor (factor XII) and factor VII, it has not been clear whether Hageman factor interacts with factor VII directly or indirectly. Recently, Gjønnaess reported experiments suggesting that plasma kallikrein was an intermediate between Hageman factor and factor VII. The present study was undertaken to elucidate the interaction of plasma kallikrein and factor VII. Incubation of Fletcher-trait plasma (deficient in a plasma prekallikrein) with kaolin at 0 degrees C. did not induce shortening of the Thrombotest time or enhancement of factor VII activity, in contrast to studies of normal plasma. Monospecific rabbit antiserum against plasma kallikrein blocked the shortening of the Thrombotest time of normal plasma brought about by kaolin. Purified Hageman factor fragments (prekallikrein activator) induced an increase in factor VII activity in normal or Hageman-trait plasma, but not in Fletcher-trait plasma. A purified plasma kallikrein preparation enhanced factor VII activity in all plasmas, including that of Fletcher-trait plasma. The effect of the kallikrein preparation was blocked by soybean trypsin inhibitor, Trasylol, or rabbit antiserum against kallikrein, but not by lima bean trypsin inhibitor or antiserum against Hageman factor. The activity of partially purified factor VII was enhanced by purified kallikrein in the presence, but not in the absence of factor VII-deficient plasma. These results further support the idea that the enhancement of factor VII activity by surface contact is via Hageman factor and plasma kallikrein, suggesting a possible link between the intrinsic and extrinsic pathway of blood clotting. The significance of this phenomenon in hemostasis in vivo remains to be elucidated.

Animals↗
PubMed1993

Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A.

Hemophilia A is due to the functional deficiency of factor VII (FVIII, gene locus F8C). Although half the patients have no detectable FVIII protein in their plasma, the more rare patients (approximately 5%) have normal levels of a dysfunctional FVIII and are termed cross-reacting material (CRM)-positive. More commonly (approximately 45%), patients have plasma FVIII protein reduced to an extent roughly comparable to the level of FVIII activity and are designated CRM-reduced. We used denaturing gradient gel electrophoresis to screen for mutations within the F8C gene of 11 patients (6 CRM-positive, 5 CRM-reduced) and identified 9 different mutations in 9 patients after analyses of all 26 exons, the promoter region, and the polyadenylation site. Six mutations have not been described previously. Five were missense (Ser289Leu, Ser558Phe, Val634Ala, Val634-Met, Asn1441Lys), and the sixth was a 3-bp deletion (delta Phe652). A review of the literature and the assay of FVIII antigen in 5 hemophilia A patients with previously identified missense mutations from this laboratory yielded a total of 20 other unique CRM-reduced and CRM-positive mutations. Almost all CRM-positive/reduced mutations (24/26) were missense, and many (12/26) occurred at CpG dinucleotides. We examined 19 missense mutations for evolutionary conservation using the portions of the porcine and murine F8C sequences that are known, and 18/19 amino acid residues altered by mutation in these patients were conserved. Almost 50% of mutations (11/26) clustered in the A2 domain, suggesting that this region is critical for the function of FVIII.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Further studies on factor VII Padua defect: the report of the fourth homozygous patient from the same valley.

A new patient with factor VII Padua abnormality is presented. The proposita is an 11-year-old girl who showed a mild bleeding tendency and a laboratory pattern characterized by a prolonged prothrombin time corrected by normal serum, normal partial thromboplastin time and normal Thrombotest. Factor VII assay was 10% using rabbit brain thromboplastin and 100% of normal using ox brain thromboplastin. Factor VII cross-reaction material was normal. The parents were not consanguineous but both came from the same area and were found to be heterozygous for the abnormality. The discovery of the present patient, the fourth in three years, indicates that the defect might be more frequent than originally thought.

Blood Coagulation Tests↗
PubMed1991

Investigating the presence of HIV sequences and the distribution of virological markers in hemophiliacs and their sexual partners.

In this study, we report the investigation of a hemophiliac cohort, in which the last HIV-1 seroconversion occurred in 1985. We wanted to evaluate whether 5 years later the results of serological screening and polymerase chain reaction (PCR) technology would match. We examined 61 German patients with congenital deficiencies of factors VII, VIII-c, and IX, and 16 sexual partners (15 partners of anti-HIV-1-negative hemophiliacs). Patients' and partners' anti-HIV-1 status was determined by ELISA and Western blot. Further, we applied the PCR to investigate the possible presence of HIV sequences in anti-HIV-1-negative individuals. Four sets of primers were used in four separated reactions to avoid false-negative results due to genetic variation, as well as false-positive results due to DNA carryover. The data by PCR were not different from the data attained by conventional serological methods. The prevalence of serological markers for HBV and HCV was determined.

HIV↗
PubMed1984

The formation of a thrombin-like material (TLM) following stimulation of leukocytes.

When thrombin, tissue thromboplastin or Russell's viper venom was added to a suspension of either lymphocytes or neutrophils containing normal plasma, aggregation of these cells ensued. The aggregate formed one gelatinous mass which was readily separable from the cell free supernatant, an aliquot of which caused platelet aggregation. This leukocyte derived platelet aggregatory substance had characteristics similar to thrombin but not AGEPC. When plasma deficient in Factor V was substituted for normal plasma, the platelet stimulatory substance was not produced. Substitution with plasma deficient in Factor VII, VIII, IX, X or XI was without effect. Thrombin clotting time measurements indicated a generation of activity, relative to thrombin, of about 3.0 U/5 X 10(6) cells.

Cell Aggregation↗
PubMed1989

Analysis of serum cancer procoagulant activity and its possible use as a tumor marker.

The two objectives of the study were to determine whether a procedure could be developed for measuring cancer procoagulant (CP) activity in human serum and if this procedure provided a method for distinguishing people with cancer from those without cancer. A procedure was developed for processing human serum such that the activity of other coagulation enzymes would be minimized and the activity of cancer procoagulant could be measured. In a blinded study, we collected serum from 61 individuals in serum separator tubes, removed the clot by centrifugation, extracted the serum with a simple, single step procedure and analyzed the extract for CP activity. The results indicate that this test could correctly identify about 92% of the cancer patient serum samples and about 75% of the non-cancer patients serum samples, for an overall accuracy of about 85%.

Biomarkers, Tumor↗
PubMed2006

Searching for hemostatic modifier genes affecting the phenotype of mice with very low levels of FVII.

FVII(tTA/-) mice are heterozygous for the FVII- null allele and a gene-targeted allele expressing very low levels of FVII. Approximately half the FVII(tTA/-) in a mixed C57Bl/6:129x1/SVJ background survive much longer than mice in a C57Bl/6 background, suggesting that genetic background affects the survival of mice expressing very low levels of FVII. A lineage of long-term surviving FVII(tTA/-) mice in a predominantly C57Bl/6 background was generated by selecting 16 weeks or older FVII(tTA/-) males and breeding them with C57Bl/6 FVII+/- females. It is postulated that these mice maintain 129x1/SVJ alleles at putative hemostatic modifier loci necessary for the survival of mice expressing very low levels of FVII. A SNP genomic scan was performed on DNA from long-term surviving FVII(tTA/-) mice. The scan identified 8 regions enriched for 129x1/SVJ sequences that might contain putative hemostatic modifier genes.

Animals↗