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Biomedical subjects

H Stormorken

Publications and source records attributed to H Stormorken.

At least 19 recordsLinked to original sources
PubMed2003

The discovery of factor V: a tricky clotting factor.

The paper tells the story of how FV was discovered in 1943 and installed into the Morawitz theory, a dogma that had reigned the clotting field since 1905 without serious challenges. It is a witness to the fact, many times experienced throughout scientific history, that seminal achievements may arise from serendipity under awkward conditions. Under the worst of circumstances, only a brilliant mind, scientific curiosity and devotion, could the challenge Owren met in Mary's bleeding problem, lead to such a pivotal result. On top of establishing a new clotting factor, his work spurred an unprecedented activity in the field. The thorny road to the new factor's place and role in the clotting mechanism is depicted in some detail. But the factor turned out to be more capricious than its role in coagulation seemed to indicate. Thus, in recent times it has become clear that its platelet counterpart plays an additionally important role in hemostasis as a whole. The two polymorphisms of clinical importance discovered in platelet FV lead to a bleeding disorder, whereas one in plasma FV leads to a rather frequent venous thromboembolic state. Further surprises might therefore be expected from this chameleon of a factor - reflecting the increasingly appreciated tendency that one biological compound appears in different roles.

Blood Coagulation↗
PubMed2000

Homozygous truncation of the fibrinogen A alpha chain within the coiled coil causes congenital afibrinogenemia.

The molecular basis of a novel congenital afibrinogenemia has been determined. The proposita, the only affected member in a consanguineous Norwegian family, suffers from a moderate to severe bleeding disorder due to the total absence of any detectable fibrinogen. Dot blots of solubilized platelets revealed a small amount of gamma chain but no A alpha or B beta chains, whereas no chains were detected in plasma dot blots. DNA sequencing of the A alpha chain gene revealed a homozygous C-->T transversion 557 nucleotides from the transcription initiation site. This nucleotide change predicts the nonsense mutation A alpha 149 Arg (CGA)-->stop (TGA). Early truncation of the A alpha chain appears to result in defective assembly or secretion of fibrinogen, probably due to the removal of the C-terminal disulfide ring residues that are critically required for the formation of a stable 3-chained half molecule. (Blood. 2000;96:773-775)

Adult↗
PubMed2000

Erythrocyte sedimentation rate: a possible marker of atherosclerosis and a strong predictor of coronary heart disease mortality.

AIMS: Since atherosclerosis is a chronic inflammation and the erythrocyte sedimentation rate is an appropriate test for monitoring chronic inflammatory responses, we wanted to investigate whether the erythrocyte sedimentation rate might carry prognostic information on the risk of sustaining coronary heart disease events. METHOD: The erythrocyte sedimentation rate was determined in 2014 apparently healthy men aged 40-60 years during an extensive cardiovascular survey in 1972-75, and the test was repeated in an identical follow-up examination 7 years later. Cause-specific mortality and rates of non-fatal myocardial infarction were followed for 23 years. RESULTS: The erythrocyte sedimentation rate was strongly correlated with age, haemoglobin level, smoking status, total cholesterol level and systolic blood pressure. After adjusting for all these associations in multivariate Cox regression analyses, the erythrocyte sedimentation rate emerged as a strong short- and long-term predictor of coronary heart disease mortality, particularly in men who had developed angina pectoris and/or had a positive exercise ECG test at the second survey. Increases in non-coronary heart disease deaths and in non-fatal myocardial infarctions were only seen in the upper erythrocyte sedimentation rate range. CONCLUSIONS: The erythrocyte sedimentation rate is a strong predictor of coronary heart disease mortality, and appears to be a marker of aggressive forms of coronary heart disease. The erythrocyte sedimentation rate probably gives substantial information in addition to that given by fibrinogen on the risk of coronary heart disease death.

Adult↗
PubMed1998

Iohexol, platelet activation and thrombosis. I. Iohexol-induced platelet secretion does not affect thrombus formation in native blood.

BACKGROUND: The nonionic monomer iohexol triggers in vitro platelet secretion of beta-thromboglobulin (beta-TG). This iohexol platelet activation may promote intravascular thrombosis. We studied this relationship by employing a human model of collagen-induced platelet thrombus formation at arterial flow. The ionic dimer ioxaglate, the nonionic dimer iodixanol, and glucose were included. METHODS AND RESULTS: In vitro platelet activation as measured by beta-TG secretion following a 1-min incubation of native blood with 50 vol% of iohexol was significant. Glucose solutions of 300, 580 and 825 mosmol, corresponding to the osmolalities of respectively iodixanol, ioxaglate and iohexol, increased the beta-TG secretion in parallel with the osmolalities. Ioxaglate and iodixanol were virtually inert. Continuous infusion of iohexol or 580 or 825 mosmol glucose (40 vol%) into flowing native blood at an arterial wall shear rate of 2600 s-1 in an ex vivo collagen-induced platelet thrombus formation device triggered pronounced secretion of beta-TG. However, the platelet thrombus formation in blood mixed with iohexol was within the same range as that observed with ioxaglate or iodixanol. Increasing glucose osmolality induced increasing beta-TG secretion, which paralleled gradually decreasing platelet thrombus formation. CONCLUSION: Iohexol and 580 or 825 mosmol glucose trigger platelet secretion of beta-TG. This secretion is not associated with enhanced collagen-induced platelet thrombus formation at high arterial shear.

Blood Donors↗
PubMed1998

Iohexol, platelet activation and thrombosis. II. Iohexol-induced platelet secretion does not affect collagen-induced or tissue-factor-induced thrombus formation in blood that is anticoagulated with heparin and aspirin.

BACKGROUND: There is a dispute about the potential effects of radiographic contrast media (CM) on thrombogenesis. The nonionic CM iohexol triggers platelet beta-thromboglobulin (beta-TG) secretion, and thus may activate the platelets and promote thrombosis. We addressed this topic in a study employing a human model of arterial thrombus formation in the presence of aspirin and heparin. This was a follow-up to our initial study (on thrombus formation in native blood) which did not include antithrombotic drugs. The nonionic CM iohexol (monomer) and iodixanol (dimer) and the ionic CM ioxaglate (dimer) were compared. METHODS AND RESULTS: Thrombus formation was triggered by a surface rich in either collagen or tissue factor, positioned in a parallel-plate perfusion chamber device at an arterial wall shear rate of 2600 s-1. Blood from healthy volunteers, following ingestion of 1 g aspirin, was mixed with 40 vol% CM and 2.0 IU/ml heparin and passed over the surfaces. Thrombus formation in the presence of either CM showed no difference, despite the fact that iohexol triggered a pronounced platelet beta-TG secretion; iodixanol or ioxaglate were virtually inert. CONCLUSION: There was no association between iohexol-induced beta-TG secretion and thrombus formation on collagen (platelet-driven) or on tissue factor (thrombin-driven) in the presence of a standard antithrombotic regimen of aspirin and heparin as used in the clinic. The notion of a thrombotic risk due to platelet activation by iohexol was thus not substantiated by this study.

Anticoagulants↗
PubMed1998

Characterization of a factor VII molecule carrying a mutation in the second epidermal growth factor-like domain.

A missense mutation at codon 100 in the second epidermal growth factor-like domain, resulting in Gln100-->Arg, was detected in 19 out of 21 available severely factor VII (FVII) deficient patients in Norway. Seventeen patients were homozygous, and the two remaining were compound heterozygotes. In the homozygous patients, FVII antigen was measured to 10-28%, and activity to 0.6-6.5% of that in normal pooled plasma. Recombinant FVII containing the mutation was expressed transiently in CHO cells to a mean antigen level of 57% of the wild type FVII protein, and with a specific activity of 6% of wild type. The mutant protein had a 14-fold reduction in affinity for tissue factor (TF), whereas binding of FX seemed unaffected. In line with the experimental data, molecular modelling of the mutation based on the coordinates of the tissue factor/FVIIa complex showed that substituting arginine for glutamine disrupts the interface between the catalytic and second epidermal growth factor-like domains.

Adolescent↗
PubMed1997

A peptide sequence from the EGF-2 like domain of FVII inhibits TF-dependent FX activation.

We have found that synthetic peptides derived from the two epidermal growth factor-like domains of factor VII are inhibitors of tissue factor dependent factor X activation. Inhibition was most pronounced for a constrained sequence of amino acids corresponding to positions 91-102 of factor VII, Cys-Val-Asn-Glu-Asn-Gly-Gly-Cys-Glu-Gin-Tyr-Cys. The biological activity appeared to be localized to the tripeptide 'motif', Glu-Gln-Tyr, within the larger sequence. The cyclic peptide was also an inhibitor of tissue factor induced coagulation of plasma, using lipidated tissue factor or tissue factor expressed on the surface of living cells. However, it did not interfere with intrinsic coagulation. Inhibition of factor X activation was dose-dependent with an IC50 value of 350 microM. Kinetic analyses revealed non-competitive inhibition with respect to factor X and suggested that the peptide sequence interferes with the factor VII/tissue factor/factor X complex formation and function. A pentapeptide analog of the putative pharmacophore was also a dose-dependent inhibitor of factor X activation with an IC50 value of 560 microM, but the tripeptide, Glu-Gin-Tyr, alone was without effect. Our results suggest a direct role for the second epidermal growth factor-like domain of factor VII, and in particular its loop I, in the formation and function of the factor VII/tissue factor/factor X complex.

Amino Acid Sequence↗
PubMed1997

Role of ADP and thromboxanes in human thrombus formation in ex vivo models.

Adenosine diphosphate (ADP) and prostaglandin derivatives play important roles in thrombogenesis. Their roles in platelet function have been extensively studied for more than three and two decades, respectively. Of further importance for thrombogenesis, and perhaps for atherogenesis as well, is that these compounds are involved in the regulation of vascular wall tone, both as constrictors and dilators. The aim of this brief essay is to highlight the relative importance of ADP and TxA(2) in collagen-induced thrombus formation at various well-defined shear conditions. To achieve this goal, we employed a human ex vivo model of thrombus formation, because well-defined and reproducible blood shear conditions are best created in such a device. The blood flow conditions varied from those encountered in healthy veins to vessels with severe atherosclerotic disease. These experiments were performed as parts of clinical phase I studies with novel antagonists of ADP- or TxA(2)-induced platelet aggregation. Probes for ADP and TxA(2) included the ADP receptor antagonist clopidogrel and the TxA(2) receptor antagonist linotroban, respectively. Their antithrombotic activities were compared with results obtained with the cyclo-oxygenase inhibitor aspirin. These studies demonstrated a significant effect of both ADP and TxA(2) on collagen-induced ex vivo thrombus formation. Whereas ADP promoted platelet thrombus formation independently of the local shear, TxA(2) promoted platelet thrombus formation at high arterial shear only, and increasingly by increasing shear.However, at blood flow conditions triggering shear-induced platelet activation and aggregation, TxA(2) formation did not affect collagen-induced platelet thrombus formation since aspirin administration was insensitive to the thrombotic response. This contrasts with the need for ADP in shear-induced platelet aggregation. Thus, the function of ADP in human ex vivo platelet thrombus formation appears more global than the role of TxA(2). These observations are in agreement with recent published clinical findings.

Journal Article↗
PubMed1996

Characterisation of cell-surface procoagulant activities using a microcarrier model.

A novel model is described for characterisation of cell-surface procoagulant activities and their inhibitors. Microcarrier beads were used to present living cells to recalcified blood plasma in the stirred measuring wells of an electromagnetic coagulometer. By this means the procoagulant activity on the surface of the cells could be automatically determined as clotting time. Procoagulant activity was investigated on normal and transformed cells, and representing hemopoietic, endothelial, muscle and connective tissue phenotypes. The procoagulant activity on each cell type was characterised by the use of specifically immunodepleted plasmas and specific inhibitors, including monoclonal antibodies. The predominant cell surface trigger of coagulation found in this series was tissue factor, and only blood monocytes provided some evidence for direct activation of factor X independent of FVII. Human ECV304 transformed endothelial cells were more closely studied as representative of a cell type constitutively expressing procoagulant. Coagulation mediated by ECV304 cells was found to be strictly dependent on tissue factor, as shown by an inhibitory monoclonal antibody, and on coagulation factors V, VII and X. ECV304 procoagulant activity was strongly inhibited by active-site-inactivated FVIIa, a synthetic peptide inhibitor of FXa (Tenstop) and the thrombin inhibitor, hirudin. While not appropriate for routine clinical assessment of coagulation factor function, we have found this model to be valuable in characterising the procoagulant activity on different cell types and particularly useful as a drug discovery tool in the search for new anticoagulants.

Blood Coagulation↗
PubMed1996

Immunologic quantification of fibrin deposition in thrombi formed in flowing native human blood.

We describe a new method for quantification of fibrin in thrombi formed in native human blood at venous and arterial shear conditions in a parallel-plate perfusion chamber device. Thrombi consisting of various proportions of fibrin and platelets were digested by plasmin. Fibrin deposition (micrograms/cm2) was calculated from the measured D-dimer levels. Fibrin deposition in thrombi formed on a tissue factor (TF)-rich surface increased with increasing shear rate from 37 micrograms/cm2 at 100/s to 77 micrograms/cm2 at 2600/s (significant at 95%, ANOVA). The plasma levels of thrombin-antithrombin III complexes (TAT) increased in concert. In contrast, fibrin deposition in thrombi formed on collagen fibrils and the corresponding TAT plasma levels were independent of the shear rate and much lower than those elicited by the TF-rich surface (significant at 95%, ANOVA). The intra-individual variation in fibrin deposition was on average 10%, whereas the inter-individual differences were > 500%. Such a large inter-individual difference has not been detected by morphometry which usually is employed in similar studies. The present method is more accurate and less time-consuming than the morphometric approach. The novel method measures fibrin on the surface and in and around the thrombi, thus total deposited fibrin. In contrast, the morphometry approach quantifies surface coverage with fibrin only, thus being semiquantitative at best.

Collagen↗
PubMed1996

Effects of ionic and nonionic contrast media on endothelium and on arterial thrombus formation.

BACKGROUND: The aims of the present study were to investigate whether ionic and nonionic contrast media (CM) affect: 1) the procoagulant and fibrinolytic activities of cultured human vessel endothelium; and 2) early events of tissue-factor-induced arterial thrombus formation under conditions which may follow a percutaneous transluminal coronary angioplasty (PTCA) procedure. The following 3 CM were studied: iohexol (nonionic monomer, Omnipaque); iodixanol (nonionic dimer, Visipaque); and ioxaglate (ionic dimer, Hexabrix). Saline (0.9%) and glucose (40 vol%) were used as control. METHODS AND RESULTS: Exposing endothelium to 40 vol% CM for 10 min did not affect the selected parameters of cellular procoagulant (tissue factor), anticoagulant (thrombomodulin), fibrinolytic (tissue plasminogen activator) or antifibrinolytic (plasminogen activator inhibitor-1) activity or antigen. However, ioxaglate had a profound impact on the cell morphology, which was noted already after one minute of exposure. The cells contracted and rounded, exposing large areas of extracellular matrix. Iohexol showed this phenomenon to a considerably lesser extent, whereas iodixanol induced a slight swelling of the cells without detectable exposure of extracellular matrix. The effect of the respective CM on tissue-factor-driven thrombus formation at an arterial shear rate of 2600 s-1 was studied in an ex vivo parallel-plate perfusion chamber device. In this model, human native blood was passed over a tissue factor/phospholipid-rich surface following 30 s exposure to 100% CM. The CM was washed out by nonanticoagulated blood drawn directly from an antecubital vein by a pump positioned distal to the perfusion chamber. Such a pre-exposure of the procoagulant surface to iodixanol reduced the fibrin deposition around the platelet thrombi by 50% (p<0.01). However, iohexol and ioxaglate did not affect fibrin deposition. None of the 3 CM affected the recruitment of platelets in the thrombi, since similar values were obtained with pre-exposure to 40 vol% of saline. CONCLUSION: Iodixanol appears to be most biocompatible with endothelium, and has a moderate inhibitory effect on fibrin deposition in flowing blood. This differs from iohexol, and in particular from ioxaglate, which induce endothelial changes in morphology with no effect on fibrin deposition. Since none of the CM affected the platelet aggregate formation, and since ioxaglate has been reported to have stronger anticoagulant and antithrombotic properties than iodixanol or iohexol in in vitro assays, it is apparent that these properties were not reflected in thrombus formation under the experimental conditions of high arterial shear.

Angioplasty, Balloon, Coronary↗
PubMed1996

Mutation spectrum in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia: identification of twelve different mutations in the WASP gene.

Twelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

Base Sequence↗