Significance of soluble P-selectin, von Willebrand factor, and other adhesion molecules in hypercholesterolemia and peripheral artery disease.
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Biomarkers↗
Biomedical subjects
R Fijnheer
Publications and source records attributed to R Fijnheer.
Soluble P-selectin in diabetes.
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Biomarkers↗
Progressive vascular damage in hypertension is associated with increased levels of circulating P-selectin.
OBJECTIVE: To assess whether increased shedding of adhesion molecules in plasma provides an index for endothelial damage in hypertension. DESIGN AND METHODS: Three groups of hypertensive patients with increasing severity of vascular damage were studied: 20 essential hypertensives, 21 atherosclerotic, renovascular hypertensives and four malignant hypertensives. Twenty healthy subjects were included as a control group. Levels of P-selectin, E-selectin, intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor in venous blood were measured, using sandwich-type enzyme-linked immunosorbent assay. RESULTS: For essential hypertensives a trend for increased P-selectin and E-selectin values compared with those in controls was observed (159+/-44 versus 132+/-40 ng/ml, P = 0.062 and 40+/-13 versus 34+/-17 ng/ml, P = 0.055, respectively). P-selectin (210+/-84 ng/ml, P = 0.0021) and E-selectin (42+/-12 ng/ml, P = 0.012) levels in renovascular hypertensives were significantly higher than those in healthy controls. There were no significant increases in circulating levels of intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor either in essential hypertensives or in renovascular hypertensives. Marked increases in circulating levels of adhesion molecules and von Willebrand factor relative to those in controls were observed in malignant hypertensives (P-selectin 634+/-332 versus 132+/-40 ng/ml, P = 0.0004; vascular cell adhesion molecule 968+/-187 versus 493+/-139 ng/ml, P = 0.0004; and von Willebrand factor 259+/-75 versus 130+/-72 U/dl, P = 0.016). CONCLUSIONS: Progression of vascular damage in essential, renovascular and malignant hypertension is associated with a rise in circulating levels of P-selectins and, to a lesser extent, E-selectins, whereas levels of intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor are elevated only in diseases associated with acute severe vascular damage, including malignant hypertension. Our data suggest that selectins may be useful as indicators of vascular damage in hypertension.
Adult↗
Homocysteine, methylenetetrahydrofolate reductase polymorphism, antiphospholipid antibodies, and thromboembolic events in systemic lupus erythematosus: a retrospective cohort study.
OBJECTIVE: To examine the relationship between plasma homocysteine, 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism, and the risk of arterial and/or venous thrombosis in systemic lupus erythematosus (SLE). METHODS: Plasma homocysteine and MTHFR polymorphism were determined in a retrospective cohort of 175 patients with SLE. Associations between homocysteine levels and antiphospholipid antibodies, renal function, and drug therapy were analyzed. RESULTS: Patients with arterial thrombosis had higher homocysteine concentration than nonthrombotic patients (20.6+/-10.2 vs 13.2+/-6.8 micromol/l; p < 0.001). The crude odds ratio for arterial thrombosis for the highest versus lowest quartile of homocysteine was 4.4 (95% CI 1.3-14.9). After adjustment for other risk factors the odds ratio remained significant (3.7; 95% CI 1.2-13.0). Increased plasma homocysteine was not associated with venous thrombosis. A significant correlation was found between homocysteine and creatinine (r=0.57, p < 0.0001) or the use of methotrexate. Homocysteine levels were higher in patients using corticosteroids and lower in patients using oral contraceptive drugs. This finding may be biased by impaired renal function in patients using corticosteroids and the advice to stop estrogen-containing contraceptives in female patients upon an episode of thrombosis. The distribution of MTHFR genotypes was 50% for homozygous wild type, 42% for heterozygous, and 8% for homozygous mutant, with a similar distribution among patients with or without a history of thrombosis. CONCLUSION: Raised levels of homocysteine are associated with arterial thrombosis in patients with SLE. Mutation in the MTHFR gene does not explain the raised levels, and renal failure is by far the most frequent cause.
Adolescent↗
Cyclosporin for thrombotic thrombocytopenic purpura after autologous bone marrow transplantation.
Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT) is a serious complication that, in contrast to classic TTP, is generally not responsive to therapeutic plasma exchange. We describe the remission of TTP after autologous BMT by administration of cyclosporin in four patients, either after failure of plasmapheresis (two patients) or as primary treatment modality (two patients). Cyclosporin may be an attractive drug for post autologous BMT-TTP.
Adolescent↗
Improvement of platelet storage conditions by using new polyolefin containers.
BACKGROUND: Storage of pooled platelet concentrates (PCs) with yields above 3.0 x 10(11) platelets per unit in a 1-L PL-732 polyolefin container for 5 days often results in a drop in pH to below 6.0. Recently, new oxygen-permeable platelet containers (1-L PL-2410, 1-L and 1.5-L Compoflex) have been developed. The maximal platelet storage capacities of the new containers and the PL-732 were compared. STUDY DESIGN AND METHODS: Large platelet pools (n = 27) with platelet concentrations between 1.2 and 1.4 x 10(11) per L were made from 3 to 5 PCs prepared from buffy coats. The pools were divided in equal volumes among the PL-732 and the three new platelet containers. Platelet counts in the PCs ranged from 1.0 to 5.0 x 10(11) per unit. All PCs were stored on a flatbed shaker at 22 +/- 2 degrees C and evaluated on Days 1, 3, 5, and 7 by measuring platelet count, pH, pO2, pCO2, HCO3-, glucose, lactate, platelet swirling, and soluble p-selectin. RESULTS: Day 7 storage of PCs (n = 6) with yields between 3.0 and 4.0 x 10(11) platelets in PL-732 showed mean +/- SD pH values of 5.93 +/- 0.05 and lactate values of 32.3 +/- 7.9 mmol per L; in 4 of these 6 PCs, pH was below 6.0. In contrast, storage of these PCs in 1-L PL-2410 and 1.5-L Compoflex containers and of 2 of these 6 PCs in 1-L Compoflex containers showed pH values above 6.8. Lactate values were 15.5 +/- 1.3, 15.3 +/- 1.8, and 19.5 +/- 4.7 mmol per L, respectively (p < 0.001 vs. PL-732). The platelet storage capacity of the new containers with platelet yields between 4.0 and 5.0 x 10(11) per unit (n = 6) was evaluated. Day 7 storage of these PCs in the 1.5-L Compoflex showed an average pH value of 6.74 +/- 0.20; in 2 of 6 PCs, pH was below 6.8. The average pH value in the PL-2410 was 6.38 +/- 0.31, and in all PCs, pH was below 6.8. Average lactate values were 17.8 +/- 5.7 and 25.8 +/- 5.6 mmol per L (p < 0.05), respectively. Soluble p-selectin values on Day 7 of storage increased approximately twofold in all PCs. CONCLUSION: The new oxygen-permeable containers showed platelet quality comparable to that with the PL-732 and for longer storage periods and at higher platelet counts.
Blood Platelets↗
Soluble adhesion molecules reflect endothelial cell activation in ischemic stroke and in carotid atherosclerosis.
BACKGROUND AND PURPOSE: Activation of endothelial cells and platelets plays an important role in the development of atherosclerosis and thrombotic disorders. Soluble adhesion molecules originating from these cells can be demonstrated in plasma. We hypothesized that elevated plasma concentrations of soluble P-selectin (sP-selectin), soluble intercellular adhesion mole-cule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin) can reflect activation of endothelial cells and/or platelets in acute ischemic stroke and in previously symptomatic internal carotid artery stenosis. METHODS: Plasma was sampled from patients within 2 days of acute ischemic stroke (n = 28), from patients with a previous (> 1 week) transient or persistent ischemic neurological deficit associated with stenosis of the internal carotid artery (n = 34), and from control patients without a history of vascular disease (n = 34). Concentrations of sP-selectin, sICAM-1, sVCAM-1, and sE-selectin were measured by means of an enzyme-linked immunosorbent assay. RESULTS: Compared with control subjects, sP-selectin and sE-selectin were significantly elevated in the acute stage of ischemic stroke (P < .0001 and P = .001, respectively) as well as in previously symptomatic carotid stenosis (P < .0001 and P = .0007). sICAM-1 and sVCAM-1 were not increased. CONCLUSIONS: The elevated levels of sE-selectin indicate that endothelial cell activation occurs both in the acute stage of ischemic stroke and in previously symptomatic carotid atherosclerosis. Increased sP-selectin concentrations reflect endothelial cell activation as well but may also be caused by platelet activation.
Arteriosclerosis↗
The origin of P-selectin as a circulating plasma protein.
P-selectin is a 140 kD protein found in the alpha-granules of platelets and the Weibel-Palade bodies of endothelial cells. On cell activation it is expressed on the cell surface and also secreted into plasma. Whether the circulating soluble P-selectin (sP-selectin) originates from platelets, endothelial cells, or both, is not known. We studied the level of sP-selectin in diseases with different platelet counts, with or without evidence of endothelial cell activation. Endothelial cell activation was confirmed by the detection of sE-selectin and ED1-fibronectin. A significant positive correlation between platelet count and sP-selectin concentration was observed in healthy controls, and in patients with thrombocytopenia due to bone marrow aplasia, or with thrombocytosis (r = 0.85; n = 47; p < 0.001). In patients with idiopathic thrombocytopenic purpura (ITP) the sP-selectin concentration was 110 +/- 39 ng/ml (n = 10), compared to 122 +/- 38 ng/ml in healthy controls (n = 26). However, their mean platelet count was lower (58 x 10(9)/l versus 241 x 10(9)/l in the control group). Accordingly, the levels of sP-selectin expressed per platelet increased to significantly higher levels (2.0 +/- 1.2 versus 0.6 +/- 0.2 fg/platelet in the control group; p < 0.0001). This suggests increased platelet turnover in patients with ITP. High levels of sP-selectin were found in patients with sepsis (398 +/- 203 ng/ml; n = 15) and with thrombotic thrombocytopenic purpura (TTP; 436 +/- 162 ng/ml; n = 12). Compared with patients with ITP, the concentration of sP-selectin per platelet was higher in patients with sepsis (4.8 +/- 4.3 fg/platelet; p < 0.005) or TTP (17.1 +/- 9.5 fg/platelet; p < 0.001). Endothelial cells are very likely to be the source in these patients and the presence of endothelial cell activation was confirmed by increased levels of circulating E-selectin and ED1-fibronectin. This study suggests that platelets are the major source of circulating sP-selectin in healthy individuals. Endothelial cell activation is associated with an increased sP-selectin concentration per platelet.
Adult↗
Factor V Leiden, antiphospholipid antibodies and thrombosis in systemic lupus erythematosus.
Thromboembolic complications are frequently observed in patients with systemic lupus erythematosus (SLE). Significant associations have been reported between these complications and the presence of antiphospholipid antibodies, notably the lupus anticoagulant and anticardiolipin antibodies. Factor V Leiden is a genetic disorder associated with an increased risk of venous thrombosis. We studied these factors in 173 patients with SLE in relation to both arterial and venous thrombosis. The frequency of factor V Leiden in SLE patients in comparable to that in the Dutch population (5%) and a risk factor for venous thrombosis (odds ratio 4.9; CI 1.2-19.6), but not for arterial thrombosis. The lupus anticoagulant is a risk factor for both arterial thrombosis (odds ratio 7.1: CI 2.9-17.4) and venous thrombosis (odds ratio 6.4; CI 2.7-15.4). From multivariate analysis, both the lupus anticoagulant and factor V Leiden appeared independent risk factors for venous thrombosis.
Adolescent↗
Soluble P-selectin as parameter for platelet activation during storage.
Platelet concentrates stored at room temperature deteriorate. The so-called storage lesion is characterised by morphological changes and a loss of functionality. To find an assay for early platelet activation in platelet concentrates the morphological score, beta-TG release and P-selectin expression were determined, and compared with the amount of soluble P-selectin. An ELISA was used to quantify soluble P-selectin in the storage medium. We found a significant correlation between the amount of soluble P-selectin and the percentage of P-selectin positive platelets (flow-cytometric analysis) (r = 0.7449; p < 0.0001) or the amount of beta-TG release (r = 0.6837; p < 0.0001). The morphological score also correlated significantly (negative) with the amount of soluble P-selectin (r = -0.7669; p = 0.0002). From day 0 till day 8, the amount of soluble P-selectin increased constantly from 219 +/- 49.2 ng/ml to 556 +/- 102.3 ng/ml. The detection of soluble P-selectin can be used to quantify activation of platelets during storage. The immuno-assay for soluble P-selectin is more sensitive than flow-cytometric analysis of the percentage of P-selectin-positive cells and allows earlier detection of platelet activation.
Biomarkers↗
[Psychiatric drugs as risk factor in fatal heat stroke].
Two men aged 33 and 31 years suffered a fatal heat stroke on a warm summer day. One of them used pimozide and clomipramine, the other zuclopenthixol, dexetimide, droperidol, promethazine and propranolol as psychiatric medication. Both of them had a body temperature > 42.3 degrees C, without perspiring. At first only a comatose situation with practically normal laboratory values existed; this was rapidly followed by massive liver damage, disseminated intravascular coagulation, anaemia, thrombopenia and acute renal failure. In spite of adequate and rapid treatment these complications were fatal. Both patients used medication with an antidopaminergic and anticholinergic (side) effect. The set point of the temperature regulation centre can be elevated by the antidopaminergic activity of antipsychotics. Use of anticholinergic medication can disturb the thermoregulation via inhibition of the parasympathicomimetically mediated sweat secretion. It is recommended to point out the danger of unusually high outdoor temperatures to patients using this medication.
Adult↗
An erythropoietin-producing endometrium carcinoma.
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Adenocarcinoma↗
Stored platelets release nucleotides as inhibitors of platelet function.
It is well known that the function of platelets decreases progressively during storage of platelet concentrates at room temperature. To investigate this phenomenon in more detail, we have resuspended platelets that had been stored for 24 h or 72 h in fresh plasma, and we have measured the aggregation response and the ATP secretion. Conversely, the effect of plasma in which platelet concentrates (PC) had been stored for 24 h or 72 h, was tested on fresh platelets. Both the aggregation response to collagen and ADP and the collagen-induced ATP secretion of stored platelets partially recovered after incubation with fresh plasma (p < 0.05). The same parameters measured with fresh platelets incubated in stored PC-plasma were found to be significantly reduced in comparison with the response of fresh platelets in fresh plasma (p < 0.05). Finally, platelets were stored in a plasma-free medium, suitable for platelet storage and the supernatant was tested. This supernatant inhibited the function of fresh platelets in a storage time-dependent fashion. Boiling of these supernatants did not change the inhibiting capacities, whereas filtration over active charcoal did. Analysis of this supernatant revealed AMP and diadenosine tetraphosphate, which both inhibit platelet function. These data show that stored platelets release nucleotides that inhibit platelet function in a reversible manner. This phenomenon may contribute to the decrease of platelet function during storage and the recovery of platelet function after transfusion.
Adenosine Diphosphate↗
Loss of thrombin-induced Ca2+ mobilization in a subpopulation of platelets during storage.
Thrombin-induced changes in cytosolic free Ca2+ ([Ca2+]i) were studied in human platelets that had been stored for up to 6 days. Changes in [Ca2+]i were measured with Indo-1-loaded platelets and quantitated with two different methods: (i) measurement of the changes in total fluorescence; (ii) measurement of the [Ca2+]i changes in individual platelets in a flow cytometer, allowing the detection of non-responding platelets. The maximal concentration of [Ca2+]i after stimulation with 0.5 U of thrombin/ml decreased from 544 +/- 58 nM (mean +/- SEM, n = 6) on day 0, to 276 +/- 9 nM on day 3 and to 203 +/- 23 nM on day 6. The percentage of platelets responding to 0.5 U of thrombin/ml declined from 90 +/- 2% on day 0 to 72 +/- 4% on day 3, and to 47 +/- 8% on day 6. Nevertheless, also the responding platelets showed a decreased rise in [Ca2+]i. The study shows that during platelet storage a decrease in the rise in [Ca2+]i upon thrombin stimulation occurs. This decrease is partly due to the formation of a subpopulation of platelets that is completely unresponsive and partly due to a decreased responsiveness in the remainder of the platelets; it is not due to a gradual decline in [Ca2+]i rise in all platelets. This phenomenon provides new insight in the functional defect of stored platelets.
Blood Platelets↗
In vitro evaluation of buffy-coat-derived platelet concentrates stored in a synthetic medium.
Human blood platelets, prepared by the buffy-coat method, were prepared and stored in different synthetic media. In a synthetic medium based on gluconate, acetate and citrate (GAC), the pH was 6.8 on day 6. This medium was chosen for further evaluation. The total platelet count and the leukocyte contamination were significantly lower in the platelet concentrates (PCs) prepared in GAC compared to PCs prepared in plasma. Platelets stored in plasma or in GAC were equally functional when tested for aggregation and adenosine triphosphate (ATP) secretion. Only stimuli that act through the arachidonic-acid pathway induced a lower platelet response in GAC. Platelet morphology was quantified by measuring the difference in light transmission during stirring at different rates in an aggregometer; no significant differences for platelets stored in GAC as compared to plasma were observed. Activation of platelets was measured by binding of monoclonal antibodies (McAb) against the Gp IIb/IIIa complex and against activation-dependent antigens (GMP 140 from the alpha-granules and a 53-kD glycoprotein from the lysosomal granules). There was no difference in binding of these McAb between platelets prepared and stored in plasma or GAC. We conclude that platelets prepared by the buffy-coat method and stored in GAC have the same in vitro qualities as platelets stored in plasma, except for the lower aggregation response by the arachidonic-acid pathway. This is probably due to an acetate-induced decrease in intracellular pH.
Adenosine Triphosphate↗
Beneficial effect of pre-transfusion warming of platelets prepared from buffy coats.
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Adult↗
Depletion of dense granule nucleotides during storage of human platelets.
The energy metabolism of human platelets was studied during storage of platelet concentrates. The platelets were prepared from buffy coats in PVC/DEHP bags and stored for 7 days at room temperature at a concentration of 1.0 x 10(9)/ml with horizontal agitation. The total amount of ATP and ADP decreased with 40% during this storage. This decrease correlated with the disc-to-sphere transformation associated with the loss of platelet viability. During storage, the ability to incorporate 3H-adenosine into metabolic ATP and ADP (45 min at 37 degrees C) decreased with 50%. Via measurement of the specific activity of actin-bound ADP and the amount of incorporated radioactivity into total ATP and ADP, we calculated the content of the metabolic and storage pools of ATP and ADP. The results indicate that the decrease in adenine nucleotide levels during storage was mainly caused by a depletion of ATP and ADP from the storage pool, whereas the metabolic pool remained nearly intact. After 7 days, the ATP:ADP ratio of the storage pool had decreased from 1.0 to 0.3, indicating hydrolysis of ATP. Diadenosine-triphosphate and diadenosine-tetraphosphate (present in the storage pool) decreased with only 30%, and the serotonin content remained nearly constant. Therefore, it is unlikely that the storage pool was completely secreted. Probably, the storage pool of nucleotides serves as an internal supply for maintaining the contents of the metabolic pool of ATP and ADP during storage of platelets.
Adenine Nucleotides↗
Detection of platelet activation with monoclonal antibodies and flow cytometry. Changes during platelet storage.
To investigate whether changes in platelet condition during platelet storage correlate with an altered expression of platelet membrane proteins, the binding of monoclonal antibodies (MoAbs) to fresh platelets was compared with MoAbs' binding to thrombin-activated platelets and to platelets stored as platelet concentrates. The MoAbs included antibodies against the platelet glycoprotein (GP) IIb/IIIa complex and against two activation-dependent antigens, one of which was a component of the internal platelet alpha-granule membrane (GMP 140) and the other of which was a 53-kD protein derived from platelet lysosomes. The binding of MoAbs to platelets fixed with 1 percent paraformaldehyde was measured by flow cytometry. In thrombin-activated platelets, a threefold increase was found in the expression of GP IIb/IIIa over that in fresh platelets. The binding of the activation-dependent MoAbs increased from 2 to 3 percent to 70 to 80 percent of the platelets. Storage of platelet concentrates for 5 days resulted in a 60 percent increase in GP IIb/IIIa expression compared to Day 0 and increased binding of the MoAbs directed against GMP-140 from 3 to 16 percent and against the 53-kD protein from 2 to 8 percent of the platelets, respectively. These changes correlated with modifications in platelet morphology (decrease in swirling), leakage of lactate dehydrogenase, and release of beta-thromboglobulin. These data indicate that platelets become activated and are damaged during the storage of platelet concentrates.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies, Monoclonal↗