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PubMed1996

Transcriptional repression of specific host genes by the mycovirus Cryphonectria hypovirus 1.

The hypovirus CHV1, which infects the plant-pathogenic fungus Cryphonectria parasitica, causes a distinct range of symptoms in its host that include reduced virulence expression, reduced sporulation, and reduced pigmentation. The virus, however, has little or no effect on fungal growth in culture. The visual symptoms are associated with reduced accumulation of a small number of host mRNAs and proteins. Four of the host genes encoding these down-regulated mRNAs have been characterized; they include two genes encoding a fungal sex pheromone (Vir1 and Vir2), a gene encoding an extracellular laccase (Lac1), and a gene encoding a cell wall hydrophobin (Crp). Expression of most other host proteins appears to be unaffected by the virus. These four genes can serve as reporter genes in studies of the effect of the virus on host gene expression. It is hypothesized that the four genes are coordinately down-regulated by the virus and probably are associated in a regulatory cascade. This hypothesis was tested by measuring the relative transcription rate of each gene in virus-infected and uninfected isogenic strains of the fungus by using nuclear run-on assays. The effects of the virus on transcription of these genes generally mirrored the observed effects of the virus on relative accumulation of the mRNAs of each gene. Although repressed transcription cannot account for all of the effects of the virus on mRNA accumulation of these four reporter genes, it is the predominant effect.

Amanitins↗
PubMed1992

The role of natural IgM in the hyperacute rejection of discordant heart xenografts.

The mechanism of xenograft hyperacute rejection in discordant species combinations remains controversial. The purpose of this work was to study the role of natural antibodies in the hyperacute rejection of guinea pig hearts transplanted into rats, a highly discordant combination. This study was conducted in vitro, ex vivo, and in vivo. The endothelial cells of the graft being the first targets damaged in the process of hyperacute rejection, the binding of rat natural antibodies to guinea pig endothelial cells was studied by immunofluorescence. The study was carried out in vitro on guinea pig endothelial cells in culture, and ex vivo on isolated guinea pig hearts perfused with either rat serum or immunoglobulins or immunoglobulin fragments bearing the antigen-binding site. In vitro and ex vivo, rat natural IgM were found to bind specifically to guinea pig endothelial cells, since IgM fragments bearing the antigen-binding site (Fab mu and Fab' mu) could be detected on these cells. IgM fragments were able to inhibit the fixation of native IgM molecules. In contrast, rat IgG only bound to endothelial cells through Fc portions. Thus rat natural IgM might play a role in hyperacute rejection by binding to the graft endothelial cells and triggering the complement cascade activation. In order to test the role of natural IgM in vivo, isolated guinea pig hearts were first perfused with rat Fab' mu, which inhibit the binding of IgM and are unable to activate the complement cascade. These hearts were then transplanted into Lewis rats. The rejection time of Fab' mu-perfused guinea pig hearts was prolonged compared with hearts perfused with buffer or IgG F(ab')2. Therefore, in the guinea pig to rat combination, preventing the binding of the recipient's natural IgM to the graft endothelium delays the hyperacute rejection. In addition, natural IgM are likely to play a greater role than natural IgG.

Animals↗
PubMed1998

Transit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics.

Delayed effects for pharmacodynamic responses can be observed for many signal transduction processes. Three approaches are summarized in this report to describe such effects caused by cascading steps: stochastic process model, gamma distribution function, and transit compartment model. The gamma distribution function, a probability density function of the waiting time for the final step in a stochastic process model, is a function of time with two variables: number of compartments N, and the expected number of compartments occurring per unit time k. The parameter k is equal to 1/tau, where tau is the mean transit time in the stochastic process model. Effects of N and k on the gamma distribution function were examined. The transit compartment model can link the pharmacokinetic profile of the tested compound, receptor occupancy, and cascade steps for the signal transduction process. Time delays are described by numbers of steps, the mean transit time tau, and the amplification or suppression of the process as characterized by a power coefficient gamma. The effects of N, tau, and gamma on signal transduction profiles are shown. The gamma distribution function can be utilized to estimate N and k values when the final response profile is available, but it is less flexible than transit compartments when dose-response relationships, receptor dynamics, and efficiency of the transduction process are of concern. The transit compartment model is useful in pharmacokinetic/pharmacodynamic modeling to describe precursor/product relationships in signal transduction process.

Animals↗
PubMed1998

Comparison of beta-protein/A4 deposits and Alz-50-stained cytoskeletal changes in the hypothalamus and adjoining areas of Alzheimer's disease patients: amorphic plaques and cytoskeletal changes occur independently.

Alzheimer's disease is characterized neuropathologically by senile plaques and cytoskeletal changes. It has been proposed that amorphic plaques would locally induce anterograde propagation of cytoskeletal changes in consecutive neurons followed by amorphic plaque deposition at their axonal terminals. The Alzheimer changes would spread in this way along neural pathways. To test the 'primary amyloid anatomical cascade hypothesis', Congo red staining, beta-protein/A4 (Abeta) antiserum and Alz-50, which recognizes cytoskeletal changes, were applied to the hypothalamus and adjoining brain areas of five Alzheimer's disease patients of 40-90 years of age and five age- and sex-matched controls. The results showed that (1) virtually all Abeta plaques in the hypothalamus were of the Congo red-negative amorphic type; (2) amorphic plaques and Alz-50-stained cytokeletal changes were observed not only in all Alzheimer's disease patients but also in a non-demented, 90-year-old control subject; (3) the density of amorphic plaques in the hypothalamus was unrelated to the duration of the dementia; (4) the density of amorphic plaques was unrelated to that of Alz-50-stained cytoskeletal changes; (5) double-labeling with anti-Abeta and Alz-50 did not show an evident topical relationship between amorphic plaque deposition and the occurrence of cytoskeletal changes; and (6) the distribution of Abeta and Alz-50 staining in five brain areas, for which essential anatomical information is available, did not support the primary amyloid anatomical cascade hypothesis. Amorphic plaques and cytoskeletal changes rather occur independently.

Adult↗
PubMed1988

Evidence for extracellular, but not intracellular, generation of angiotensin II in the rat adrenal zona glomerulosa.

Based on the observation that high levels of renin and angiotensin II (Ang II) are found in the adrenal zona glomerulosa (ZG), it has been postulated that Ang II is formed intracellularly by the renin-converting enzyme cascade in this tissue. To test this hypothesis, we examined renin-angiotensin system components in subcellular fractions of the rat adrenal ZG. Renin activity and immunoreactive-Ang II (IR-Ang II) were observed in vesicular fractions but were not colocalized. In addition, angiotensinogen, angiotensin I, and converting enzyme were not observed in the renin or IR-Ang II-containing vesicular fractions. These data do not support the hypothesis that Ang II is formed intracellularly within the renin-containing vesicles of the ZG. Rather, since modulatable renin release from adrenal ZG slices was observed and renin activity was found in dense vesicular fractions (33-39% sucrose), it is likely that Ang II formation in the ZG is extracellular and initiated by the release of vesicular renin. Receptor-mediated endocytosis and subsequent degradation of Ang II in ZG lysosomes have been shown by others. The presence of IR-Ang II in light vesicular fractions (15% sucrose) and the finding of a high correlation between ZG IR-Ang II and Ang II receptor levels suggest that the primary occurrence of this peptide in the ZG is by receptor-mediated endocytosis. In ZG lysosomal fractions 125I-labeled Ang II was degraded to 125I-labeled des-[Phe8]Ang II. Since Ang II antibodies do not recognize des-[Phe8]Ang II, these findings explain why IR-Ang II in the ZG is due predominantly to Ang II and not to its C-terminal immunoreactive fragments.

Adrenal Cortex↗
PubMed1996

Characteristics of clodronate-induced apoptosis in osteoclasts and macrophages.

Bisphosphonates (BPs), such as clodronate and pamidronate, are inhibitors of bone resorption and are used on a widespread basis in the treatment of hyper-resorptive bone diseases. At the cellular level, BPs inhibit osteoclasts, but the precise molecular mechanisms are unclear. BPs have also been shown to affect the survival of macrophages, cells ontogenetically related to osteoclasts. We show that both clodronate and pamidronate induce apoptosis in isolated osteoclasts. Clodronate, when administered in liposomes, also induced apoptosis in rat peritoneal macrophages in vitro and in liver macrophages of mice in vivo but not in murine macrophage-like RAW-264 cells. The subcellular localization and staining intensity of Bcl-2, an anti-apoptotic protein known to protect several cell types against drug-induced apoptosis, were similar in RAW-264 and peritoneal macrophage cells, as revealed by immunofluorescence. The clodronate-induced apoptotic pathway was further characterized in isolated osteoclasts cultured on glass coverslips through the use of clodronate-containing liposomes and several inhibitors of the apoptotic cascade. None of the agents tested could totally prevent clodronate-induced osteoclast death. Partial protection was, however, obtained by the addition of staurosporine or homocysteine. The results suggest that primarily cytoplasmic, protein kinase C-activated mechanisms are involved in the execution of clodronate-induced apoptosis of osteoclasts.

Acid Phosphatase↗
PubMed1990

Common biochemical pathway of dysmorphogenesis in murine embryos: use of the glucocorticoid pathway by phenytoin.

Phenytoin (5,5-diphenylhydantoin), a common anticonvulsant drug, is known to produce anomalies in the craniofacial region of animals and humans. Furthermore, recent evidence suggests that phenytoin disrupts craniofacial and neural tube morphogenesis by inhibiting the arachidonic acid cascade, a pathogenesis already implicated for glucocorticoids and hyperglycemia in the palate. This study tested the hypothesis that phenytoin interferes with the arachidonic acid cascade via the same biochemical pathway demonstrated for glucocorticoids. The proposed pathway was tested at two levels. First, indomethacin, an inhibitor of the enzyme cyclooxygenase, was used in culture to block the correction of phenytoin-induced defects by arachidonic acid. Second, cortexolone, an anti-glucocorticoid that binds at the glucocorticoid receptor binding site, was tested for its ability to prevent phenytoin-induced teratogenicity. Eighty-four percent of the embryos cultured in phenytoin and 93% of those cultured in phenytoin plus arachidonic acid and indomethacin had neural tube and/or craniofacial deformities. In contrast, only 14% of the embryos cultured in phenytoin plus cortexolone were affected. Indomethacin itself produced anomalies in 83% of the exposed embryos. These data are consistent with the hypothesis that the teratogenic action of phenytoin in murine embryo cultures occurs via the glucocorticoid anti-inflammatory pathway. Thus, the glucocorticoid receptor appears to be responsible for mediating phenytoin-induced teratogenicity.

Animals↗
PubMed1993

Experimental evidence for 60 Hz magnetic fields operating through the signal transduction cascade. Effects on calcium influx and c-MYC mRNA induction.

We tested the hypothesis that early alterations in calcium influx induced by an imposed 60 Hz magnetic field are propagated down the signal transduction (ST) cascade to alter c-MYC mRNa induction. To test this we measured both ST parameters in the same cells following 60 Hz magnetic field exposures in a specialized annular ring device (220 G (22 mT), 1.7 mV/cm maximal E(induced), 37 degrees C, 60 min). Ca2+ influx is a very early ST marker that precedes the specific induction of mRNA transcripts for the proto-oncogene c-MYC, an immediate early response gene. In three experiments influx of 45Ca2+ in the absence of mitogen was similar to that in cells treated with suboptimal levels of Con-A (1 micrograms/ml). However, calcium influx was elevated 1.5-fold when lymphocytes were exposed to Con-A plus magnetic fields; this co-stimulatory effect is consistent with previous reports from our laboratory [FEBS Lett. 301 (1992) 53-59; FEBS Lett. 271 (1990) 157-160; Ann. N.Y. Acad. Sci. 649 (1992) 74-95]. The level of c-MYC mRNA transcript copies in non-activated cells and in suboptimally-activated cells was also similar, which is consistent with the above calcium influx findings. Significantly, lymphocytes exposed to the combination of magnetic fields plus suboptimal Con-A responded with an approximate 3.0-fold increase in band intensity of c-MYC mRNA transcripts. Importantly, transcripts for the housekeeping gene GAPDH were not influenced by mitogen or magnetic fields. We also observed that lymphocytes that failed to exhibit increased calcium influx in response to magnetic fields plus Con-A, also failed to exhibit an increase in total copies of c-MYC mRNA. Thus, calcium influx and c-MYC mRNA expression, which are sequentially linked via the signal transduction cascade in contrast to GAPDH, were both increased by magnetic fields. These findings support the above ST hypothesis and provide experimental evidence for a general biological framework for understanding magnetic field interactions with the cell through signal transduction. In addition, these findings indicate that magnetic fields can act as a co-stimulus at suboptimal levels of mitogen; pronounced physiological changes in lymphocytes such as calcium influx and c-MYC mRNA induction were not triggered by a weak mitogenic signal unless accompanied by a magnetic field. Magnetic fields, thus, have the ability to potentiate or amplify cell signaling.

Animals↗
PubMed1994

Preservation of humidity and heat of respiratory gases in patients with a minute ventilation greater than 10 L/min.

OBJECTIVE: To compare the temperature and humidification output of one heated humidifier system (Bennett Cascade 2 Humidifier) and two heat and moisture exchangers (Pall Ultipor, BB 50, and Humid-Vent Filter) in intensive care unit (ICU) patients submitted to a minute ventilation of > 10 L/min. DESIGN: Prospective, controlled, randomized, unblinded study. SETTING: ICU of a university hospital. PATIENTS: Eleven sedated and paralyzed patients who required controlled mechanical ventilation with a minute ventilation of > 10 L/min for > 3 days. INTERVENTIONS: After a randomized selection process, the patients were ventilated for 24-hr periods with the humidifier and one of the heat and moisture exchangers. Both heat and moisture exchangers were first tested for 45 mins; then, the heat and moisture exchanger that demonstrated the best performance in terms of temperature and water preservation was tested for 24 hrs. MEASUREMENTS AND MAIN RESULTS: During the inspiration phase for each patient, the following measurements were performed: mean and minimum values of temperature, relative and absolute humidity of inspired gases. During the 45-min test period, the Humid-Vent Filter had a better temperature and humidification output than the Pall Ultipor Filter and thus was tested for 24 hrs. The Bennett Cascade 2 Humidifier and the Humid-Vent Filter had a better thermic capacity than the Pall Ultipor Filter (p < .001). No difference was ever observed between the Bennett Cascade 2 Humidifier and the Humid-Vent Filter regarding relative humidity. The Pall Ultipor Filter had a lower temperature and humidification output when compared with the other two systems (p < .007). Concerning absolute humidity of inspired gases, the Pall Ultipor Filter achieved a lower performance than any other tested systems (p < .02). A small but significant decrease in temperature and absolute humidity, but not in relative humidity, was seen after 24 hrs of use with the Humid-Vent Filter. However, with this heat and moisture exchanger, all patients had an absolute humidity of > 28 mg H2O/L and a relative humidity of > 93% after 24 hrs of use. CONCLUSIONS: In patients with a minute ventilation of > 10 L/min (> 10.5 to 16.0 L/min), the Humid-Vent Filter had a temperature and humidification output close to the reference system (the Bennett Cascade 2 Humidifier). The Pall Ultipor Filter had a significantly lower temperature and humidification output in these patients.

Acute Disease↗
PubMed1998

Structure-function analysis of Lymantria testis ecdysiotropin: a search for the active core.

A structure-function study was performed on the synthetic 21 residue neuropeptide, Lymantria testis ecdysiotropin (LTE), originally isolated from brains of Lymantria dispar pupae. The peptide induces ecdysteroid synthesis by testis sheaths of various lepidopteran species. LTE, as well as synthetic LTE 1-11, 11-21, and 11-15, stimulated synthesis in larval and pupal testes of Lymantria dispar at concentrations of 10(-9) to 10(-15) M; LTE 16-21 was weakly active, and an elongated LEU-LTE was inhibitory to synthesis at all but extremely low concentrations (10(-15) M). Since the sequence and polarity of residues in LTE 1-11, 11-15, and 11-21 are quite different, several parts of the molecule must activate receptors which initiate the cascade, resulting in ecdysiogenesis in Lepidopteran testes.

Amino Acid Sequence↗
PubMed1987

The effect of modulating the synthesis of arachidonic acid cascade products on HSV lesion recurrence.

Induction of HSV lesion recurrence may be achieved by a variety of stimuli. Trauma of almost any kind (physical, chemical, electromagnetic and thermal) to the healed primary lesion site has been successful for induction of recurrence. In common with each of these mechanisms is the release of inflammatory mediators (arachidonic acid (AA), complement, kinins, etc.) following trauma. Because blockade of the AA cascade with steroids has been noted to abort HSV skin lesions, and because steroids have numerous side effects making them a poor therapeutic choice in ocular lesions, we decided to test several relatively different types of AA cascade inhibitory drugs in mouse ear HSV recurrence models. In this series of experiments, it was found that topical steroids gave the greatest initial decrease in lesion number (80% fewer than control on day 3 post recurrence induction (PRI), while meclofenamate resulted in the greatest reduction of lesions by day 5 PRI (85% fewer lesions than control and 60% fewer than the steroid treated group). The NDGA treated group exhibited the least reduction in recurrence severity (27% fewer lesions than control on day 5 PRI and 200% more lesions than the steroid group. Chlorpromazine (thorazine) acted roughly equivalent to the steroid treated group by day 5 PRI (70% fewer lesions than the untreated control group). Relative efficacy in lesion reduction between groups by day 5 PRI is: meclofenamate greater than steroid = chlorpromazine greater than NDGA greater than control. Meclofenamate, steroid and chlorpromazine significantly reduced lesions (p less than .05) when compared with the saline treated control mice. NDGA did not significantly reduce lesions by day 5 PRI.

Animals↗
PubMed1996

Plasminogen modulation of IL-1-stimulated degradation in bovine and human articular cartilage explants. The role of the endogenous inhibitors: PAI-1, alpha 2-antiplasmin, alpha 1-PI, alpha 2-macroglobulin and TIMP.

The studies described here examine the involvement of the fibrinolytic cascade and its endogenous inhibitors in the regulation of activity of matrix metalloproteinases and cartilage degradation related to non-inflammatory joint disease, like osteoarthritis. An interleukin-1-induced model of degradation using [35S]-labeled bovine and human articular cartilage explants was utilized. One goal of these studies was to compare the responses of bovine and human articular cartilage. Degradation was not inhibited by alpha 1-PI, PAI-1, alpha 2-macroglobulin, alpha 2-antiplasmin or TIMP-2, when IL-1 alone was added. Addition of human plasminogen to bovine explants, at concentrations found in human synovial fluid, increased degradation by three to four-fold. Under these conditions, the degradation was inhibited effectively by all of the endogenous inhibitors tested, indicating the presence of a cascade where activated chondrocytes are a source of u-PA. Plasminogen activated by u-PA gives plasmin, which is known to further activate pro-stromelysin. Stromelysin is essential for activation of collegenase. Not only TIMP, but also inhibitors at earlier steps of activation like PAI-1, alpha 2-antiplasmin, alpha 1-PI and alpha 2-macroglobulin inhibited degradation, and could provide cartilage protection in vivo. An experiment with human articular cartilage explants showed that very little or no degradation occurred when human articular cartilage explants were stimulated with interleukin-1 alone. Addition of human plasminogen (at physiologically relevant concentrations) resulted in significant degradation, which was inhibited in the same manner as in bovine explants, by inhibitors of the fibrinolytic cascade and TIMP. TIMP is much more efficient in human explants, indicating the limited participation of human plasmin in the degradation of human cartilage. Although speculative, it is possible that in vivo, cartilage degradation could be promoted not only by TIMP/MMP imbalance, but also accelerated by decreased levels of certain serpins in synovial fluid (e.g. PAIs, alpha 2-antiplasmin and alpha 1-PI).

Animals↗
PubMed1990

Glucocorticoid endangerment of hippocampal neurons is NMDA-receptor dependent.

The adrenal stress hormones glucocorticoids (GCs) impair the ability of hippocampal neurons to survive neurological insults, including hypoxia-ischemia and seizure. These insults are thought to be toxic via a cascade of excessive synaptic concentrations of excitatory neurotransmitters (e.g. glutamate), activation of the NMDA receptor, and pathologic mobilization of cytosolic calcium post-synaptically. We tested whether GCs exacerbate these insults by exacerbating this 'NMDA cascade'. We sought a toxin which damaged independently of the NMDA cascade, and whose toxicity was enhanced by GCs. After testing a number of neurotoxins, we found that the antimetabolite 3-acetylpyridine (3AP) fit this requirement. We then tested if blockade of the NMDA receptor blocks the ability of GCs to enhance 3AP toxicity. Hippocampi were microinfused with 160 micrograms of 3AP. Elevating circulating GC concentrations to the range seen during major stressors for a week before and after microinfusion caused a significant increase in 3AP-induced damage (when compared to adrenalectomized rats kept GC-free for the same period). Infusing the NMDA receptor blocker APV with 3AP did not alter the toxicity in adrenalectomized rats. However, APV reduced 3AP-induced damage in GC-treated rats to levels seen in adrenalectomized rats. This suggests that GCs endanger hippocampal neurons by enhancing glutamatergic signals and/or enhancing vulnerability to such signals. As a possible explanation for this observation, GCs inhibit glucose uptake into hippocampal neurons, and numerous steps in the NMDA cascade are exacerbated when neuronal energy stores are diminished.

Adrenal Glands↗
PubMed1998

Cooperating morphogens control hoxd gene expression in the developing vertebrate limb.

A mechanism was recently proposed which controls the expression of Hoxa genes in the developing vertebrate limb. This is a three-dimensional diffusion model of a morphogen Ma secreted at the apical ectodermal ridge. The morphogen Ma is at the same time degraded by first order chemical kinetics. The emerging diffusion gradient, supplemented with a natural sequence of thresholds, can explain the spatial and temporal collinearities of the Hoxa gene expression domains. In the present model it is assumed that a second diffusing morphogen Mz is produced at the zone of polarizing activity. A concentration superposition of morphogens Ma and Mz can then explain the observed pattern of expression of Hoxd-10, 11, 12, and 13 during normal limb development (spatial and temporal collinearity). The associated thresholds for gene expression increase sequentially from Hoxd-10 to Hoxd-13 (threshold collinearity). The observed deformations or deletions of these expression domains in manipulated limbs are also explained by the model. Additional model predictions are proposed to test the validity of the model. In patterning two mechanisms are mainly considered as responsible for signalling: (i) a gradient of a long-range morphogen created by passive diffusion; and (ii) a short-range inducer initiating a cascade of consecutive signals. A time-test is proposed which distinguishes the modes of specific gene expressions for these distinct signalling mechanisms.

Animals↗
PubMed1995

Antiinflammatory mechanism of cordiachromene A action.

The mechanism of antiinflammatory action of cordiachromene A, isolated from the chloromethylenic extract of the ascidian Aplidium antillense or chemically synthesized, was studied using different in vivo and in vitro inhibition tests on enzymes of the cyclooxygenase cascade. Cordiachromene A inhibits prostacyclin synthesis and arachidonic acid metabolism but not phospholipase A2 and peroxidase. The mechanism of action, already known to be stereospecific, operates by cyclooxygenase inhibition.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Anticoagulant effects of protamine sulfate in a canine model.

Protamine sulfate is considered a weak anticoagulant, yet little is known concerning the mechanism of this effect or its relation to prior heparin exposure. This investigation defined the influence of increasing doses of protamine, with and without prior heparin anticoagulation, on the activated clotting time (ACT), thrombin clotting time (TCT), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen level, platelet count, and platelet aggregation to ADP in dogs (n = 8). Four doses of intravenous protamine sulfate (1.5, 3.0, 6.0, and 15.0 mg/kg) were studied in each animal, with at least 5 days between individual studies. Four dogs received heparin, 150 IU/kg 10 min prior to protamine sulfate administration, and four dogs received protamine sulfate alone. Protamine sulfate caused anticoagulation, both in the presence and absence of heparin, with significant changes occurring in the ACT, PTT, platelet count, and platelet aggregation. Relevant changes did not occur in the TCT, PT, or fibrinogen levels. Platelet effects were capable of causing bleeding with standard or excess use of protamine sulfate, especially if platelet numbers were already decreased, as might occur in surgical procedures where thrombocytopenia commonly accompanies major blood loss and replacement. The ACT, reflecting both the coagulation cascade and platelet function, was the test most profoundly affected by protamine overdosage, and therefore may be misleading as a measure of protamine reversal of heparin. The TCT, which is sensitive to heparin anticoagulation but not protamine-induced anticoagulation, should be more accurate in differentiating inadequate heparin reversal from the effects of excess protamine.

Animals↗
PubMed1994

Quality of plasma for fractionation--does it matter?

Many plasmapheresis techniques cause greater activation of platelets, complement and coagulation than does simple whole blood collection. Activation of the coagulation cascade has been particularly evident in tests for potential thrombogenicity in prothrombin complex concentrates made from apheresed plasma. Attempts to improve the factor VIII content and fractionation yield of source plasma have centred on rapid freezing, increased concentration of anticoagulants and the exploitation of anticoagulants optimal for the preservation of coagulant, rather than cellular, activities. The cumulative advantage is of the order of 10% over recovered plasma. There are potential pitfalls in applying low-citrate anticoagulation strategies to plasmapheresis. Recalcification of citrated plasma, under cover of an optimal concentration of heparin, might be explored more vigorously.

Chemical Fractionation↗