scholarly journals Large, chronic doses of erythropoietin cause thrombocytopenia in mice [see comments]

Blood ◽  
1992 ◽  
Vol 80 (2) ◽  
pp. 352-358 ◽  
Author(s):  
TP McDonald ◽  
RE Clift ◽  
MB Cottrell
Keyword(s):  
Production Rates ◽  
Short Term ◽  
Cell Competition ◽  
Mean Cell Volume ◽  
Platelet Production ◽  
Platelet Counts ◽  
Chronic Doses ◽  
Blood Volumes ◽  
Megakaryocytic Cell

Abstract Both large, acute doses of erythropoietin (EPO) and short-term hypoxia increase platelet counts in mice, but long-term hypoxia causes thrombocytopenia. Therefore, we tested the hypothesis that EPO injected in large, chronic doses (a total of 80 U of EPO over a 7-day period) might cause thrombocytopenia. EPO caused increased red blood cell (RBC) production, ie, increased hematocrits, RBC counts, mean cell volume (MCV), and reticulocyte counts (from P less than .05 to P less than .0005), and decreased thrombocytopoiesis, ie, decreased platelet counts, percent 35S incorporation into platelets, and total circulating platelet counts (TCPC) (P less than .0005). Femoral marrow megakaryocyte size was unchanged, but megakaryocyte number was significantly (P less than .005) reduced in mice treated with EPO. EPO- injected mice had increased spleen volumes (P less than .0005), but blood volumes (BV) were unchanged. In EPO-treated, splenectomized mice, RBC production was also increased (P less than .05 to P less than .0005) and platelet counts, TCPC, and percent 35S incorporation into platelets were decreased (P less than .05), but BV was not altered. Therefore, the decrease in platelet counts observed in EPO-treated mice was not due to increased BV or to an enlarged spleen. In other experiments, mice were rendered acutely thrombocytopenic to increase thrombocytopoiesis, and platelet and RBC production rates were determined. In mice with elevated thrombocytopoiesis, RBC counts, hematocrits, percent 59Fe RBC incorporation values, and MCV were decreased (P less than .05 to P less than .0005). Because 59Fe RBC incorporation and MCV were not elevated, the decrease in RBC counts and hematocrits does not appear to be due to bleeding. Therefore, we show that large, chronic doses of EPO increase erythropoiesis and decrease thrombocytopoiesis. Conversely, acute thrombocytopenia causes increased thrombocytopoiesis and decreased erythropoiesis. These findings support the hypothesis of competition between precursor cells of the erythrocytic and megakaryocytic cell lines (stem-cell competition) as the cause of thrombocytopenia in EPO-treated mice and the cause of anemia in mice whose platelet production rates were increased.

scholarly journals Large, chronic doses of erythropoietin cause thrombocytopenia in mice [see comments]

Blood ◽  
1992 ◽  
Vol 80 (2) ◽  
pp. 352-358 ◽  
Author(s):  
TP McDonald ◽  
RE Clift ◽  
MB Cottrell
Keyword(s):  
Production Rates ◽  
Short Term ◽  
Cell Competition ◽  
Mean Cell Volume ◽  
Platelet Production ◽  
Platelet Counts ◽  
Chronic Doses ◽  
Blood Volumes ◽  
Megakaryocytic Cell

Both large, acute doses of erythropoietin (EPO) and short-term hypoxia increase platelet counts in mice, but long-term hypoxia causes thrombocytopenia. Therefore, we tested the hypothesis that EPO injected in large, chronic doses (a total of 80 U of EPO over a 7-day period) might cause thrombocytopenia. EPO caused increased red blood cell (RBC) production, ie, increased hematocrits, RBC counts, mean cell volume (MCV), and reticulocyte counts (from P less than .05 to P less than .0005), and decreased thrombocytopoiesis, ie, decreased platelet counts, percent 35S incorporation into platelets, and total circulating platelet counts (TCPC) (P less than .0005). Femoral marrow megakaryocyte size was unchanged, but megakaryocyte number was significantly (P less than .005) reduced in mice treated with EPO. EPO- injected mice had increased spleen volumes (P less than .0005), but blood volumes (BV) were unchanged. In EPO-treated, splenectomized mice, RBC production was also increased (P less than .05 to P less than .0005) and platelet counts, TCPC, and percent 35S incorporation into platelets were decreased (P less than .05), but BV was not altered. Therefore, the decrease in platelet counts observed in EPO-treated mice was not due to increased BV or to an enlarged spleen. In other experiments, mice were rendered acutely thrombocytopenic to increase thrombocytopoiesis, and platelet and RBC production rates were determined. In mice with elevated thrombocytopoiesis, RBC counts, hematocrits, percent 59Fe RBC incorporation values, and MCV were decreased (P less than .05 to P less than .0005). Because 59Fe RBC incorporation and MCV were not elevated, the decrease in RBC counts and hematocrits does not appear to be due to bleeding. Therefore, we show that large, chronic doses of EPO increase erythropoiesis and decrease thrombocytopoiesis. Conversely, acute thrombocytopenia causes increased thrombocytopoiesis and decreased erythropoiesis. These findings support the hypothesis of competition between precursor cells of the erythrocytic and megakaryocytic cell lines (stem-cell competition) as the cause of thrombocytopenia in EPO-treated mice and the cause of anemia in mice whose platelet production rates were increased.

Ultrastructural investigations of MDL 19,660-induced effects on the canine platelet and megakaryocyte

1990 ◽  
Vol 48 (3) ◽  
pp. 374-375
Author(s):  
D.E. Loudy ◽  
J. Sprinkle-Cavallo ◽  
J.T. Yarrington ◽  
F.Y. Thompson ◽  
J.P. Gibson
Keyword(s):  
Antidepressant Drug ◽  
Beagle Dogs ◽  
Long Term Effects ◽  
Short Term ◽  
Platelet Counts ◽  
Toxicological Studies ◽  
Induced Aggregation ◽  
Internal Architecture

Previous short term toxicological studies of one to two weeks duration have demonstrated that MDL 19,660 (5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3Hl, 2,4-triazole-3-thione), an antidepressant drug, causes a dose-related thrombocytopenia in dogs. Platelet counts started to decline after two days of dosing with 30 mg/kg/day and continued to decrease to their lowest levels by 5-7 days. The loss in platelets was primarily of the small discoid subpopulation. In vitro studies have also indicated that MDL 19,660: does not spontaneously aggregate canine platelets and has moderate antiaggregating properties by inhibiting ADP-induced aggregation. The objectives of the present investigation of MDL 19,660 were to evaluate ultrastructurally long term effects on platelet internal architecture and changes in subpopulations of platelets and megakaryocytes.Nine male and nine female beagle dogs were divided equally into three groups and were administered orally 0, 15, or 30 mg/kg/day of MDL 19,660 for three months. Compared to a control platelet range of 353,000- 452,000/μl, a doserelated thrombocytopenia reached a maximum severity of an average of 135,000/μl for the 15 mg/kg/day dogs after two weeks and 81,000/μl for the 30 mg/kg/day dogs after one week.

scholarly journals The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3286-3293 ◽  
Author(s):  
Martine Loo ◽  
Yves Beguin
Keyword(s):  
Iron Deficiency ◽  
Recombinant Human Erythropoietin ◽  
Negative Impact ◽  
Cell Competition ◽  
Functional Iron Deficiency ◽  
Platelet Production ◽  
Platelet Counts ◽  
Human Erythropoietin ◽  
Iron Supply ◽  
The Impact

The effect of recombinant human erythropoietin (rHuEpo) on megakaryopoiesis remains controversial. Treatment with rHuEpo in renal failure patients has been associated with a slight elevation of platelet counts. In animal studies, high doses of rHuEpo produced an increase of platelet counts followed by a gradual return to normal after 7 to 15 days or even a substantial degree of thrombocytopenia. However, because iron deficiency is also known to be associated with thrombocytosis, (functional) iron deficiency during rHuEpo could be contributing to these observations. We investigated the impact of iron supply on changes in platelet counts induced by rHuEpo. Rats were either fed normal food (normal rats) or received 1% carbonyl iron for 2 weeks or 3 months, as well as during the experiment, to achieve iron supplementation or overload, respectively. Rats of all three categories then received daily intravenous injections of rHuEpo (10, 50, or 150 U) or normal saline (0 U) for 20 days. With 0 to 10 U rHuEpo, platelets remained stable. In normal rats receiving 50 to 150 U rHuEpo, platelets increased to 120% to 140% of baseline at 4 to 12 days to level off at 120% at 16 to 20 days. This response was less sustained in splenectomized animals. Iron-supplemented rats receiving 50 to 150 U rHuEpo also increased platelets initially, but the peak was at day 4, followed by a gradual return to baseline and even a moderate thrombocytopenia later on. Iron-overloaded rats receiving 50 to 150 U rHuEpo also had increased platelets at day 4, but the duration of platelet increase was shorter, and they experienced a more pronounced degree of thrombocytopenia in proportion to the dose of rHuEpo. Because the early elevation of platelets was of larger magnitude than hematocrit changes, it is unlikely that it could be accounted for by shrinkage of plasma volume. Because it was observed in all three iron conditions, there appears to be some direct positive effect of rHuEpo on platelet production. However, after this transient effect, expanded erythropoiesis appears to exert a negative impact upon platelet production. Secondary thrombocytopenia was not related to splenic pooling, and its very slow correction after cessation of rHuEpo therapy is not compatible with changes in platelet survival. Rather, it is consistent with stem cell competition between erythroid and megakaryocytic development. However, this secondary thrombocytopenia is masked by (functional) iron deficiency in rats not receiving an adequate iron supply from food or stores.

Evaluation of Bleeding and Thrombotic Events during Long-Term Use of Romiplostim in Patients with Chronic Immune Thrombocytopenic Purpura.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3422-3422 ◽  
Author(s):  
Michael Tarantino ◽  
Usha Sunkara ◽  
James George ◽  
Louis M. Aledort ◽  
Matthew Guo ◽  
...  
Keyword(s):  
Phase Iii ◽  
Extension Study ◽  
Bleeding Events ◽  
Thrombocytopenic Purpura ◽  
Platelet Production ◽  
Platelet Counts ◽  
Phase Iii Trials ◽  
Life Threatening ◽  
Grade 3

Abstract Immune thrombocytopenic purpura (ITP) is an autoimmune hematologic disorder of increased platelet destruction and sub-optimal platelet production. Patients (pts) often have low platelet counts (<50 x 109/L) and present with bleeding, purpura, and petechiae; at very low counts, there is a risk of spontaneous intracranial or other life-threatening bleeding. Romiplostim is an investigational thrombopoiesis-stimulating Fc-peptide fusion protein (peptibody) that increases platelet production via binding to and activating the megakaryocyte thrombopoietin receptor. Objective: This study evaluated bleeding and thrombotic events (TEs) occurring in adults with ITP treated with romiplostim during two phase III, randomized, placebo-controlled, 24-week studies, and an open-label extension study. Patients with platelet counts <50 x 109/L were eligible to enter the extension study in which all pts received romiplostim; rates of bleeding events (up to 48 weeks of treatment) and TEs (up to 84 weeks) for these pts were analyzed. Results: In the phase III trials, 84 pts received weekly subcutaneous injections of romiplostim (initial dose 1μg/kg, dose adjusted to maintain platelet counts of 50–200x109/L) and 41 pts received placebo. 115 pts completed the phase III trials, and 101 pts (romiplostim N=68; placebo N=33) entered the extension study. Bleeding events were captured as adverse events (AEs) and graded according to severity. Clinically significant bleeding AEs (i.e. severity grade ≥2 or higher, where 2= moderate, 3=severe, 4=life-threatening, or 5=fatal) were noted in 16% of romiplostim- and 34% of placebo-treated patients (P=0.018). The percentage of pts experiencing bleeding AEs ≥ grade 3 severity was 7% and 12% in the romiplostim and placebo groups, respectively (P=0.36) None of the pts with bleeding events ≥ grade 3 had achieved a durable platelet response (defined by platelet count of ≥50x 109/L during at least 6 of the last 8 weeks of treatment). No bleeding AEs ≥ grade 3 occurred in pts with platelet counts >20 x 109/L while no bleeding AEs of grade ≥2 occurred at counts >50 x 109/L. During the extension study, the percentage of pts with a bleeding AE of any severity decreased from 36% (Weeks 1–12) to 12% (Weeks 36–48). The percentage of pts with bleeding AEs of grade 2 or higher severity decreased steadily from 16% (Weeks 1–12) to 5% (Weeks 37–48). In the phase III studies, the incidence of TEs was 2.4% in both the romiplostim and placebo groups. In the romiplostim group, one patient had a cerebrovascular accident while another had a right popliteal arterial embolism; one placebo-treated patient had a fatal pulmonary embolism. During the extension study, 7 additional TEs occurred in four more pts (patient incidence: 4%): one patient with coronary artery occlusion; one with a calf vein thrombosis; two pts with multiple events. Platelet counts at the time of TEs in all studies ranged from 3 x 109/L to 948 x 109/L. Seven of the 10 TEs occurred at counts below the median peak platelet count for all pts treated with romiplostim in both the phase III and extension studies (167 x 109/L). Furthermore all pts who experienced thrombotic AEs had multiple risk factors for thrombosis including congestive heart failure, antiphospholipid antibodies, coronary artery disease, hypertension, cancer, and/or a history of thrombotic events. Conclusion: Romiplostim appears to be an efficacious and well-tolerated treatment for adults with chronic ITP. The severity of bleeding events decreased during short-term (24-weeks) treatment, and long-term (up to 48 weeks) treatment resulted in further decreases in severe bleeding AEs and overall bleeding frequency. Thrombosis occurred in pts with risk factors, but did not appear to be related to higher than normal platelet counts.

scholarly journals Effects of short-term hypoxia on platelet counts of mice

Blood ◽  
1978 ◽  
Vol 51 (1) ◽  
pp. 165-175 ◽  
Author(s):  
TP McDonald ◽  
M Cottrell ◽  
R Clift
Keyword(s):  
Short Term ◽  
Platelet Counts

Recent studies have shown that long-term hypoxia causes decreased platelet counts in mice and short-term hypoxia increased platelet counts. In an attempt to explain the mechanism that increases platelet counts of mice after exposure to short-term hypoxia, we measured platelet counts, total circulating platelet counts (TCPC), total circulating platelet masses (TCPM), percentages of 35S incorporation, and platelet sizes. Platelet counts, as well as TCPC and TCPM of mice, increased after 1–3 days of hypoxia, but these values were decreased after 6–7 days of hypoxia. Although platelet counts were increased in hypoxic mice, the percentage 35S incorporation into platelets and platelet sizes did not show a concurrent increase. After 6 days of hypoxia, average platelet diameters began to increase as platelet counts decreased. Splenic release did not account for the increase in platelet counts of mice after short-term hypoxia. It seems possible, therefore, that megakaryocytes “shed” platelets into the circulation in response to hypoxia. The platelets that enter the circulation in response to short-term hypoxia are smaller and incorporate less 35S than platelets that are produced in response to acute thrombocytopenia.

scholarly journals Does the Warren Shunt Correct Hypersplenism?

HPB Surgery ◽  
1990 ◽  
Vol 2 (1) ◽  
pp. 41-49 ◽  
Author(s):  
J. Peter A. Lodge ◽  
Andrew I. D. Mavor ◽  
Geoffrey R. Giles
Keyword(s):  
Shunt Surgery ◽  
Short Term ◽  
Platelet Counts ◽  
Warren Shunt ◽  
Haematological Values

It has been suggested that patients with bleeding varices and hypersplenism will show significant improvements in leucocyte and platelet counts following distal splenorenal (Warren) shunt surgery. Whilst this may be true in the short term, this report shows that in the long term hypersplenism is not relieved, whereas the lienorenal shunt is associated with a return of normal haematological values.

scholarly journals Effects of short-term hypoxia on platelet counts of mice

Blood ◽  
1978 ◽  
Vol 51 (1) ◽  
pp. 165-175 ◽  
Author(s):  
TP McDonald ◽  
M Cottrell ◽  
R Clift
Keyword(s):  
Short Term ◽  
Platelet Counts

Abstract Recent studies have shown that long-term hypoxia causes decreased platelet counts in mice and short-term hypoxia increased platelet counts. In an attempt to explain the mechanism that increases platelet counts of mice after exposure to short-term hypoxia, we measured platelet counts, total circulating platelet counts (TCPC), total circulating platelet masses (TCPM), percentages of 35S incorporation, and platelet sizes. Platelet counts, as well as TCPC and TCPM of mice, increased after 1–3 days of hypoxia, but these values were decreased after 6–7 days of hypoxia. Although platelet counts were increased in hypoxic mice, the percentage 35S incorporation into platelets and platelet sizes did not show a concurrent increase. After 6 days of hypoxia, average platelet diameters began to increase as platelet counts decreased. Splenic release did not account for the increase in platelet counts of mice after short-term hypoxia. It seems possible, therefore, that megakaryocytes “shed” platelets into the circulation in response to hypoxia. The platelets that enter the circulation in response to short-term hypoxia are smaller and incorporate less 35S than platelets that are produced in response to acute thrombocytopenia.

Conceptual short-term memory (CSTM) supports core claims of Christiansen and Chater

2016 ◽  
Vol 39 ◽  
Author(s):  
Mary C. Potter
Keyword(s):  
Working Memory ◽  
Rapid Serial Visual Presentation ◽  
Language Comprehension ◽  
Short Term Memory ◽  
Visual Presentation ◽  
Long Term Memory ◽  
Short Term ◽  
Term Memory ◽  
Use Of Knowledge

AbstractRapid serial visual presentation (RSVP) of words or pictured scenes provides evidence for a large-capacity conceptual short-term memory (CSTM) that momentarily provides rich associated material from long-term memory, permitting rapid chunking (Potter 1993; 2009; 2012). In perception of scenes as well as language comprehension, we make use of knowledge that briefly exceeds the supposed limits of working memory.

Comparison of Auditory, Language, Memory, and Attention Abilities in Children With and Without Listening Difficulties

2020 ◽  
Vol 29 (4) ◽  
pp. 710-727
Author(s):  
Beula M. Magimairaj ◽  
Naveen K. Nagaraj ◽  
Alexander V. Sergeev ◽  
Natalie J. Benafield
Keyword(s):  
Auditory Processing ◽  
Short Term Memory ◽  
Group Differences ◽  
Long Term Memory ◽  
Short Term ◽  
Significant Group ◽  
Term Memory ◽  
Memory And Attention ◽  
Speed And Accuracy

Objectives School-age children with and without parent-reported listening difficulties (LiD) were compared on auditory processing, language, memory, and attention abilities. The objective was to extend what is known so far in the literature about children with LiD by using multiple measures and selective novel measures across the above areas. Design Twenty-six children who were reported by their parents as having LiD and 26 age-matched typically developing children completed clinical tests of auditory processing and multiple measures of language, attention, and memory. All children had normal-range pure-tone hearing thresholds bilaterally. Group differences were examined. Results In addition to significantly poorer speech-perception-in-noise scores, children with LiD had reduced speed and accuracy of word retrieval from long-term memory, poorer short-term memory, sentence recall, and inferencing ability. Statistically significant group differences were of moderate effect size; however, standard test scores of children with LiD were not clinically poor. No statistically significant group differences were observed in attention, working memory capacity, vocabulary, and nonverbal IQ. Conclusions Mild signal-to-noise ratio loss, as reflected by the group mean of children with LiD, supported the children's functional listening problems. In addition, children's relative weakness in select areas of language performance, short-term memory, and long-term memory lexical retrieval speed and accuracy added to previous research on evidence-based areas that need to be evaluated in children with LiD who almost always have heterogenous profiles. Importantly, the functional difficulties faced by children with LiD in relation to their test results indicated, to some extent, that commonly used assessments may not be adequately capturing the children's listening challenges. Supplemental Material https://doi.org/10.23641/asha.12808607

Sign in / Sign up

Export Citation Format

Share Document