Circulating thrombopoietin concentrations in thrombocytopenic patients, including cancer patients following chemotherapy, with or without peripheral blood progenitor cell transplantation

Meng, Yuesheng; Martin, Thomas G.; Peterson, Myron; Shuman, MA; Cohen, R. L.; Wong, Wai Lee

doi:10.1046/j.1365-2141.1996.d01-1933.x

Cited by 60 publications

(42 citation statements)

References 18 publications

(23 reference statements)

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“…Much higher concentrations are found in patients with thrombocytopenia (about 10 ng/ml) (Meng et al, 1996) or thrombocytosis (up to 500 ng/ml) (Moliterno et al, 1998). Based on our in vitro studies, one might expect that, under physiological conditions and under conditions of mild thrombocytopenia, platelets are continuously sensitized by TPO.…”

Section: Discussionmentioning

confidence: 70%

Thrombopoietin increases platelet adhesion under flow and decreases rolling

Os¹,

Wu²,

Pouwels³

et al. 2003

Br J Haematol

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Summary. Thrombopoietin (TPO) is known to sensitize platelets to other agonists at 20 ng/ml, and above 100 ng/ml it is an independent activator of aggregation and secretion. In studies with a perfusion chamber, TPO, between 0AE01 ng/ml and 1 ng/ml, increased platelet adhesion to surface-coated fibrinogen, fibronectin and von Willebrand Factor (VWF) but not to a collagen-coated surface. Increased adhesion was observed at shear rates of 300/s and 800/s in perfusions with whole blood as well as in suspensions of platelets and red blood cells reconstituted in plasma. The by the cyclooxygenase inhibitor, indomethacin, and the thromboxane A 2 -receptor blocker, SQ30741, abolished the stimulation by TPO. The effect of TPO was mimicked by a very low concentration (10 nmol/l) of the thromboxane TxA 2 analogue, U46619. Real-time studies of platelet adhesion to a VWF-coated surface at a shear of 1000/s showed that about 20% of the platelets were in a rolling phase before they became firmly attached. TPO (1 ng/ml) pretreatment reduced this number to < 5%, an effect again abolished by indomethacin. Thus, TPO potentiates the direct and firm attachment of platelets to surface-coated ligands for a IIb b 3 , possibly by increasing the ligand affinity of the integrin.

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Section: Discussionmentioning

confidence: 70%

Thrombopoietin increases platelet adhesion under flow and decreases rolling

Os¹,

Wu²,

Pouwels³

et al. 2003

Br J Haematol

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“…This is consistent with the conclusion of other studies that endogenous TPO levels are reflective of the total Mk rather than platelet mass. [24][25][26][27][28] Catabolism of TPO is not limited to clearance by the platelet mass, since c-Mpl is also present on the Mk and its progenitors. 24 This may account for the low levels of circulating TPO observed in transcription factor NF-E2 −/− mice, which have a maturation defect with platelet production, 25 and humans with idiopathic thrombocytopenic purpura (ITP), who have increased platelet destruction.…”

Section: Discussionmentioning

confidence: 99%

“…24 It has therefore been proposed that serum TPO levels are reflective of total Mk mass. [24][25][26][27][28] With the recent development of sensitive ELISAs, [28][29][30] changes in endogenous TPO levels may be used as an indicator of the Mk reserve of patients undergoing PBPCT.…”

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confidence: 99%

Changes in endogenous TPO levels during mobilization chemotherapy are predictive of CD34+ megakaryocyte progenitor yield and identify patients at risk of delayed platelet engraftment post-PBPC transplant

Maharaj¹,

Steinberg²,

Gouvea³

et al. 1999

Bone Marrow Transplant

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Summary:Patients with delayed platelet recovery post-PBPC transplant (PBPCT) are a high-risk group for thrombocytopenic bleeding and platelet transfusion dependence. Total CD34 ؉ cell dosage has been proposed as the most important factor influencing the rate of platelet recovery. To achieve the shortest time to platelet engraftment, a minimum leukapheresis target of 10 ؋ 10 6 CD34 ؉ cells/kg was established for 30 patients. Of the 29 evaluable patients, 62% had rapid (group I: time to platelets Ͼ20 ؋ 10 9 /l р10 days and 50 × 10 9 /l р14 days) platelet recoveries while 38% had delayed (group II: 20 ؋ 10 9 /l Ͼ10 days and 50 × 10 9 /l Ͼ14 days) recoveries. Groups I and II were compared for: (1) pretreatment variables; (2) mobilizing capability of CD34 ؉ cells and subsets including megakaryocyte (Mk) progenitors; (3) infused dose of these cells at transplant; (4) changes in endogenous levels of Mpl ligand (or TPO) during mobilization and myeloablative chemotherapy. Group II patients received significantly more platelet transfusions (6 vs 2.1, P ‫؍‬ 0.002) post-PBPCT, had a higher proportion of patients with a prior history of BM disease (64% vs 6%, P ‫؍‬ 0.001), and showed a reduced ability to mobilize differentiated (CD34 ؉ /38 ؉ , CD34 ؉ /DR ؉ ) and Mk progenitors (CD34 ؉ /42a ؉ , CD34 ؉ /61 ؉ ). Only the number of Mk progenitors reinfused at transplant was significantly different between the groups (group II vs group I: CD34 ؉ /42a ؉ ‫؍‬ 1.02 vs 2.56 ؋ 10 6 /kg, P ‫؍‬ 0.013; CD34 ؉ /61 ؉ ‫؍‬ 1.12 vs 2.70 ؋ 10 6 /kg, P ‫؍‬ 0.015). The ability to mobilize Mk progenitors correlated with percentage changes in endogenous levels of TPO from baseline to platelet nadir during mobilization chemotherapy (CD34 ؉ /42a ؉ : r ‫؍‬ 0.684, P ‫؍‬ 0.007; CD34 ؉ /61 ؉ : r ‫؍‬ 0.684, P ‫؍‬ 0.007), with group II patients experiencing lower percentage changes. An inverse trend but no correlation was observed between serial TPO levels and platelet counts. TPO levels remained elevated in group II patients throughout a prolonged period of thrombocytopenia (median days to 50 × 10 9 /l = 25 vs 11 for group I), indicating that delayed engraftment was not due to a

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“…The data are somewhat in conflict with recent observations that the megakaryocyte mass, reflected in the rate of platelet production, is the major determinant of TPO levels but consistent with reports of elevated TPO levels following cytoreductive therapy and stem cell transplantation. [15][16][17] However, in contrast to normal subjects, TPO levels in our patients were elevated at baseline and remained high post transplant, even though platelet counts tended to increase after platelet engraftment. Some investigators have hypothesized that a persistent defect of thrombopoiesis may exist in these patients before the start of conditioning therapy and elevated levels of endogenous TPO may be required to maintain normal counts in the circulation.…”

Section: Discussionmentioning

confidence: 99%

Plasma thrombopoietin levels in marrow transplant patients with veno-occlusive disease of the liver

Tahara

Bouvier

et al. 1998

Bone Marrow Transplant

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Summary:Platelet transfusion requirements are higher among patients with veno-occlusive disease (VOD), compared to patients without VOD. One possible explanation is inadequate production of thrombopoietin (TPO), a protein synthesized in the liver. We prospectively studied 28 patients to test the hypothesis that plasma TPO levels were decreased in patients who developed VOD. Plasma TPO levels to day +30 were measured by ELISA (normal, 0.36 ؎ 0.15 fmol/ml). VOD developed in 18/28 patients. Platelet transfusion requirements were significantly different in patients with and without VOD (97 ؎ 46.1 units vs 51 ؎ 33.2 units, P = 0.008). Plasma TPO levels were elevated at baseline (10.8 ؎ 13.0 fmol/ml) and increased after transplant, with peak values of 32.3 ؎ 10.3 fmol/ml at day +7. TPO levels were significantly higher at days +7 and +17 among patients with VOD than among those without VOD (P Ͻ 0.01). Regression analysis of TPO levels vs platelet counts showed a significant inverse relationship. We conclude that TPO levels were higher in patients with VOD and were inversely correlated with platelet counts, suggesting that regulation of TPO levels was related to platelet mass. Thrombocytopenia in patients with VOD cannot be explained by inadequate hepatic synthesis of TPO. Keywords: thrombopoietin; thrombocytopenia; platelets; marrow transplantation; cytoreductive therapy; venoocclusive disease Veno-occlusive disease of the liver (VOD) is a clinical syndrome caused by high-dose cytoreductive therapy that is used to prepare patients for hematopoietic stem cell transplantation. 1 The clinical signs and symptoms of VOD (hepatomegaly, weight gain and jaundice) are a result of widespread damage to hepatocytes, sinusoidal endothelial cells, and venular endothelium in zone 3 of the liver acinus. 2 Another prominent feature of patients with VOD is thrombocytopenia. Platelet transfusion requirements are significantly higher in the first 20 days post transplant The mechanisms for thrombocytopenia in patients with VOD are not well understood. There are three possibilities: underproduction of platelets, more rapid destruction, or a combination of these. Cytoreductive therapy greatly reduces host megakaryocytes and platelet production is decreased until engraftment of donor platelet progenitor cells. Thrombocytopenia is therefore an expected consequence of myeloablative therapy, but patients with VOD require more transfused platelets than patients who do not develop VOD, suggesting that there is increased destruction of platelets in the early phases of VOD. However, even after engraftment, patients with VOD often remain thrombocytopenic. 3 One possible explanation is inadequate production of thrombopoietin, a protein synthesized predominantly in the liver 5 and the most important physiological regulator of platelet homeostasis. 6 Several investigators have reported increased blood levels of TPO following hematopoietic stem cell transplantation. 7-9 However, one report noted significantly lower TPO levels after transplant among patie...

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Circulating thrombopoietin concentrations in thrombocytopenic patients, including cancer patients following chemotherapy, with or without peripheral blood progenitor cell transplantation

Cited by 60 publications

References 18 publications

Thrombopoietin increases platelet adhesion under flow and decreases rolling

Thrombopoietin increases platelet adhesion under flow and decreases rolling

Changes in endogenous TPO levels during mobilization chemotherapy are predictive of CD34+ megakaryocyte progenitor yield and identify patients at risk of delayed platelet engraftment post-PBPC transplant

Plasma thrombopoietin levels in marrow transplant patients with veno-occlusive disease of the liver

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