Platelet factor 4 platelet levels are inversely correlated with steady‐state platelet counts and with platelet transfusion needs in pediatric leukemia patients

Lambert, Michele P.; Reznikov, Alisa; Grubbs, A.; Nguyen, Yvonne; Xiao, Liang; Aplenc, Richard; Rauova, Lubica; Poncz, Mortimer

doi:10.1111/j.1538-7836.2012.04767.x

Cited by 5 publications

(7 citation statements)

References 12 publications

(35 reference statements)

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“…PF4 content influences megakaryopoiesis in mice and patients and HSC replication . These findings imply that there is steady‐state free PF4 within the BM intramedullary space, and the level of free PF4 increases under stress.…”

Section: Resultssupporting

confidence: 91%

“…PF4 expression has been noted in other hematopoietic lines , but the RNA levels show ≥2 orders of magnitude less abundant expression than in megakaryocytes , where PF4 is the third most abundant mRNA and the protein makes up 3% of granular content . We and others have shown that PF4 has an important intramedullary function in regulating the number of megakaryocytes: platelet PF4 levels are inversely related to steady‐state platelet counts ; the degree of both chemotherapy and radiation‐induced thrombocytopenia in murine models is inversely related to PF4; and the level of PF4 expression in platelets inversely correlates with the need for transfusion after chemotherapy in patients . This negative paracrine effect of PF4 on megakaryocytes is mediated by low‐density lipoprotein receptor–related protein 1 (LRP1, CD91) .…”

Section: Introductionmentioning

confidence: 99%

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Intramedullary megakaryocytes internalize released platelet factor 4 and store it in alpha granules

Lambert

Meng

Xiao

et al. 2015

Journal of Thrombosis and Haemostasis

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Summary Background Megakaryocytes express and store platelet factor 4 (PF4) in alpha-granules. In vivo, PF4 is a clinically-relevant, negative regulator of megakaryopoiesis and hematopoietic stem cell (HSC) replication. These findings would suggest a regulated source of free intramedullary PF4. Objectives Define the source of free intramedullary PF4 and it’s intramedullary life cycle. Methods We interrogated both murine and human bone marrow-derived cells during megakaryopoiesis in vitro by confocal microscopy and ELISA. Using immunohistochemistry, we examined in vivo free PF4 in murine bone marrow before and after radiation injury and in the setting of megakaryocytopenia and thrombocytopenia. Results Exogenously added human PF4 is internalized by murine megakaryocytes. Human megakaryocytes similarly take up murine PF4, but not the related chemokine, platelet basic protein. Confocal microscopy shows that internalized PF4 co-localizes with endogenous PF4 in alpha-granules and is available for release upon thrombin stimulation. Immunohistochemistry shows free PF4 in the marrow – but not another alpha-granule protein, von willebrand factor. Free PF4 increases with radiation injury and decreases with megakaryocytopenia. Consistent with the known role of low-density lipoprotein receptor related protein 1 (LRP1) in the negative paracrine effect of PF4 on megakaryopoiesis, PF4 internalization is at least partially LRP1-dependent. Conclusions Thus PF4 has a complex intramedullary life cycle with important implications in megakaryopoiesis and HSC replication not seen with other tested alpha-granule proteins.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Intramedullary megakaryocytes internalize released platelet factor 4 and store it in alpha granules

Lambert

Meng

Xiao

et al. 2015

Journal of Thrombosis and Haemostasis

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“…Use of eltrombopag in severe aplastic anemia has demonstrated interesting effects on both platelet and stem cell populations and further studies are ongoing to better understand these findings and to define patient populations. We have previously shown that PF4 levels inversely correlate with platelet transfusion need and platelet count nadir in pediatric patients with leukemia (whereas TPO levels did not correlate), 11 and baseline TPO levels in our various murine models with different PF4 expression levels also do not correlate with platelet counts or platelet count recovery. Current studies are under way to determine whether TPO stimulation would complement blocking PF4 or whether stimulating megakaryopoiesis by TPO administration might have a deleterious effect on count recovery by enhancing marrow-PF4 release.…”

mentioning

confidence: 84%

“…2,[6][7][8] Our previous studies have shown that endogenous levels of a platelet-specific chemokine, platelet factor 4 (PF4; CXCL4) are inversely correlated with bone marrow recovery after radiation injury. 9 PF4 is a known mediator of megakaryopoiesis, plays an important role in the negative regulation of megakaryopoiesis, [10][11][12] and is found at high concentrations intramedullary, allowing it to act locally within the bone marrow niche in a negative paracrine fashion to regulate local megakaryocytes 13 and stem cells. 14 We have also previously shown that this effect on megakaryopoiesis by PF4 can be blocked by preventing PF4 binding to cell surfaces using anti-PF4 antibodies or unfractionated heparin (UFH) in vitro 10,12 and F(ab9) 2 fragments of these antibodies in vivo, likely due to their ability to penetrate into the marrow.…”

Section: Introductionmentioning

confidence: 99%

2-O, 3-O desulfated heparin mitigates murine chemotherapy- and radiation-induced thrombocytopenia

et al. 2018

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Key Points• ODSH counters the inhibitory effect of PF4 on megakaryopoiesis in murine and human cell cultures.• ODSH improves platelet count recovery in murine models of both CIT and RIT.Thrombocytopenia is a significant complication of chemotherapy and radiation therapy.Platelet factor 4 (PF4; CXCL4) is a negative paracrine of megakaryopoiesis. We have shown that PF4 levels are inversely related to steady-state platelet counts, and to the duration and severity of chemotherapy-and radiation-induced thrombocytopenia (CIT and RIT, respectively). Murine studies suggest that blocking the effect of PF4 improves megakaryopoiesis, raising nadir platelet counts and shortening the time to platelet count recovery. We examined the ability of 2-O, 3-O desulfated heparin (ODSH), a heparin variant with little anticoagulant effects, to neutralize PF4's effects on megakaryopoiesis.Using megakaryocyte colony assays and liquid cultures, we show that ODSH restored megakaryocyte proliferation in PF4-treated Cxcl4 2/2 murine and human CD34 1 -derived megakaryocyte cultures (17.4% megakaryocyte colonies, P , .01 compared with PF4). In murine CIT and RIT models, ODSH, started 24 hours after injury, was examined for the effect on hematopoietic recovery demonstrating higher platelet count nadirs (9% 6 5% treated vs 4% 6 4% control) and significantly improved survival in treated animals (73% treated vs 36% control survival). Treatment with ODSH was able to reduce intramedullary free PF4concentrations by immunohistochemical analysis. In summary, ODSH mitigated CIT and RIT in mice by neutralizing the intramedullary negative paracrine PF4. ODSH, already in clinical trials in humans as an adjuvant to chemotherapy, may be an important, clinically relevant therapeutic for CIT and RIT.

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“…Prognosis CXCL4 may be a useful biomarker predicting the risk of thrombocytopenia developing with chemotherapy (CIT) (Lambert et al, 2012). Patients with low steady-state platelet CXCL4 levels would better tolerate chemotherapy, whereas high concentrations may be an indication for CIT and predict the need for a platelet transfusion.…”

Section: Chemotherapy-induced Thrombocytopenia (Cit)mentioning

confidence: 99%

PF4 (platelet factor 4)

Van¹,

Proost²,

Van³

et al. 2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Platelet factor 4 platelet levels are inversely correlated with steady‐state platelet counts and with platelet transfusion needs in pediatric leukemia patients

Cited by 5 publications

References 12 publications

Intramedullary megakaryocytes internalize released platelet factor 4 and store it in alpha granules

Intramedullary megakaryocytes internalize released platelet factor 4 and store it in alpha granules

2-O, 3-O desulfated heparin mitigates murine chemotherapy- and radiation-induced thrombocytopenia

PF4 (platelet factor 4)

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