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Megakaryocytopoiesis

Platelets:
- anucleate blood cells
- circulates in amounts of 150-400 x109L; slightly higher in women than men
- triggers PRIMARY HEMOSTASIS on exposure to: endothelial, subendothelial
and plasma
procoagulants in blood vessel injury
- arise from MEGAKARYOCYTE

Megakaryocytes:
- polyploid: possess multiple chromosome copies w/in a single cell
- multilobulated nucleus w/ a granular cytoplasm
- cluster in the extravascular compartment adjacent to the abluminal
membrane (surface opposite the lumen)
- EMPEROPOIESIS – faux phagocytosis; when myelocytic and erythrocytic
precursor cells crosses the megakaryocyte cytoplasm to reach the sinusoid
lumen
- also harvested in the LUNGS

Endomitosis
 Megakaryocyte maturation – mysterious form of mitosis – lacks
telophase and cytokinesis
 DNA replication proceeds to production of 8N, 16N, 32N ploidy
w/duplicated sets of chromosomes
 Employ their copious DNA to synthesize abundant cytoplasm
 Single megakaryocyte = 2000-4000 platelets
 There are 108 megakaryocyte producing 1011 platelets a day
 Key to endomitosis – loss of spindle fiber orientation at the point of
telophase = chromosomes do not go to polar bodies but duplicate in
place in the equatorial plate

Megakaryocyte Progenitors
Megakaryocyteerythrocyte progenitor
Thrombopoietin (TPO);
IL-3
Burst-Forming Unit (BFU
Meg)

Colony-Forming Unit
(CFU-meg)

Light-Density
CFU (L-D-CFUMeg)

promegakaryoblast. stage in w/c polyploidy is first established  Enters terminal differentiation as they lose the ability to undergo normal mitosis  Lab exams  Immunologic probes and flow cytometry  Usual flow cytometric progenitor markers: o general stem cell marker CD34 o HLA-DR o Platelet glycoprotein IIIa (GP IIb/II1. CD 41)  Platelet peroxidase o Localized in the endoplasmic reticulum of the progenitors and megakaryocytes o Cytochemical stain in transmission electron microscopy Terminal Megakaryocyte Differentiation MK – I Stage MK – II Stage MK – III Stage megakaryobla st promegarkyocyt e megakaryocyt e  MK-I stage/Megakaryoblast  May see plasma membrane blebs – blunt projections from margin that resembles platelets  Begin to develop most of its cytoplasmic ultrastructure o Procoagulant-laden alpha granules o Delta-granules (dense bodies) o Demarcation system (DMS)  Additional immunologic probes: o GP Ib – part of GP Ib/IX/V von Willebrand factor adhesion receptor (CD 42) o mpl – TPO receptor o cytoplasmic VWF – detected by histochemical immunostaining  MK-II Stage . BFU-Meg and CF-Meg  Diploid and participates in normal mitosis  Maintains a pool of megakaryocyte progenitors  LD-CFU Meg  Little proliferative capacity and produces few cells  Begins to process through endomitosis to reach increased nuclear ploidy  Transitional.

megakaryocyte maturation and platelet release . Nuclear lobularity first become apparent as an indentation at the 4N replication stage  CD 36 (GP IV) becomes visible  MK-III/Megakaryocyte  Nuclear is intensely indented and lobulated  Chromatin in variably condensed w/light and dark patches  Cytoplasm = azurophilic. liver. mpl concentration in inversely proportional to platelet and megakaryocyte mass  primary control mechanism for concentration = membrane binding and disposal by platelets  induces stem cells to differentiate into megakaryocyte progenitors in synergy w/cytokines  induces megakaryocyte progenitors to differentiate into megakaryocytes  induces proliferation and maturation of megakaryocytes  induces platelet release  USES OF RECOMBINANT TPO: o Elevates platelet count in healthy donors and in patients treated for a variety of neoplasms including leukemia o Commercial form NPlate (romilostim. and smooth muscle cells circulates in the plasma binds a megakaryocyte and platelet membrane receptor. extend into the venous bloos and release the platelets Hormones and cytokines of megakaryocytopoiesis   TPO     mRNA = kidney. Amgen) = effective in raising the platelet count in immune thrombocytopenic purpura Cell-derived stimulators of megakaryopoiesis  IL-3 o Acts w/TPO to nduce early differentiation of stem cells  IL 6 and IL 11 o Acts in the presence of TPO to enhance endomitosis. granular and platelet-like  Thrombocytopoiesis (platelet shedding)  Megakaryocyte cultures usaing transmission electron microscopy  DMS dilates  longitudinal bundles of tubules form  cytoplasmic extensions (proplatelet processes) develop  transverse constrictions appear throughout the processes  Proplatetelet processes pierce through or between sinusoid-lining endothelial cells.

lavender and granular Blood = even surface Cluster w/erythrocyte near the center of the blood vessels Platelets move laterally w/leukocytes into the white pulp of the spleen where both are sequestered  Normal peripheral blood platelet count = 150-400 10 9/L o Represents only 2/3 of the total circulating platelets since 1/3 is sequestered by the spleen  Sequestered platelets = readily available in times of demand (acute inflammation.5 um Circulating resting platelets = biconvex EDTA = induces them to round up Wright stain = circular to irregular.IL 11 = Neumega (oprelvekin) = to stimulate platelet production in patients w/chemotherapy induced thrombocytopenia  Other cytokines and hormones that participates synergistically w/TPO and interleukins: o Stem cell factor (kit ligand. endomitosis and terminal maturation phase o PLATELETS Diameter = 2. after injury. and NF E2 diminish megakaryocytopoiesis at the progenitor. major surgery or plateletpheresis)  Hypersplenism/splenomegaly = increased sequestration  thrombocytopenia  During conditions of hemostatic needs: o Become sticky and irregular o Extend pseudopods o Adhere to neighboring structures o Aggregate w/each other  Reticulated platelets  “stress platelets”  Appear in compensation for thrombocytopenia  Larger. diameter exceed 6 um  Round up in EDTA  Citrated blood = cylindrical and beaded resembling megakaryocyte proplatelet processes  Nucleic acid dyes (thiazole orange) binds w/RNA of the endoplasmic reticulum = provides quantitative evaluation of reticulated platelet        . GATA 1. mast cell growth factor) o Granulocyte-macrophage colony stimulating factor (GM-CSF) o Granulocyte colony stimulating factor (G-CSF) o Erythropoietin (EPO)  Inhibits in vitro megakaryocyte growth: o Platelet factor 4 o Beta thromboglobulin o Neutrophil activating peptide 2 o IL 8  Reduction in the transcription factor FOG.

production under stress. confounded by platelet dense granules w/c raises the reticulated platelet count by taking up nucleic acid dyes .