Case

1
Case

• 66 yo Male with Hx of refractory ITP after
  steroids, IVIg and splenectomy.
• 2005 CT scan followed by PET which notes an FDG
  avid sub-pectoral lymph node
• Excisional bx demonstrates Marginal zone
  lymphoma.
• ITP spontaneously resolves
• 2009, acute recurrence of thrombocytopenic
  purpura. Plt count 9. PET negative.
• Tx with Plt transfusion and Rituxan x 1 dose.
  Rapid resolution of thrombocytopenia, c/b macular
  rash on day 3 covering chest and trunk (no
  mucosal).

2
Questions

• Relationship of lymphoma to ITP.
• Complications of Rituxan and Plt transfusions.
• Regulation and biology of thrombopoeisis.
• What regulates platelet production?
• What regulates TPO expression?
• How do megakaryocytes release platelets?

3
c-MPL KO leads to Plt deficiency
(murine myeloproliferative leukemia virus)
4
TPO haploinsufficient unable to compensate for
lost allele
Is basal level of TPO genetically determined?
Normal WBC, Hgb, bands, neutrophils and eos.
5
(No Transcript)
6
Platelets absorb TPO
7
TPO binds to wt but not cMPL deficient Plts
Total bound
Non-specific binding
Displacement of 125I-rmTPO by Cold TPO
Binding of 125I-rmTP0 to Platelet rich plasma
8
Model of TPO-Platelet feedback
Normal
Thrombocytopenia
Thrombophilia
9
What regulates TPO?

• TPO expressed in BM, spleen and liver
• Liver expression 2/2 IL-6
• Iron deficiency vs inflammation
• BM expression is largely constitutive.
• 6 conserved splice variants
• Poor expression 2/2 5UTR ORF
• Early data suggesting that SNPs in 5UTR and
  splice junctions modify basal TPO expression and
  activity
• Familial ET
• Possible correlate of MI survival and g.4830CgtA

10
How are Platelets released?
CD41-EYFP (Red marks Megs/Plts) Visualize in
sinusoids of mouse skull
11
Shear stress releases Platelet
12
Protoplatelets can be large
Peripheral blood platelets
13
Shear stress increases Platelet numbersTPO
increases Platelet size
Grow Megs on 5 micron filter
Does HTN result in increased Plt counts? MI? Does
increased Sed rate relate to MI via Plts?
14
Megakaryocyte Model
Plt counts are higher in the pulmonary artery
than in the pulmonary vein.
Geddis and Kaushansky Science 317 1767
15
MPV PDW as diagnostic tool
63 ITP patients 71 patients with
chemotherapy Induced thrombocytopenia Sysmex
XE-2100
Mean plt volume
Plt deviation width
16
MVP as diagnostic tool
Hyper-destruction
Hypo-proliferative
Beckman-Coulter Gen-S automated counter
17
AA vs ITP
Chemo/Hem malignancy vs ITP
BJH 128 698-702
18
Immature Platelet fraction
Sysmex XE-2100
19
Summary

• Thrombopoiesis is regulated by cMPL adsorbtion of
  TPO.
• TPO drives increased ploidy Megs.
• Megs abut bone marrow blood vessels.
• Megs podocytes extend into the vessel and plts
  are released by sheer forces.
• MPV gt 11, PDW gt 15 are highly specific for a plt
  destruction process (eg ITP).

20
Miles Welch 2/3/09
21
Hypertension increases MPV
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MPV and Hypertension
23
MPV and hypertensive end-organ damage
24
Platelet graph