HemeOnc Grand Rounds

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Heme-Onc Grand Rounds

• 2/1/2008
• Elaine M. Majerus, MD PhD

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Survival on Mount Everest

• Is this a metaphor for heme-onc fellowship?
• You cant breathe and you are all alone.
• But no.you are on top of the world and that is
  so not true.

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Case Presentation

• 27 y/o WF with no signif PMHx referred for
  evaluation of asx anemia.
• PMHx Menst since 12 y/o. Cycle every 26-30
  days lasting 4-5 days with 4 pads per day
  maximum. G2P2

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Case cont.

• Meds MVI QD
• All NKDA
• FHx none
• SHx Works as a housewife. No tobacco use.
  Drinks occasionally socially. Enjoys lawn and
  garden work and runs 3 miles per day.

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Case cont.

• ROS was negative for lightheadness, easy
  fatiguability.
• Physical Exam is remarkable for pallor of nail
  beds and conjunctivae. Systolic flow murmur on
  cardiac exam. Spleen tip is palpable approx 6 cm
  below the costal margin.

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Laboratory Data

• Hb 7.0 Hct 23 MCV 99 WBC 6800 with nl diff.
  Plt 230K.
• Retic 7.5
• T. Bili 2.5. Indirect Bili 1.7
• Smear with nucleated RBCs anisocytosis,
  polychromasia, ancanthocytes.

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Diagnosis

• Well-compensated anemia with increased
  destruction.

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Pyruvate Kinase Deficiency

• Characterized by a well-compensated anemia.
• Why is the anemia well-compensated?

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No feedback inhibition in RBCs because 2,3DPG
bind deoxy HB
2,3DPG decreases oxygen affinity and stabilizes
the T or deoxy form of Hb. P50 increases. 2,3DPG
Hb leads to decreased pH.
2,3DPG increases with decreased oxygen such as
with anemia, hypoxia, and alkalosis.
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Hemoglobin

• 64.5 kDa protein with 2? and 2? chains.
• P50 is the O2 pressure where 50 of globins have
  O2 bound.
• P50 is affected by protons, CO2, and DPG.
• Curve is sigmoid-shaped.
• Normal P50 is 26.4 mm Hg

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Left-shift increases off-loading in tissues.
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ODC in PK Deficiency

• High 2,3 DPG concentration.
• Leads to right shift of ODC to increase
  off-loading of oxygen in tissue.
• Right shift of ODC is an adaptation for anemia in
  general.
• High 2,3 DPG in PK Def allows well-compensated
  anemia.

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Back to Mount Everest..

• Which way should the curve move?
• Is 2,3 DPG helpful?

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Right shift of O2 Dissociation Curve

• Is this adaptive? ?Facilitating O2 unloading in
  the tissues.
• Right shift is beneficial for anemia since it
  allows O2 unloading without compromising uptake.
• Animals indigenous to high altitude such as yaks,
  llamas, and geese that migrate over the Himalayas
  and Andes though have a high affinity Hb with a
  P50 of 10 mm Hg lower than in related low land
  species.

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High Altitude

• Alveolar hypoxia leads to impaired O2 loading on
  hemoglobin.
• Hypoxia induces an increase in RBC 2,3 DPG which
  raises P50 to 29 mm Hg at rest or 38 mm Hg with
  heavy exercise.

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Do we respond appropriately to high altitude?

• Hypoxia leads to right shift of curve in humans.
• No environmental stimulus to adapt to high
  altitude hypoxia.
• Is a left-shifted curve advantageous at altitude?

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Hemoglobin Andrew Minneapolis

• ?144K to Q with high O2 affinity. E.g. left
  shift of curve.
• 4 family members. 2 hets and 2 nl sibs.
• Baseline characteristics obtained at low altitude
  (245m) and after residing at 3100 m for 10 days.

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56 (1) 109. (1984)
J. Appl Phys.
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1984
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• At 8800 m, the oxygen tension of inspired air is
  43 mm Hg.
• Alveolar oxygen tension is 35 mm Hg and arterial
  oxygen tension of 28 mm Hg. If the P50 is 26
  like normal, then the arterial O2 sat is 55 and
  incompatible with consciousness.

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• Reinhold Messner and Peter Habeler climbed to the
  summit of Mount Everest in 1978 using fair means
  which means no Sherpas, no crevasse ladders and
  no supplementary oxygen.
• Reinhold Messner did this solo in 1980.
• It therefore, can be done.

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ODC at High altitude

• 2,3 DPG shift curve to the right by 1-2 torr.
• Arterial pH is greatly increased due to partially
  uncompensated respiratory alkalosis. This shifts
  the curve to the left. P50 at the summit in one
  individual was 20 torr.
• At this P50 , the arterial O2 sat is now 78
  which is adequate for short term survival.

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Reinhold Messner 1976
" . . .Now, after the hours of torment . . . I
have nothing more to do than breathe . . . I am
nothing more than a single, narrow, gasping
lung, floating over the mists and the summits."
By 1986, Messner had confirmed his place in
mountaineering history having climbed all 14 of
the 8000 m giants without supplementary O2.
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Oxygen uptake (alveolar oxygen tension - P50) X
diffusing capacity of lungP50-mitochondrial
oxygen tension) X diffusing capacity of tissue.
With Hyperventilation, curve shifts to the right
to optimize peripheral O2 unloading.
Low P50 enhances pulmonary oxygen loading. High
P50 enhances peripheral oxygen unloading.
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Effect of Temperature

• Increased body temperature decreses the oxygen
  affinity and shifts P50 to the right.
• In clinical labs, oxygen tension is measured at
  37oC.
• Therefore oxygen tension may be underestimated in
  hyperthermia.
• E.g. at 41oC with pO2 of 60 mm Hg at 37oC, the
  true pO2 is 72 mm Hg (20 higher)

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