Intravascular Hemolysis as a Risk Factor for

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Intravascular Hemolysis as a Risk Factor for
Pulmonary Hypertension in Sickle Cell Disease
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Case Presentation TM- 44y/o AA/F with SS
Disease Hx- long hx of complications of SS
Disease, including painful crisis and acute chest
syndrome. In Nov.04 admitted with severe chest
pain. Hgb 4.8, Bil 6.2, Retics-10, Pulse Ox-87.
Treated with fluids, blood transfusions,
antibiotics, nasal O2 and Dilaudid with
improvement. 2-D echocardiogram revealed normal
LV function, dilated RV with severe tricuspid
reguritation and elevated PA pressure (67mmHg)
V/P scan low probability (In April 03, ECHO
showed moderate TV reguritation and PA pressure
of 58). Discharged Methadone, folic acid and home
O2. In May 05, readmitted with chest pain and
SOB. Dx of probable ACS treated with fluids,
exchange transfusion, O2 and Dilaudid with rapid
improvement. Following discharge she has done
well other than sickle-type pains in her legs and
moderate DOE. Uses O2 at night. Hgb stable at
7.2. Echo on 2/20/06 showed normal LV function,
moderate global hypokinesis of RV, reguritation
at PV, moderate TV reguritation and PA pressure
of 61mmHg. Dx - Pulmonary hypertension in patient
with SS disease.
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Pulmonary Hypertension as a Risk Factor for Death
in Patients with Sickle Cell Disease Mark T.
Gladwin, M.D., Vandana Sachdev, M.D., Maria L.
Jison, M.D., Yukitaka Shizukuda, M.D., Ph.D.,
Jonathan F. Plehn, M.D., Karin Minter, M.D.,
Bernice Brown, M.D., Wynona A. Coles, R.R.T.,
James S. Nichols, R.N., Inez Ernst, R.N., B.S.N.,
R.D.C.S., Lori A. Hunter, R.N., William C.
Blackwelder, Ph.D., Alan N. Schechter, M.D.,
Griffin P. Rodgers, M.D., Oswaldo Castro, M.D.,
and Frederick P. Ognibene, M.D. NEJM 350886
(2004)
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Some Patient
Characteristics Jet
Velocity Characteristics lt2.5 2.5-2.9 gt3.0 pt
s (132) (46) (17) P Value Age 3410 39
12 38 19 0.02 Hydroxyurea Rx() 36 40 38 0.76
Hx A.C.S.() 83 85 81 0.92 Hx
Stroke() 19 7 6 0.03 gt10 Transfusions() 33 54
69 0.005 Priapism( Men) 33 63 63 0.01 Creatin
ine 0.7 1.5 1.2 lt0.001 Hemoglobin 9.9 9.2 8.5
lt0.001 LDH 320 357 491 lt0.001 ArginineOrnit
hine Ratio 0.77 0.71 0.50 0.009
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• Many Factors Contribute to Development of PAH in
  SC Disease
• These include
• Repeated Episodes of Regional Pulmonary Hypoxia
• Infection
• Bronchoreactive lung disease
• Chronic thromboembolism fat embolism
• Pulmonary fibrosis
• Intravascular hemolysis with release of Hgb and
  arginine

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Regional Pulmonary Hypoxia
? Sickling, ? Vascular adhesion, production of
vasoactive substances ? Reoxygenation
followed by reperfusion injury ? Progressive
tissue damage with altered pulmonary vascular
tone, vascular proliferation in the muscle wall
and hypercoagulable state causing pulmonary
thrombosis and progressive loss of the vascular
bed ? Obliterative Pulmonary Vasculopathy with
pulmonary hypertension
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Role of NO ?Produced by endothelial cells ?Has
vasodilative and cytoprotective effects that
counter the processes induced by
hypoxia ?However, in SC disease, levels of both
arginine (the substrate for NO) and NO are low,
diminishing the beneficial pulmonary vascular
dilation and inhibition of endothelial damage
provided by NO Why is NO low in SC Disease? Key
is intravascular hemolysis!
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JBC 27318709 (1998)
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• Repeated additions of 9µM NO into a well stirred
  4.6 µM free oxyHb (18.4 µM heme) solution.
• Top tracing, NO concentration. Bottom graph,
  oxyHb concentration. The additions of NO are
  designated by the arrows. OxyHb concentration was
  monitored by absorption measurement at 576 nm.

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• Repeated additions (denoted by the down arrows)
  of 0.9?M NO into aerated PBS containing A,
  0.62?M of oxyHb (2.48?M heme) B, 0.7106/ml RBCs
  (1.05?M heme) C, 1.4106/ml RBCs (2.1?M heme).
  Up arrows indicate the point where all oxyHb
  completely reacted with NO.

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