2009 Pulmonary Complications of Sickle Cell

8/10/2019 2009 Pulmonary Complications of Sickle Cell

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review article

T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med 359;21 www.nejm.org november 20, 20082254

Mechanisms of Disease

Pulmonary Complications of Sickle CellDisease

Mark T. Gladwin, M.D., and Elliott Vichinsky, M.D.

From the Division of Pulmonary, Allergy,and Critical Care Medicine and the Hemo-stasis and Vascular Biology Research In-stitute, University of Pittsburgh, Pitts-burgh, (M.T.G.); and Childrens Hospitaland Research Center at Oakland, Oakland,CA (E.V.). Address reprint requests to Dr.

Gladwin at the Division of Pulmonary,Allergy, and Critical Care Medicine, Uni-versity of Pittsburgh, NW 168 MontefioreHospital, 354 Fifth Ave., Pittsburgh, PA,15213, or at [email protected].

N Engl J Med 2008;359:2254-65.Copyright 2008 Massachusetts Medical Society.

The inheritance of two copies of a mutant -globin gene, one

from each parent, is the underlying cause of sickle cell disease. The muta-tion, GAGGTG, substitutes valine for glutamic acid at position 6 in the

-globin chain of hemoglobin A, resulting in a hemoglobin called hemoglobin S.1-3Sickle cell disease is one of the most common autosomal recessive disorders in theworld. Approximately 8% of black Americans are heterozygous and have the sickle

cell trait, whereas approximately 1 in 600 is homozygous and has sickle cell dis-ease. In certain areas of sub-Saharan Africa, an estimated 40 to 60% of the popu-lation is heterozygous, suggesting that 1 to 4% of babies born in this region havethe disease.4

Hemoglobin S polymerizes on deoxygenation. The polymers make the erythro-cyte rigid, distort its shape, and cause structural damage in the red-cell membrane,all of which alter the rheologic properties of the cell, impair blood flow through themicrovasculature, and lead to hemolysis and vaso-occlusive episodes.2,5The extentof hemoglobin S polymerization is a primary determinant of the severity of sicklecell disease6and is proportional to the degree and duration of hemoglobin deoxy-genation and to the concentration of intracellular hemoglobin S raised to approxi-mately the 15th power.2The presence of fetal hemoglobin in the erythrocyte re-duces the concentration of hemoglobin S and thereby inhibits its polymerization.7

The complications of sickle cell disease are myriad, but the two most commonacute events are vaso-occlusive pain crisis, caused by physical and adhesive entrap-ment of red cells containing hemoglobin S in the microcirculation, and the acutechest syndrome, a lung injury syndrome.8,9In addition, affected adults are at riskfor a progressive vasculopathy, characterized by systemic and pulmonary hyperten-sion, endothelial dysfunction, and proliferative changes in the intima and smoothmuscle of blood vessels.10-16With increasing age, chronic end-organ complicationsbegin to appear. These include chronic renal failure, hemorrhagic and nonhemor-rhagic stroke, avascular necrosis of bone, and pulmonary hypertension, which hasa remarkably high prevalence among adults with sickle cell disease.12,17From a

clinical perspective, pulmonary complications namely, the acute chest syndromeand pulmonary hypertension are the most common causes of death in patientswith sickle cell disease.8,9,12,18

Advances in our understanding of the mechanism of vaso-occlusion and thesequelae of chronic intravascular hemolysis have led to insights into the highlyvariable clinical manifestations of sickle cell disease. We present a new formulationof sickle cell disease and propose that certain of its complications are driven bythe vaso-occlusive process, whereas others result from the deleterious effects ofintravascular hemolysis on endothelial-cell and vascular function.

Copyright 2008 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org at UNIVERSITY OF PITTSBURGH on January 6, 2009 .


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n engl j med 359;21 www.nejm.org november 20, 2008 2255

Phenotypes of Sickle Cell

Disease

All patients with sickle cell disease have the sameGAGGTG substitution, but the penetrance andseverity of specific complications arising from themutant hemoglobin S gene, as well as the risk

factors for these complications and the age atwhich they occur, are highly variable. For exam-ple, the major laboratory risk factors for bothvaso-occlusive pain crisis and the acute chest syn-drome are high, steady-state leukocyte counts andhigh hemoglobin levels.1,8,9In contrast, chole-lithiasis, cutaneous leg ulceration, priapism, andpulmonary hypertension are associated with lowsteady-state hemoglobin levels and an increasedrate of intravascular hemolysis.12,17,19-23These lat-ter complications also occur in other hemolyticdiseases. For example, pulmonary hypertension

is common in thalassemia even though the acutechest syndrome does not occur in that disorder,which is not caused by hemoglobin S.24-28Pria-pism and cutaneous leg ulceration also occur inother hemolytic disorders, although to a lesser ex-tent than in sickle cell disease.21,29-34

Given the divergent clinical manifestations ofand epidemiologic risk factors for vaso-occlusivepain crisis and the acute chest syndrome (as com-pared with other vasculopathic complications,such as sudden death, pulmonary hypertension,cutaneous leg ulceration, and priapism), sicklecell disease may be best understood as the inter-action of two overlapping subphenotypes drivenby two major mechanisms: vaso-occlusion andhemolytic anemia (Fig. 1).

Vaso-occlusion

Vaso-occlusive crises are recurrent episodes ofsevere pain in sickle cell disease. The cause ofthese events is microvascular entrapment of eryth-rocytes and leukocytes, which obstruct blood flow

and bring about organ ischemia. In the microcir-culation of transgenic mouse models of sicklecell disease, hypoxia or inflammatory agents,such as tumor necrosis factor or lipopolysac-charide, increase adhesive interactions betweenendothelium, leukocytes, and erythrocytes in thepostcapillary venules, thereby initiating vascularocclusion.35-39This model indicates that cycles ofischemia and reperfusion, in addition to intra-

vascular hemolysis, cause oxidant stress, in whichthere is activation of vascular oxidases,40-42andinflammatory stress, which is characterized by theexpression of endothelial-cell adhesion moleculesand inflammatory cytokines and by leukocyto-sis.35,37,43-45Precapillary obstruction by rigid, de-formed erythrocytes with a high content of hemo-

globin S polymer probably also contributes toocclusion of the microcirculation (Fig. 1).46

Bone marrow and periosteal ischemia andreperfusion instigate cellular injury, infarction,tissue necrosis, edema, and inflammation. Theclinical manifestations of these microvascularevents are explosive episodes of pain and inf lam-mation, often accompanied by fever and leuko-cytosis and sometimes by bone marrow necrosis,with pulmonary emboli consisting of necroticmarrow fat and cellular elements.1,8,9Epidemio-logic studies of the frequency and severity of vaso-

occlusive crises indicate an association with highconcentrations of hemoglobin S, low concentra-tions of fetal hemoglobin, and high steady-stateleukocyte counts and hemoglobin levels.8Theseepidemiologic data point to polymerized hemo-globin S, inflammation, and hyperviscosity as ma-jor determinants of the severity of erythrocytevaso-occlusion.

The Acute Chest Syndrome

The acute chest syndrome is a common form oflung injury in sickle cell disease. When severe, thissyndrome is analogous to the acute respiratorydistress syndrome. In a patient with sickle cell dis-ease it is generally defined by the development ofa new pulmonary infiltrate that is consistent withalveolar consolidation but not atelectasis, involv-ing at least one complete lung segment. The radio-graphic abnormality is usually accompanied bychest pain, fever, tachypnea, wheezing, or cough.9The acute chest syndrome is the second most com-mon cause of hospitalization among patients with

sickle cell disease and the leading cause of ad-mission to an intensive care unit and prematuredeath in this patient population.8

Causes of the Acute Chest Syndrome

Three major causes of the acute chest syndromehave been proposed: pulmonary infection, em-bolization of bone marrow fat, and intravascu-lar pulmonary sequestration of sickled eryth-



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Th e n e w e n g l a n d j o u r n a l o f medicine


rocytes, resulting in lung injury and infarction(Fig. 2).

Pulmonary Infection

The most common cause of the acute chest syn-drome in children and adults is pulmonary infec-tion by a community-acquired pathogen, whichincites an excessive inflammatory response towhat often should have been a mild upper respi-ratory infection. Studies have shown that trans-genic mice that express human hemoglobin S aresusceptible to inf lammatory triggers such as lipo-

polysaccharide and episodic exposure to environ-mental hypoxia, with the development of lung

injury at doses of endotoxin or degrees of hypoxiathat do not adversely affect wild-type mice.47,48

The National Acute Chest Syndrome StudyGroup analyzed 671 episodes of the acute chestsyndrome in 538 patients with sickle cell diseaseto determine the cause, outcome, and responseto therapy.9Respiratory airway sputum and bron-choalveolar-lavage specimens were analyzed forviral and bacterial infect ions, and an infectiousagent was identified in 54% of patients who

Hemolysis, endothelial dysfunction

Precapillary arteriole

Smooth-musclecells

Postcapillary venule

Capillary

Erythrocyte

Monocyte

PlateletsVCAM-1

41

Endothelialcells

Hb

Viscosity, vaso-occlusion

NOS

Arg

ET-1

NO O2-

XO

NOx

x

Pulmonary hypertensionLeg ulcerationPriapismStroke

Pain crisisAcute chest syndrome

Osteonecrosis

Decreased NObioactivity

Increasedvaso-occlusion

Figure 1.Hypothetical Mechanisms of Clinical Subphenotypes of Sickle Cell Disease.

It is hypothesized that many of the complications of sickle cell disease can be divided into two overlapping subtypes, each driven by dis-

tinct mechanisms. Cutaneous leg ulceration, priapism, pulmonary hypertension, sudden death, and stroke are associated with low steady-

state hemoglobin (Hb) levels and an increased rate of intravascular hemolysis, shown on the left side of the figure. These vasculopathiccomplications probably result from endothelial dysfunction, mediated by both inactivation of nitric oxide (NO) by free-plasma hemoglo-bin and vascular reactive oxygen species as well as arginine (Arg) catabolism by plasma arginase. This process of hemolysis-associated

endothelial dysfunction may also cause hemostatic activation and intimal and smooth-muscle proliferation. Such clinical complications

as vaso-occlusive pain crisis, the acute chest syndrome, avascular necrosis of bones, and retinal vasculopathy are associated with highsteady-state leukocyte counts and high hemoglobin levels. These complications are likely to result from obstruction of capillaries and

postcapillary venules by erythrocytes containing polymerized hemoglobin S and by leukocytes (a monocyte is shown), as shown on theright side of the figure. ET-1 denotes endothelin 1, NOS nitric oxide synthase, O2

superoxide, VCAM-1 vascular-cell adhesion molecule 1,

and XO xanthine oxidase.



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were admitted to a hospital. Most of the agentswere atypical bacteria and viruses. Community-acquired encapsulated bacteria were isolated inless than 10% of cases, even though normalsplenic phagocytic function is rare in sickle celldisease.

Fat Emboli

The second major cause of the acute chest syn-drome is the fat emboli syndrome. It is associated

with a severe vaso-occlusive pain crisis involvingmultiple bones, especially the pelvis and femur,which results in infarction and edema of thebone marrow. The bone marrow undergoes ne-crosis, and its contents, including fat, cells, andeven bony spicules, are released into the blood-stream and travel to the lung, where they causeacute pulmonary hypertension, severe lung in-f lammation, and hypoxemia.49-51Secretory phos-pholipase A2is thought to convert bone marrow

il ll

Increased polymerizationand erthyrocyte rigidity

Increased endothelialVCAM-1 expression

and adhesion

Increased erythrocyteadhesion in lung causing

pulmonary infarction

Acute chest syndrome

Vaso-occlusive crisis

Secretoryphospholipase

Pulmonaryinfection

Hypoventilaton and

atelectasis resulting fromrib and vertebral infarction

Fat

Microvasculature occlusion

and bone marrow infarction

Erythrocyte

NO

Shunt

Desaturatedhemoglobin

Decreasedoxygen delivery

Regionalhypoxia

NO

41

VCAM-1

Figure 2.The Vicious Cycle of the Acute Chest Syndrome.

The acute chest syndrome is a lung injury syndrome initiated by three major triggers, all related to vaso-occlusion

by sickle cells: infection, embolization of bone marrow fat, and intravascular sequestration of red cells, all of whichcause lung injury and infarction. Lung injury results in ventilationperfusion mismatch and hypoxemia, which leads

to increased deoxygenation of hemoglobin S, followed by hemoglobin polymerization and erythrocyte vaso-occlu-sion, which in turn promote bone marrow infarction and pulmonary vaso-occlusion. NO denotes nitric oxide, and

VCAM-1 vascular-cell adhesion molecule.



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phospholipids to free fatty acids, which initiatean inflammatory response and lung injury in aprocess analogous to that triggered by intravenousadministration of oleic acid in mouse models ofthe acute respiratory distress syndrome.52

Oil red O staining of lipid accumulationswithin alveolar macrophages is diagnostic of the

fat emboli syndrome, and the lipid accumula-tions can be identified in more than 16% of casesof the acute chest syndrome in adults and chil-dren.9A study compared induced sputum sam-ples of alveolar macrophages with samples ob-tained using bronchoalveolar lavage and found amodest but significant correlation between thetwo methods (r = 0.65).53 In this study, patientswith lipid-laden macrophages in induced sputumsamples had significantly greater extrathoracicpain, more neurologic symptoms, lower plateletcounts, and higher aminotransferase levels than

patients without evidence of fat emboli. The acutechest syndrome can be part of the spectrum ofdisorders in the systemic fat emboli syndrome.This latter syndrome should be suspected in pa-tients with abrupt multiorgan failure, rapid de-velopment of the acute respiratory distress syn-drome, acute increases in pulmonary arterialpressures, evidence of hepatic injury, alterationsin mental status, seizures, prominent thrombo-cytopenia, and in rare cases, coagulopathy.54,55

Pulmonary Infarction

Pulmonary infarction, or vaso-occlusion, may alsocontribute to the development of the acute chestsyndrome. In a small number of patients, wedge-shaped lung infarction, sometimes followed bycentral cavitation, develops.9,56

Clinical Aspects of the Acute Chest Syndrome

In most adults with sickle cell anemia, the acutechest syndrome develops 24 to 72 hours after theonset of severe pain in the arms, legs, or chest.The acute chest syndrome is associated with

marked systemic inflammation, with a mean peaktemperature of 38.9C and a mean white-cellcount of 23,000 per cubic millimeter.9Althougha high steady-state hemoglobin level (without paincrisis) is a major risk factor for the acute chestsyndrome, in hospitalized patients with vaso-occlusive pain crisis, an abrupt drop in the hemo-globin level (a mean decrease of 0.78 g per deci-liter from steady-state levels) and an increase in

markers of hemolysis often precede the develop-ment of the acute chest syndrome. The plateletcount also falls before the onset of the acutechest syndrome; a platelet level of 200,000 percubic millimeter or less is an independent riskfactor for severe manifestations of the syndromeand is associated with increased risks of neuro-

logic complications and the need for mechanicalventilation.

The mean length of hospitalization for adultswith the acute chest syndrome is 10.5 days, ascompared with only 3 to 4 days for uncomplicat-ed vaso-occlusive pain crisis. Mechanical ventila-tion is required in 13% of patients with the syn-drome, and 3% die. The outcome for patients onmechanical ventilation is actually quite good, witha mortality rate of only 19%, as compared withthe outcome for all patients with the acute chestsyndrome, for whom the mortality rate is approx-

imately 30%.9Rapid simple or exchange transfu-sion, ideally with antigen-matched blood, removesthe trigger for acute lung injury sickled erythro-cytes allowing rapid recovery in young pa-tients.

Sickle cell disease is often accompanied byasthma. Reactive airway disease occurs in 13% ormore of patients with the acute chest syndromeand in up to 53% of children between birth andthe age of 9 years.9,57 Although a number ofstudies suggest that asthma is a risk factor forthe acute chest syndrome and stroke in patientswith sickle cell disease,58-60it remains uncertainwhether there is an increase in the prevalence ofasthma among children with sickle cell diseasein the steady state, as compared with matchedcontrols.59,61During steady-state sickle cell dis-ease, the major abnormality in pulmonary func-tion is a restrictive ventilatory impairment, char-acterized by a mild reduction in total lungcapacity, and reduced diffusion capacity for car-bon monoxide.62,63These abnormalities worsenwith age and are associated with increases in

pulmonary-artery pressures.63,64

Hemolysis, Endothelial-Cell

Dysfunction, a nd Vasculopathy

Catabolism of Hemoglobin

A complex biochemical and cellular system clearsand detoxifies the hemoglobin that red cells re-lease into the plasma during normal oxidative and



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mechanical stress.65The hemoglobin dimer bindswith an unusually high proteinprotein aff inityto haptoglobin.66The resulting complex exposes aneoepitope recognized by the hemoglobin scaven-ger protein CD163, a transmembrane glycopro-tein that initiates the uptake of hemoglobin intomacrophages and monocytes. The uptake of he-

moglobin by these cells activates interleukin-10and induces expression of heme oxygenase-1 andbiliverdin reductase.67-69These enzymes catabo-lize heme and signal potent antiproliferative, anti-oxidant, and antiinflammatory reactions.68-70Thedownstream activities of these molecules takeplace in response to the oxidative and inflamma-tory effects of free heme, iron, and oxygen: thebinding of haptoglobin to hemoglobin limitsheme-mediated lipid peroxidation,71biliverdin re-ductase catalytically generates NADPH and reduc-es glutathione,69and heme oxygenase-1 generates

carbon monoxide and biliverdin, both of whichlimit proliferative and thrombotic vascular inju-ry.68New therapeutic approaches, such as hapto-globin infusions, inhaled carbon monoxide gasand carbon monoxidereleasing compounds, andgenetic or pharmacologic induction of heme oxy-genase are being studied in animal models for thetreatment of vascular injury in sickle cell disease.72

Hemolysis

Effect on Nitric Oxide

In sickle cell disease, the hemoglobin and hemescavenging systems are saturated and over-whelmed, even in the steady state.73,74Free plasmahemoglobin, in addition to generating reactiveoxygen species, such as the hydroxyl and super-oxide radicals (through the Fenton and peroxidaseand auto-oxidation chemical reactions),75,76is alsoa potent scavenger of nitric oxide.74,77Nitric oxide,which is normally produced by the endothelium,regulates basal vasodilator tone; inhibits plateletand hemostatic activation; inhibits transcriptionalexpression of nuclear factor Bdependent adhe-

sion molecules, such as vascular-cell adhesionmolecule 1, intercellular adhesion molecule 1,and the selectins; and reduces superoxide levelsthrough radicalradical scavenging.78-82The half-life of nitric oxide in the blood is extremely shortbecause of its rapid reaction with hemoglobin toform methemoglobin and nitrate.83Actually, thevasodilator activity of nitric oxide is possible onlybecause most hemoglobin is normally compart-

mentalized within erythrocytes. Flowing bloodproduces a cell-free zone along the endotheli-um; this zone and an area of nonflowing bloodaround the outside of the erythrocyte (called theunstirred layer) constitute major diffusion barriersagainst nitric oxide entry into red cells.84-86Thesebarriers reduce the rate at which nitric oxide reacts

with intracellular hemoglobin by two to threeorders of magnitude. The release of hemoglobininto plasma during hemolysis circumvents thesediffusion barriers and serves as a potent inhibi-tor of all nitric oxide bioactivity, leading to aclinical state of endothelial-cell dysfunction andnitric oxide resistance.14,74,77,87-92

Effect on Arginine

Hemolysis also releases erythrocyte arginase 1 intoplasma. Arginase metabolizes plasma arginineinto ornithine, reducing the required substrate for

nitric oxide synthesis and compounding the re-duction in the bioavailability of nitric oxide insickle cell disease (Fig. 1).93 In one study, theplasma levels and enzymatic activity of arginase1 were significantly increased in 228 patients withsickle cell disease as compared with black controlsubjects; moreover, arginase 1 modulated themetabolic profile of arginine by reducing argi-nine levels and increasing the production of orni-thine relative to that of citrulline.93These abnor-malities were associated with severe pulmonaryhypertension and an increased risk of death. Intra-vascular hemolysis has also been shown to beassociated with reduced availability of nitric oxideand arginine in animal models and in humanswith severe falciparum malaria.94,95In the studyof malaria, impairment of nitric oxidedependent,flow-mediated vasodilatation developed and wasassociated with hemolysis and high levels of ar-ginase and lactate dehydrogenase.95

The Hypercoagulable State

Chronic depletion of nitric oxide and arginine

may also contribute to the hypercoagulable statein hemolytic diseases. Since nitric oxide is a po-tent inhibitor of platelet activation, the depletionof nitric oxide and arginine (the substrate for ni-tric oxide synthesis) in sickle cell disease allowsfor platelet activation.96Arginine consumption iscompounded by increased intracellular plateletexpression of arginase.97

Recent studies of sickle cell disease showed



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correlations between the intrinsic rate of hemo-lysis and the levels of procoagulant factors inblood.98-100 In addition to the release of freehemoglobin, hemolysis is associated with the for-mation of red-cell microvesicles containing phos-phatidylserine, an activator of tissue factor.100,101Patients with sickle cell disease who have func-

tional asplenia and patients with thalassemiawho have undergone surgical splenectomy haveincreased levels of plasma hemoglobin and red-cell microvesicles, which are potential mecha-nisms for the hypercoagulability associated withboth diseases, with possible exacerbation by asple-nia.100

Additional support for the idea that hemolysisimpairs nitric oxide signaling comes from trans-genic mouse models of sickle cell disease andspherocytosis and from mouse models of allo-immune hemolysis and malaria.42,94,102In these

models, there is impaired vasodilatation in re-sponse to nitric oxide donors and endothelial-dependent vasodilators, and pulmonary hyperten-sion and right heart failure develop.42,102

Pulmonary Hypertension

in Sickle Cell Disease

A major risk factor for pulmonary hypertensionin sickle cell disease is the severity of hemolyticanemia, which can be determined by measuringsteady-state hemoglobin levels and levels of lac-tate dehydrogenase, indirect bilirubin, and retic-ulocytes.12,19,23,103,104An association between thedevelopment of pulmonary hypertension and theintensity of hemolytic anemia has been observedin three prospective screening studies of adultswith sickle cell disease12,103,104and in a growingnumber of pediatric studies.105-108 Pulmonaryhypertension is a reported complication of otherforms of chronic hereditary or acquired hemo-lytic anemia, including thalassemia intermediaand thalassemia major, paroxysmal nocturnal

hemoglobinuria, spherocytosis, stomatocytosis,pyruvate kinase deficiency, alloimmune hemo-lytic anemia, glucose-6-phosphate dehydrogenasedeficiency, unstable hemoglobin variants, and themicroangiopathic hemolytic anemias.65,109 Al-though data from cohort screening studies areavailable only for sickle cell disease and thalas-semia, there are growing numbers of case reportsand case series involving pulmonary hypertension

in other chronic hereditary and acquired hemo-lytic anemias.

Echocardiography

Three prospective screening studies using echo-cardiography have shown that 20% of adults withsickle cell disease have borderline or mild pul-

monary hypertension, defined by a pulmonaryartery systolic pressure greater than 35 mm Hg;10% of these adults have moderate to severe pul-monary hypertension, defined by a pressure great-er than 45 mm Hg.12,103,104Despite pulmonaryartery systolic pressures that are much lower thanthose in idiopathic or hereditary pulmonary hyper-tension, in sickle cell disease borderline or mildpulmonary hypertension is associated with anextremely high risk of death.12,103,104,110-112It re-mains to be determined whether elevations inpulmonary pressures are a marker for vasculopa-

thy and a risk factor for cardiovascular death orwhether the elevations contribute directly to deathdue to progressive or acute right heart failure.The implications of borderline elevations in pul-monary artery systolic pressure in the pediatricpopulation remain unknown.

Adults with sickle cell disease should bescreened for pulmonary hypertension with trans-thoracic Doppler echocardiography.12 The thinbody habitus of these adults, along with dilatedand hyperdynamic heart chambers, allows easydetection of the regurgitation of blood backwardacross the tricuspid valve during right ventricu-lar systole (Fig. 3). The tricuspid regurgitant jetvelocity is used to estimate the right ventricularand pulmonary-artery systolic pressures (whichare approximately four times the tricuspid regur-gitant jet velocity squared) after the addition ofan estimate of the central venous pressure. Insickle cell disease, these estimated pulmonarysystolic pressures correlate well with measure-ments obtained by means of right heart catheter-ization.12A value of 2.5 m per second or more

corresponds to an estimated pulmonary-arterysystolic pressure of 35 mm Hg, which is approxi-mately 2 SD above the normal mean value; forpatients less than 40 years of age, the referencevalue for the mean pulmonary-artery systolicpressure, estimated with the use of Doppler echo-cardiography, is 27.514.2 mm Hg (95% confi-dence interval [CI], 19.3 to 35.5).113Although amore traditional definition of pulmonary hyper-



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tension would be a tricuspid regurgitant jet veloc-

ity of 3.0 m per second or more, values between2.5 and 2.9 m per second are associated with anincreased risk of death among patients withsickle cell disease.12,103,104A follow-up analysisof the National Institutes of Health (NIH) pulmo-nary-hypertension screening cohort12showed thatwith a tricuspid regurgitant jet velocity of 2.5 to2.9 m per second, as compared with a velocity ofless than 2.5 m per second, the rate ratio for death

was 4.4 (95% CI, 1.6 to 12.2; P


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pulmonary hypertension.64,110The mean pulmo-nary-artery pressure in patients with sickle celldisease and pulmonary-artery hypertension is ap-proximately 40 mm Hg, and pulmonary vascularresistance is approximately 250 dyn sec cm5.The relatively low pulmonary vascular resistanceis caused by the high cardiac output that is char-

acteristic of anemia. Approximately 60% of cath-eterized patients with a tricuspid regurgitant jetvelocity that is 3.0 m per second or more meetthe definition of pulmonary-artery hypertension,indicating that vasculopathy primarily involves thepulmonary arterial system. In the other 40% ofpatients, the left ventricular end diastolic pres-sures are greater than 15 mm Hg, indicating acomponent of left ventricular diastolic dysfunc-tion.64Patients with both pulmonary vascular dis-ease and echocardiographic evidence of diastolicdysfunction are at particularly high risk for death

(relative risk ratio, 12.0; 95% CI, 3.8 to 38.1;P


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are the leading complications associated withdeath in adults with sickle cell disease. In patientswho die of the acute chest syndrome, abrupt in-creases in pulmonary pressures and right heartfailure are common, indicating a major interac-tion between these clinical entities. The currenttreatment of these complications is based on lim-

ited evidence or expert opinion, highlighting thecritical need for randomized clinical trials in thisarea. Identification, prevention, and expert man-

agement of these complications by hematologistsand pulmonologists will be a challenge as thepopulation of patients with sickle cell diseaseages and increases worldwide.

Dr. Gladwin reports receiving grant support from the U.S.government and INO Therapeutics in the form of a CollaborativeResearch and Development Agreement, from the Intramural

Research Division of the National Heart, Lung, and Blood Insti-tute, and from the Institute for Transfusion Medicine and theHemophilia Center of Western Pennsylvania. No other potentialconflict of interest was reported.

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2009 Pulmonary Complications of Sickle Cell