EDITORIALS
Thrombosis in sickle cell disease
Abbreviations: anti-PA = antibody directed against protein-phosphatidic acid; anti-PS = anti-
body against protein-phosphatidylserine; PS = phosphatidylserine; SC = sickle-hemoglobin C
disease; SS = sickle cell disease (homozygous); TAT = thrombin-antithrombin complex
ascular occlusion is a major complication in
V patients with sickle cell disease. Although the
microvasculature may be occluded by masses
of sickled erythrocytes, larger vessels can
become thrombosed by fibrin clots.1,2 Such thrombi
may occur in association with fat emboli,3 but most
often they are probably caused by vascular occlusion
by irreversibly sickled erythrocytes.4 It has been pro-
posed that the adherence of sickle cells to endothelial
cells may promote thrombosis by increasing circulato-
ry stasis and red cell agglutination.5,6 The stimulus for
this event may be a flipping of the sickle erythrocyte
lipid bilayer membrane to expose inner leaflet PS.7,8
The exposure of membrane phospholipids, and the
subsequent binding of proteins with high affinity for
phospholipids (β2-glycoprotein-1, annexin V, prothrom-
bin, and others), may result in neoantigen formation
and elicit antiphospholipid antibodies.9 In the study of
Westerman et al10 reported in this issue of the Journal,
significantly increased concentrations of anti-PS and
anti-PA were observed in patients with SS disease, and
the anti-PS antibodies were much higher in SS patients
than in SC patients (P < .05). Because hypercoagula-
bility occurs frequently in association with the
antiphospholipid antibody syndrome,11,12 patients with
sickle cell disease were investigated for evidence of the
activation of coagulation. As compared with findings
in healthy control subjects, levels of TAT, prothrombin
fragment 1.2 (F1.2), and D-dimer were all significant-
ly elevated, and fibrinopeptide A was more variably
increased. Others have also recorded elevated concen-
trations of markers of coagulation activation in
J Lab Clin Med 1999;134:329-30.
Copyright © 1999 by Mosby, Inc.
0022-2143/99 $8.00 + 0 5/1/100361
homozygous SS disease,13 but this is the first report that
these markers are increased in patients with SC disease
as well. In keeping with the clinical observation that
SC disease is usually milder than SS disease, Wester-
man et al10 observed that TAT, F1.2, and D-dimer were
all significantly lower in patients with SC than in those
with SS.
In 1988 Francis14 noted that protein S was lower in
patients with SS than in healthy control subjects. The
study by Westerman et al10 confirms that both protein
S antigen and protein S activity are decreased in
patients with SS disease but that levels of this coagula-
tion inhibitor are significantly higher in patients with
SC disease. They also report that the levels of protein
S vary inversely with the titer of antiphospholipid anti-
bodies. A similar inverse relationship between protein
S and anticardiolipin antibodies has been noted in
patients with systemic lupus erythematosus15 and
human immunodeficiency virus infection.16 It has
recently been suggested that β2-glycoprotein I plays an
important role in preventing the inactivation of protein
S by its circulating inhibitor, C4b-binding protein.17
Antiphospholipid antibodies may indirectly decrease
free protein S by inhibiting the binding of protein S to
the protective β2-glycoprotein I. High titers of anti-PS
antibodies and low protein S enhance thrombogenicity.
Westerman et al10 note that the titers of anti-PS anti-
bodies were highly correlated with the levels of fib-
rinopeptide A, TAT, and D-dimer. The strongest asso-
ciation was between D-dimer and anti-PS and anti-PA
antibodies in both SS disease and SC disease (P < .001).
Emerging research supports the following scenario
for the pathophysiology of vascular occlusion in sickle
cell disease. Sickling of the erythrocyte exposes nega-
tively charged phospholipids whose thrombogenic
activity is quenched by annexin V and β2-glycoprotein-
I. However, these complexes of protein and membrane
329

330 Editorial
phospholipid are antigenic, and the antiphospholipid
antibodies formed compete with annexin V for binding
to anionic phospholipid18 and interfere with the ability
of β2-glycoprotein-I to protect the anticoagulant, pro-
tein S, from inhibition by C4B-binding protein.17 This
sets the stage for the activation of coagulation and
thrombin generation. Thrombin creates inter-endothe-
lial cell gaps, promoting the adherence of sickle cells
to the vessel wall basement membrane.19 Thrombin
converts fibrinogen to fibrin and activates platelets.20
The activated platelets release eicosanoids that further
enhance sickle cell adhesion.21 Exposure of the suben-
dothelium also results in the adhesion of platelets and
neutrophils.22 The adherence of these cells results in
the continued activation of coagulation and accumula-
tion of sickle cells, ultimately leading to complete loss
of vessel patency.
DAVID GREEN, MD, PhD
Division of Hematology/Oncology
Department of Medicine
Northwestern University Medical School
345 E Superior Street, Room 1407
Chicago, IL 60611
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