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Blood, 1 January 2002, Vol. 99, No. 1, pp. 36-43
REVIEW ARTICLE
The hypercoagulable state in thalassemia
Amiram Eldor and
Eliezer A. Rachmilewitz
From the Institute of Hematology, Tel-Aviv Sourasky
Medical Center, Sackler Faculty of Medicine, Tel-Aviv University,
Tel-Aviv, Israel; and Department of Hematology, Edith Wolfson Medical
Center, Holon, Israel.
 |
Abstract |
Thalassemia is a congenital hemolytic disorder caused by a
partial or complete deficiency of  - or  -globin chain synthesis. Homozygous carriers of -globin gene defects suffer from severe anemia and other serious complications from early childhood. The disease is treated by chronic blood transfusion. However, this can
cause severe iron overload resulting in progressive organ failure. Some
forms of thalassemia are also associated with a similar clinical
picture. Despite the difficulties associated with treatment, standards
of care for thalassemic patients have improved in recent years,
resulting in almost doubling of the average life expectancy. As a
consequence, additional previously undescribed, complications are now
being recognized. In particular, profound hemostatic changes have been
observed in patients with -thalassemia major (-TM) and
-thalassemia intermedia (-TI) and also in patients with thalassemia (hemoglobin H disease). The presence of a higher than
normal incidence of thromboembolic events, mainly in -TI, and the
existence of prothrombotic hemostatic anomalies in the majority of the
patients, even from a very young age, have led to the recognition of
the existence of a chronic hypercoagulable state in thalassemic
patients. Despite the appearance of numerous publications on the
frequent occurrence of thromboembolic complications in thalassemia,
this complication has not been emphasized or comprehensively reviewed.
This review summarizes the current literature and discusses possible
mechanisms of the lifelong hypercoagulable state that exists in thalassemia.
(Blood. 2002;99:36-43)
© 2002 by The American Society of Hematology.
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Thromboembolic manifestations in  thalassemia |
Cerebral thrombosis
There have been numerous reports of
thromboembolic complications associated with thalassemia, many
describing cerebral thrombotic events. As early as 1972, Logothetis et
al,6 reviewing 138 cases of -thalassemia major (-TM)
in Greece, described a "stroke syndrome" in 2 patients and
neurologic deficits compatible with transient ischemic attacks in about
20% of the cases. An Italian multicenter study of 735 patients with
-TM reported 16 individuals with cerebral thromboembolic events
accompanied by a clinical picture of headache, seizures, and
hemiparesis.7 Cerebral thrombosis was also found in
patients with thalassemia/hemoglobin E disease and in thalassemia.8,9 All these reports were from patients who
were not given regular transfusions and were not associated with an
individual blood transfusion. Other reports have described cases of
hypertension, convulsion, and cerebral hemorrhage in thalassemic
patients following blood transfusion.10-13 Asymptomatic brain damage has also been reported; results from magnetic resonance imaging (MRI) on 41 patients with -thalassemia intermedia
(-TI) revealed asymptomatic brain damage including ischemic lesions as a frequent occurrence affecting 37% of patients.14
Damage was inversely correlated with hemoglobin levels in patients with -TI and increased with age.
Deep venous thrombosis and pulmonary embolism
Deep venous thrombosis (DVT), pulmonary
embolism, and recurrent arterial occlusion have been described
in patients with -TM and -TI from many
countries.9,15-19 In most cases, thrombosis was
spontaneous and there were no known risk factors, although some
patients with thrombocytosis after splenectomy developed venous
thrombosis. Following these sporadic reports, several multicenter studies were carried out to determine the incidence of thromboembolism in patients with -TM and -TI. In one Italian multicenter study, 32 of 735 patients (4.35%) experienced thromboembolic events. The
incidence was 3.95% among 685 -TM patients and 9.61% among 52 patients with -TI.7 The same group reported a lower
incidence (1.1%) of thromboembolic complications among 1146 patients
with -TM who were followed for 37 years.7 Another study
showed a 5.3% overall incidence of thrombotic complications among 495 patients with thalassemia whose median age was 28 years.1,2 In this study, the prevalence of thromboembolic
events was 3.3% among 421 patients with -TM and 16.2% among 74 patients with -TI, although 15.3% of these patients had
predisposing congenital or acquired factors contributing to the
hypercoagulability.2 Recently, Cappellini et
al19 observed a high incidence of venous thromboembolic
events (VTEs) in a group of 83 patients with -TI who were followed
for 10 years. Twenty-four patients (29%) developed either pulmonary
embolism, DVT, or portal vein thrombosis, and recurrent VTEs occurred
in 9 of these cases. All patients except one had undergone splenectomy.
Autopsy findings in patients with thalassemia have clearly demonstrated
hypercoagulability as a pathologic feature.20,21 Autopsies
on 17 splenectomized and 2 nonsplenectomized patients of 43 with thalassemia/hemoglobin E disease showed atherosclerotic changes and
obstructive lesions consisting of organized, recanalized thrombi in the
pulmonary arteries and microvasculature. No evidence of thromboembolism
was found elsewhere, although routine dissection of the veins in the
legs was not performed.20 Similar findings of multiple
microthrombi in the pulmonary arterioles, composed mainly of platelets,
were found in autopsies performed on 2 thalassemic patients.21 Asymptomatic pulmonary vascular disease that
could result from silent, recurrent thromboembolic events has been
found in many patients with -TM and -TI. This was suggested by
echocardiographic studies in 35 -TM patients who had no clinical
signs or symptoms of thromboembolic disease. Many of the patients
showed pulmonary hypertension and right heart failure, which were more
prevalent than left heart failure.22 In addition, reduced
lung volumes and flow rates, hypoxemia, reduced carbon monoxide
diffusion in the lung (DLCO), and pulmonary hypertension were found in
these patients.22 In another study of 15 thalassemic
patients, the mean total lung capacity, mean residual volume, and mean
forced vital capacity were significantly reduced.23 In
addition, the DLCO was low, and hypoxemia was present in 6 of 13 patients tested.23 These findings suggest that the early
right ventricular dysfunction, which precedes left heart failure in
many patients with -TM and -TI, may be due to pulmonary
hypertension and not cardiomyopathy resulting from excessive iron
deposition.24,25 In support of this idea, a Doppler
echocardiography study in which pulmonary artery pressure was measured
in 33 patients with -TM (aged 2-24 years) showed that 28 patients
had evidence of pulmonary hypertension.26 Pulmonary artery
hypertension was also detected by M-mode and Doppler echocardiography
in 15 of 16 children, aged 5 to 14 years, with homozygous thalassemia and thalassemia/hemoglobin E disease.27 Right ventricular dysfunction was detected earlier than left
ventricular dysfunction in these children, suggesting that the right
heart failure and pulmonary hypertension seen in thalassemia could
result from microembolization in the lungs. Indeed, autopsy findings revealed a high frequency of thrombotic lesions in the pulmonary arteries and the development of cor pulmonale consistent with a
long-standing pulmonary vascular embarrassment.20,21 The venous and arterial thrombotic events have not received much attention and were not mentioned in comprehensive reviews on
thalassemia.5
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Hemostatic changes in thalassemia |
Platelet activation
In 1978, Eldor28 and a year later Houssain et
al29 found defective platelet aggregation in response to
adenosine diphosphate, epinephrine, or collagen in -TM patients.
Most of the patients had undergone splenectomy and had high platelet
counts. At that time, these anomalies were interpreted as signs of a
mild bleeding disorder because many thalassemic patients experience
frequent epistaxis as well as easy bruising.28 However, in
1981 Winichagoon et al30 found increased circulating
platelet aggregates in 71% of splenectomized and 35% of
nonsplenectomized patients with -TI/hemoglobin E disease, an
observation compatible with in vivo platelet activation and the
existence of a hypercoagulable state. Supporting evidence for this
finding came from platelet kinetic studies in -TM and -TI
patients using autologous platelets labeled with indium In 111 oxine.31 A significant shortening of platelet life span was observed in 13 of 14 patients examined. The mean platelet life span
in 10 patients (8 -TM and 2 -TI) who underwent splenectomy was
107 ± 36 hours compared to 248 ± 51 hours in healthy individuals who underwent splenectomy because of trauma (P < .001).
The mean platelet life span in 4 nonsplenectomized patients (2 -TM
and 2 -TI) was 102 ± 64 hours compared to 224 ± 23 hours in
healthy individuals (P < .01). Analysis of the data
suggested that the shortened platelet life span was caused by enhanced
platelet consumption,31 a feature usually associated with
active thrombotic disease, severe atherosclerosis, diabetes mellitus,
and other chronic hypercoagulable states.
Further evidence for the existence of chronic platelet activation in
thalassemia was provided by the measurement of urinary metabolites of
thromboxane A2 (TXA2) and prostacyclin
(PGI2). A study of 9 splenectomized patients with -TM
who were regularly transfused, 5 nonsplenectomized patients with -TI
who received occasional blood transfusions, and 20 healthy
individuals3,32 found a significant 4- to 10-fold increase
in the urinary excretion of 2,3-dinor-TXB2,
11-dehydro-TXB2, and 2,3-dinor-6-keto-prostaglandin (PG)
F1 in patients with -TM and -TI compared to
healthy controls. The concentration of metabolites in patients with
-TM and -TI was not significantly different, and 6 patients who
received aspirin (20 mg/d) for 7 days showed a significant decrease in their urinary concentrations of 2,3-dinor-TXB2 and
11-dehydro-TXB2 derived from platelets. In contrast, levels
of urinary 2,3-dinor-6-keto-PGF1, reflecting vascular
production, and TXB2 and 6-keto-PGF1 originating from the kidney were not significantly
changed.32 The results of this study are consistent with
enhanced production of TXA2 due to chronic endogenous
platelet activation and reflect the increased concentrations of urinary
thromboxane metabolites found in other diseases associated with in vivo
platelet activation including unstable coronary disease, severe
atherosclerosis, and type II diabetes mellitus.33-36 In
another more recent study,4 urinary prostaglandin
metabolites were determined in a group of 62 -TM patients comprising
26 children (aged 2-18) and 36 adults. All the thalassemic children
(including the youngest, aged 2-8 years) and the adults had highly
elevated levels of the urinary prostaglandin metabolites,
11-dehydro-TXB2 and 2,3-dinor-6-keto-PGF1. None of the thalassemic children had experienced clinical signs or
symptoms suggestive of venous or arterial thrombosis, indicating that
platelet activation in thalassemic patients persists from early in
childhood when clinical thrombotic events are extremely rare.
The existence of chronic platelet activation in thalassemia was further
confirmed by flow cytometric studies, which demonstrated the presence
of an increased fraction of platelets carrying the activation markers
CD62P (P selectin) and CD63.37,38 In addition, morphologic changes in thalassemic platelets, elevated plasma platelet
factor 3 (PF3), and increased spontaneous whole blood platelet
aggregation were reported.39-41
The results from these studies show that, in addition to their
increased number in splenectomized patients, chronic platelet activation is present in -TM and -TI. This may explain the weak response of thalassemic platelets to aggregation agonists reported previously28 as the activated platelets become refractory
to additional stimulation.32 The presence of morphologic
platelet abnormalities in splenectomized patients with thalassemia/hemoglobin E disease may also contribute to an enhanced
risk of vascular complications.42
Endothelial, monocyte, and granulocyte activation
The detection of elevated levels of endothelial adhesion proteins
(intercellular adhesion molecule-1 [ICAM-1], E-selectin [ELAM-1],
vascular cell adhesion molecule-1 [VCAM-1], von Willebrand factor
[VWF], and thrombomodulin) in serum and plasma of thalassemic patients suggested that endothelial activation or injury may be a
feature of the disorder.43,44 The adherence of red blood cells (RBCs) to endothelial cells (ECs) correlates with microvascular occlusions in sickle cell disease (SCD) and malaria and is considered a
major contributor to microcirculatory disorders.45 RBCs
from patients with -TM and -TI showed enhanced adhesion to
cultured ECs (10- to 25-fold increase compared to normal
RBCs).46 Similar findings were described in
SCD45,47 where the interaction of sickle RBCs with ECs
induced a state of oxidative stress leading to enhanced
transendothelial migration of blood monocytes.48
Monocyte activation may also play a significant role in heightening
endothelial activation or injury in both thalassemia and SCD. High
serum levels of monocyte colony-stimulating factor and increased
monocyte phagocytic activities (antibody-dependent cell cytotoxicity
[ADCC]) toward RBCs were found in patients with hemoglobin H
disease and -TM.49 Recently, it was shown that ECs
incubated with sickle mononuclear leukocytes were activated to a
greater extent than those incubated with normal mononuclear leukocytes, as judged by the increased endothelial expression of adhesion molecules
and tissue factor and the adhesion of polymorphonuclear leukocytes.50 Sickle monocytes, which had 34% more
interleukin 1 and 139% more tumor necrosis factor- per cell than
normal monocytes, caused the nuclear translocation of endothelial
nuclear factor  B, an event indicating EC activation.50
It is possible that a similar mechanism may operate in thalassemia.
Activated granulocytes could also contribute to the endothelial damage
and the hypercoagulable state in thalassemia. Elevated granulocyte
phagocytic function, as manifested by enhanced chemiluminescence, was
observed in patients with -TM, with greater prominence of the
abnormality in patients older than 5 years.51 Removal of leukocytes from transfused blood with a Leukostop filter resulted in
improved pulmonary function tests (forced expiratory volume in 1 second/forced vital capacity ratio) in 4 patients with -TM, 6 months
after the procedure.52 This clinical observation
illustrates the deleterious effect that activated granulocytes can
induce in the lungs of patients with thalassemia.
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Coagulation factors and inhibitors |
Studies of the coagulation proteins provide strong evidence for
the existence of a chronic hypercoagulable state in thalassemia. Several investigators have reported profound changes in the levels of
coagulation factors, coagulation factor inhibitors, and components of
the fibrinolytic system.
In a study by Eldor et al,4 plasma prothrombin levels were
significantly lower in adult patients (aged 19-30 years) with -TM
(68% ± 11.5%) compared to age-matched
healthy controls (86.1% ± 12.3%), whereas
the levels of factors V, VII, X, and plasminogen were similar.
Similarly reduced levels of prothrombin
(61.1% ± 6.5%) were observed in a group of
children, aged 2 to 18 years, with -TM, suggesting that this anomaly
is related to the thalassemia rather than to hepatic dysfunction due to
hemosiderosis, which is a rare occurrence in children.4
Low levels of the coagulation inhibitors, protein C and protein S, have
been observed in patients with thalassemia from a variety of ethnic
backgrounds.4,19,53,54 In Israeli patients mostly of
Kurdish Jewish, Yemenite Jewish, or Arabic origin, protein C (antigen
and activity) and free protein S were significantly decreased in both
adults and children.4 Mean protein C antigen levels were
51.2% ± 11.2% in adult -TM patients and 46% ± 9.1% in
-TM children (aged 2-13 years); they were 94.1% ± 21% in
healthy individuals (P < .001). Similar values were
obtained for protein C activity: 52.3% ± 12.1% in -TM adults,
48.8% ± 14.7% in -TM children, and 99.2% ± 16.1% in
healthy controls (P < .001). Levels of free protein S
were 49.3% ± 9.6% in -TM adults, 43.4% ± 8.7% in -TM
children, and 85.1% ± 18.2% in the control group
(P < .001). The decreased levels of free protein S were
not due to low C4b-binding protein levels that were similar in -TM
patients and the controls.4 No correlation was found
between the levels of protein C and protein S and the levels of
prothrombin or any other coagulation factors. Furthermore, protein C
and protein S levels in -TM patients were not related to levels of
serum transaminases,  -glutamyl transferase, or albumin, eliminating hepatic dysfunction as a cause of these anomalies.4
Similar results were obtained in studies of -TI patients in
Italy19 and patients with - or -TM in Thailand and
Turkey.53,54 Some thalassemic patients from Italy and
Turkey had low antithrombin III (ATIII) levels in addition to protein C
and protein S deficiencies, whereas no ATIII deficiency was found in
the Israeli patients.4,19,55
Low levels of heparin cofactor II (HCII), known to be associated with
increased thrombotic risk, have been found in thalassemic patients.56 Frequent blood transfusions resulted in a slow
normalization of HCII levels, suggesting that the low HCII levels could
be related to increased RBC turnover that had been suppressed by
hypertransfusion.56
The possibility of a genetic basis for the hypercoagulable state in
thalassemic patients seems unlikely because a study of 25 Israeli
-TM patients (18 adults, 7 children) found no increased prevalence
of congenital thrombophilic mutations, including the factor V
Leiden, MTHFR C677T, and prothrombin G20210A mutations. In addition, none of the patients showed evidence of anticardiolipin antibody.4
In conclusion, it seems that the low levels of protein C and free
protein S seen in thalassemic patients may be acquired at an early age.
The extent to which the imbalance between coagulation inhibitors and
clotting factors contributes to the hypercoagulable state in
thalassemia remains to be determined.
| |
Plasma markers of hypercoagulability |
The existence of a chronic and lifelong hypercoagulable state in
thalassemia was further supported by the elevated levels of
thrombin-ATIII (TAT) complexes found in about 50% of adults and
children with -TM.4 Increased TAT levels were detected on repeated examinations in many of the patients, of whom none had any
clinical signs of overt thrombosis. In this group of patients the
levels of the prothrombin fragment, F1.2, were
normal.4 However, significantly elevated levels of
F1.2 and fibrinopeptide A (FPA) were found in
splenectomized patients with -TI, and these patients also had high
plasma D-dimer levels, a manifestation of enhanced
fibrinolysis.19 Elevated TAT levels were also observed in
patients with thalassemia (unpublished results, January 2001).
| |
Contribution of abnormal thalassemic RBCs to the
hypercoagulable state |
The mechanism of the hypercoagulable state in thalassemia has not
been fully elucidated. However, evidence from studies of other types of
hemolytic anemia, such as SCD and paroxysmal nocturnal hemoglobinuria
(PNH), in which thrombosis is also a major clinical entity, may be
helpful in understanding the etiology of the latter phenomena.57-59
A comparison of normal RBCs with those isolated from patients with
-TM or -TI by our group suggests that thalassemic RBCs may
provide a source of negatively charged phospholipids, which can
increase thrombin generation, as measured by prothrombinase assay.60,61 These results were confirmed in a similar
assay using RBCs from splenectomized -TI patients as a source of
phospholipids.19 The procoagulant effect of thalassemic
RBCs seems to be due to an increased surface expression of anionic
phospholipids such as phosphatidylethanolamine (PE) and
phosphatidylserine (PS). This was demonstrated by experiments that
showed that annexin V, which binds anionic phospholipids, could block
the procoagulant effect of isolated thalassemic RBCs.61
These data suggest that the procoagulant effect of thalassemic RBCs may
contribute to the hypercoagulable state in thalassemia by amplifying
thrombin generation and initiating platelet activation.
To substantiate these findings, we measured the ability of RBCs from
thalassemia patients to bind annexin V using dual-color flow
cytometry.38 Significantly higher (P < .01)
fractions of fluorescein isothiocyanate (FITC)-annexin V-labeled RBCs
were found in 30 -TM patients (2.9% ± 1.9%; range, 0.5%-7.5%)
and 6 -TI patients (2.5% ± 2.8%; range, 0.9%-6.9%) compared
to 25 healthy individuals (0.5% ± 0.3%; range, 0.1%-1.2%).
Results of tests on patients with myelodysplastic syndrome and severe
anemia were similar to those observed for a healthy control
group.38 Moreover, in the thalassemic patients, a highly
significant correlation (P < .001) was found between the
number of RBC-bound annexin V molecules and the fraction of CD62P (P
selectin) or CD63+ platelets.38 This
association between annexin V binding and the expression of platelet
activation markers was also found in individual thalassemic patients
over time and was not dependent on whether the patients had undergone
splenectomy. These results support the idea that the procoagulant
surface of thalassemic RBCs promotes thrombin generation in vivo
leading to platelet activation.38
The asymmetrical distribution of membrane phospholipids seen in normal
RBCs seems to be the result of a direct interaction of PS and PE with
membrane skeletal proteins (mostly spectrin) and an adenosine
triphosphate (ATP)-dependent unidirectional translocation of PS and PE
from the outer toward the inner membrane leaflet (Figure
1).62-65 This reaction is
catalyzed by the aminophospholipid translocase enzyme that recognizes
both PS and PE.63,64 Aged RBCs contain higher amounts of
PS on the outer leaflet of their membranes compared to young cells and
this may serve as a signal for their recognition and removal by the
reticuloendothelial system.65 Deoxygenated (sickled) RBCs
from patients with SCD show an abnormal distribution of membrane
phospholipids that is caused by an accelerated trans-bilayer diffusion
of phosphatidyl choline (PC) and a reduced rate of ATP-dependent
transport of PS and PE.57,58 The existence of such
membrane phospholipid asymmetry in the RBCs of patients with
thalassemia was recently demonstrated.66 The membrane
damage in thalassemic RBCs may be related to the primary abnormality in
RBC lipids caused by lipid membrane peroxidation mediated by free
iron.67 In fact, increased amounts of membrane-bound
hemichromes and immunoglobulins were found in the RBCs of -TM and
-TI patients and the membrane band 3 protein showed oxidative
modifications such as aggregation and a decrease in sulfhydryl
groups.68,69 The membrane phospholipid abnormalities in
thalassemic and sickle RBCs may partly explain the increased adherence
of PS-exposing RBCs to ECs (Figure 1). When human umbilical vein
endothelial cell monolayers were incubated with PS-exposing RBCs, the
ECs retracted and the RBCs adhered primarily in the gaps that had been
opened between the ECs. Pretreatment of RBCs with annexin V
significantly reduced adherence by shielding PS on the RBCs. This
suggests an important contribution of the PS-exposing RBCs to the
vascular damage observed in thalassemia and sickle cell anemia.45
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| Figure 1.
The hypercoagulable state in thalassemia.
Thalassemia is associated with partial or complete deficiency of -
or -globin chain synthesis, which leads to denaturation and
degradation of the remaining globin chains. This process is associated
with loss of the normal asymmetrical distribution of the RBC membrane
phospholipids and translocation of PS to the external membrane leaflet
(flip-flop). The membrane damage may be related to lipid peroxidation
mediated by free iron and increased amounts of membrane-bound
hemichromes and immunoglobulins and modifications in the membrane band
3 protein and spectrin. The membrane changes may partly explain the
enhanced aggregation of PS-exposing RBCs, their increased adherence to
ECs, and their capacity to enhance thrombin generation via the assembly
of the prothrombinase complex. The enhanced thrombin generation leads
to activation of platelets, monocytes, granulocytes, and ECs and
expression of tissue factor, which further enhances the thrombotic
process. The low levels of the coagulation inhibitors, protein C and
protein S, further facilitate the resultant hypercoagulable state.
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Several studies have suggested that RBCs from thalassemic patients also
demonstrate enhanced cohesiveness, which may contribute to the
hypercoagulable state. Using a novel image analysis system to measure
RBC aggregation in a flow chamber, an increased cohesion of TM RBCs was
detected, demonstrated by the formation of large aggregates.70 Normal rouleaux formation was absent and
higher shear stress was required to disperse the aggregates. It is
noteworthy that RBC aggregate size was reduced to normal after patients
received a blood transfusion and this observation was confirmed by in
vitro experiments where the addition of normal RBCs to thalassemic RBCs resulted in reduced aggregation under flow.70 These in
vitro findings could partly explain the recent clinical observation that patients with -TI who do not receive transfusions regularly had
a much higher incidence of thrombotic events compared to the incidence
of such events in those receiving regular transfusions.19
The contribution of the abnormal RBCs to the thrombotic process has
been also demonstrated in animal models of congenital hemolytic
anemias.71-74 A lethal hypercoagulable state manifested by
large thrombotic lesions in the heart and the liver and large venous
thrombi was found in mice in which the expression of erythroid band 3 had been eliminated via targeted mutagenesis.71 The
abnormal RBCs from these mice significantly shortened the Russell viper venom clotting time of normal plasma in a dose-dependent fashion, whereas RBCs from normal mice had no effect. These experiments suggested that the membrane of band 3 null RBCs provides a suitable surface for activation of the prothrombinase complex and, indeed, PS
exposure on the outer membrane leaflet of the affected RBCs was
demonstrated by increased FITC-annexin V binding.71 A high incidence of thrombosis in the heart and brain was also found in
-spectrin- and -spectrin-deficient mice with hereditary
spherocytosis.72 Thrombosis incidence in these animals was
significantly reduced following the transfusion of normal RBCs or
transplantation of normal bone marrow.73 The presence of
normal RBCs in the peripheral circulation of these
-spectrin-deficient mice prolonged the survival of young animals
and abrogated the development of thrombosis in adult
animals.73
| |
Similarity of thromboembolic manifestations and hemostatic changes
in thalassemia and SCD |
Similar thrombotic complications and hemostatic abnormalities,
characteristic of a chronic hypercoagulable state, have been described
in SCD (Table 1). Although much of the
morbidity in SCD is caused by tissue ischemia and infarction (sickle
cell crisis) resulting from microvascular occlusions caused by the
abnormal sickling RBCs, these events are not associated with an
activation of the hemostatic system.74-76 However, both
adults and children with SCD are known to have an ill-defined but
increased thrombotic risk associated with large blood
vessels.76 Stroke occurs in 7% to 8% of children with
SCD (hemoglobin SS) and is a major cause of
morbidity.77-79 Silent brain lesions revealed by MRI are
common and are associated with impairments of cognitive
function.80,81 Sporadic cases of DVT, pulmonary embolism,
portal vein thrombosis, aseptic necrosis of bone, leg ulcers,
retinopathy, and miscarriage have also been reported.82-86
Hemostatic abnormalities, including low protein C and protein S levels,
and elevated plasma concentrations of TAT, F1,2, and
D-dimer complexes have been found in sickle cell
patients.61,75,87-89 In addition, chronic platelet
activation was indicated by the elevated plasma levels of platelet
factor 4 (PF4) and -thromboglobulin (-TG) and the expression of P
selectin and enhanced binding of annexin V to the SCD
platelets.89 These markers of platelet activation,
thrombin generation, and enhanced fibrinolyisis were significantly
elevated in asymptomatic subjects with SCD and further increased during
episodes of pain.89
Evidence for endothelial activation in SCD was provided by the elevated
urinary levels of 11-dehydro-TXB2 and the
2,3-dinor-6-PGF174 and increased numbers of
circulating microvascular endothelial cells (CD36+)
overexpressing ICAM-1, VCAM-1, E selectin, P selectin, and tissue factor found in these patients.89-91 Sickle RBCs
expressing anionic phospholipid surfaces, manifested by enhanced
annexin V binding, have been shown to have a procoagulant effect and
are thought to be significant in the pathogenesis of the thrombotic
manifestations.57,58,61,90 In support of this idea,
significant reductions in the rates of stroke recurrence in sickle cell
patients from 46% to 90% to less than 10% have been achieved by
chronic blood transfusions and maintenance of hemoglobin S levels at
less than 30%.92,93 Transfusion has also been shown to
greatly reduce the risk of a first stroke in children with SCD who have
abnormal results on transcranial Doppler
ultrasonography.94
Thrombotic manifestations were also observed in 2 knockout-transgenic
mouse models of SCD.95,96 These animals, which had exclusively human sickle hemoglobin, showed all the major features of
human SCD, including thrombotic infarcts and vascular occlusions in the
spleen, liver, and kidneys, and these thrombotic events were already
observed at a relatively young age.95,96
Other congenital hemolytic anemias also carry an increased risk for
thromboembolic events.59 PNH is reported to be associated with an increased tendency for DVT and portal vein
thrombosis,97,98 and frequent thrombotic episodes were
reported in 9 patients with hereditary stomatocytosis. Data on abnormal
hemostatic parameters in these disorders are currently not
available.99
| |
Summary and conclusions |
A range of laboratory tests has provided solid evidence for the
existence of a chronic hypercoagulable state in thalassemia and,
particularly, in splenectomized patients with -TI who do receive
regular transfusions. Thalassemic patients have low levels of protein C
and protein S, show enhanced platelet consumption, and show ongoing
platelet, monocyte, granulocyte, and endothelial activation. Increased
plasma levels of activation peptides, TAT, F1,2, FPA, and
D-dimer, are suggestive of continuous thrombin generation and enhanced fibrinolysis.
Thrombosis is typically an episodic complication associated with a
temporary activation of hemostasis. In contrast, markers of platelet
and coagulation activation are persistently and consistently elevated
in most thalassemic patients (adults and children alike), even in the
absence of overt thromboembolic events.4 The presence of a
persistent hypercoagulable state combined with the infrequent occurrence of significant thrombotic events suggests that thrombosis is
largely a subclinical process in thalassemia and has been associated with autopsy findings of platelet and fibrin thrombi in the
microvasculature in the lungs and the brain.20,21 These
thrombi could contribute to the pulmonary hypertension, low lung
capacity, hypoxemia, and diffusion defects associated with right heart
failure (cor pulmonale)22-27 and to the high frequency of
ischemic brain lesions associated with asymptomatic brain damage as
detected by MRI.14
Several etiologic factors may play a role in the pathogenesis of the
hypercoagulable state in thalassemia. The specific changes in the lipid
membrane composition of the abnormal RBCs and the hemosiderosis may
contribute to the activation of the coagulation process and the
activation of other blood cells, including the platelets, monocytes,
and granulocytes, alone or together, and may induce activation of the
vascular endothelium, which further contributes to the thrombotic
process. The exact order of these events is still unclear, and the
murine models of congenital hemolytic anemias may shed some light on
the role of these anomalies in the induction of the hypercoagulable
state.71-73
Venous thrombosis is more prevalent in -TI patients who are not
receiving regular transfusions and who have undergone splenectomy. These patients may be more susceptible to thromboembolism because they
have more circulating damaged RBCs and increased platelet counts. The
beneficial role of regular blood transfusions is illustrated by the
observation that thromboembolic manifestations are more frequently
recorded in less developed countries with limited transfusion resources
and ex vivo and in vitro experiments that show that normal RBCs can
eliminate the abnormal aggregation observed with thalassemic
RBCs.70
The addition of prophylactic antithrombotic therapy has only recently
been suggested for high-risk patients with -TI who are exposed to
transient thrombotic risk factors (eg, surgery, immobilization,
pregnancy).19 Thalassemia major patients who had developed
an acute thrombotic event should be considered for prolonged
antithrombotic therapy, as for any patients with thrombophilia, in view
of their profound hemostatic anomalies. What remains to be seen is
whether lifelong treatment with antithrombotic agents is indicated in
patients with thalassemia to prevent any subclinical thrombosis
in the lungs and brain. It is noteworthy that some thalassemic patients
responded to treatment with platelet inhibitor drugs (aspirin and
dipyridamole) with a rise in their arterial oxygen
content.21
Dr Amiram Eldor tragically passed away on
Saturday, November 24, 2001, returning home from a scientific meeting
in Germany; his many contributions to hematology will be remembered,
and his presence in our community will be greatly missed. Ed
| |
Footnotes |
Submitted December 28, 2000; accepted August 27, 2001.
Amiram Eldor died on November 24, 2001.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Eliezer A. Rachmilewitz, Department of Hematology,
Edith Wolfson Medical Center, PO Box 5, Holon, Israel; e-mail:
rachmilewitz{at}wolfson.health.gov.il.
| |
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Abstract
Thromboembolic manifestations...