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REVIEW ARTICLE
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.
Thalassemia is a congenital hemolytic disorder caused by a
partial or complete deficiency of Cerebral thrombosis
Deep venous thrombosis and pulmonary embolism
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
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 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 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 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
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 Low levels of the coagulation inhibitors, protein C and protein S, have
been observed in patients with 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
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.
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
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
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 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
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 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
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
Evidence for endothelial activation in SCD was provided by the elevated
urinary levels of 11-dehydro-TXB2 and the
2,3-dinor-6-PGF1 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
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 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 The addition of prophylactic antithrombotic therapy has only recently
been suggested for high-risk patients with 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.
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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Top
Abstract
Thromboembolic manifestations...
- or 
thalassemia
in patients with 
B, an event indicating EC activation.
-glutamyl transferase, or albumin, eliminating hepatic dysfunction as a cause of these anomalies.
Ed