Recent studies suggest that sickle cell disease (SCD) is a hypercoagulable state contributing to vaso-occlusive events in the microcirculation, resulting in acute and chronic sickle cell–related organ damage. In this article, we review the existing evidence for contribution of hemostatic system perturbation to SCD pathophysiology. We also review the data showing increased risk of thromboembolic events, particularly newer information on the incidence of venous thromboembolism. Finally, the potential role of platelet inhibitors and anticoagulants in SCD is briefly reviewed.
Key points
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Although the pathogenesis of sickle cell disease (SCD) lies in disordered hemoglobin structure and function, downstream effects of sickle hemoglobin include changes in the hemostatic system that overall result in a prothrombotic phenotype.
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These changes include thrombin activation, decreased levels of anticoagulants, impaired fibrinolysis, and platelet activation.
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Limited studies to date suggest that biomarkers of activation can be affected by currently available antithrombotic drugs, and provocative data from pilot studies indicate there may be improvement in clinically important outcomes.
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Therefore, clinical trials with antithrombotic therapies are justified with both SCD-related complications (vaso-occlusive crisis, pain) and thrombotic complications as outcome events of interest.
Introduction
Sickle cell disease (SCD) is the result of homozygous or compound heterozygous inheritance of mutation in the β-globin gene. The resulting substitution of the hydrophilic amino acid glutamic acid at the sixth position by the hydrophobic amino acid valine, leads to the production of hemoglobin S (HbS). HbS polymerizes when deoxygenated and this polymerization is associated with cell dehydration and increased red cell density. The dense, rigid, and sickling red cells lead to vaso-occlusion and impaired blood flow, and is thought to underlie acute (painful episodes, acute chest syndrome) and chronic (avascular necrosis, renal insufficiency) complications of the disease. Also, intracellular polymerization ultimately damages the red cell membrane and leads to chronic and episodic extravascular and intravascular hemolytic anemia, hemolysis-linked nitric oxide (NO) dysregulation, and endothelial dysfunction, resulting in leg ulcer, pulmonary arterial hypertension (PAH), priapism, and stroke.
Several investigators have reported increased thromboembolic events and alteration in hemostatic system in SCD both under steady state and during acute events. This suggests that perturbation in the hemostatic system may contribute to SCD pathophysiology. Changes that have been described include increased expression of tissue factor (TF) on blood monocytes and endothelial cells, abnormal exposure of phosphatidylserine on the red cell surface, and increased microparticles, which both promote activation of the coagulation cascade, and high incidence of antiphospholipid antibodies. In fact, SCD meets the requirements of the Virchow triad (slow flow, activated procoagulant proteins, and vascular injury); therefore, it should not be surprising that sickle disease is accompanied by thrombosis. Clinical manifestations of the prothrombotic state of patients with SCD include venous thromboembolism (VTE), in situ thrombosis, and stroke.
In this section, we highlight the existing evidence for contribution of hemostatic system perturbation to SCD pathophysiology. We will also review the data showing increased risk of thromboembolic events, particularly newer information on the incidence of VTE. Finally, the potential role of platelet inhibitors and anticoagulants in SCD will be briefly reviewed.
Introduction
Sickle cell disease (SCD) is the result of homozygous or compound heterozygous inheritance of mutation in the β-globin gene. The resulting substitution of the hydrophilic amino acid glutamic acid at the sixth position by the hydrophobic amino acid valine, leads to the production of hemoglobin S (HbS). HbS polymerizes when deoxygenated and this polymerization is associated with cell dehydration and increased red cell density. The dense, rigid, and sickling red cells lead to vaso-occlusion and impaired blood flow, and is thought to underlie acute (painful episodes, acute chest syndrome) and chronic (avascular necrosis, renal insufficiency) complications of the disease. Also, intracellular polymerization ultimately damages the red cell membrane and leads to chronic and episodic extravascular and intravascular hemolytic anemia, hemolysis-linked nitric oxide (NO) dysregulation, and endothelial dysfunction, resulting in leg ulcer, pulmonary arterial hypertension (PAH), priapism, and stroke.
Several investigators have reported increased thromboembolic events and alteration in hemostatic system in SCD both under steady state and during acute events. This suggests that perturbation in the hemostatic system may contribute to SCD pathophysiology. Changes that have been described include increased expression of tissue factor (TF) on blood monocytes and endothelial cells, abnormal exposure of phosphatidylserine on the red cell surface, and increased microparticles, which both promote activation of the coagulation cascade, and high incidence of antiphospholipid antibodies. In fact, SCD meets the requirements of the Virchow triad (slow flow, activated procoagulant proteins, and vascular injury); therefore, it should not be surprising that sickle disease is accompanied by thrombosis. Clinical manifestations of the prothrombotic state of patients with SCD include venous thromboembolism (VTE), in situ thrombosis, and stroke.
In this section, we highlight the existing evidence for contribution of hemostatic system perturbation to SCD pathophysiology. We will also review the data showing increased risk of thromboembolic events, particularly newer information on the incidence of VTE. Finally, the potential role of platelet inhibitors and anticoagulants in SCD will be briefly reviewed.
Evidence for increased thromboembolic events in SCD
Stroke has an overall prevalence of 3.75% in patients with SCD and 11% in patients younger than 20 years with sickle cell anemia (HbSS), and is most often caused by large vessel arterial obstruction with superimposed thrombosis. New and old thrombi in the pulmonary vasculature are prevalent in autopsy series. The analysis of a large discharge database in Pennsylvania from 2001 to 2006 found that the incidence of pulmonary embolism was 50-fold to 100-fold higher in the SCD population (0.22%–0.52%) than in the general Pennsylvania population (0.0039%–0.0058%). A retrospective study of reported discharge diagnoses showed that patients with SCD younger than 40 years were more likely to be diagnosed with pulmonary embolism compared with African Americans without SCD (0.44% vs 0.12%); however, the prevalence of deep vein thrombosis was similar between the 2 groups. In contrast, in a retrospective study of 404 patients with SCD cared for at the Sickle Cell Center for Adults at Johns Hopkins between August 2008 and January 2012, 25% of the patients had a history of VTE (18.8% non–catheter related), with a median age at diagnosis of 30 years. Sickle cell variant genotypes, such as HbSC or HbSβ + thalassemia, were associated with increased risk of non–catheter-related VTE compared with HbSS. A history of non–catheter-related VTE was an independent risk factor for death in adults with SCD.
SCD also appears to be a significant risk factor for pregnancy-related VTE, with an odds ratio of 6.7. A retrospective study showed that patients with SCD had more antenatal complications than those with sickle cell trait, without affecting the fetal outcome. Sickle cell trait is generally benign, but one study suggested that sickle cell trait increases the risk of VTE in pregnancy compared with race-matched controls, with an odds ratio of about 2.5. Although in another study of pregnancy, sickle cell trait was associated with pulmonary embolism (PE) rather than deep vein thrombosis. In a recent larger study, investigators could not detect a statistically significant difference in peripartum VTE or PE incidence between women with and without sickle cell trait in a large hospital cohort study.
Evidence of hemostasis system alteration in SCD
The pathophysiology of hypercoagulability in SCD is multifactorial and is a result of alteration in almost every component of the hemostasis system ( Table 1 ). These alterations in platelets, and procoagulant, anticoagulant, and fibrinolytic systems are overall prothrombotic.
| Increased Levels | Decreased Levels |
|---|---|
| Platelet activation Platelet aggregation Phosphatidylserine-rich platelets Thrombin-antithrombin complexes Prothrombin fragment F 1.2 Plasmin-antiplasmin complexes Fibrinogen and fibrin-fibrinogen complex Fibrinopeptide A D-dimer Plasminogen activator inhibitor | Factor V Factor XII Factor IX Protein C Protein S |
Activation of the Coagulation Cascade
Many investigators have shown biomarker evidence for ongoing activation of the coagulation cascade both during steady state (clinically well) and during vaso-occlusive crisis (VOC). These markers denote an ongoing hypercoagulable state in SCD. Thrombin generation is increased in SCD, evidenced by increased prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complexes, plasma fibrinogen products, D-dimer, and decreased factor V. Also, Factor VII and activated Factor VII are decreased in SCD compared with non-SCD individuals, most likely due to accelerated FVII turnover by increased TF activity. High levels of thrombin-antithrombin complex, prothrombin fragment F1.2, and D-dimer are associated with an activated vascular endothelium in patients with SCD with PAH (defined by echocardiographic criteria), and this correlates with the rate of hemolysis in these patients. However, in a cohort of patients with SCD with mild pulmonary hypertension, there was no association between the hypercoagulable state of SCD and the early phase of PAH.
Alterations in proximal intrinsic pathway proteins have been reported as well. In a small study of homozygous SS disease, plasma prekallikrein levels were decreased during steady state with a further reduction during VOC. In a concomitant study, there was an additional 50% decrease in kininogen during VOC compared with low levels of kininogen at baseline. High molecular weight kinonogen (HMWK) was not directly evaluated, but plasma kallikrein almost exclusively digests HMWK; therefore, contact activation is the likely cause of the decrease in plasma kininogen levels. The levels of Factor XII, HMWK, and prekallikrein are slightly decreased in children with homozygous SS disease in steady state. Because components of the contact system are mediators of inflammation, including pain and local vasodilatation, activation of this system might play a role in inflammatory pathway perturbations as wells as coagulation pathway abnormalities that contribute to SCD pathophysiology.
Reduction in Physiologic Anticoagulant Level
Decreases in anticoagulant proteins of hemostasis system would further promote a hypercoagulable state and have been reported in SCD. Onyemelukwe and Jibril described significantly lower level of plasma antithrombin III (AT-III, now called antithrombin or AT) in patients with SCD compared with healthy non-SCD controls. The anticoagulants protein C and S are low in patients with SCD in steady state (crisis free), and tend to decrease to even lower levels during crisis episodes. In a survey of patients with SCD in steady state from Turkey, protein C and AT were significantly lower compared with non-SCD controls. Also, significantly decreased levels of proteins C and S were reported in patients with SCD who developed thrombotic strokes compared with neurologically healthy children with SCD. However, the association with stroke was not seen in the report by Liesner and colleagues, despite demonstrating a reduction in proteins C and S and increased thrombin generation (denoted by increased thrombin-antithrombin complexes and prothrombin fragment 1 + 2) in the steady state, which was only partially reversed by transfusion. Plasma levels of the serine protease inhibitor, heparin cofactor II (HCII), are also decreased in SCD. In total, these findings suggest a possible alteration in either anticoagulant synthesis related to liver disease or chronic consumption due to increased thrombin production.
Impaired Fibrinolysis
The thrombophilia in SCD is also associated with abnormalities in the fibrinolytic system, characterized by increased plasma levels of plasminogen activator inhibitor (PAI)-1 in both steady state and during sickle acute events compared with the healthy population. This may be a result of increased synthesis of PAI-1 by damaged endothelial cells and activated platelets, and might participate in the pathogenesis of VOC in SCD. Elevations in plasma plasmin-antiplasmin complexes (PAP) were also observed in patients with SCD in the noncrisis, steady state. The frequency of pain episodes in patients with SCD correlated with the extent of fibrinolytic activity (assessed by D-dimer levels) in the noncrisis steady state, suggesting that D-dimer levels may predict the frequency of pain crises.
Activated Platelets
Platelet abnormalities (function, number, and survival) both in baseline crisis-free state and acute events were some of the earliest hemostatic changes documented in SCD. Several biomarkers have been measured to document the functional abnormalities. Urinary thromboxane-A2 and prostaglandin metabolites are increased, and platelet trombospondin-1 level is decreased in SCD. These findings suggested ongoing platelet activation. Increased platelet activation markers, such as P-selectin (CD62), CD63, activated glycoprotein (GP) IIb/IIIa, plasma soluble factors (PF)-3, PF4, β-thromboglobulin, and platelet-derived soluble CD40 ligand (sCD40L) were reported in patients with SCD using cytofluorimetric approaches. Also, platelet adherence to fibrinogen was found to be increased through modulation of intracellular signaling pathways associated with increased αIIβ3-integrin activation. Platelet aggregation in adults has been found to be increased, perhaps because of an increase in the number of megathrombocytes in the peripheral circulation or as a result of increase in levels of platelet agonists, such as thrombin, adenosine diphosphate, or epinephrine. In contrast to adults, platelet aggregation in children was normal or reduced, perhaps because of better preservation of splenic function or fewer circulating megathrombocytes. Increased phosphatidylserine-rich platelets have also been described in patients with SCD, which might accelerate the activation of the coagulation system.
Platelet number and survival are also abnormal in both steady state and acute events. In steady state there is moderate thrombocytosis in older children and adults with sickle cell anemia. The number of circulating megathrombocytes, which are young and metabolically active platelets, is also increased. These findings have been attributed to the functional asplenia exhibited by these patients. Although studies performed during steady state suggest normal platelet survival, decrease in platelet lifespan has been reported in VOC. Platelet and megathrombocyte counts may decrease markedly, especially when the crisis is severe. These decreases are followed by marked rebound increases in platelet and megathrombocyte counts, with levels peaking 10 to 14 days after the onset of the crisis.
All of these findings suggest that both shortened platelet survival and enhanced platelet consumption occur during VOCs, possibly because platelets are being deposited at sites of vascular injury or vascular occlusion. It has been demonstrated that labeled platelets accumulate at the putative sites of vaso-occlusion.
Pathophysiology of hemostasis system activation in SCD
As shown previously, in SCD there is a chronic increase in plasma markers of thrombin generation, decrease in natural anticoagulants, and inhibited fibrinolytic system, and some data show these changes are accentuated during a VOC. Although the role of genetic predisposition for thrombophilia in SCD (separate from the sickle cell mutation itself) is still under investigation, several other factors have been identified as contributors to the altered hemostatic system in SCD. Although some of these play major roles in the pathophysiology of SCD, such as altered red blood cell (RBC) membrane, inflammation due to vaso-occlusion/reperfusion oxidative stress, hemolysis resulting in cell-free hemoglobin, abnormal bioavailability of NO, and endothelial dysfunction, the role of others remains under investigation. These include activated circulating endothelial cells, monocytes, microparticles, and platelets. All of these factors have potential to activate the coagulation cascade by increased TF expression on endothelial cells, monocytes, and circulating microparticles derived from RBCs, monocytes, endothelial cells, and platelets. Possible mechanisms for increased TF expression in SCD are (1) increased cell-free heme from hemolysis inducing TF expression on vascular endothelial cells ; (2) ischemia-reperfusion (hypoxia and inflammation), in fact, in an experimental mouse model, 3 hours of exposure to a hypoxic environment and subsequent return to 18 hours of ambient air resulted in an increase in pulmonary vein TF expression, suggesting that ischemia-reperfusion injury in patients with SCD may play a role in activation of procoagulant proteins ; and (3) platelet activation and exposure of CD40 ligand.
Role of RBC Membrane
There has been extensive research on the abnormal RBC membrane and its role in pathophysiology of SCD, which is beyond the scope of this review. In summary, abnormal phosphatidylserine (PS) exposure of the sickle cell RBC membrane alters the adhesive properties of sickle RBCs, leading to an increase in capillary transit time and stasis, enhancing the potential for the activation of coagulation factors and cellular elements in the microvasculature and postcapillary venules. Additionally, the exposed PS functions as a docking site for procoagulant proteins. The number of PS-positive sickle RBCs significantly correlates with plasma levels of prothrombin fragment 1.2, D-dimer, and PAP complexes, and may contribute to increased risk of stroke in SCD. These PS-positive RBCs are a signal for apoptosis and lead to TF-positive microparticle generation. Antiphospholipid antibodies against PS are also markedly elevated in homozygous SCD and correlate strongly with plasma D-dimer, suggesting a role for antiphospholipid antibodies in coagulation activation in SCD. The mechanism may be inhibition of protein S binding to β 2 -glycoprotein-1, resulting in inactivation of protein S by circulating C4b-binding protein. In addition, RBCs with increased PS exposure may bind directly to protein S, contributing to reduction in free protein S.
Role of Hemolysis-Free Hemoglobin-NO-Spleen Axis
Physiologically, endothelial-derived NO is protected from the scavenging effects of intracellular hemoglobin by the erythrocyte membrane barrier and the cell-free zone that forms along endothelium in laminar flowing blood. Also, haptoglobin, CD163, hemoxygenase, and biliverdin reductase detoxify cell-free hemoglobin after hemolysis. However, during intravascular hemolysis, the haptoglobin-hemoxygenase-biliverdin reductase system is overwhelmed. Consequently, the cell-free hemoglobin is accumulated in plasma and interacts with NO, generating reactive oxygen species. In addition, arginase I, which is released from the RBC during hemolysis, metabolizes arginine, which is the substrate for NO synthesis.
NO not only regulates the vascular tone and inhibits endothelial adhesion molecule expression, but also has potent antithrombotic effects. NO inhibits platelet activation via cycle guanosine monophosphate-dependent signaling. Nitric oxide may also inhibit TF expression.
In addition to scavenging NO, cell-free hemoglobin can inhibit ADAMTS13 activity affecting von Willebrand factor (vWF) cleavage in patients with thrombotic thrombocytopenic purpura. In fact, ADAMTS13 activity and ADAMTS13-to-vWF antigen ratio is decreased in patients with SCD compared with healthy controls. This would decrease the proteolysis of vWF and could lead to the accumulation of ultra-large adhesive vWF on the vascular endothelium surface and thrombosis. This mechanism may be a novel mechanism contributing to the complex microvascular pathophysiology of SCD. As mentioned earlier, free heme can also induce endothelial TF expression.
The spleen clears senescent, oxidized, and phosphatidylserine-exposing red cells from the circulation and thus limits intravascular cell microvesiculation, hemolysis, and phosphatidylserine exposure. Increase in the plasma concentration of cell free hemoglobin and red cell microparticles after splenectomy could increase NO scavenging, vascular injury, and thrombosis. Interestingly, because priapism may also be a complication of hemolytic anemia and low NO bioavailability, an increase in intravascular cell free plasma hemoglobin and red cell microparticles after splenectomy could also explain the observed development of priapism after splenectomy. It is also well established that splenectomy in other patient populations is associated with increased risk of VTE.
The Microparticles
Microparticles (MPs) are small membrane vesicles released from cells when activated or during apoptosis. MPs in the blood can originate from platelets, erythrocytes, leukocytes, and endothelial cells. In healthy individuals, circulating MPs are mainly derived from platelets and to a lesser extent leukocyte and endothelial cells. Elevated numbers of circulating microparticles have been reported in patients suffering from a variety of diseases with vascular involvement and hypercoagulability, including SCD. The exact mechanism by which circulating microparticles trigger coagulation in SCD remains unclear. Most circulating microparticles in SCD originate from erythrocytes and platelets and by exposure of phosphatidylserine facilitate coagulation cascade complex formation.
Additionally, increased exposure of TF has been demonstrated on monocyte-derived microparticles. TF-positive microparticles derived from RBCs, platelets, endothelial cells, and monocytes are elevated in patients with SCD both in steady state and during acute events compared with healthy controls, suggesting their possible role in the sickle cell prothrombotic state. The high levels of erythroid and platelet-derived microparticles in sickle cell patients may further increase during acute vaso-occlusive events, although this has not been a consistent finding.
The erythroid-derived microparticles are able to activate the coagulation system independent of the TF and their level correlates with markers of hemolysis, von Willebrand factor, D-dimer and F1+2 levels, pain crisis, and elevated tricuspid regurgitant jet velocity measured by echocardiogram. Their ability to activate the coagulation system through factor XIIa could explain this third pathway. The increase in thrombin generation seems to primarily be caused by erythroid-derived microparticles and hydroxyurea is associated with decreased circulating microparticles compared with untreated patients.
Genetic predisposition for thrombophilia in SCD
Genetic modifiers with functional effects on the hemostatic system have been studied in patients with SCD. Many of the thrombophilic mutations described to date are not prevalent in people of African descent. However, in some populations, patients with SCD might be carrying thrombophilic mutations more than the general population. Studies of human platelet alloantigen (HPA) polymorphism showed a possible prothrombotic role in these patients. Few investigators have studied the role of genetic modifiers of vascular endothelium as well.
Thrombophilic Mutations
Many studies reported the low frequency of thrombophilic mutations (Factor V Leiden [FVL], MTHFR C677T, and prothrombin G20210A) and the lack of association between these mutations and risk of thromboembolism in African American, sub-Saharan African, West Indies, Maghrib, Brazilian, Jamaican, and eastern Saudi Arabian patients with SCD, likely because of the low frequency of these genes in the related general population. However, despite the moderate prevalence of FVL mutation (2.97%–5.50%) among the general population of Iran, the prevalence of FVL mutation is higher (14.30%) among Iranian patients with SCD with a significant association between this mutation and SCD (odds ratio = 6.5). Also, a study from Brazil suggests that MTHFR C677T might be a risk factor for vascular complications in SCD. Also, 3 studies of inherited risk factors of venous thromboembolism in patients with SCD from southern Mediterranean countries report high prevalence of thrombophilic mutations in patients with SCD and their association with thromboembolic events. Among Lebanese sickle/β 0 -thalassemia patients, a high prevalence of the thrombophilic mutations of FVL (42%), homozygous and heterozygous MTHFR C677T (59%), and prothrombin G20210A (8%) has been reported. In this report, patients with sickle/β-thalassemia were 5.24-fold and 4.39-fold more likely to have FVL mutation as compared with the healthy controls and patients with thalassemia intermedia, respectively. Also, the presence of extensive large vessel thrombosis in a patient with sickle/β 0 -thalassemia from Lebanon who was homozygous for FVL and heterozygous for MTHFRC677T has been reported. In another case report, a patient with SCD from Israel with recurrent cerebrovascular accident and deep venous thrombosis, was found to be heterozygous for FVL and MTHFR C677T. Therefore, the prevalence of thrombophilic mutations in the non-African SCD population may be of clinical relevance.
Human Platelet Alloantigen Polymorphism
Polymorphisms in HPA genes may determine platelet reactivity and have been associated with variable risk of thrombotic events, mostly arterial. Studies on polymorphisms of HPA show a possible prothrombotic role in different thrombotic disorders and in patients with SCD with cerebrovascular events. In a case-control study, Al-Subaie and colleagues reported that the HPA-3 variant, which has an isoleucine-to-serine substitution close to the C-terminus of the GPIIb heavy chain, is an independent risk factor for acute vaso-occlusive events in SCD.
Genetic modifiers affecting vascular endothelium in patients with SCD have been evaluated in a few studies; however, the mechanism by which they affect the vascular endothelium needs to be investigated further and in larger patient populations.
Therapeutic implications of hemostatic system activation in SCD
Although hemostatic activation is somewhat downstream in the SCD pathophysiological cascade, it is plausible that a therapy targeted at decreasing platelet and coagulation activation might ameliorate or prevent sickle cell–related complications. This is analogous to the use of platelet inhibitors in atherosclerotic vascular disease and anticoagulants in venous thromboembolism. The underlying pathogenesis is not targeted; nonetheless, blocking downstream effects does decrease the incidence and severity of complications. In addition, emerging data suggesting increased venous thromboembolism in patients with SCD provides further rationale for treatment with either platelet inhibitors or anticoagulants. Finally, platelet inhibitors and anticoagulants are widely used and studied, and their safety profiles are well known in diverse populations. All of this makes study of these agents attractive in SCD.
Trials of Platelet Inhibitors in SCD
To date, there are only 3 studies in humans evaluating the therapeutic effect of aspirin in SCD ( Table 2 ). These studies were conducted in the 1980s and results are limited by the study design. When hemoglobin was incubated with aspirin in vitro, the acetyl group was incorporated into hemoglobin and led to increased oxygen affinity. Subsequently, Osamo and colleagues investigated the therapeutic effect of aspirin in 100 patients aged 11 to 20 years with homozygous SCD. In this study, half of patients were randomized to receive a total daily dose of 1200 mg soluble aspirin for 6 weeks, whereas the other half received placebo in addition to usual care. Hemoglobin levels and oxygen saturation increased in the aspirin arm with increased red cell survival in the 3 patients whose red cell survival was measured. There were no comparative values for the placebo arm. There were no serious hemorrhagic events in the treatment group. Pain was not formally assessed. However, in a double-blind placebo-controlled crossover study of a lower dose of aspirin (3–6 mg/kg) for a longer period of time (21 months) in 49 children aged 2 to 17 years with HbSS, HbSC, or HbSO-Arab, there was no difference in the number of painful episodes, number of total days in pain, duration of pain crisis, or pain severity during crisis between the aspirin-treated and placebo-treated periods using pain assessment forms completed by their parents. Irrespective of the treatment, there was a marked decrease in the number of pain crises after the first 6 months of study. Similarly, a single-blind crossover study of 29 patients aged 4 to 31 years receiving 17 to 45 mg/kg per day of aspirin for 5 months followed by no aspirin for the next 5 months, did not find a difference in the painful events.
| Author | Genotypes | Study Type (n) | Therapy | Overall Result |
|---|---|---|---|---|
| Chaplin et al, 1980 | HbSS | Nonrandomized crossover (3) | Aspirin and diypyridamole | Decrease in pain frequency, platelet count, and fibrinogen |
| Osamo et al, 1981 | HbSS | Randomized (100) | Aspirin | Increase in oxygen affinity, Hb, and red cell life span Pain not formally assessed |
| Greenberg et al, 1983 | HbSS/SO-Arab/SC | Randomized (49) | Aspirin vs placebo | No decrease in pain frequency |
| Semple et al, 1984 | HbSS/Sβ thalassemia | Randomized (9) | Ticlopidine vs placebo | No change in pain, but decrease in platelet activation biomarkers |
| Cabannes et al, 1984 | HbSS | Randomized (140) | Ticlopidine vs placebo | Reduction in frequency and duration of vaso-occlusive crisis |
| Zago et al, 1984 | HbSS/Sβ thalassemia | Randomized (29) | Aspirin vs placebo | No change in pain episodes or laboratory values |
| Wun et al, 2013 | HbSS/Sβ thalassemia/SC | Randomized Phase 2 (62) | Prasugrel vs placebo | Decrease in platelet activation and trend to decreased pain frequency and rate |
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