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Hypercoagulability in hemoglobinopathies: Decoding the thrombotic threat

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American Journal of Hematology
Authors:
Rayan Bou-Fakhredin at University of Milan
Rayan Bou-Fakhredin
Maria Domenica Cappellini
Maria Domenica Cappellini
Maria Domenica Cappellini
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Ali T Taher at American University of Beirut
Ali T Taher
Lucia De Franceschi
Lucia De Franceschi
Lucia De Franceschi
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Abstract and Figures

Beta (β)‐thalassemia and sickle cell disease (SCD) are characterized by a hypercoagulable state, which can significantly influence organ complication and disease severity. While red blood cells (RBCs) and erythroblasts continue to play a central role in the pathogenesis of thrombosis in β‐thalassemia and SCD, additional factors such as free heme, inflammatory vasculopathy, splenectomy, among other factors further contribute to the complexity of thrombotic risk. Thus, understanding the role of the numerous factors driving this hypercoagulable state will enable healthcare practitioners to enhance preventive and treatment strategies and develop novel therapies for the future. We herein describe the pathogenesis of thrombosis in patients with β‐thalassemia and SCD. We also identify common mechanisms underlying the procoagulant profile of hemoglobinopathies translating into thrombotic events. Finally, we review the currently available prevention and clinical management of thrombosis in these patient populations.
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CRITICAL REVIEW
Hypercoagulability in hemoglobinopathies: Decoding
the thrombotic threat
Rayan Bou-Fakhredin
1,2
| Maria Domenica Cappellini
2
| Ali T. Taher
3
|
Lucia De Franceschi
4
1
Department of Clinical Sciences and
Community, University of Milan, Milan, Italy
2
Fondazione IRCCS Ca’Granda Ospedale
Maggiore Policlinico, SC Medicina ad Indirizzo
Metabolico, Milan, Italy
3
Division of Hematology and Oncology,
Department of Internal Medicine, American
University of Beirut Medical Center, Beirut,
Lebanon
4
Department of Medicine, University of
Verona, and Azienda Ospedaliera Universitaria
Verona, Verona, Italy
Correspondence
Ali T. Taher, Division of Hematology and
Oncology, Department of Internal Medicine,
American University of Beirut Medical Center,
Beirut 1107 2020, Lebanon.
Email: ataher@aub.edu.lb
Abstract
Beta (β)-thalassemia and sickle cell disease (SCD) are characterized by a hypercoagul-
able state, which can significantly influence organ complication and disease severity.
While red blood cells (RBCs) and erythroblasts continue to play a central role in the
pathogenesis of thrombosis in β-thalassemia and SCD, additional factors such as free
heme, inflammatory vasculopathy, splenectomy, among other factors further contrib-
ute to the complexity of thrombotic risk. Thus, understanding the role of the numer-
ous factors driving this hypercoagulable state will enable healthcare practitioners to
enhance preventive and treatment strategies and develop novel therapies for the
future. We herein describe the pathogenesis of thrombosis in patients with
β-thalassemia and SCD. We also identify common mechanisms underlying the pro-
coagulant profile of hemoglobinopathies translating into thrombotic events. Finally,
we review the currently available prevention and clinical management of thrombosis
in these patient populations.
1|INTRODUCTION
Hemoglobinopathies are world-wide distributed hereditary red blood
cell (RBC) disorders with increased morbidity and mortality.
1–3
Among
hemoglobinopathies, beta (β)-thalassemia and sickle cell disease (SCD)
are the most common. Although they are caused by different molecu-
lar defects, both disorders are characterized by an increased risk of
thrombosis compared with a healthy population matched for gender,
age, and ethnicity.
4–8
Noteworthy, in patients with hemoglobinopa-
thies, the occurrence of mutations on coagulation factors or polymor-
phism on methylenetetrahydrofolate reductase, prothrombin, or
Factor V Leiden genes is similar to that observed in healthy subjects.
This highlights the unique prothrombotic profile of patients with
β-thalassemia and SCD compared with the healthy population.
β-thalassemia is characterized by a molecular defect in the syn-
thesis of the globin chain, resulting in an imbalance in hemoglobin
(Hb) production. This leads to varying degrees of anemia, with two
major clinical phenotypes: transfusion-dependent thalassemia (TDT)
and non-transfusion-dependent thalassemia (NTDT). Patients with
TDT require lifelong and regular blood transfusion to survive.
9
On the
contrary, NTDT patients may require occasional or short-course blood
transfusions in certain clinical settings or for the management of
certain complications.
10
Clinical complications in β-thalassemia are
related to the underlying pathophysiological mechanisms, namely inef-
fective erythropoiesis, chronic hemolytic anemia, and iron over-
load.
11,12
SCD is characterized by the presence of abnormal HbS,
which polymerizes under deoxygenation conditions. The cyclic poly-
merization and depolymerization process result in severe RBC mem-
brane damage and activation of the ion transport pathway with the
generation of dense, dehydrated red cells. These play a key role in
the main clinical manifestation of SCD, which are chronic hemolytic
anemia and recurrent acute vaso-occlusive crises (VOCs).
13
Along
with dense RBCs, neutrophils, inflammatory vasculopathy, and soluble
factors such as cytokines or proadhesion molecules (e.g., IL-1β,
endothelin-1, vascular adhesion molecule-1) have been described as
contributors to the biocomplexity of SCD.
8,14
Different antiplatelet and anticoagulation agents have been used
as therapeutic approaches for the management of thrombosis in
β-thalassemia and SCD. Understanding the numerous factors that
drive this hypercoagulable state as a thrombo-inflammatory
Received: 2 August 2024 Revised: 17 September 2024 Accepted: 2 October 2024
DOI: 10.1002/ajh.27500
Am J Hematol. 2025;100:103–115. wileyonlinelibrary.com/journal/ajh © 2024 Wiley Periodicals LLC. 103
... For instance, sickle cell disease is linked to endothelial activation precipitated by the release of DAMPs, including heme [32]. Heme also functions as a DAMP in platelet activation and ferroptosis, contributing to pulmonary thrombotic disease [33], and it exacerbates the thrombotic risk in β-thalassemia and sickle cell disease [34]. Thrombin generation has been employed to elucidate coagulation mechanisms that remain incompletely understood and to investigate hyper-or hypocoagulability in clinical scenarios associated with an elevated risk of thrombosis or hemorrhage [35]. ...
Initiation of Progressive Morphological Transition Towards an Echino-Stomato-Spherocytic Phenotype by Phosphatidylserine Externalization and Its Implication in Thrombosis
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Morphological changes in erythrocytes during disease, aging, or reactions to external agents are significant as they can influence disease progression. However, the exact mechanisms behind these temporary alterations and their potential to cause dysfunction remain unclear. Using a saponin-induced erythrocyte shape transition (EST) model, we studied the gradual shift of erythrocytes towards echino-stomato-spherocytic forms and its link to hemolysis and thrombosis. We observed that different saponin concentrations elicited varying shape transformations. At low concentrations, erythrocytes transition from discocytic shapes to echinocytic, echino-stomatocytic, and ultimately stomatocytic forms. As the concentration moderately increases, the morphology evolves into stomato-spherocytic forms. At higher saponin concentrations, the erythrocytes completely transform into spherocytic forms. Regardless of the transformation degree, all forms showed increased phosphatidylserine exposure (PS) and microvesicle (MV) production, primarily due to increased scramblase and decreased flippase activity, which were influenced by elevated calcium levels and caspase 3 activity, effectively managing PS distribution and influencing cell membrane expansion and invagination. These alterations increased thrombin production, erythrocyte adhesion, and aggregation, promoting thrombosis in rats. Altogether, our findings indicate that the shift towards echino-stomato-spherocytic forms fosters a hypercoagulable state through PS externalization, heightening thrombotic risk.
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... As the disease progresses, luminal narrowing occurs due to intimal proliferation involving smooth muscle cells and fibroblasts, resulting in occlusive vasculopathy. Reduced arterial oxygen content and chronic inflammation also contribute to cerebral infarction [24]. Sickle vasculopathy is strongly linked to intravascular hemolysis, with elevated lactate dehydrogenase (LDH)-a marker of hemolysis-being associated with an increased risk of cerebrovascular complications [25]. ...
Comparison of Asymptomatic Brain Lesions Between Thalassemia Major and Sickle Cell Anemia Patients
Article
Full-text available
Background and Objectives: This study aimed to identify asymptomatic brain lesions in patients with β-thalassemia major (TM) and sickle cell anemia (SCA) and evaluate the correlation of these lesions with factors such as splenectomy, thrombocytosis, and blood transfusions. Materials and Methods: A total of 26 patients with thalassemia major and 23 patients with sickle cell anemia were included. Ischemic lesions were categorized as lacunar, small vessel, or multifocal. Variables including age, years of education, presence and type of MRI-detected ischemia, smoking status, hemoglobin, hematocrit, platelet count, ferritin levels, vitamin B12 levels, fasting blood sugar, splenectomy status, chelation therapy, and hydroxyurea treatment were compared between the two groups. Results: The mean age was 27.33 years in the thalassemia major group and 32.65 years in the sickle cell anemia group (p = 0.010). No statistically significant difference was observed in the distribution of ischemia types between the groups (p = 0.303). The thalassemia major group had a lower mean hemoglobin level (8.37 g/dL) compared to the sickle cell anemia group (9.57 g/dL) (p = 0.003). Ferritin levels were significantly higher in the thalassemia major group (2018.92 ng/mL) than in the sickle cell anemia group (660.39 ng/mL) (p < 0.001). Conclusions: Although ischemic lesions were more frequently observed in patients with sickle cell anemia, the difference was not statistically significant. These findings emphasize the importance of ongoing surveillance and individualized management to mitigate cerebrovascular risks in both patient populations.
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Evaluation of microstructural changes in the brain in transfusion dependent thalassemia patients with advanced magnetic resonance imaging techniques
Article
Full-text available
  • Jul 2024
  • NEURORADIOLOGY
Purpose Transfusion-dependent thalassemia (TDT) is associated with iron accumulation in the body and an increased tendency for thrombosis. With the increased life expectancy in these patients, the detection of neurocognitive complications has gained importance. This study investigates the microstructural changes in TDT patients using advanced diffusion MRI techniques and their relationship with laboratory parameters. Methods The study included 14 TDT patients and 14 control subjects. Tract-based spatial statistics (TBSS) were used to examine differences in DTI parameters such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in thalassemia patients using multi-shell DWI images. The mean kurtosis (MK) difference was investigated using diffusion kurtosis imaging. Fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC) differences were examined using fixel-based analysis. In the patient group, correlative tractography was used to investigate the relationship between DTI parameters and platelet (PLT) and ferritin levels. Results Increase in RD and MD was observed, particularly in the white matter tracts of the corona radiata in patient group. Additionally, an increase in AD was detected in a limited area. Correlative tractography in thalasemia patients showed a positive correlation between increases in RD, MD, and AD with PLT and ferritin. Fixel-based analysis demonstrated a dispersed distribution in white matter fibers, with a more pronounced decrease in FD, FC, and FDC in the internal capsule. Conclusion There is widespread involvement in the white matter and fiber tracts in thalassemia patients, which is highly correlated with thrombotic parameters.
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Diagnosis and management of chronic thromboembolic pulmonary hypertension (CTEPH) in sickle cell disease: A review
Article
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  • May 2024
Pulmonary hypertension in sickle cell disease (SCD) is a complex phenomenon resulting from multiple overlapping etiologies, including pulmonary vasoconstriction in the setting of chronic hemolytic anemia, diastolic dysfunction, and chronic thromboembolic disease. The presence of pulmonary hypertension of any cause in SCD confers a significant increase in mortality risk. Evidence to guide the management of patients with sickle cell disease and chronic thromboembolic pulmonary hypertension (CTEPH) is scant and largely the realm of case reports and small case series. Centered on a discussion of a complex young patient with hemoglobin hemoglobin SC who ultimately underwent treatment with pulmonary thromboendarterectomy, we review the available literature to guide management and discuss and overview of treatment of CTEPH in SCD, considering the unique considerations and challenges facing patients suffering from this multisystem disease.
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Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology
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Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD), affecting 6–10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of this disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is currently focused on the potential role of genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the transforming growth factor-beta (TGF-β) pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future, as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield reliable results that will allow a better understanding of SCD-related PH as a part of the disease’s clinical spectrum. This review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients.
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Evaluating thromboprophylaxis in the sickle cell disease population: Navigating the evidence gap
Article
Full-text available
Sickle cell disease (SCD) arises from beta‐globin gene mutations, with global estimates indicating around 500 000 affected neonates in 2021. In the United States, it is considered rare, impacting fewer than 200 000 individuals. The key pathogenic flaw lies in mutant haemoglobin S, prone to polymerization under low oxygen conditions, causing erythrocytes to adopt a sickled shape. This leads to complications like vascular occlusion, haemolytic anaemia, inflammation and organ damage. Beyond erythrocyte abnormalities however, there is a body of literature highlighting the hypercoagulable state that is likely a contributor to many of the complications we see in SCD. The persistent activation of the coagulation cascade results in thromboembolic events, notably venous thromboembolism (VTE) which is independently associated with increased mortality in both adults and children with SCD. While the increased risk of VTE in the SCD population seems well established, there is a lack of guidelines for thromboprophylaxis in this population. This Wider Perspective will describe the hypercoagulable state and increased thrombosis risk in the SCD population, as well as advocate for the development of evidence‐based guidelines to aid in the prevention of VTE in SCD.
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THromboprophylaxis In Sickle Cell Disease with central venous catheters (THIS): an internal pilot randomised controlled trial protocol
Article
Full-text available
  • Jan 2024
Introduction Individuals with sickle cell disease (SCD) and central venous catheters (CVC) are at high risk for venous thromboembolism (VTE). Minimal data exist regarding the use of anticoagulation as thromboprophylaxis of VTE in this demographic, and as a result, clinical equipoise exists. Prophylactic dose rivaroxaban, a direct oral anticoagulant, is efficacious and safe as thromboprophylaxis in other demographics, and may be an optimal agent in SCD with CVC. Prior to conducting a full clinical trial to assess rivaroxaban as thromboprophylaxis in SCD with CVC, a pilot study is needed to gauge its feasibility. Methods and analysis THromboprophylaxis In Sickle Cell Disease pilot trial is an investigator-initiated, multicentre, double-blinded, randomised controlled trial (RCT) assessing if it is feasible and safe to conduct an adequately powered RCT comparing rivaroxaban to matching placebo as thromboprophylaxis in those with SCD and CVC. Fifty adult patients with SCD and CVC will be randomised to receive either rivaroxaban 10 mg daily or matching placebo for the duration of the CVC in situ for up to 1 year. After randomisation, follow-up visits will occur every 3 months. The primary outcomes pertain to the feasibility of a full trial and include numbers of eligible and recruited participants. Exploratory outcomes include overall incidence of VTE and bleeding complications, as well as quality of life. If the full trial is feasible, blinding will be maintained and patients in the pilot study will be included in the full trial. Ethics and dissemination The trial was initially approved by the University Health Network Research Ethics Board (REB) in Toronto, Canada. All sites will obtain approval from their respective REB prior to commencement of study activities. Study results will be disseminated through presentations at medical conferences and peer-reviewed publications. Trial registration number NCT05033314.
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High-mobility group box 1 increases platelet surface P2Y12 and platelet activation in sickle cell disease
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  • Mar 2024
Thrombosis and inflammation are intimately linked and synergistically contribute to the pathogenesis of numerous thromboinflammatory diseases, including sickle cell disease (SCD). While platelets are central to thrombogenesis and inflammation, the molecular mechanisms of crosstalk between the 2 remain elusive. High-mobility group box 1 (HMGB1) regulates inflammation and stimulates platelet activation through Toll-like receptor 4. However, it remains unclear whether HMGB1 modulates other thrombotic agonists to regulate platelet activation. Herein, using human platelets, we demonstrate that HMGB1 significantly enhanced ADP-mediated platelet activation. Furthermore, inhibition of the purinergic receptor P2Y12 attenuated HMGB1-dependent platelet activation. Mechanistically, we show that HMGB1 stimulated ADP secretion, while concomitantly increasing P2Y12 levels at the platelet membrane. We show that in SCD patients, increased plasma HMGB1 levels were associated with heightened platelet activation and surface P2Y12 expression. Treatment of healthy platelets with plasma from SCD patients enhanced platelet activation and surface P2Y12, and increased sensitivity to ADP-mediated activation, and these effects were linked to plasma HMGB1. We conclude that HMGB1-mediated platelet activation involves ADP-dependent P2Y12 signaling, and HMGB1 primes platelets for ADP signaling. This complementary agonism between ADP and HMGB1 furthers the understanding of thromboinflammatory signaling in conditions such as SCD, and provides insight for therapeutic P2Y12 inhibition.
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Pulmonary Artery Hypertension in Transfusion-Dependent Thalassemia
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  • Jan 2024
Patients with transfusion-dependent thalassemia (TDT) are at risk of developing pulmonary artery hypertension (PAH) due to chronic hemolysis, iron overload, hypercoagulability and splenectomy. The objective of the study was to assess the prevalence and predictors of PAH in patients with TDT. Patients aged 6–18 years with TDT were included. 2D-echocardiography was done to measure the pulmonary artery systolic pressure (PASP) and left ventricular ejection fraction (LVEF). T2* MRI was done to evaluate cardiac iron overload. N-terminal-pro brain natriuretic peptide (NT-pro BNP) level was also assessed. Out of 60 participants, PAH was noted in 19 (31.6%). Mean (SD) age of the patients with PAH and without PAH was 12.2 (3.8) and 9.6 (3.5) years, respectively (P = 0.016). Five of 19 patients with PAH (26.3%) had undergone splenectomy as against 5 of 41 patients without PAH (12.2%) (P = 0.17). Years since splenectomy was higher in the PAH group. Mean (SD) NT-Pro BNP levels were also higher in patients with PAH [63.80 (25.89) vs 41.97 (23.95), P = 0.01]. Significantly higher number of patients with PAH had cardiac T2* value of < 10 ms (P = 0.04). Age (OR 4.11; 95% CI 1.46–8.77), years since splenectomy (OR 3.24; 95% CI 1.30–7.86), NT-Pro BNP levels (OR 4.43; 95% CI 2.14–9.60) and cardiac T2* MRI (OR 2.46; 95% CI 2.18–6.90) values were predictors of PAH in patients with TDT. PAH was observed in 31.6 % of patients, with older age and years since splenectomy being important risk factors. NT-Pro BNP can be used as screening test for detecting PAH.
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