Elsevier

Blood Reviews

Volume 30, Issue 4, July 2016, Pages 245-256
Blood Reviews

REVIEW
Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies

https://doi.org/10.1016/j.blre.2015.12.003Get rights and content

Abstract

Sickle cell disease (SCD) is a hypercoagulable state. Patients exhibit increased platelet activation, high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis “steady state.” Furthermore, SCD is characterized by an increased risk of thrombotic complications. The pathogenesis of coagulation activation in SCD appears to be multi-factorial, with contributions from ischemia–reperfusion injury and inflammation, hemolysis and nitric oxide deficiency, and increased sickle RBC phosphatidylserine expression. Recent studies in animal models suggest that activation of coagulation may contribute to the pathogenesis of SCD, but the data on the contribution of coagulation and platelet activation to SCD-related complications in humans are limited. Clinical trials of new generations of anticoagulants and antiplatelet agents, using a variety of clinical endpoints are warranted.

Introduction

Sickle cell disease (SCD) refers to a group of genetic disorders defined by the presence of sickle hemoglobin (HbS), chronic hemolysis and multi-organ morbidity. More than 300 000 children were born with sickle cell anemia (SCA), the homozygous form of SCD, in 2010 [1] and it is predicted that more than 400 000 children will be born annually by 2050 [2]. Comprehensive care in resource-rich countries, including newborn screening, infection prophylaxis with penicillin, and hydroxyurea therapy, has improved the survival as well as the quality of life of individuals with SCD [3]. In addition to its well-known hemolytic and vaso-occlusive complications, SCD is characterized by a variety of thrombotic complications, including ischemic stroke [4]. Furthermore, multiple recent studies show that patients with SCD have an increased risk of venous thromboembolism [5], [6], [7], [8]. The high prevalence of thrombotic complications, combined with the well documented hemostatic alterations in the direction of a procoagulant phenotype shows that SCD can be considered to be a true hypercoagulable state [9], [10], [11], [12], [13]. In an attempt to improve our understanding of the role of hypercoagulability in the pathogenesis of SCD, many groups have addressed the link between coagulation activation and various clinical manifestations of the disease. Using data from animal models and patients, the current review provides an update on coagulation abnormalities in SCD, their relationship with selected clinical complications, the effect of current disease-modifying treatments, and summarizes the published studies of anticoagulants and anti-platelet agents.

Section snippets

In vivo thrombin and fibrin generation

Chronic activation of coagulation is commonly observed in patients with SCD at ‘steady-state’ compared to healthy control subjects with normal hemoglobin. This is evidenced by increased plasma levels of in vivo markers of thrombin and fibrin generation, including thrombin–antithrombin complexes (TAT), prothrombin fragment 1.2 (F1.2), fibrinopeptide A, D-dimers and plasmin–antiplasmin complexes (PAP) [14], [15], [16], [17], [18], [19], [20], [21]. There are conflicting reports regarding further

Vasculopathy of SCD

Vasculopathy is a term that has been used to describe the progressive remodeling of the arterial vasculature, leading to impaired blood flow. The pathogenesis of vasculopathy in SCD is not fully elucidated. Several distinct concepts, histologic [112], [113], [114], [115], radiologic [116], [117], [118], [119], [120] and mechanistic [121], [122], all using the term ‘sickle vasculopathy’ have been described in the literature. Mechanistically, the term has been used to describe a generalized form

Venous thromboembolism (VTE)

Until recently, venous thromboembolism (VTE) has been overlooked as a cardiovascular complication of SCD. Two retrospective studies based on data from administrative databases of hospital discharge records addressed the risk of VTE in the SCD population [5], [6]. A significantly higher discharge diagnosis of pulmonary embolism (PE) was reported in African-Americans with SCD younger than 40 years than in African-Americans without SCD (0.44% vs 0.12%), although a similar rate of deep venous

Hydroxyurea

Hydroxyurea is approved by the US Food and Drug Administration specifically for treating SCD. It has been shown to reduce the frequency of acute painful episodes, dactylitis, acute chest syndrome, hospitalizations, and the need for blood transfusions in children and adults with sickle cell anemia [162], [163]. Observational studies have reported a reduction of TCD velocity [164], [165], [166], rate of first stroke [167] and the rate of stroke recurrence [168], [169], [170], [171] in SCD

Conclusion

SCD is a hypercoagulable state characterized by chronic activation of coagulation in vivo and increased risk of both arterial and venous thrombosis. There is increasing evidence that the activation of coagulation in SCD is not just a secondary event, but may contribute to disease pathogenesis. Although treatment with hydroxyurea and chronic blood transfusion has important clinical benefits, patients continue to experience clinical complications, including thrombotic complications. Defining the

Practice points

  • -

    Patients with SCD are at increased risk of thrombotic complications.

  • -

    Treatment with hydroxyurea results in decreased frequency of acute pain episodes, acute chest syndrome, transfusion requirement, lower TCD velocity and perhaps mortality.

  • -

    Blood transfusion remains the standard of care for primary and secondary prevention of stroke in SCD.

Research agenda

  • -

    Improvement of our understanding of the role of coagulation and platelet abnormalities in the development of clinical complications of SCD.

  • -

    Define the contribution of the contact system to the pathophysiology of SCD.

  • -

    Need for longitudinal studies to define the effects of hydroxyurea and chronic blood transfusion on coagulation activation in SCD.

  • -

    Need for well-designed clinical trials with new generations of anticoagulants and antiplatelet agents using a variety of clinical endpoints.

Conflict of interest

The authors declare no relevant conflicts of interest.

Funding source

This work was supported by NIH grant U01HL117659. Support for this work was also provided by an award from the North Carolina State Sickle Cell Program.

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