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 Table of Contents  
Year : 2021  |  Volume : 6  |  Issue : 1  |  Page : 1-5

Hemostatic alteration in sickle cell disease: Pathophysiology of the hypercoagulable State

Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

Date of Submission01-Mar-2021
Date of Acceptance18-Apr-2021
Date of Web Publication31-Jul-2021

Correspondence Address:
Naif Mohammed Alhawiti
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, P.O. Box 22490, Riyadh 11481
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/KKUJHS.KKUJHS_7_21

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Sickle cell disease (SCD) is a monogenic genetic disease inherited in an autosomal recessive manner and distinguished by the presence of defective hemoglobin, known as homozygous sickled hemoglobin disease (HbSS). Sickled red blood cells lead to blood vessel obstruction, hemorrhage, and critical hemostatic function alterations. Defective hemoglobin that associated with serious health problems, such as thromboembolism among SCD patients, is clearly documented. Empirical evidence indicates that hypercoagulability states and proinflammatory phenotypes in patients with SCD are a substantial contribution of thromboembolic complications, with promoting morbidity and mortality. This review discusses the involvement of vascular endothelial cell, platelet, and coagulation cascade in the thrombogenesis of SCD.

Keywords: Hypercoagulability, sickle cell disease, thromboembolic events

How to cite this article:
Alhawiti NM. Hemostatic alteration in sickle cell disease: Pathophysiology of the hypercoagulable State. King Khalid Univ J Health Sci 2021;6:1-5

How to cite this URL:
Alhawiti NM. Hemostatic alteration in sickle cell disease: Pathophysiology of the hypercoagulable State. King Khalid Univ J Health Sci [serial online] 2021 [cited 2022 May 27];6:1-5. Available from: https://www.kkujhs.org/text.asp?2021/6/1/1/322886

  Introduction Top

Sickle cell disease (SCD) is known as a congenital qualitative disease and is widespread within the Mediterranean basin, Africa, and Middle East and Southeast Asia, leading to severe morbidity and mortality.[1],[2],[3] SCD is globally affecting around 20–25 million people.[4],[5] In the United States, there are around 75,000–100,000 persons with SCD, and most of them state to be African origin model.[6],[7] Approximately 200,000 kids are annually delivered with SCD, and more than 4 million individuals have heterozygous hemoglobin S carrier (HbSA) in Africa.[2],[8] In Saudi Arabia, Saudi Premarital Screening Program reported that about 4.2% of individuals have HbSA, while 0.26% of individuals with HbSS.[2] However, the incidence of HbSS in Saudi Arabia is slight variations from province to another. The highest incidence of HbS gene was found within the Eastern and Southwestern province, with about 17% for the carrier status and 1.2% for the disease.[9],[10]

SCD is a chronic hemolytic anemia formed by nucleotide substitution made inside the β-globin chain. Consequently, substituting the amino acid glutamic acid at the sixth position by valine inside the beta-globin gene leads to the production of HbS, as a mutated version of hemoglobin.[11],[12],[13] As stated in the literature, the characterizations of HbS molecular basis are well identified, but the clear pathogenesis of thromboembolic complications and microvascular occlusion crisis remains not fully illustrated. Polymers of HbS molecules inside erythrocytes that are due to biochemical dysfunction of mutant hemoglobin are associated with the development of HbS.[11],[14] During deoxygenated HbS, polymerization is recruited to form a fibrous network that significantly promotes sickling red cells development and augmented red cell rigidity and raised blood viscosity, which leads to slow blood flow and blood vessel occlusive progression. Episodic hemolysis and vaso-occlusive crisis are the major pathogenic processes associated with SCD.[14],[15],[16],[17],[18] The intricate pathophysiology of genetic abnormality in SCD implicates the reactivity of coagulation pathways and endothelial cells, evidenced by the elevated risk of thromboembolic events.[11]

Circulating rigid and sickled erythrocytes significantly enhance the development of acute and/or chronic vascular occlusion and thrombosis, which could potentiate serious complications within multiple organs of SCD, such as sickle cell nephropathy,[19] brain (stroke and cerebrovascular accident),[20] spleen (splenic infarction and splenomegaly),[21] lungs (pulmonary embolism),[22],[23] and heart (myocardial infarction).[17],[24] Conversely, destruction of the red blood cell (RBC) membrane, which is initially thought to be due to intracellular HbS polymerization, leads to chronic hemorrhage episodes among SCD patients.[15],[24] In addition, intravascular hemolytic anemia is occurred as a result of the associated of blood vascular damage and hemostatic alterations, including endothelial dysfunction and impaired coagulation system, which are involved in the background of genetic susceptibility.[25],[26] The occurrence of thromboembolic complications among SCD patients is a significant contributor to the health burden of SCD in the world.[27],[28] The mechanism of pathological thrombus formation among SCD patients is intricate and involves many factors, all endogenous alterations associated with SCD pathophysiology.[15],[29] As stated in the literature, a hypercoagulable state, endothelial dysfunction, platelet activation, increased leukocyte recruitment, increased tissue factor expression, and deceased nitric oxide (NO) are believed to contribute to pathogenesis in SCD, triggering primary or secondary clinical manifestations.[16],[25],[30],[31] This review discusses the hemostatic alteration in SCD and emphasizes on the impact of endothelial cell, platelet, and coagulation abnormalities in the progression of thromboembolic complications.

  Endothelial Cell Dysfunction in Sickle Cell Disease Top

The endothelial cell certainly has a significant function in thromboembolic complications among patients with SCD, and a damaged endothelium is documented within those patients.[32],[33] It is well elucidated that healthy endothelial cells play an important function in the production of enormous molecules that maintain and regulate vasomotor tone, blood fluidity, and thromboresistance.[34],[35] In addition, endothelial cell has important function in the regulation of platelet and coagulation functions through secreting vasodilator molecules, such as NO and prostaglandin, as well as producing vasoconstrictor molecules, such as endothelin and angiotensin.[36],[37] However, upregulation of thrombogenic molecule production significantly enhances pathological vascular progression among patients with SCD.[38],[39] Increased generation of reactive oxygen species (ROS) accompanied with a reduction in NO bioavailability concentration is involved in the stimulation of protein kinase C, which plays a crucial role in SCD-mediated endothelial abnormality.[32],[40],[41] As a consequence, it increases NO consumption and secretes arginase into circulation, resulting in resistance to NO-dependent vasodilation affects, which significantly recruit the progression of pulmonary hypertension and eventually lead to shortened life expectations of SCD patients.[42],[43],[44] Dysregulation of adhesive substances and production of proinflammatory molecules, such as cytokines, chemokines, and generation of plasminogen activator inhibitor and tissue factors, potentially contribute to the enhancement of inflammatory responses and prothrombic phenotypes in SCD.[32],[37],[45]

SCD is distinguished by intermittent painful crises and organ failure that are consequences of microthrombus formation.[17],[46] Furthermore, damaged endothelial cells are interacted with sickle erythrocyte to contribute in the occurrence of vascular thromboembolism in those patients. In the literature, dysregulation of multiple adhesion molecules in sickle erythrocytes significantly promotes sickle erythrocyte adhesion into platelets and leukocytes in vivo.[47],[48],[49] Although patients with HbSS have leukocytosis (high white blood cell counts) in the bloodstream, those patients commonly suffer from the recurrence of infections subsequent to the incidence of thromboembolic events.[11],[45],[50] It is stated that the interaction of circulating leukocytes with sickle red cells through binding their ligand which called P selectin glycoprotein ligand 1 (PSGL-1), and relocated on the surface membrane of activated endothelium significantly causing sluggish blood flow and enhances microvascular occlusion formation.[32],[51],[52] interaction of leukocytes with activated endothelium and pro-inflammatory events was observed in transgenic sickle cell mice models.[53] As cited in the literature, many vascular cell adhesion molecules including vascular cell adhesion molecule, and intercellular adhesion molecule and E-selectin, are significantly induced and expressed result in increased circulating sickle cells that amplify oxidative stress.[32],[54] As consequences of expression these proinflammatory adhesion molecules, vasoconstriction and hemostatic dysfunction are significantly promoted amplified which lead to the enhancement of thrombogenesis in SCD patients.[55],[56]

  Platelet Activation in Sickle Cell Disease Top

Platelets are well known as important components of hemostasis and they also have a central function in pathological thrombus formation through the secretion of adhesive substances by their interaction with activated endothelial cells.[57],[58],[59] In normal conditions, platelets circulate within the blood vessels in inactive conditions. However, platelet activation is initiated when they roll and adhere to the injured endothelial cells that are exclusively regulated by the binding platelet surface receptors, glycoprotein VI and glycoprotein Ib/IX/V, with their ligands collagen and the von Willebrand factor (VWF), respectively.[60],[61] Activated platelets release many adhered substances such as P selectin,[62],[63] platelet derived soluble CD40 ligand (CD40 L), platelet factor 4, and proinflammatory cytokines to contribute in the development of atherosclerotic and atherothrombotic mechanisms.[64],[65] Stimulated platelets potentially enhance the interaction of sickle erythrocytes into the impaired endothelium and contribute to thromboembolic complications and pulmonary hypertension.[31] Activated platelets can also be aggregated with leukocytes, mainly neutrophils, and monocytes, which is apparent by the exposure of thrombocytes bioactive markers included P-selectin and CD40 L.[31],[66] Furthermore, experiments in mice with SCD have shown that the aggregation of thrombocytes and leukocytes are elevated, which significantly contributes to thromboembolism.[67],[68] The occurrence of vaso-occlusion events is highly promoted by interaction of sickle erythrocytes to thrombocytes and vascular endothelium that because of the existence of enormous thrombogenic adhesion substances.[25],[54] Consequently, the potential adhesiveness of platelets, leukocytes, and sickle cells significantly enhance hypercoagulability and thromboembolic development among those patients.[29],[47]

Hemorrhage episodes with the secretion of RBC-free hemoglobin due to intravascular hemolysis display substantial platelet activation in vivo and propose that hemorrhage is a possible mechanism that participates in platelet reactivity and thrombus formation.[44] Moreover, NO is an important molecule that released from the intact endothelial cells to negatively regulate the platelet function within bloodstream;[37],[63],[69] however, SCD patients produce great levels of ROS, which interact with NO in the vascular system and lead to NO bioavailability reduction. Consequently, diminished NO bioavailability has been found to be a natural defective endothelial function and to contribute in the mechanism of thrombus formation among SCD patients.[70],[71] In addition, SCD has increased secretion of circulating plasma-free hemoglobin to consume NO molecules, to generate inert nitrate as well as methemoglobin, which is disabled for carrying oxygen.[72],[73] Therefore, the activation of platelets is not just a secondary episode participating in the promotion of pathologic thrombosis; but it also contributes to vascular inflammation.[36] The aggregation between activated platelets and endothelial cells highly enhanced proinflammatory and prothrombotic phenotypes within sickle cell patients.[31],[55],[67]

  Coagulation Cascade Activation in Sickle Cell Disease Top

SCD patients have chronic coagulation factors activation both during a steady state and in the absence of vaso-occlusive crises.[11],[20] In normal situations, activation of the extrinsic coagulation cascade (FVIIa) and intrinsic coagulation cascade (FXIIa, FXIa, FIXa, and FVIIIa) subsequently induces common coagulation pathways (FXa and FIIa), which convert fibrinogen to soluble fibrin. At last, insoluble fibrin is mediated by FXIIIa and linked with activated platelets to generate solid fibrin clots.[74],[75] Tissue factor (TF) is a transmembrane protein that derived from endothelial cells and monocytes to act as a chief motivator of coagulation pathways through binding with factor VII to form the TF-FVII complex.[59],[76] This complex triggers the activation of serine proteases, including FIX and FX, with subsequent thrombin generation platelet aggregation and fibrin production.[77] The coagulation reactivity has been well established in SCD that associated with potentiation of chronic inflammation and pathogenesis.[78] Consequently, upregulation and downregulation of thrombogenic factors such as TF-FVII complex, thrombin, fibrinogen, and VWF are also play critical role in SCD thrombogenesis.[76],[78] Furthermore, data evidently revealed increased TF expression derived from monocytes and endothelial during SCD crises.[78] The biomarker evidence indicated an ongoing hypercoagulable state in those patients.[71] The augmentation of TF expression, thrombin generation, and fibrinogen concentration with accompanying diminishment of coagulation factor levels, such as Factors VII, X, and XII, are documented in individuals with homozygous HbS in a steady state.[1],[78] In addition, the significant reduction of natural antithrombotic molecules such as NO, antithrombin III, protein C, and protein S, was found in SCD.[79] Moreover, the available data showed a prolongation in both prothrombin time (measuring extrinsic coagulation cascade) and activated partial thromboplastin time (measuring intrinsic coagulation cascade) but a shortened thrombin clotting time in the plasma of SCD patients.[80],[81]

A defective fibrinolytic system was observed in SCD, which is further biomarker evidence for a hypercoagulable state. Fibrin clot degradation is primarily mediated by plasminogen activator inhibitor type 1 (PAI-1) that is derived from endothelial cells and thrombocytes to inactivate tissue plasminogen activator, thus preventing the cleavage of plasminogen to plasmin (active form).[77],[82] Plasmin is a nonspecific proteolytic enzyme able to lyse the fibrin clots in degradation products, being a D-dimer, and these degradation fragments are extensively used as activating markers for coagulation pathways.[77],[81],[83] In addition, increased levels of D-dimer and decreased PAI-l levels are reported in patients with HbSS both a noncrisis condition and vaso-occlusive crisis compared to healthy individuals.[33],[84]

  Conclusion Top

SCD is considered as a public health crisis associated with hypercoagulable state that contributes to augmented risks of thromboembolic events, leading to a significant morbidity and mortality. The hypercoagulable condition within those patients will be high complex in the existence of risk factors of thromboembolism. Accumulative data evidence proposes that the thrombogenic tendency in SCD patients is related to different underlying pathophysiological mechanisms, including endothelial dysfunction, platelet activation, and coagulation reactivity. Future research investigated on the influence of risk factors of thromboembolism on the incidence of vaso-occlusive crisis among these people will explain the certain risk of thrombotic phenotypes in SCD patients.

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