|Year : 2021 | Volume
| Issue : 1 | Page : 1-5
Hemostatic alteration in sickle cell disease: Pathophysiology of the hypercoagulable State
Naif Mohammed Alhawiti
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 Submission||01-Mar-2021|
|Date of Acceptance||18-Apr-2021|
|Date of Web Publication||31-Jul-2021|
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
Source of Support: None, Conflict of Interest: None
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|| |
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.,, SCD is globally affecting around 20–25 million people., In the United States, there are around 75,000–100,000 persons with SCD, and most of them state to be African origin model., Approximately 200,000 kids are annually delivered with SCD, and more than 4 million individuals have heterozygous hemoglobin S carrier (HbSA) in Africa., In Saudi Arabia, Saudi Premarital Screening Program reported that about 4.2% of individuals have HbSA, while 0.26% of individuals with HbSS. 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.,
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.,, 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., 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.,,,, 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.
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, brain (stroke and cerebrovascular accident), spleen (splenic infarction and splenomegaly), lungs (pulmonary embolism),, and heart (myocardial infarction)., 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., 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., The occurrence of thromboembolic complications among SCD patients is a significant contributor to the health burden of SCD in the world., The mechanism of pathological thrombus formation among SCD patients is intricate and involves many factors, all endogenous alterations associated with SCD pathophysiology., 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.,,, 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|| |
The endothelial cell certainly has a significant function in thromboembolic complications among patients with SCD, and a damaged endothelium is documented within those patients., 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., 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., However, upregulation of thrombogenic molecule production significantly enhances pathological vascular progression among patients with SCD., 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.,, 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.,, 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.,,
SCD is distinguished by intermittent painful crises and organ failure that are consequences of microthrombus formation., 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.,, 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.,, 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.,, interaction of leukocytes with activated endothelium and pro-inflammatory events was observed in transgenic sickle cell mice models. 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., 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.,
| Platelet Activation in Sickle Cell Disease|| |
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.,, 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., Activated platelets release many adhered substances such as P selectin,, platelet derived soluble CD40 ligand (CD40 L), platelet factor 4, and proinflammatory cytokines to contribute in the development of atherosclerotic and atherothrombotic mechanisms., Stimulated platelets potentially enhance the interaction of sickle erythrocytes into the impaired endothelium and contribute to thromboembolic complications and pulmonary hypertension. 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., Furthermore, experiments in mice with SCD have shown that the aggregation of thrombocytes and leukocytes are elevated, which significantly contributes to thromboembolism., 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., Consequently, the potential adhesiveness of platelets, leukocytes, and sickle cells significantly enhance hypercoagulability and thromboembolic development among those patients.,
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. Moreover, NO is an important molecule that released from the intact endothelial cells to negatively regulate the platelet function within bloodstream;,, 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., 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., 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. The aggregation between activated platelets and endothelial cells highly enhanced proinflammatory and prothrombotic phenotypes within sickle cell patients.,,
| Coagulation Cascade Activation in Sickle Cell Disease|| |
SCD patients have chronic coagulation factors activation both during a steady state and in the absence of vaso-occlusive crises., 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., 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., This complex triggers the activation of serine proteases, including FIX and FX, with subsequent thrombin generation platelet aggregation and fibrin production. The coagulation reactivity has been well established in SCD that associated with potentiation of chronic inflammation and pathogenesis. Consequently, upregulation and downregulation of thrombogenic factors such as TF-FVII complex, thrombin, fibrinogen, and VWF are also play critical role in SCD thrombogenesis., Furthermore, data evidently revealed increased TF expression derived from monocytes and endothelial during SCD crises. The biomarker evidence indicated an ongoing hypercoagulable state in those patients. 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., In addition, the significant reduction of natural antithrombotic molecules such as NO, antithrombin III, protein C, and protein S, was found in SCD. 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.,
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)., 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.,, 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.,
| Conclusion|| |
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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Al-Qurashi MM, El-Mouzan MI, Al-Herbish AS, Al-Salloum AA, Al-Omar AA. The prevalence of sickle cell disease in Saudi children and adolescents. A community-based survey. Saudi Med J 2008;29:1480-3.
Jastaniah W. Epidemiology of sickle cell disease in Saudi Arabia. Ann Saudi Med 2011;31:289-93.
] [Full text]
Little I, Vinogradova Y, Orton E, Kai J, Qureshi N. Venous thromboembolism in adults screened for sickle cell trait: A population-based cohort study with nested case-control analysis. BMJ Open 2017;7:e012665.
Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:480-7.
Aygun B, Odame I. A global perspective on sickle cell disease. Pediatr Blood Cancer 2012;59:386-90.
Creary M, Williamson D, Kulkarni R. Sickle cell disease: Current activities, public health implications, and future directions. J Womens Health (Larchmt) 2007;16:575-82.
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al.
Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:1033-48.
Babadoko AA, Ibinaye PO, Hassan A, Yusuf R, Ijei IP, Aiyekomogbon J, et al.
Autosplenectomy of sickle cell disease in Zaria, Nigeria: An ultrasonographic assessment. Oman Med J 2012;27:121-3.
Alhamdan NA, Almazrou YY, Alswaidi FM, Choudhry AJ. Premarital screening for thalassemia and sickle cell disease in Saudi Arabia. Genet Med 2007;9:372-7.
Nasserullah Z, Alshammari A, Abbas MA, Abu-Khamseen Y, Qadri M, Jafer SA, et al.
Regional experience with newborn screening for sickle cell disease, other hemoglobinopathies and G6PD deficiency. Ann Saudi Med 2003;23:354-7.
Steinberg MH, Rodgers GP. Pathophysiology of sickle cell disease: Role of cellular and genetic modifiers. Semin Hematol 2001;38:299-306.
Ballas SK, Smith ED. Red blood cell changes during the evolution of the sickle cell painful crisis. Blood 1992;79:2154-63.
Josephs R, Jarosch HS, Edelstein SJ. Polymorphism of sickle cell hemoglobin fibers. J Mol Biol 1976;102:409-26.
Vekilov PG. Sickle-cell haemoglobin polymerization: Is it the primary pathogenic event of sickle-cell anaemia? Br J Haematol 2007;139:173-84.
Embury SH. The clinical pathophysiology of sickle cell disease. Annu Rev Med 1986;37:361-76.
Hidalgo A, Chang J, Jang JE, Peired AJ, Chiang EY, Frenette PS. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nat Med 2009;15:384-91.
Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997;337:762-9.
Zhou Z, Behymer M, Guchhait P. Role of extracellular hemoglobin in thrombosis and vascular occlusion in patients with sickle cell anemia. Anemia 2011;2011:918916.
Scheinman JI. Sickle cell disease and the kidney. Nat Clin Pract Nephrol 2009;5:78-88.
Verduzco LA, Nathan DG. Sickle cell disease and stroke. Blood 2009;114:5117-25.
Olaniyi JA, Abjah UM. Frequency of hepatomegaly and splenomegaly in Nigerian patients with sickle cell disease. West Afr J Med 2007;26:274-7.
Lakkireddy DR, Patel R, Basarakodu K, Vacek J. Fatal pulmonary artery embolism in a sickle cell patient: Case report and literature review. J Thromb Thrombolysis 2002;14:79-83.
Minter KR, Gladwin MT. Pulmonary complications of sickle cell anemia. A need for increased recognition, treatment, and research. Am J Respir Crit Care Med 2001;164:2016-9.
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376:2018-31.
Rickles FR, O'Leary DS. Role of coagulation system in pathophysiology of sickle cell disease. Arch Intern Med 1974;133:635-41.
Stuart MJ, Nagel RL. Sickle-cell disease. Lancet 2004;364:1343-60.
Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, et al.
Effect of physical inactivity on major non-communicable diseases worldwide: An analysis of burden of disease and life expectancy. Lancet 2012;380:219-29.
Wastnedge E, Waters D, Patel S, Morrison K, Goh MY, Adeloye D, et al.
The global burden of sickle cell disease in children under five years of age: A systematic review and meta-analysis. J Glob Health 2018;8:021103.
Francis RB Jr., Johnson CS. Vascular occlusion in sickle cell disease: Current concepts and unanswered questions. Blood 1991;77:1405-14.
Naik RP, Streiff MB, Haywood C Jr., Nelson JA, Lanzkron S. Venous thromboembolism in adults with sickle cell disease: A serious and under-recognized complication. Am J Med 2013;126:443-9.
Kenny MW, George AJ, Stuart J. Platelet hyperactivity in sickle-cell disease: A consequence of hyposplenism. J Clin Pathol 1980;33:622-5.
Kaul DK, Nagel RL, Chen D, Tsai HM. Sickle erythrocyte-endothelial interactions in microcirculation: The role of von Willebrand factor and implications for vasoocclusion. Blood 1993;81:2429-38.
Austin H, Key NS, Benson JM, Lally C, Dowling NF, Whitsett C, et al.
Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007;110:908-12.
Harrison DG, Widder J, Grumbach I, Chen W, Weber M, Searles C. Endothelial mechanotransduction, nitric oxide and vascular inflammation. J Intern Med 2006;259:351-63.
Massberg S, Enders G, Leiderer R, Eisenmenger S, Vestweber D, Krombach F, et al.
Platelet-endothelial cell interactions during ischemia/reperfusion: The role of P-selectin. Blood 1998;92:507-15.
Jackson SP. The growing complexity of platelet aggregation. Blood 2007;109:5087-95.
Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: Structure, function and inhibition. Biochem J 2001;357:593-615.
Lucia De Franceschi M, Cappellini MD, Olivieri O. Thrombosis and sickle cell disease. Semin Thromb Hemost 2011;37:226-36.
Shet AS, Lizarralde-Iragorri MA, Naik RP. The molecular basis for the prothrombotic state in sickle cell disease. Haematologica 2020;105:2368-79.
Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd
, Schechter AN, et al.
Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002;8:1383-9.
Chirico EN, Pialoux V. Role of oxidative stress in the pathogenesis of sickle cell disease. IUBMB Life 2012;64:72-80.
Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 2007;110:2166-72.
Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 2017;127:750-60.
Gladwin MT, Kanias T, Kim-Shapiro DB. Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease. J Clin Invest 2012;122:1205-8.
Pathare A, Kindi SA, Daar S, Dennison D. Cytokines in sickle cell disease. Hematology 2003;8:329-37.
Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin 2005;19:785-802.
De Franceschi L, Cappellini MD, Olivieri O. Thrombosis and sickle cell disease. Semin Thromb Hemost 2011;37:226-36.
Hebbel RP. Adhesion of sickle red cells to endothelium: Myths and future directions. Transfus Clin Biol 2008;15:14-8.
Hebbel RP, Vercellotti GM. The endothelial biology of sickle cell disease. J Lab Clin Med 1997;129:288-93.
Chies JA, Nardi NB. Sickle cell disease: A chronic inflammatory condition. Med Hypotheses 2001;57:46-50.
Matsui NM, Borsig L, Rosen SD, Yaghmai M, Varki A, Embury SH. P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood 2001;98:1955-62.
Embury SH, Matsui NM, Ramanujam S, Mayadas TN, Noguchi CT, Diwan BA, et al.
The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo
. Blood 2004;104:3378-85.
Turhan A, Weiss LA, Mohandas N, Coller BS, Frenette PS. Primary role for adherent leukocytes in sickle cell vascular occlusion: A new paradigm. Proc Natl Acad Sci U S A 2002;99:3047-51.
Kaul DK, Finnegan E, Barabino GA. Sickle red cell–endothelium interactions. Microcirculation. 2009;16:97-111.
Sultana C, Shen Y, Rattan V, Johnson C, Kalra VK. Interaction of sickle erythrocytes with endothelial cells in the presence of endothelial cell conditioned medium induces oxidant stress leading to transendothelial migration of monocytes. Blood 1998;92:3924-35.
Laurance S, Lansiaux P, Pellay FX, Hauchecorne M, Benecke A, Elion J, et al.
Differential modulation of adhesion molecule expression by hydroxycarbamide in human endothelial cells from the micro- and macrocirculation: Potential implications in sickle cell disease vasoocclusive events. Haematologica 2011;96:534-42.
Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002;22:1381-9.
Ni H, Freedman J. Platelets in hemostasis and thrombosis: Role of integrins and their ligands. Transfus Apher Sci 2003;28:257-64.
Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost 2011;105 Suppl 1:S13-33.
Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009;94:700-11.
Romo GM, Dong JF, Schade AJ, Gardiner EE, Kansas GS, Li CQ, et al.
The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med 1999;190:803-14.
Furie B, Furie BC, Flaumenhaft R. A journey with platelet P-selectin: The molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost 2001;86:214-21.
Gibbins JM. Platelet adhesion signalling and the regulation of thrombus formation. J Cell Sci 2004;117:3415-25.
Ruggeri ZM. Mechanisms initiating platelet thrombus formation. Thromb Haemost 1997;78:611-6.
Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002;8:1227-34.
Merten M, Thiagarajan P. P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation 2000;102:1931-6.
Wood KC, Hebbel RP, Granger DN. Endothelial cell P-selectin mediates a proinflammatory and prothrombogenic phenotype in cerebral venules of sickle cell transgenic mice. Am J Physiol Heart Circ Physiol 2004;286:H1608-14.
Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Investig 2000;106:411-20.
Gkaliagkousi E, Ferro A. Nitric oxide signalling in the regulation of cardiovascular and platelet function. Front Biosci (Landmark Ed) 2011;16:1873-97.
Kato GJ, McGowan V, Machado RF, Little JA, Taylor J 6th
, Morris CR, et al.
Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 2006;107:2279-85.
Sparkenbaugh E, Pawlinski R. Interplay between coagulation and vascular inflammation in sickle cell disease. Br J Haematol 2013;162:3-14.
Perelman N, Selvaraj SK, Batra S, Luck LR, Erdreich-Epstein A, Coates TD, et al.
Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood 2003;102:1506-14.
Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, et al.
Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 2004;18:1746-8.
Siljander PR, Munnix IC, Smethurst PA, Deckmyn H, Lindhout T, Ouwehand WH, et al.
Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood. Blood 2004;103:1333-41.
Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: Initiation, maintenance, and regulation. Biochemistry 1991;30:10363-70.
Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2007;27:1687-93.
Hoffman M, Monroe DM. Coagulation 2006: A modern view of hemostasis. Hematol Oncol Clin North Am 2007;21:1-1.
Qari MH, Dier U, Mousa SA. Biomarkers of inflammation, growth factor, and coagulation activation in patients with sickle cell disease. Clin Appl Thromb Hemost 2012;18:195-200.
Lim MY, Ataga KI, Key NS. Hemostatic abnormalities in sickle cell disease. Curr Opin Hematol 2013;20:472-7.
Nasimuzzaman M, Malik P. Role of the coagulation system in the pathogenesis of sickle cell disease. Blood Adv 2019;3:3170-80.
Pakbaz Z, Wun T. Role of the hemostatic system on sickle cell disease pathophysiology and potential therapeutics. Hematol Oncol Clin North Am 2014;28:355-74.
Jones CI, Barrett NE, Moraes LA, Gibbins JM, Jackson DE. Endogenous inhibitory mechanisms and the regulation of platelet function. Methods Mol Biol 2012;788:341-66.
Adam SS, Key NS, Greenberg CS. D-dimer antigen: Current concepts and future prospects. Blood 2009;113:2878-87.
Famodu AA, Adedeji MO, Reid HL. Serial plasma fibrinogen changes accompanying sickle cell pain crisis. Clin Lab Haematol 1990;12:43-7.