History of Sickle Cell Disease
Sickle cells disease is not a new concept. It has been affecting people for many years. It was discovered in 1910 for the first time in the United States in a patient from West Indies by a cardiologist named Herrick. In 1951 a Nobel Prize winner chemist Pauling with his team found that the oxygen-transporting proteins named hemoglobin had an altered structure in a patient with SCD. Ingram and Hunt in 1956 discovered the replacement of glutamic acid by valine on 6th position. In 1970 the relation between the abnormal structure of hemoglobin and RBCs has been discovered. The cure of this disease has been reported by bone marrow transplantation which was applied on a child. The preventive treatment for this disease is proposed in 1995 and to stop the complications of SCD, Hydroxyurea was found to be a proven drug (Information Centre for Sickle Cell and Thalassemia Disorder, 2002). Some of the studies suggested that the history of sickle cell disease is thousands of years old in Africa and known by various different names in different languages (Serjeant, 2013).
Sickle cells disease is a genetic disorder inherited from parents to the children’s. It is associated with defect or abnormality in red blood cells (World Health Organisation, 2006). The normal red blood cells are disc-shaped but the changes occurred in hemoglobin causes the sickle shape of erythrocytes (Brent Sickle Cell & Thalassemia Centre, 2015). These cells with altered shape are rigid and may be burst when transported via blood vessels. This may become the reason for the decreased amount of red blood cells inside the body and causes anemia. When abnormalities or inheritance occur in oxygen-carrying proteins hemoglobin S also called sickle hemoglobin, it leads to the sickle cell anemia (a sickle cell disease). Inheritance word itself indicated that the disease is this disease is transfer to the next generation by passing abnormal haemoglobin genes. Some of the diseases associated to sickle cell disease are: haemoglobin SC disease, sickle cell anaemia and haemoglobin Sβ thalassemia, haemoglobin SS disease, haemoglobin SC, haemoglobin SB 0 or β0 thalassemia, haemoglobin SD, SE and SO (Healthline, 2017). This thesis also involves the discussion of hemoglobin and glycoprotein role in platelet activation and aggregation. Other molecules and processes associated with sickle cell disease also will be discussed. Hemoglobin is the molecule that maintains the highly conserved state in different species within erythrocytes. The main role of hemoglobin is to carry oxygen to various tissues form lungs. Persons with sickle cell disease Hb changes to stiff rods inside the RBCs. Hb the depletion of nitric acid by Hb produces hydroxyl radicals which trigger peroxidation of lipid membrane which results in cellular damage. Increased level of Hb in plasma associated with vascular and organ abnormality like hemolysis. Release of Hb during hemolysis produces ROS, which results in platelet activation (Helms et al. 2013). Various studies suggested that when these Hb binds to GP1bα, the platelet activation has been triggered. This interaction of hemoglobin to GP1bα stimulates some events like change in platelet shape, secretion of granules and signalling process which leads to activate the function of integrin’s. These pathways involved in activation of platelets mediated by GP1bα. This glycoprotein is a surface membrane of platelet is consists of heterodimers where one alpha chain and one beta chain linked to each other via a disulfide bond. This glycoprotein works as a receptor for VWF (Madabhushi, Zhang, Kelkar, Dayananda, and Neelamegham, 2014). It is also initiated events of intracellular signaling like the increased level of calcium in the cytoplasm, protein kinase pathway activation which leads to activation of platelets. The initiation of GP1b alpha by Hb is responsible for platelet apoptosis (Annarapu, Singhal, Sheetal, Ojha and Guchhait, 2016).
Causes of Sickle Cell Disease
Some methods like measurement of platelet activation markers by using flow cytometry, extracellular hemoglobin measurement by using ELISA, Coagulation essay, VWF: RCO assay and platelet activation will be discussed in this dissertation to understand the activation of platelets by binding of Hb to GP1bα. The epidemiological aspects, genetical aspects involved in this study will also be discussed to provide a better understanding of this topic.
The Normal haemoglobin is composed of total four protein chains and about four short non protein molecules called heme. There are two alpha globin chains and two beta globin chains in single haemoglobin. Each globin chains associated with heme prosthetic group, it is the site for binding and release of oxygen. During binding and release of an oxygen compound a αβ dimer moves (Weatherall and Clegg 2001). Haemoglobin S which is the altered form of normal haemoglobin is a tetramer contains four subunits, where two subunits are of α and other two are beta globin. The structure of two alpha subunits is same as in normal haemoglobin but beta subunits are different. These subunits are the site for valine residues substitution to glutamic acid. Alpha subunit contains 141 amino acids and on the other hand primary structure of beta subunit has 146 amino acid (Marengo-Rowe, 2006). There are single heme binding sites for all four subunits; these sites are responsible for oxygen transport. The secondary structure of haemoglobin s contains complete alpha helicase which is separated and joint by random coils. In secondary structure there is no beta sheet. Both alpha and beta subunits made consists of eight alpha helicase. The binding between these four subunits is strongly bounded with salt bridges and hydrogen bonds (Mackey, no date). The tertiary structure is similar as secondary. In quaternary structure there are two confirmations called T and R protein states are same as wild-type hemoglobin A R confirmation which is open and in the mobile state responsible for keeping home binding pocket open. These pockets also unhindered by salt bridges and hydrogen bonds. At the distal end of an alpha chain between heme binding pockets the T state has been constricted and stabilize by salt bridges. In a normal haemoglobin A, this T confirmation accounts for decreasing oxygen affinity. It is also responsible for promoting polymerisation of haemoglobin S in haemoglobin S both the subunits are divided as valine acceptors and donors. The polymerisation occurred in Hb S is a primary pathogenic event that occurs in SCD (Steinberg, 2018).
In a hydrophobic binding pocket the donating subunit contains beta val- 6 and accepting beta subunit receives beta val-6. There are two residues in acceptor beta chains: BetaPhe-85 and BetaLeu-88. There is a seven double-stranded structure has been found in hemoglobins tetramer after betaGlu-6 to betaVal-6 mutation. These strands are twisted toward one another with the helical pitch of 2,900 Å. The basic fibre of haemoglobin is 210 Å thick. The building blocks of this fibre is called Wishner-love double strand which contains single helical twist (Roufberg, and Ferrone, 2000).
Associated Diseases
Sickle cell disorder has been found to be the most common monogenic disorder which has affects many peoples every year in all over the world. About 5- 7 % of the total population of the world affected by the abnormality in hemoglobin gene and sickle cell disease is found to be most common. In Africa and Asian region, this disease impacts with the greatest burden and the prevalence are ranges from 10 to 45 % in various areas of Africa. Particularly in Nigeria Carrier prevalence is approximately 20 to 30 %. Sickle cell disease affecting 2 to 3 % of the total population of Nigeria which is more than 160 million. https://www.hindawi.com/journals/anemia/2015/791498/. According to a study conducted by Jastaniah (2011) this severe disorder affected around 72,000 people in the United States, more than 200000 infants in Africa are born every year with sickle cell disease. Around 250,000 children are born yearly with sickle cell anemia in all over the globe. Particularly in Brazil 2500 children’s are born annually with SCD. Among the non-white population which is 44.66 % by 2000, of Brazil around 1 to 6 % found to have Hb S gene (Lervolino, Baldin, Picado, Calil, Viel and Campos, 2011). This is expected that by 2050 the number of affected children will be reached to 400000 and the number of this disease cases will be increased nearly 30 % in all over the world. Mostly it will affect sub-Saharan Africa (DeBaun and Galadanci, 2018).
It was also estimated that SCD affects 100000 people approximately. It has been studied that prevalence of affected infants is 2.55 per 1000. Mostly the children with the traits of this disease born in high-income countries and survives but in low-income countries the children with this disorder die earlier the developed countries facilitate diagnosis and care for the patient which becomes the reason of survival for them but on the other hand in poor countries, the children were not diagnosed. (Before 5 years of age). Now talking about mortality this disorder accounts for 3.4 % of mortality among 5 years aged children’s globally and 6.4 % particularly in Africa (Piel et al. 2013). It was also estimated that 10 to 40 % population carries the gene of sickle cell and results in 2 % SCD prevalence. Hemoglobin disorders were affecting 75 % of birth but now it is common in 89 % of births in 71 % of countries. A significant variant of this disorder has been carried by around 5.2 % of the total population and around 1.1 percent couples are at risk of giving birth with hemoglobin disorders worldwide. In western Pacific region among all the population of 1761 million 2 % of births are recorded under 5 % mortality and in South East Asia it is 1.6 %.
In urban areas of Britain, sickle cell disease is common and they estimated that in London nearly 2000 patients are affected by this disorder. Nearly 14000 people in UK living with sickle cell disease which is equivalent to 1 in 4600 person. Screening of infants indicated that 1 in every 2000 screened with positive SCD. Another study published in journal of clinical pathology shows reported that SCD is became common disease in England. It was also reported that 1.47 % of all infants in England born with sickle cell gene. Geographical frequency has been highlighted and it was found that in London and nearby urban area babies are affected more. With Highest prevalence of the traits of sickle cell particularly in Africa occurs between a latitudes of 15 degree north and 20 degree south with prevalence rate of 10 % to 40 %. A Study conducted by Agasa et al. (2010) stated that around 19 % neonates found to have defected haemoglobin level. In that it was also reported after studying 2000 infants in a hospital of Tanzania that the haemoglobin levels altered in the bases of geographical regions.
Role of Hemoglobin and Glycoprotein in Platelet Activation and Aggregation
The parents from coastal areas had 35.6 % incidence rate among their new-borns and 6.7 % in northern areas (Mulumba and Wilson, 2015). As the awareness and knowledge has been raised in various countries about this disease results in increasing the number of survivals, specifically in Africa around 40% population is now urbanised and the healthcare facilities are improved in past few years. Low cost and simple mechanisms to diagnose adult and children’s are there now. World health organisation indicated that around 50 % of participated states will be having SCD control program in coming few years. Prevalence of positive tests found particularly in England was 1:2000. Among 5.2 percent patient with sickle cell disease suffers severe pain 3 to ten times in a year (Yale, Nagib, and Guthrie, 2000). It was estimated that prevalence of this-this disease carriers in twenty-five states of Europe is nearly 1/150 (Orphanet, 2018).
Sickle cell disease is inherited in the pattern of autosomal recessive which indicates the two copies of gene in every cell develop mutation (Genetic Home Reference, 2018). Autosomal word refers to that mutation is not only occur in X and Y chromosome therefore it affects both male and females. The recessive word indicates that the mutation have to be there in both the parents if it going to occur in new-born. When both male and female carries asymptomatic genetic disease, each infant has probability of 25 % to receive defective genes, 50% chances of having one abnormal gene and 25 % chances of acquiring unaffected genes. The infants may have a trait of sickle cell if particularly one parent is affected with the disease. The children do not have side effects if only one gene is mutated (Smith, 2015). . The genes that is responsible for controlling the production of protein in RBCs, (red blood cells) known as haemoglobin. Haemoglobin attached O2 in lungs and transfers it to peripheral tissues like liver and muscle. Some of the person has one normal and one sickle haemoglobin gene. This is known as sickle cell trait. A person with this trait has less probability of developing sickle cell disease with increasing age. On conception time People may receive a gene of sickle cell or not. That is why sickle cell trait and sickle cell disease cannot contract. If an infant is born with the traits of sickle cells will be having this trait throughout his or her life. The same will happened if the baby is born with sickle cell genes. Illness is not occurred in the case of sickle cell traits. With the time the sickle cell severity can be changed which is not because of change in genes of sickle cell (Frenette and Atwah, 2007). People with inherited sickle hemoglobin genes develop sickle cell disease.
The above diagram shows the inheritance pattern of sickle cell disease from parents to their children it also shows the ratio and probability of occurrence of this disorder in next generation. According to an article published in Genesis international by Agbabiaka (2015), a person inherits a single set of genes from mother or father to their children. It has been reported that either two normal HbA genes can be inherited in a person, one unaffected gene and one abnormal gene (HbS), or two mutated genes, which depends on parent genes composition. When a single HbS and one HbA gene carried by a person, the normal gene may overcome the effects of abnormal hemoglobin gene, to stop the occurrence of symptoms of SCD. This type of person has sickle cell traits and acts as a carrier for these traits and may transfer it to their babies. When a baby inherits two affected HbS genes from both the parents, they develop sickle cell disease. They carry only affected genes to transfer to their children.
Methods for Studying Platelet Activation
As mentioned above hemoglobin consist four subunits of protein. HBB gene provides messages for making beta globin. The mutations occur in this gene causes different versions of beta globin. Single specific HBB gene mutation results in an affected beta globin called Hemoglobin S. Various other mutation occurs in this gene causes a decreased level of beta globin, this abnormality is known as beta thalassemia. In a person with SCD one beta globin is replaced by hemoglobin S in hemoglobin subunits but on the other hand in sickle cell anemia both beta globins has been changed with hemoglobin S.in other disease related to sickle cell single subunit is replaced with HbS in hemoglobin. Other subunits have been replaced with various effected variants like hemoglobin C. People with HbS thalassemia disorder have mutation where hemoglobin S and beta thalassemia occur together. The defected versions of this beta globin cause red blood cells to become sickle-shaped. The death of these immature RBCs results in anemia (Genetic Home References, 2018)
An abnormal hemoglobin is produced because of point mutation occurred in Beta-globin gene. The mutation occurred in the beta-globin gene where the 17th nucleotide is exchanged from thymine to adenine and instead of 6th amino acid becoming glutamic acid it changes to valine. A hydrophilic motif has been produced in an HbS tetramer and leads to binding between beta 1 and beta 2 chains of 2 molecules of hemoglobin (Rees, Williams and Gladwin, 2010). A polymer has been produced by this crystallization, which grows and ensures the filling of erythrocyte; it also disrupts the structure and flexibility and leads to dehydration in a cell. The extension and rate of polymerization in sickle hemoglobin is same as to the extension and timespan of deoxygenation in hemoglobin, in erythrocyte the fetal hemoglobin is present which results in the reduction in HbS concentration (Vekilov, 2007). The determination of severe SCD is mainly depended on the rate and extent of polymerization in HbS. Similarly by inhibiting the transport of cation channels stops dehydration of erythrocyte and reduced concentration of HbS, hemolysis reduction; hemoglobin concentration is increased by hydroxycarbamide, hemolysis reduction, and acute vaso-occlusion prevention. The pathophysiological process is involved to trigger these manifestations: one is vaso occlusion and another one is hemolytic anemia.
Vaso occlusions are found to be the hallmark of SCD. VOC involved in pain occur in various parts of the body such as legs, back, knees, chest, and stomach. The acute vaso occlusion has occurred when erythrocyte and leucocyte entrapped in microcirculation, which results in vascular obstruction and ischemia of tissues. HbS polymerisation is required for this process to be occurred. Among the hemolytic anemias, the vasculopathy of SCD makes it different. Vaso occlusion is depended upon features of erythrocyte such as the content of the polymer, cellular damage which interacts with factors associated with the environment of the cell, endothelial injury, the vascular tone and other cells (Manwani and Frenette, 2013). The initial pain occurred is associated with the reduction of dense cells, this gives an idea that less dense cells might be the reason for vaso occlusion. At that time microvasculature, the dense cells have been destroyed. The adhesive interaction has been enabled by cellular damage between sickle cells, the endothelial cells and white blood cells. Another term associated with vaso occlusion is vaso-occlusive crisis also known as sickle cell crisis is occurred due to the injury of ischemic tissues. Chronic pain has been reported in patients with SCD which is caused due to the destruction of bones. Factors involved in VOC are less oxygen level, dehydration, acidosis and many more. Studies evidenced that hemolysis may triggers VOC (Chiang and Frennete, 2005).
Epidemiological and Genetic Aspects
Another process of pathophysiology in SCD is hemolytic anemia initiated by HbS polymerization. Hemolysis is found to be the reason of anemia and lethargy, but some of the studies show that it is also associated with progression of vasculopathy. It has been also studied that glycoprotein is also associated with SCD. According to a study published in Blood Advances Journal vaso occlusion triggers acute painful VOC (vaso occlusive crisis) and increase in blood platelets and leukocyte counts are associated with VOC. In SCD patient the elevation of aggregated neutrophil platelet in blood circulation has been reported. The neutrophil-platelet aggregation enabled by neutrophils binds to glycoprotein Ibα or GPIbα on platelets. Binding site Mac-1 is found within terminal flanking regions of leucine-rich COOH. (Jimenez, Novelli, Shaw and Sundd, 2017).
Interaction of GP1bα to binding site Mac-1 also takes part in an aggregation of neutrophil-platelet in sickle cell disease and the antagonist of GP1bα can be beneficial to stop VOC. Alpha IIb and beta3 integrin also mediate adhesion and aggregation of platelets (Estevez and Du, 2017). Some of the studies also mentioned the role of VWF in the pathophysiology of sickle cell disease. Activation of VWF (von Willebrand Factor) by endothelial cells in large quantity is able to bind platelets and erythrocytes mostly sickle cells. Increased plasma levels of VWF observed in sickle cell disease (Chen, Hobbs, Le, Lenting, Groot and López, 2011). VWF triggers the adherence of platelet to collagen with the help of GP1b receptor.
Platelet activation and aggregation
The platelets found in blood are the important mediators, which starts the pathway of the coagulation cascade. The platelets circulate in vessels are undamaged and they remain in their unactivated state. In the absence of factors that activates platelets and prostacyclin release by healthy endothelium takes part to maintain this state. The Activation, adhesion, and aggregation processes involved in hemostasis which is encouraged by platelets. This function has been regulated by the involvement of ADP (adenosine diphosphate) the aggregation process has been induced by stimulation of 2 different ADP receptors that are: P2Y1 and p2Y12 (Periayah, Halim, Yaacob, Saad, Hussein, Rashid and Ujang, 2014). In persons with sickle cell disorder, the in-vitro aggregation of platelets to respond for epinephrine and ADP were found to be decreased (DeBaun, 2016) the fast flow shear pressure also takes part in, activation and aggregation of platelets. When there is a break in endothelium by platelets, it activates molecules that start the activation process. One of the molecules is collagen which can be found in every part of the body except the inner side of blood vessels. Some of the other factors associated with activation of platelets are thromboxane, A2, ADP, and thrombin.
When a platelet is activated the changes occurred are
- The alpha granules and the beta granules undergo exocytosis.
- Phospholipase A2 which is the enzyme of a membrane is activated which results in thromboxane A2 formation.
- Change in the shape has been formed with Projecting fingers.
Platelets attached to other platelets and collagen inside endothelium results in the formation of the platelet plug. Glycoproteins like GPIb, GPIIa, and VWF receptors adhere on the surface of platelets which is already activated. The attachment of platelets to each other caused by binding of fibrinogen GPIIb and GPIIa. Collagen reaction takes place on the surface (Sangkuhl, Shuldiner, Klein Altman, 2011).
The activations of platelets by thrombin is an important process to form hemostasis and thrombin. Platelets are activated through thrombin by cleaving an N-terminal region of GPCPAR) G-protein coupled protease-activated receptor. GPIb which acts as a thrombin binding site also takes part in the platelet activation by lowering the thrombin concentration. Glycoprotein Ib is an important component of platelet membrane which takes part in adhesion of platelet to VWF on the damaged vascular walls. The subunits of glycoprotein such as GPIbα and GPIbβ found to be associated with GPIX and GPV (Adam, Guillin and Jandrot-Perrus, 2003).
The platelet activation has been found to be another factor of hemostatic activation in SCD patient. During the steady state in patients, the platelets are activated and this increases during a crisis of Vaso- occlusion. The activation of platelets may also contribute to Sickle cells adhesion to human vascular endothelium with the help of thrombospondin secretion, and this may induce hypertension and thrombosis in Sickle cell disease. Aggregation formation may also occur due to binding of platelets to red blood cells (RBC), monocytes and neutrophils m (Polanowska-Grabowska, Wallace, Field, Chen, Marshall, Figler, Gear, and Linden, 2010). Binding of activated platelet and neutrophils results in aggregation in the P-selectin dependent manner. Various studies have reported that vassal occlusion in SCD is occurred due to the contribution of hypercoagulation and thrombosis. The free Hb abundance in circulation found to be the major contributor in platelet activation, which changes the platelet functions by maintaining the limitation of nitric acid bioavailability. The study indicated that particularly mature Hb can directly bind to GP1bα on the surface of platelet and initiate its activation. It has been also reported that sickle hemoglobin also attached to GP1bα on platelets and start its activation. Thrombus formation has been promoted by activation of platelets which is mediated by HbS. The increased plasma Hb is related to the platelet activation in SCD patients. Collagens also contribute to initiating platelet activation under static condition. Collagen receptors (α2β1 and GPVI) directly bind to collagen.
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