HAEMATOLOGY

It is the process of the formation of blood cellular components. Erythropoiesis is the process of erythrocyte or RBCs production. Erythrocytes descend from complex line of cells, and the production process is strictly regulated to maintain adequate number of erythrocytes in blood and to avoid overproduction. Each day, 2.5 billion red cells/kg are produced. 

Erythropoiesis production sites vary between age milestones. In adults, bone marrow in only certain bones is capable to do erythropoiesis, these include vertebrae, ribs, sternum, sacrum, pelvis and proximal femur. Some medical cases cause extra needs to produce erythrocytes such as haemoglobulinopathies that may include thalassaemias, sickle cell disease and myelofibrosis. On the other hand, erythropoiesis in children occur in the bone marrow of any bone. In the early fatal life, yolk sac is responsible for this process, then liver and spleen take the place from 2 – 5 months of gestation, after this period, it would be as in children. 

All blood cells (RBCs, WBCs and platelets) begin as a multipotent hematopoietic stem cell (HSC) or haemocytoblast. HSC will become common myeloid progenitor (CMP) cell. In turn, CMP may differentiate into a red blood cell, platelet or mast cells. CMP cell that differentiates eventually to an erythrocyte is developed into megakaryocyte-erythroid progenitor cell (MEP).To become an erythrocyte, MEP becomes eryhthroblasts or normoblasts. Normoblasts pass a losing nucleus process to become reticulocytes. Reticulocytes considered as immature RBCs. Normally, they only present 1-2% of erythrocytes in blood. Eventually, reticulocytes lose their organelles to become mature red blood cells. Maturation process of erythrocytes could also detect some blood abnormalities by the presence of immature or nucleated red blood cells in blood or bone marrow sample. This can occur in pathology such as thalassaemias, severe anaemia or haematological malignancy.

Erythropoietin (EPO) is a glycoprotein cytokine hormone produced by peritubular cells in kidneys. It is always present in tiny amounts to regulate the process of erythropoiesis. A feedback loop run this process strictly. When partial pressure of oxygen (pO2) in kidney is reduced due to hypoxic status, renal interstitial peritubular cells respond by a rise in EPO secretion. This leads to a rise in pO2 levels due to increase haemoglobin levels, in turn EPO levels fall again and the loop is complete. 

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Erythrocytes or red blood cells (RBCs) are the most common formed element of blood. A male and female human have around 5.4 million and 4.8 million per µL respectively. Their main function is to carry gases through specific protein called hemoglobin (Hb). Hemoglobin levels are normally 14-17 g/dL for males and 12-15 g/dL for females. Erythrocytes are empty of nucleus and most organelles. They have biconcave disk shape, which prove greater surface area for gas exchange. They have also specific proteins in cell membrane which allow them for stack, bend and flex. RBCs typically degenerate in about 120 days. Hematocrit or packed red cells volume is the percentage of RBCs in blood. It is a measurement test according to the number and size of erythrocytes. 

Bone marrow is the center of erythrocytes production. It has two distinct areas red and yellow; both contain blood vessels and capillaries. In adults, these two areas are almost equal, but a person is born with whole red bone marrow, then part of is transformed to yellow gradually by age. Red bone marrow produces erythrocytes in a process called erythropoiesis from erythrotropietic cells, a type of haematopoietic cell, which are stem cells responsible for producing blood cells. Another type of stem cells presented in bone marrow are stromal cells, which produce fat, cartilage and bone. Erythropoiesis is triggered by EPO or Erythropoeisis stimulating hormone. 

Leukocytes are commonly known as WBCs. A human body contains normally 4000 to 11,000 per µL. They are whole cells of nuclei and organelles. They have distinctive ability to move by a process called margination. WBCs also have the ability to being attracted to chemicals which called chemotaxis. Of course, they have immune functions against pathogens, toxins, eliminating wastes and abnormal or damaged cells. 

By staining blood cells, scientists observed two types of leukocytes: (1) Granular leukocytes which contain granules within cytoplasm, and include neutrophils, eosinophils, basophils and (2) Agranular leukocytes which do not have granular appearance and include monocytes and lymphocytes. 

Platelets are also called thrombocytes, and account normally 150,000–400,000 per µL. They play a major role in hemostasis. Although the name may suggest that platelets are type of cells, but this is not accurate. They considered as fragments of cytoplasm, surrounded by membrane, and lack of nucleus or organelles except for mitochondria with mitochondrial DNA. Third of platelets amount migrate to spleen and act as a reservoir, in case of further demands of platelets. Platelets normally live 7-10 days. 

Megakaryocytes, which considered the largest progenitor cells of the bone marrow, are the site of platelets production. Platelets are characterized by the presence of two major storage granules: α and dense granules. α granules are more abundant, and contain coagulation proteins, like von Willebrand Factor (vWF) and fibrinogen, in addition to membrane proteins such as P-selectin. These proteins are of high molecular weight. On the other hand, dense granules contain low molecular weight molecules, include catecholamines, serotonin, calcium, (ADP), and (ATP). Platelets receptors are of two major functions, they either in activation of platelets like collagen, thrombin, and ADP, they called as agonist receptors; or they act as adhesive molecules, which promote the adhesion of platelets to other platelets, the vessel wall or leucocytes, depending on the receptor stimulated. Examples include the glycoprotein IIb-IIIa receptor, which is targeted by antiplatelets such as tirafiban.

Platelet's primary role is well known in primary haemostasis. While circulating in blood, they are located in proximity of vessel wall, which facilitate their role in clot formation. To accomplish this, the process run through three stages: beginning with adhesion, then activation, and finally aggregation. 

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Blood groups are blood classification based on differences in antigen located on surface of red blood cells, differences in white blood cells, platelets, and antibodies in plasma. All these factors contribute to formulation of blood group, but we will discuss the two most common and important subtypes, ABO group system and the Rhesus (Rh) type system. ABO group system, which consists of 4 main types: A, B, AB and O, depends on the presence or not of specific inherited antigens and antibodies. Rhesus (Rh) type system has two probabilities, being positive or negative depending on the presence or not of D antigen on RBCs. Knowing this difference is of great importance to avoid serious complications during medical procedures. 

In 1901, an Austrian-born American biologist called Dr Landsteiner, has first noticed clustering of serum blood for certain people to antibodies in blood of others. This observation has led him to formally coin three blood group types: A, B and O; after one year, AB group has been also discovered. Thus, we have eventually four contradictory blood groups (A, B, AB, O) depending on the presence or absence of the two specific antigens, A and B. Later in his career Landsteiner identified the Rhesus factor.

As we have noticed, ABO system is based on glycoprotein ABO antigens on the surface of Red blood cells or erythrocytes (erythro- “red” +‎ -cyte “cell”), although other types of antigens are existed. Subsequently, a group blood A person has antigen A attached to RBC surface; a group blood B person has antigen B attached to RBC surface; a group blood AB person has both antigen A and antigen B attached to RBC surface; finally, a group blood O person has no antigen(s) attached to RBC surface. These characteristics are inherited by two alleles, one from each parent. A and B alleles are of dominant inheritance, which means they will appear by producing the A and B antigens respectively, if they were existed. 

Other determinants of ABO blood group system are the presence of ABO antibodies, which are of IgM mostly, in the plasma. These antibodies develop over the first months and years of life. Antibodies clump with their counterpart antigens located on surface of RBCs, that is why it is of great concern in blood transfusions. Individuals with group A have anti-B antibodies; Group B have anti-A antibodies; Group AB have neither antibody; and Group O – have both anti-A and anti-B antibodies. 

Accordingly, ABO system is based on presence of antigen and absence of its corresponding antibody, and vice versa. Therefore, blood group ABO system will be as follows:

• Group A: a antigen attached to RBCs and B antibodies in plasma. 
• Group B: b antigen attached to RBCs and A antibodies in plasma. 
• Group AB: a and b antigen attached to RBCs and no antibodies in plasma. 
• Group O: no antigen attached to RBCs and A and B antibodies in plasma; which considered as universal donor.

In 1940, Karl Landsteiner and A.S. Weiner have discovered Rh blood group system. They observed immune interactions between rabbits’ blood injected by Rhesus monkey’s blood by 85% of human blood. After that, they named Rhesus blood group after Rhesus monkeys, depending on the presence or not of Rhesus (Rh) antigens. Now Rhesus antigens include over 50 antigens, but the most 5 clinically important are D, C, c, E, and e. 

Rh D is particularly of importance because it is the most suspectable to immune reactions. Therefore, it is more likely to involve in transfusion reactions. A person will have specific Rh blood groups by inheritance of Rhesus (Rh) factor with pair of genes. An individual could be either Rh positive or negative: Rh positive means having Rh D antigens attached to RBCs and those can receive both Rh+ and Rh- blood; Rh negative means having no Rh D antigens and they are able to receive Rh- blood only. 

Rh negative is generally rare, but it occurs in about (15%) of Caucasians in Europe, Afro-Caribbean (8%) and Asian (1%). 

Individuals with Rh- do not have Anti-D antibodies in their plasma, unless they have exposed to Rh+, which trigger their immune system to produce antibodies against foreign Rh antigens, what lead to hemolytic reactions in the next exposure. This could happen during transfusion or throughout placenta in the case of Rh- mother and Rh+ baby, causing subsequently abortions to the next fetus. 

Of course, many other group systems are present beside ABO and Rh blood groups, but they are less common to cause immune reactions. 

Blood transfusion is the procedure on which a recipient be provided by blood, or its components taken from donor. It is used to replace blood in case it is low due to surgery, injury or medical conditions such as anemia, sickle cell disease or thalassemia. A whole blood containing both plasma and cellular parts could be transfused, or just one component like RBCs which called “packed RBCs”. As we mentioned before, human blood contains antigens and antibodies, thus, a blood being transfused should be suitable to the blood type of the recipient or it will be clumped with it causing serious immune reaction called agglutination. To be on safe side, it is better to transfuse ABO and Rh blood groups of the same type of the recipient. Because it is not always available, the rule says of not having the recipient antibodies against antigens in the donor’s blood. If this rule has broken, a serious or even agglutination of the red blood cells in the donated blood will occur. 

According to ABO blood group system, the antibodies in the recipient blood would attack ABO antigens on RBCs of donor’s blood, thus blood transfusion procedure should be monitored cautiously, especially at the start of each unit. The same rule is applicated on Rh blood group system. Hence, O- considered as universal donors, because they do not have any type of antigens on the surface of RBCs could be attacked by recipient’s antibodies. Vice versa, AB+ group are universal recipients, because they do not have any antibodies in their plasma, and possibly will not cause any immune reactions. 

We know that O blood type can give blood to any other ABO blood types but can only receive type O blood. While AB blood is considered as universal recipient, thus receiving any blood type but giving blood only to AB group. An individual with A blood can receive A and O groups, similarly, group B receives blood from B and O; both A and B groups give blood to their same group and AB group. On the other hand, Rh group should always be consistent. 

In some instances, due to mismatched transfusion or unpredictable allergic response, donor’s cells are attacked by the recipient’s plasma antibodies. This interaction will lead to hemolytic reaction presents with low oxygen prefusion, clumped RBCs causing micro-occlusions, precipitation of hemoglobin in kidneys causing renal failure. 

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Polycythemia rubra vera is a blood disorder results in over production of erythrocytes. It is considered as part of blood cancer group called myeloproliferative neoplasm (MPN). MPN causes overproduction of different blood cells due to dysregulation at the level of the haematopoietic stem cell. A mutation of the Janus kinase–2 gene (JAK2) is the most likely source of polycythemia. It is observed also that mutations induce production even though EPO release is cut off. Polycythaemia is often discovered after the age of 60. A miner proportion of cases (3%) transform to acute leukemia, some cases suffer from thrombotic events, and the majority of cases tolerate the condition for many years. However, regular monitoring is still crucial. 

Iron deficiency is when iron amounts do not meet body’s needs; thus, it is a sign not a disease. It can result from lack of intake resources or increase in iron requirements due to physiologic reason such as growth and pregnancy. It could be also a sign of illnesses like occult bleeding from the GI tract. That is why seeking for iron deficiency is of great importance. 

HHC is hereditary disease with an autosomal recessive pattern. It is a result of mutations in the HFE gene, which is located on chromosome 6q. HHC is an iron overload disorder where body absorb excessive iron from diet. Major presentation includes the triad of diabetes mellitus, cirrhosis, and pigmentation; other presentations are adrenal insufficiency, heart failure and arthritis. These symptoms are consistent with organs where iron is being accumulates like liver, adrenal glands, heart, joints, and pancreas. HHC patients are managed with phlebotomy by removing certain amounts of blood within specified intervals. 

A condition where there is over production of platelets from bone marrow. This leads to an increased risk of thrombotic events either in arteries like stroke, TIA, or peripheral emboli, or in vein like deep vein thrombosis and Budd-Chiari syndrome. Although it is odd but thrombocythemia may increase risk of bleeding, because of the presence of abnormal platelets in blood. It is divided into primary or essential that does not have specific cause but it involves acquired genetic mutations; secondary thrombocythemia which results from medical conditions like bleeding, some autoimmune diseases (rheumatoid arthritis/IBD), trauma, hypersplenism, or infections. Thrombocythemia could be treated by aspirin only if platelet count does not exceed 1000×109/L. 

It is the most common bleeding disorder, involves deficiency or abnormal vWF, causing impaired platelets adhesion and reduced factor VIII activity. Signs and symptoms include mucocutaneous bleeding like bruising and epistaxis; women experience menorrhagia and heavy menstrual bleeding, when delivery they suffer from heavy blood loss and post-partum hemorrhage. Von Willebrand’s disease is an inherited disorder, with autosomal dominant pattern. Its management include administrating desmopressin which triggers releasing intrinsic stores of vWF and factor VIII, and antifibrinolytics like tranexamic acid to support haemostasis. 

Hemophilia is a general term describes the condition in which a deficiency in coagulation factors leads to dysfunction in coagulation system. It affects individuals in different grade of deficiency; thus, it is presented with different severities. Common signs include easily bruised, bleeding spontaneously especially from mucous membranes, and persistent of bleeding longer than normal range. Hemophilia is classified according to the deficient coagulation factor into three types: type A: factor VIII, type B: factor IX; these two factors are X-linked disorders, which means, a male (XY) receiving mutated chromosome will be affected. Type C is factor XI deficiency. 

Dysfunction of one anticoagulation system components lead to stop inhibition of clotting, and this leads to subsequent over-coagulation and predispose for diseases, such as deep vein thrombosis and stroke. Protein C deficiency is one of these conditions that could be either inherited or acquired. 

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