Blood and blood cells  

Doutor Pedro Silva

Assistant Professor, Universidade Fernando Pessoa

  • Digestion
  • Introduction to endocrynology
  • Reproductive Physiology
  • Blood, blood cells and clotting
  • Immune response
  • Blood groups
  • Blood, blood cells and clotting

    An adult human body contains about 5 liters of blood. The liquid component of blood is plasma, and contains (besides water) proteins, nutrients, hormones, electrolytes and metabolic waste products. Its yellow color is due to the presence of bilirrubin (a waste product of haem degradation). Plasma proteins are synthesized by the liver and play a large variety of roles: transport of small molecules, mantaining osmotic pressure and clotting. Blood cells may be:
  • erythrocytes (or red blood cells). These are the most common (>99%) blood cells and contain hemoglobin. They are bereft of nucleus and organelles. They are produced in the bone marrow, and (after about 120 days) are degraded in the spleen and liver. Their production requires iron, folic acid, and vitamin B12, and is stimulated by the hormone erythropoietin, which is secreted by the kidneys as a response to inadequate O2 supply.
  • platelets (or thrombocytes). These are cell fragments issued from megakaryocytes (large polyploid cells present in the bone marrow close to blood vessels). They have very important roles in blood clotting.
  • leukocytes (or white blood cells). These cells are in charge of the immune response. They can be classified as:
  • monocytes (these cells may leave the bloodstream and differentiate into phagocytic cells: macrophages);
  • linfocytes;
  • polymorphonucleated granulocytes
  • basophiles, which secrete histamine, a mediator of the inflamatory response;
  • eosinophiles, which attack multicellular parasytes, and are also involved in allergic reactions;
  • neutrophiles, which perform phagocytosis.
  • All blood cells arise in the bone marrow from adult stem cells which differentiate under the control of a large array of hematopoietic factors.

    Blood clotting

    When veins rupture, blood loss is relatively slow (due to low blood pressure) and can often be controlled by raising the affected region above the level of the heart. If the hemorrhage occurs towards the surrounding tissue, blood accumulation (hematome) may itself be enough to rise the pressure of the interstitial fluid to the level of the venal pressure, thus stoping blood loss.
    Hemorrhages due to the rupture of medium or large arteria canot ussually be controlled by the organism. However, the physiological clotting mechanism are quite effective in dealing with lesions to small vessels, which are the most common in daily life. The most immediate body response to a vascular lesion is the constriction of the affected blood vessel, leading to a decrease of blood flow through the injured area. Such constriction presses the endothelial surfaces of the vessel towards each other, thus inducing a contact that blocks it. However, this mechanism is only able to block permanently the rupture in the thinnest capillaries, and termination of bleeding usually depends on two further mechanisms, which require platelet intervention:
  • formation of a platelet plug
    Blood vessel rupture exposes the underlying connective tissue. Platelets adhere to collagen present in this tissue through a plasma protein (the von Willebrand factor) secreted by endothelial cells and platelets. As platelets adhere to collagen, they are induced to release the molecules (serotonin, ADP, etc.) present in their secreting vesicles. These molecules act on the platelets themselves, and lead to changes in their metabolism, shape, and surface proteins, in a process dubbed platelet activation . Some of these changes make new platelets adhere to the initial platelet layer through fibrinogen molecules, and to the formation of a platelet plug. Platelet adhesion induces them to secrete thromboxane A2, which further stimulates platelet aggregation. The platelet plug thus formed is able to seal small ruptures on blood vessels. The platelet plug only forms around the affected area, since healthy areas of the blood vessel continually secrete prostacyclin, which inhibits platelet aggregation. The platelet plug is thus prevented from expanding towards non-ruptured areas of the blood vessel.
  • clotting.
    Upon the lesion of a blood vessel, the surrounding cells release
  • thromboplastin (also called tissue factor, or factor III). This protein then binds a plasma protein,
  • factor VII, and activates it. This new thromboplastin-factor VIIa * complex catalyzes the activation of factors X and IX.
  • Factor Xa, in the presence of factor Va, catalyzes the conversion of prothrombin into
  • thrombin, which cleaves factor XIII and converts fibrinogen into
  • fibrin. Factor XIIIa then catalyzes the formation of covalent bonds between the fibrin molecules, which precipitate and form a clot that blocks the vessel lesion.
  • This clotting pathway is called extrinsic pathway, because it needs a factor (thromboplastin) which is initially absent from the plasma. Blood clotting observed when blood is collected into a glass tube (and therefore in the absence of thromboplastin) is due to a second clotting pathway: the intrinsic pathway). Initially, factor XII is activated by contact with collagen, or a wettable surface sucg as glass. This factor activates
  • factor XI, which activates
  • factor IX, which in the presence of VIIIa activates
  • factor X. From this point onwards, the mechanism is the same as that of the extrinsic pathway.
  • Under physiological conditions, blood clotting is started by the extrinsic pathway. Plasma however contains an inhibitor of the tissue factor pathway, which inhibits the activation of factor X by the thromboplastin-factor VIIa complexo. Thrombin formation through the extrinsic pathway is therefore limited. Clotting is completed by the intrinsic pathway: the small amount of thrombin produced by the extrinsic pathway activate factors V, VIII and XI, which allow the intrinsic pathway to operate. Apart from the two first steps in the intrinsic pathway, all steps in the clotting cascade require the presence of Ca2+.
    Besides the inhibitor of the tissue factor pathway, there are other ways to control blood clotting. Thrombomodulin, in the presence of thrombin, activates a protein (protein C), which inactivates factors VIIIa and Va. Thrombin may also be inactivated by the joint activity of antithrombin III and heparin.
    The clot must eventually be dissolved. This is acomplished by the fibrinolytic system. Like the clotting pathways this system involves the sequential activation of series of proteins, and yields the activation of plasminogen into plasmin. Plasmin degrades fibrin, thereby dissolving the blood clot.

  • N.B.: the letter a in subscript means the "activated form" of the plasmatic clottig factors.

    Several strategies towards anticoagulant therapy are available:
  • Aspirin inhibits cyclooxygenase (the enzyme which synthesizes the precursor of thromboxane A2), thereby inhibiting platelet aggregation.
  • oral anticoagulans interfere with the activity of vitamin K , which is necessary for the synthesis of several clotting factors (prothrombin, VII, IX and X)
  • heparin
  • fibrinogen blockers interfere with platelet aggregation.
  • plasminogen activators.
  • Immune response

    Tissue damage caused by pathogens causes the release of chemical messengers that stimulate vasodilation around the affected area, as well as an increase in protein permeability of the blood vessels' epithelium. This permeability increase leads to protein (and plasma) diffusion into the affected area (edema). As the inflammatory response progresses, circulating neutrophiles (atracted by chemotactic molecules like leukotrienes) adhere to endothelial cells in the concerned region. Adhesion prevents neutrophiles from being washed away by the blodstream, and allows their local accumulation. Neutrophils then "squeeze" through the interstitialspaces beteen endothelial cells and migrate into the interstitial fluid - diapedesis. Monocytes also migrate towards the interstitial fluid, and then mature into macrophages. Contact between the fagocytic cell (neutrophile or macrophage) and the lipids and carbohydrates present on the bacterail pathogen cell wall then trigger fagocytosis. The fagocyte surrounds the foreign cell, and upon endocytosis attacks it with the hydolitic enzymes form its lysossomes. Further enzymes release powerful and highly toxic oxidizing substances (NO, hydrogen peroxide, hypochlorite).
    A set of plasma proteins (called complement) (which, like coagulation factors, activate each other through a cascade) is also able to ellicit extracellular destruction of pathogens. Complement is activated in response to infection and leads to the formation of a membrane attack complex (MAC). The MAC is able to fuse with the membrane of the pathogen, thereby forming a water-filled channel that disrupts the pathogens osmotic balance and lysing it. Some components of the complement system are also opsonins, i.e., they are able to facilitate the phagocytosis of the pathogen.
    The mechanisms described above are non-specific. Specific immunity (which is responsible, e.g. for immunization) depends on the action of molecules (immunoglobulins) that can recognize specific molecular markers (the antigens) present on the foreign cell. Immunoglobulins are produced by lymphocytes and contain conserved regions, as well as variable (and hypervariable) sequences which are responsible for selective binding to the antigens. Immunoglobulin synthesis entails random rearrangement of specific regions in each lymphocyte's immunoglobulin genes, and each lyphocyte therefore produces only own immunoglobulin, which is different from those of other lymphocytes. When a lymphocyte recognizes an antigen, it becomes activated, and undergoes accelerated division. Each daughter cell will be specific for the same antigen recognized by its mother cell. Some daughter cells initiate the immunological response, while others are kept in reserve, as "immunological" memory". There are three types of lymphocytes:
  • lymphocytes B - maturation occurs in the bone marrow. Upon activation, they differentiate into plasmocytes, which secrete immunoglobulins into the bloodstream. These soluble immuniglobulins are commonly called antibodies
  • lymphocytes T - These are synthesized in the bone marrow, but they mature in the thymus. There are two kinds of T lymphocytes:
  • CD8 (or cytotoxic T cells) - Upon activation, they bind their targets through their membrane-bound immunoglobulin-like T cell receptors, and secrete toxic substances. CD8 lymphocytes act against "self" cells that have become oncogenic or infected by viruses (or microorganisms which, like viruses, have incorporated themselves into the cells).
  • CD4 (or helper T cells) - Upon activation, they secrete cytokines, which are essential for proper functioning of B lymphocytes, NK cells and cytotoxic T lymphocytes T.
  • natural killer (NK) cells - like CD8 lymphocytes, these cells attack cancer cells and virus-infected cells. However, they do not recognize their targets specifically, since they lack immunoglobulin domains. They recognize the constant regions of soluble immunoglobulins which have bound the target cell. They therefore require the assistance of plasmocytes, which secrete such immunoglobulins.

  • Besides the functions referred to above, antibodies may also trigger other mechanisms: they can activate the complement cascade (thereby leading to pathogen lysis), they may complex toxins (and form extensive antibody-toxin-antibody-toxin-etc. comlpexes) in order to allow their phagocytosis, and they can also act as opsonins.

    Blood groups

    The surface of erythrocytes contains a high number of glycoproteins, grouped in families called "blood groups". The most imoprtant groups are the ABO and Rhesus systems.
    ABO system - It includes carbohydrate H and two similar variants, known as A and B. An individual may therefore be A, AB, B or O (if it only carries antigen H). Every individual carries specific antibodies against those carbohydrates it lacks: an A person carries anti-B antibodies, an O person carries anti-A and anti-B antibodies, and an AB person carries neither (there are no anti-H antibodies, since the H antigen is the core carbohydrate of both A and B antigens, and an anti-H antibody would also react against the A and B carbohydrates). During a blood transfusion, the donor's antibodies quickly get diluted in the receptor's blodstream, and (in)compatibility effects arise from the interaction between the receptor's antibodies and the antigens present in the donor's blood. If the receptor carries specific antibodies against the donor's erythorocytes, they will agglutinate (cross-linked through the receptor's antibodies) and form a thrombus.
    Rhesus system- This system is dependent on the presence or absence of the D antigen. Unlike the ABO system, no anti-D antibodies exist in the bloodstream of an individual wo has never been exposed to the antigen. This becomes relevant during mother-fetus interaction. In parturition, the rupture of placental blood vessels leads to contact between the mother and the baby's blood. Should the mother be Rh- and the baby be Rh+, this leads to exposure of the mother to the D antigen, and she will start to produce anti-D antibodies. In future pregnancies, these antibodies may cross the placenta and lead to agglutination of the erythocytes of a Rh+ baby, leading to sever anemia, or even death. Nowadays, this is prevented through inffusion of anti-D antibodies to the Rh- mother immediatlly after the birth of a Rh+ baby. These antibodies bind to the D antigens of the baby's erythocytes that are present in the mother's bloodstream, thereby preventing them to induce the mother to synthesize antibodies. These problems do not arise in the ABo system because anti-A and anti-B antibodies are IgM antibodies, too large to cross the placenta.


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