Haematology lecture 1-

what is haemopoesis? the process by which the cellular components of blood are formed.

what are these components? Red blood cells which carry oxygen, white blood cells which offer prevention and recovery from disease, and platelets which function in blood clotting.

Red blood cells- most numerous type of cell in the, normal range is between 4.0 to 5.5 × 10^12/L, diameter is between 6.7-7.7 micrometers, they have a biconcave disk shape, contain haemoglobin, carry O2 from lungs and tissue, transport CO2 from tissues to lungs, their survival is between 110-120 days
 Contain haemoglobin

white blood cells- leat numerous cells in the blood, total white blood count: 3.5-10.0 × 10^9/L, there are 5 different types each with a different role: Monocytes, Basophils, Eosinophils, Neutrophils, Lymphocytes

What are granulocytes? They are a type of white blood cell that contain granules in their cytoplasm.

what are the 3 types of granulocytes? Basophils, Eosinophils, Neutrophils

Neutrophils- normal range is 1.5 to 7.5 × 10^9/L, they fight against infection, they have 3 lobes, have fine faint granules, the produce pus cells, they are phagocytic, they have a half life of 7 hours in circulation

eosinophils- normal range is 0.03 to 0.60 × 109/L, they have 2 lobes, they have coarse orange granules, they release histamine in allergic reactions, they regulate hypersensitivity reactions, they are considered effector cells for antibody dependent damage to parasites

basophils- normal range is 0.01-0.15 × 10^9/L, they have 2 lobes, they have dark coarse azurophilic granules, the granules contain enzymes, they’re responsible for moderate inflammatory responses, they release heparin and proteases.

what does azurophilic mean? azurophilic refers to granules in the cytoplasm of certain cells particularly in white blood cells, that stain readily with azure dyes and are indicative of the presence of enzymes that play a role in various immune responses.

lymphocytes- the normal range is 1.2-3.5×10^9/L, they fight viral infections, they circulate between the blood and lymphatic system, they have a variable life span from a few hours to 4-5 years in circulation

monocytes- normal range is 0.2-0.8×10^9/L, they fight bacterial infection, they phagocytose bacteria and cells coated with antibodies, they are the precursors of tissue macrophages, they have a lifespan of up to 70 hours

platelets- they are the second most numerous cell in the blood, the normal range is 150-400 × 10^9/L, they are small discoid structures, diameter is between 3-5 micrometers, they have a lifespan of 7-10 days in circulation, they are important in blood clotting (haemostasis), they form a plug at the site of injury- primary haemostasis, they initiate secondary haemostasis .

sites of haemostasis- 2 week embryo-yolk sack, 12-16 week embryo-liver and spleen, at birth- born marrow (all bones), adult-proximal ends of long bones, flat bones such as sternum, pelvis and vertebrae - red marrow (active marrow), yellow marrow (inactive marrow)

what does haemopoiesis involve? proliferation (multiplication), differentiation (change form), and apoptosis (programmed cell death)

regulation of haemopoiesis- its regulated by growth factors. there are 2 main classes: colony stimulating factors and interleukins. growth factors inhibit apoptosis.

sites of production of haemopoietic growth factors- haemopoietic growth factors are glycoproteins

produced by: stromal cells, T lymphocytes, liver, kidney

bone marrow produces: more than 1 million red cells per minute, similar number of white cells and platelets

All blood cells develop from a haemopoietic stem cell (HSC): This is a cell which gives rise to all other blood cells, derived from mesoderm- found in the early stages of embryronic development, located in the bone marrow.

the haemopoietic stem cell:

• a cell that can differentiate into separate cell lineages

• it is rare- perhaps 1:20 million nucleated cells in the marrow

• exact phenotype is unkown

• CD34+

• CD38-

• negative lineage specific

• has an appearence of a small lymphocyte

• has thr ability to self renew

• can find its way back home to the bone marrow

  Erythropoiesis- Red cell production

• 10² red blood cells produced each day- contain haemoglobin

• this red cell production is regulated by erythropoietin which is a hormone produced in the kidney

• it has a feedback mechanism

• the earliest erythroid precursor mechanism is in the bone marrow and is called Pronormoblast or (proerythroblast)

• this just means they are committed to becoming red blood cells

• during the maturation process normoblasts progressively become smaller by cell division

• there are three stages to this cell division: early, intermediate and late

• during the maturation process, the nucleus gets extruded

• a reticulocyte contains ribosomal RNA and is released into the bloodstream into a fully functional erythrocyte.

  Red blood cells

• have a flexible membrane (biconcave disk) so they can pass through capillary microtubules

• the cause of their cell death is loss of red cell enzymes which maintain the shape and flexibility

• they are destroyed by the bone marrow, spleen and liver

• much of the cellular content is recycled - this includes protein, lipid and iron.

• the breakdown products of haemoglobin are excreted through the liver, faeces and urine.

• Red blood cells are unable to traverse the endothelial membrane

  granulopoiesis and monopoiesis

• granulocytes and monocytes are produced from common myeloid precursor cells

• these are regulated by combined actions of haemopoietic growth factors

• including: IL3 which works to prolong the life of neutrophils, basophils and monocytes. - GM-CSF (granulocyte macrophage colony stimulating factor) which is another growth factor. it is involved in promoting the proliferation and differentiation of myeloid progenitor cells in the bone marrow into granulocytes, macrophages and dendritic cells. - IL5- which drives the growth, differentiation and maturation of eosinophils

  the stages of granulopoiesis (becoming a granulocyte)

• Myeloblast

• promyelocyte

• metamyelocyte

• band forms

• mature granulocyte

  om tissues to
  stages of Monocytopoiesis (becoming a monocyte)

• monoblast

• promonocyte

• marrow monocyte

• and finally a blood monocyte

  
  Blood monocytes

• 24-72 hours in circulation

• they have variable morphology

• they are mononuclear and have a greyish cytoplasm

• they phagocytose and destroy bacteria

  vival 110-120 days

Lymphopoiesis:

this is regulated by IL 2, 4, 6 and 7

stages: lymphoblast, prolymphocyte

there are 2 types of lymphopoiesis: B lymphopoiesis and T lymphopoiesis

lymphocyte development

• lymphoid stem cells in bone marrow gene generate B or T cell lymphocyte progenitors

• b cells undergo maturation in marrow and then migrate via the blood to peripheral lymphoid tissues (lymphoid, spleen)

• T cell progenitors produced in the marrow: -they migrate from the marrow via the blood to the thymus, t cells mature in the thymus and then the t cells migrate to peripheral lymphoid organs

b lymphocytes:

• responsible for humoral immunity

• carry surface receptors which recognise and bind to foreign antigens

• they trigger cell proliferation into plasma cells

• they secrete antibodies against foreign antigens

• they produce a rapid response to further contact with the same antigen

T-lymphocytes

• these are responsible for cellular immunity

• activation of t lymphocytes is antigen specific

• the antigen must be processed and presented by macrophages for activation to occur

• there are 5 main subsets of t lymphocytes: T helper, T memory, T regulator, T cytotoxic, natural killer

Thrombopoiesis- platelet development

• platelets are important in blood clotting

• they form a platelet plug at the site of injury

• they initiate secondary haemostasis

• thrombopoiesis is regulated by thrombopoietin

The main functions of platelets

• they interact with von Willebrands Factor to form initial barrier to blood loss

• Von Willebrands Factor is a glycoprotein that allows platelets to adhere to exposed subendothelium and to respond to changes in blood flow.

• the interaction with von Willebrands Factor allows platelet aggregation to form a thrombus

• platelets provide a negatively charged lipid surface to support coagulation (blood thinning)

• platelets localise thrombus (blood clot) formation

• platelets promote vasoconstriction (this narrows blood vessels and helps reduce blood loss at the site of injury)

• platelets promote vessel repair

stages of Thrombopoiesis

• Megakaryoblast

• promegakaryocyte

• megakaryocyte

• platelets

Thrombopoiesis

• Replication of DNA without nuclear or cell division (endomitotic replication)

• the cell then becomes progressively larger with each complete cycle of endomitosis

• large uninucleate cells with 64x DNA content are formed

• a large number of platelets are produced in the cytoplasm of a mature megakaryocyte

• these are rapidly discharged into the bone marrow

• the bare nucleus of megakaryocyte is phagocytosed by macrophages

• the process takes 2-3 days

• each megakaryocyte produces 2000-7000 platelets

Platelet structure and function

• Anucleate (no nucleus) fragments of megakaryocyte cytoplasm

• they are small discoid structures - 0.3-0.5 micrometers in diameter

• they circulate in the blood in a dormant/ resting state

• normal range is 140-400 × 10^9/L

• they are capable of rapid response to vessel injury

• the shape and size results in them circulating towards the edges of blood vessels

• they are crucial in blood clotting (primary haemostasis)

events of primary haemostasis

• primary haemostasis consists of a series of events:

• platelet activation

• platelet adhesion

• platelet aggregation

• these events lead to the formation of a plug of platelets and initiate the process of secondary haemostasis

secondary haemostasis

A platelet plug alone is not usually sufficient to stem blood loss

it needs to be reinforced- by a series of biochemical reactions

• transforms soluble fibrinogen to a meshwork of insoluble fibrin

• intertwines with cellular components of the forming thrombus

• forms a supporting scaffold