Blood 2

What are the two main components of haemostasis?

Primary haemostasis (local vasoconstriction, formation of temporary platelet plug/not stable, for rapid arrest of bleeding). Secondary haemostasis (blood coagulation, form stable clot, longer term arrest of bleeding sufficient to allow repair)

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Outline the process for haemostasis (1)

Damaged vessel wall (expose external cells/TF, activates extrinsic clotting pathway, activation of thrombin, converts fibrinogen to fibrin), exposes collagen, platelets adhere to wall and form plug

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Outline the process for haemostasis (2)

Release PAF, ADP TXA2, vasoconstrictors (primary), fibrin strands laid down to stabilise clot (secondary). Also activation of intrinsic clotting pathway (also activates thrombin and converts fibrinogen to fibrin)

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State the components of a clot

Fibrin strands, platelets and trapped red blood cells

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Describe features of primary haemostasis (1)

Requires platelets to form temporary plug. Results in release of vasoconstrictors to reduce blood flow to damaged area, results in release of other factors which assist further aggregation of platelets/clot formation by intrinsic pathway

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Describe features of primary haemostasis (2)

Effectiveness can be assessed by measuring 'bleeding time'. Inhibited by aspirin (inhibits production of TXA2 - factor which promotes platelet aggregation)

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Describe features of secondary haemostasis - clotting cascade (1)

Coagulation of blood to produce stable clot. FX - FXa - FV, Ca - prothrombin (FII) - thrombin - fibrinogen - fibrin - (FXII/Ca) - fibrin/fibrils (activation processes proteolytic/cleaved by protease, factors activate each other, amplify signal)

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Describe features of secondary haemostasis - clotting cascade (2)

Cleavage of prothrombin to form thrombin, cleave fibrinogen to form fibrin, cross-linked with FXII in the presence of calcium to form fibrin/fibrils. Factors need calcium as a co-factor (helps to anchor factors into cell membrane of platelets)

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Describe features of secondary haemostasis - clotting cascade (3)

Initial/extrinsic pathway - TF in cell membranes of damaged tissues binds (FVII plasma to FVIIa active). Endothelial cells don't have cell membranes. Activate FXa in the presence of calcium

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Describe features of secondary haemostasis - clotting cascade (4)

Intrinsic/amplification pathway (contact with collagen in connective tissue activates FXII, FXI - FXIa - FIX - FIXa - FX (in the presence of FVIII and Ca))

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Describe features of secondary haemostasis - clotting cascade (5)

Thrombin can activate FXII, FV, FVIII and FXI (positive feedback and amplifies intrinsic pathway). Synthesis is vitamin K dependent

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Describe features of direct oral anticoagulants

Direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban). Direct thrombin inhibitors (dabigatran)

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Summarise features of secondary haemostasis (1)

2 pathways which differ in factors which set them off, but share common features and work together in vivo. Both are based on enzymatic activation of protein factors carried in the plasma. In both each activation step provides an amplification factor

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Summarise features of secondary haemostasis (2)

Resulting in a very rapid cascade of reactions. In both, several steps require the presence of Ca. Final steps are the same, producing a clot (mass of strands of fibrin and trapped cells). Extrinsic/initial phase pathway is quicker to start

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Summarise features of secondary haemostasis (3)

But intrinsic/amplification phase pathway is the larger contributor to the final clot

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What limits clot formation to the damaged area? (1)

Cascade of reactions is a form of positive feedback (why doesn't all the blood clot?). Due to key clotting factors only working effectively when in contact with platelet plug

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What limits clot formation to the damaged area? (2)

Also due to 3 anti-clotting systems to prevent further expansion of the clot (all involving endothelial cells)

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What are the anti-clotting systems? (1)

1. Inhibitory factor produced by endothelial cells which limits activity of activated FVII. 2. Circulating anti-thrombin III binds to surface of nearby endothelial cells, inactivates clotting factors diffusing away from damaged area

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What are the anti-clotting systems? (2)

3. Thrombomodulin protein on endothelial cells binds excess thrombin, complex binds a circulating anti-clotting factor (protein C) causing it to inhibit factors FVIIIa and FVa

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In secondary haemostasis how is the efficacy of clotting by the intrinsic pathway assessed?

By measuring the clotting time in vitro. Deficiency of clotting factors increases clotting time. Deficiency of protein C or other anti-coagulants cause abnormally high risk of clotting. Several of the clotting factors are made in the liver

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What is a thrombus?

Stable clot blocking a blood vessel

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What is an embolus?

Clot which breaks free and travels around the bloodstream

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When a clot is formed why does it gradually retract?

Due to the action of the trapped platelets pulling on the fibrin fibrils (helps to pull wound edges together for repair)

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Describe features of fibrinolysis (1)

Eventual fate of clot is to be broken down once repair is complete. Fibrinokinases (hydrolytic enzymes in plasma) are released by tissues during repair processes. Convert plasminogen (in plasma) to plasmin (very efficient protease)

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Describe features of fibrinolysis (2)

Fibrinolytic drugs also promote this process. Hydrolyse fibrin strands to soluble fragments. Plasmin to prevented from attacking other plasma proteins by the binding of an endogenous inhibitor (also present in plasma and displaced only by fibrin)

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Describe features of thrombin (1)

Key to several processes - cell growth, vascular endothelial stimulation, formation of thrombomodulin-thrombin complex (activate protein C - anti-coagulation), endothelium releases TPA (fibrinolysis), convert fibrinogen to fibrin

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Describe features of thrombin (2)

Activates steps in clotting pathway (plasma coagulation). Conversion to prothrombin - TF, contact activation, increase platelet adhesion, promote release of factors/activation (platelet activation/aggregation),

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What are the causes of clotting defects? (1)

Deficiency (thrombocytopenia) of dysfunction of platelets. Deficiency of vitamin K (required for synthesis of some clotting factors). Hereditary defects in genes coding for clotting factors or accessory factors

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What are the causes of clotting defects? (2)

E.g. FVIII (haemophilia A - excessive bleeding), protein C (inhibitory factor - excessive clotting). Liver disease (affects production of clotting factors, can prolong clotting time, may not result in reduced clotting)

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Describe features of anti-coagulants (1)

Used in vitro to prevent blood clotting. Calcium chelators (block clotting cascade), citrate (suitable for retransfusion), oxalate, EDTA (samples for assays only). Heparin (blocks conversion of prothrombin to thrombin - useful for some assay samples)

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Describe features of anti-coagulants (2)

In vivo as anti-coagulation therapy. Heparin (and derivatives) activate antithrombin III, coumarin derivatives (warfarin) used for long term therapy (block activation of vitamin K in clotting factor synthesis). DOACs (target FII/FX)

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Describe features of haematopoeisis (1)

Formation of blood cells. Occurs in red bone marrow (in pelvis), most active/proliferate tissue, cell multiplying tissue, stem cells differentiate to form rbc, wbc, platelets. Stem cells taken therapeutically can lead to production of blood cells

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Describe features of haematopoeisis (2)

Bone marrow transplant. In adults, takes place in red bone marrow. In embryonic/early foetal life takes place in liver/spleen. All blood cells derive from a common pluripotent stem cell in processes

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Describe features of haematopoeisis (3)

Proliferation (produce large numbers of cells). Differentiation (acquire mature characteristics, become multipotent). Stem cell progency differentiate first into separate progenitor lineages for different cell types

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Describe features of haematopoeisis (4)

Rbc complete differentiation in bone marrow but wbc carry out final stages in lymphoid tissue

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Describe features of haematopoeitic stem cells

Originate from aorta of embryo. Move to bone marrow in adult life. Keep self-renewing until person dies. Divide rarely (mostly dormant). Can travel through blood circulation, are essential for bone marrow/cord blood transplants

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Describe features of lineage progenitors (1)

Differentiate from multi-lineage progenitors to more specific ones. Sometimes called - burst forming units (BFU, BFU-Erythrocyte) or colony forming units (CFU, CFU-GEMM). Provide several rounds of proliferation through subsequent cell divisions

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Describe features of lineage progenitors (2)

Can turn into cancer stem cells, the type of leukaemia depends on progenitor that is affected

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Describe features of blood-cell precursors (1)

When cells reach this stage, the devision about the cell fate is made. Cells proliferate further (e.g. up to 16 fold expansion for rbc). With each cell division they mature further (acquire equipment to fulfil their specific function e.g. Hb for rbc)

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Describe features of blood-cell precursors (2)

Sometimes called blasts e.g. lymphoblasts or erythroblasts

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Describe features of erythropoiesis (1)

Making red blood cells. Common haematopoietic stem cell differentiates until it becomes on the erythrocyte line (progenitors). Precursor stage (fate determined), terminal differentiation. Doubling of precursors with each step

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Describe features of erythropoiesis (2)

Requires Fe, B12, folate (Fe - Hb synthesis, folate - Hb prevalent). Fe deficiency (results in anaemia). Last stage (normoblast contains nucleus - removed by macrophage/RNA and organelles digested to form reticulocyte - mature to form rbc)

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Describe features of erythropoiesis (3)

Pace of precursor stage is controlled by EPO (increases mitosis, reduces cell death, regulation). E.g. CKD (may need to replace EPO)

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Describe features of thrombopoeisis

Making platelets. Megakaryocyte (MK) is resident in bone marrow. Buds off fragments of cytoplasm (platelets)

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What are the regulating hormones for haemopoeisis? (1)

Proliferation/differentiation of CFU progenitor cells is regulated by specific haemopoietic growth factors e.g. EPO (rbc), thrombopoeitin (platelets), colony stimulating factors (granulocytes, monocytes)

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What are the regulating hormones for haemopoeisis? (2)

Leucocyte production stimulated by some cytokines (IL1, 3). Additional maturation of lymphocytes takes place in thymus to produce T-cells. Proliferation of mature lymphocytes in response to antigenic challenge takes place in secondary lymphoid tissue

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What are the regulating hormones for haemopoeisis? (3)

Lymph notes, gut-associated lymphoid tissue (GALT), marrow-associated lymphoid tissue (MALT)

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Describe the failure of haemopoeisis (1)

Can affect all cell types (pancytopenia) e.g. due to administration of cytotoxic drugs, as a result of high doses of irradiation, aplastic myelosis (insufficient stem cell proliferation)

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Describe the failure of haemopoeisis (2)

Or be specific to one cell type e.g. failure of erythropoeisis (leading to anaemia) due to lack of folic acid/Vit B12 (needed for division of immediate precursors) or lack of EPO due to renal failure (EPO produced by kidney)

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