Haemostasis & Haematopoeisis Flashcards
Haemostasis =
What’re its 3 components?
A series of regulatory processes that culminate in the formation of a blood clot to limit bleeding from an injured vessel
3 components: platelets, vascular wall and coagulation cascade
Haemorrhage =
Extravasation of blood into extravascular spaces
What’s the role of the endothelium and platelets in haemostasis?
Endothelium: has antiplatelet, anticoagulant and fibrinolytic properties to act as a barrier expressing factors which limit clotting to site of injury (prevent thrombosis)
Platelets: form the initial haemostatic plug, providing a surface for recognition of coagulation factors
What’re the 3 ways platelets form the initial plug and recruit coagulation factors?
Adhesion to ECM at sites of vascular injury
Activation by secretion of granules
Aggregation of platelets
What’s the coagulation cascade?
Two pathways extrinsic and intrinsic lead to final common pathway of FXa + FVa + Ca2+>prothrombin>thrombin>fibrinogen>fibrin which stabilises the clot
Intrinsic: FXIIa>FXIa>FIXa>FVIIIa> FXIa + FVIIIa + Ca2+
Extrinsic: TF>FVIIa> TF + FVIIa + Ca2+
What are the 3 stages of haemostasis?
1: Vasoconstriction - minimises blood loss and activated by endothelin release and neurogenic reflex
2: Primary haemostasis - initial platelet plug formed as vWF expressed on endothelial cells to recruit platelets, change platelet shape to enhance platelet-platelet interactions by secretory granules released
3: Secondary haemostasis - platelet plug consolidation by TF expression on subendothelial cells which binds to and activates factor VII and thrombin to initiate coagulation cascade. Thrombin cleaves circulating fribinogen to fibrin.
What drugs interfere with the coagulation cascade?
Heparin - binds to antithrombin III to inactivate thrombin and FXa
Warfarin - affects metabolism of vitamin K therefore affecting production of prothrombin, factors VII, X, IX
New oral anticoagulant: Dabigatran, reversible inhibitor of Thrombin
Step 4: clot stabilisation, resorption and role of fibrinolytic system
Fibrin and platelet aggregates undergo contraction to form permanent plug
Counterregulatory mechanisms limit clot to site of injury
Involves fibrinolytic system: inactive circulating plasminogen converted to plasmin which breaks down fibrin to reduce size of clot and contribute to later dissolution
How is coagulation controlled? Why is it important?
Needs to be restricted to the site of injury
Fibrinolytic cascade
Requires negatively charged surface (platelets)
Anticoagulation factors are expressed on adjacent intact endothelium
Circulating inhibitors eg antithrombin III
Dilution
Thrombosis =
Formation of a sold mass of blood products in a vessel lumen (thrombus)
Pathological process leading to vascular occlusion/ischaemia/infarct
What is Virchow’s triad? What are its 3 features?
Predisposition to thrombosis
Endothelial injury, abnormal blood flow, hypercoagulability
What are the fates of thrombi?
Propagation
Embolisation
Resolution/dissolution
Organisation
Embolism =
A detached intravascular solid/liquid/gas that is carried by the blood to a site distant from origin
What are common embolisation sites?
Lower extremities - limb ischaemia
CNS - stroke
Intestines - bowel ischaemia
Kidney/spleen - may be asymptomatic
Infarction =
Area of ischaemic necrosis caused by inadequate blood supply
What’s haematopoiesis?
The production of all types of mature blood cells
What causes megaloblastic anaemia?
Folic acid (vitamin B9) and cobalamin (vitamin B12) deficiency
What causes pernicious anaemia?
Intrinsic factor deficiency (maybe by autoimmune destruction of parietal cells) meaning reduced vitamin B12 absorption in the terminal ileum
What’s the composition of blood? Plasma?
Cells + plasma = blood
Plasma: h20, small organic compounds, electrolytes, proteins (globulins, albumin, fibrinogen)
Where are haematopoietic stem cells located? How do they give rise to cell lineages?
Bone marrow
Stem cells proliferate -> differentiate -> mature
What are the 5 different types of stem cell in order of their potency?
Totipotent - any cell type
Pluripotent - any cell type of the embryo
Multipotent - several related cell types
Oligopotent - small number of very closely related cells
Unipotent - can produce more of the identical cell type
What are the 2 common progenitor cells from a multipoint haematopoietic stem cell that starts the 2 lineages?
Common myeloid progenitor -> erythrocytes, thrombocytes, granulocytes, macrophages
Common lymphoid progenitor -> lymphocytes
Outline Erythropoiesis, including what’s needed for it
Proerythroblast -> erythroblast -> reticulocyte -> erythrocyte
Controlled by EPO, requires Iron, folic acid and vitamin B12
What are the 4 changes in erythrocyte maturation?
Acquisition of biconcave disc shape
Loss of organelles, including nucleus
Decrease in cell size
Haemoglobin production
What’s the point of the biconcave disc shape of erythrocytes?
Maximises surface area
Minimises distance from surface
Increases flexibility
Simple internal structure, simplified metabolism, structural proteins maintain shape
What 2 things does DNA synthesis require?
Folic acid Vitamin B12 (and intrinsic factor for absorption)
What does haemoglobin synthesis require?
a and B globin chains
Haem (containing iron), vitamin B6 + Fe2+
Where are folic acid and vitamin B12 absorbed?
Folic acid - duodenum and jejunum
B12 - terminal ileum
What are inherited disorders of haem synthesis called?
Porphyrias
Once iron is absorbed, where is it stored? What regulates iron absorption and how?
Bone marrow to make haem
Remainder stored in liver and spleen
Regulated by Hepcidin - released by liver when iron levels are raised so it decreases Ferroportin activity on the basolateral membrane of intestinal epithelial cells to inhibit absorption
How are types of anaemia classified?
Microcytic hypochromic
Normocytic normochromic
Macrocytic
What are types of leukocytes?
Granulocytes: neutrophils, eosinophils, basophils
Monocytes
Lymphocytes
What are some white cell count disorders?
Leukocytosis - high WCC
Leukopenia - low WCC
Neutrophillia - acute bacterial infections
Eosinophillia - allergic disorders eg asthma
Lymphocytosis - viral infections
Outline thrombopoiesis
Megakaryoblast -> Promegakaryoblast -> Megakaryocyte -> Thrombocytes (platelets)
What are 2 platelet count disorders?
Thrombocytosis - high platelet count
Thrombocytopenia - low platelet count (reduced production or increased destruction)
Role of Erythropoietin?
Released by fibroblasts in the kidneys in response to hypoxia to stimulate erythropoiesis in bone marrow
Binds to specific receptors on proerythroblasts to stimulate cell survival
Role of Thrombopoietin?
Produced in the liver to stimulate differentiation of megakaryocytes and thrombocytes
What 3 things does haemostasis allow?
Prevention of haemorrhage
Blood to be in fluid state in normal vessels
Formation of localised haemostatic clot at sites of vascular injury
Outline blood vessel histology
Intima: endothelium, basement membrane, connective tissue, internal elastic lamina
Media: circumferentially arranged smooth muscle
Adventitia: connective tissue containing vascular and neural supply
Which coagulation factors are dependent on vitamin K?
VII
IX
X
Prothrombin
Outline the intrinsic pathway
Measured as partial thromboplastin time (PTT)
Initiated when FXII comes into contact with negatively charged surface (activated platelet)
FXIIa -> FXIa -> FIXa -> FVIIIa
FIXa + FVIIIa + Ca2+ activate final common pathway (FX)
Outline the extrinsic pathway
Measured as prothrombin time (PT)
Initiated by tissue factor
TF activates FVII -> FVIIa + Ca2+ activates final common pathway (FX)
What’s the final common pathway in the coagulation cascade?
FXa + FVa + Ca2+ = Prothrombinase complex for conversion of Prothrombin -> Thrombin
Thrombin converts Fibrinogen -> Fibrin
Fibrin monomers polymerise to form insoluble network around primary platelet plug
Clot further stabilised by FXIIIa forming strong cross links
What’s the difference between unfractionated and low molecular weight Heparin?
Unfractionated: inactivates both FXa and Thrombin
LMWH: primarily inactivates FXa
