Brandon Ong's M1 Anki Deck__3. Physiology__A. Blood Flashcards
Where does erythropoiesis occur?
Fetus: yolk sac then liver/spleen/lymph nodes
Infant: all bone marrow
Adult: bone marrow of ribs, sternum, vertebrae, proximal ends of long bones
What are the steps and requirements of erythropoiesis?
- Proerythroblasts from haematopoietic stem cells
- Early erythroblasts: ribosome synthesis
- Late erythroblasts: Hb accumulation; ejection of nucleus
- Reticulocytes: complete Hb synthesis, leave bone marrow by diapedesis and mature in blood
Requires:
- Vitamin B9 (folic acid) & B12 (cobalamin)
- Iron
How is erythropoiesis regulated?
- Hypoxia
- Secretion of erythropoietin by kidneys and liver
- EPO stimulates haematopoietic stem cells to form proerythroblasts and increases proliferation rate of proerythroblasts and erythroblasts
Where does leukopoiesis occur?
Bone marrow
T-lymphocytes migrate to thymus where they mature
B-lymphocytes complete maturation in bone marrow
How is leukopoiesis regulated?
Cytokines
1. Interleukin-2: stimulate differentiation of myeloid stem cell
2. Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF): stimulate differentiation of progenitor cells
3. Granulocyte Colony Stimulating Factor (G-CSF): stimulate differentiation of myeloblast
4. Macrophage Colony Stimulating Factor (M-CSF): stimulate differentiation of monoblast
What does haemostasis consist of?
Haemostasis = prevention of blood loss
1. Vasoconstriction
2. Platelet plug (Primary Haemostasis)
3. Blood clotting (Secondary Haemostasis)
4. Repair
What are the measurements used for disorders of blood clotting?
- Prothrombin Time (PT): extrinsic pathway and common pathway
- activated Partial Thromboplastin Time (aPTT): intrinsic pathway and common pathway
What causes Hemophilia A?
Factor VIII deficiency resulting in excessive bleeding
What causes Hemophilia B?
Factor IX deficiency
What is thrombocytopenia?
Insufficient platelets with bone marrow destruction (spontaneous, widespread hemorrhage)
Associated w chemotherapy
What are the thrombotic disorders of blood clotting?
- Factor V Leiden: mutated factor V cannot be deactivated (excessive thrombin formation)
- Activated Protein C (APC) resistance: poor anticoagulant response to activated protein C (normal protein C cannot result in anticoagulation)
- Deep vein thrombosis: immobility (post-op or air travel) and clot travels to pulmonary arteries
What is the mechanism of heparin?
Combines with anti-thrombin III to bind thrombin
What is the mechanism of coumarins eg. warfarin?
- Vitamin K antagonist, prevent activation of factors II,VII,IX,X and protein C & S
- Requires rundown of Vitamin K stores first (pregnancy is contraindication)
What are the characteristics of von Willebrand’s Factor (vWF)?
- Bound to Factor VIII while FVIII is inactive in circulation to increase its half-life; only released by the action of thrombin
- Binds to collagen beneath endothelial cells when it is exposed due to damage of blood vessel (endothelium also releases vWF which forms additional links between platelets’ gpIb/IX/V and collagen fibrils)
- Mediates platelet adhesion in face of high shear stress
- Produced and stored in alpha granules of platelets
- Cleaved by a metalloprotease (ADAMTS13)
What is the primary haemostasis mechanism (platelet plug)?
- Platelet adhesion: gpIa/IIa, gpVI»_space; collagen
- Platelet adhesion under shear stress: vWF & gpIb/V/IX»_space; collagen
- Platelet aggregation: gpIIb/IIIa, fibrinogen
- Alpha granules release: factor V, factor IX, vWF, fibrinogen, platelet derived growth factor, vascular endothelial growth factor
- Dense granules release: ADP (increase platelet stickiness), histamine, serotonin
- Link to coagulation: thrombin
- Thromboxane A2 released: aids in platelet aggregation
What is the secondary haemostasis mechanism (blood clotting)?
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What is the importance of post-translational modification by vitamin K?
- Vitamin K dependent gla residues that are inhibited by warfarin
- Required for Factors II, VII, IX, X
- Required for Protein C and S
What is anti-thrombin III activity?
- Inhibits serine protease activity
- Inhibits thrombin, Factor 9a, 10a, 11a, 12a
- Potentiated by heparin
What is the Protein C anticoagulant pathway?
Thrombin binds to thrombomodulin which activates Protein C with cofactor Protein S
Activated Protein C inactivates Factor 5a and 8a (which is required for coagulation pathway)
What is the fibrinolytic pathway?
- Endothelial cells express thrombomodulin which binds to thrombin to activate protein C (stops coagulation cascade)
- Injured tissues slowly release tissue-plasminogen activator (t-PA) that converts plasminogen to plasmin to convert fibrin to fibrin degradation products
- Small quantities of heparin continually secreted by mast cells and basophils which bind to anti-thrombin III to remove thrombin
What is the Direct Coombs Test used for?
Detects and shows the effect of antibodies causing RBC destruction i.e. autoimmune hemolytic anaemia
What is the purpose of mixing studies?
- Performed on blood plasma of patients or test subjects to distinguish factor deficiencies from factor inhibitors, such as lupus anticoagulant, or specific factor inhibitors, such as antibodies directed against factor VIII
- If factor inhibitors, the timing for mixing studies will increase
What does Thrombin Clotting Time test for?
Fibrinogen abnormalities; common pathway
What does bleeding time test for?
Tests for platelet function and number (duration of time for clot to form)
