| Question | Answer |
| Physiological challenges | Do not harm when all is normal - do not obstruct
Automatically seal vascular punctures
Prevent loss of blood
Recruit healing helpers
Resolve when healed |
| Stages of hemostasis | Vascular spasm in response to injury
Primary - platelet plug formation
Secondary - blood clotting (coagulation)
Removing clots (fibrinolysis) |
| Arteriolar vasoconstriction | Damaged endothelium initiates sympathetic reflex (noradrenaline and neuropeptides) releases endothelin-1, a vasoconstrictor
Arteriolar smooth muscle contraction restricts flow |
| The platelet | Small cytoplasmic fragments of megakaryocytes
Life span of 8-10 days
Abundant in blood
Packed with granules |
| Platelet aggregation reaction | Adhesion to vessel wall - platelet GPIa/IIa binds collagen and GPIIb/IIIa binds fibronectin
Activating platelet changes shape releasing granule contents
Aggregation of platelets
Release of ADP and TxA2
GPIb binds vWF to induce further aggregation |
| Platelet granule functions | Further activation
Leukocyte recruitment
Endothelial repair
Secondary hemostasis
Further aggregation
Defence protein |
| Thrombopoiesis | TPO produced by liver and kidneys acts at every stage
HSC - MPP - CMP - EMk - MkP
All have CD110 receptors
Negative feedback - platelets internalise TPO to reduce production |
| Platelet disorders | Hereditary thrombocytopenia
Small platelets e.g. Wiskott-Aldrich syndrome
Large platelets e.g. Bernard-Soulier syndrome
Extreme folate/Vit B12 deficiency
Infections
Drugs
Autoimmunity |
| The coagulation cascade | Signal amplification by a series of protease reactions
Initiated by exposed charged surface and release of tissue factor and phospholipid from endothelium
Generates insoluble fibrin mesh
Regulated |
| Fibrinogen | Present in plasma at high concentrations
High molecular weight
Made in the liver
6 polypeptides - 2 alpha, 2 beta and 2 gamma
Fibrinopeptides cleaved by thrombin to allow aggregation |
| Fibrin polymerization | Thrombin cleaves fibrinopeptides in fibrinogen
Exposed regions spontaneously aggregate
Meshwork traps platelets, rbc etc to stabilise plug
Further crosslinking GLN-LYS by factor XIIIa to form gamma dimers |
| Vitamin K dependent zymogens | Signal peptide
Gla domain - gamma carboxylated glutamate
Kringle domains for regulation - cleaved off by prothrombinase
Catalytic domain - serine protease |
| Vitamin K deficiency | Needed for gamma carboxyglutamate
Gla residues bind 7 calciums to orientate hydrophobic residues into the membrane
Epoxide reductase needed for VitK reduction inhibited by warfarin |
| The common pathway | Prothrombin
Activated by FXa
Also by FVa
Requires phospholipid
Restricts reaction to surface of activated platelets
Serine protease that activates factors I V VIII XI XIII |
| Inhibitors of clotting | Endothelial glycosaminoglycans e.g. heparan sulphate
Activated Protein C
Thrombomodulin
EPI
Anti thrombin III |
| Antithrombin III | A serine protease inhibitor encoded in the human genome
Also alpha 1 anti trypsin, Complement C1q inhibitor, PLA-1
ATIII-thrombin interaction enhanced 1000 fold by hepSO4 GAG and heparin |
| Haemophilia | X linked
Often a recent mutation due to elderly spermatogenesis
Cannot produce tenase complex
Treated with clotting factors
May be able to recombinantly produce these from DNA clones in mammalian cells |
| Fibrinolysis | Breakdown clots - used in treatment of clotting e.g. in strokes
Plasminogen broken down to plasmin which is a serine protease - converts fibrin to fibrin degradation products |
