Lecture 13: Blood + Hemostasis Flashcards
Plasma
Organic and inorganic substances dissolved in water (90% water). Most solutes by weight are plasma proteins
3 groups of plasma proteins
- Albumins
- Globulins
- Fibrinogen
Serum
Plasma w/ fibrinogen and other clotting proteins removed
RBC shape
High surface area:volume of isc shape enables fast diffusion and flexibility
RBC removal
Spleen and liver destroy old/damaged RBCs, producing bilirubin
Active red marrow
Children: most bones
Adults: only chest, skull base, vertebrae, pelvis, limb ends
Hemostasis
Stoppage of bleeding. Most effective in small vessel injuries
Hematoma
Accumulation of blood in tissues from bleeding
Hemostasis processes
2 interdependent processes
1. Formation of platelet plug
2. Blood coagulation (clotting)
Both involve platelets
Constriction of injured vessels
Immediate intrinsic response of injured/severed vessels is constriction due to local substance changes from endothelium/blood cells. Slows blood flow and presses opposed endothelia together to induce “stickiness”
Formation of platelet plug
- CT exposure
- Platelet-collagen binding + secretory vesicle release
- Platelet activation and aggregation
- Fibrinogen binding
- Clot retraction
CT exposure
Platelets must adhere to surface; vessel injury disrupts endothelium and exposes CT collagen
Platelet-collagen binding
Plasma von Willebrand factor (vWF) intermediates platelet-collagen adhesion
von Willebrand factor
vWF secreted by endothelial cells/platelets, binds+changes conformation of exposed collagen fibers as to bridge btwn damaged vessel wall and platelets
Platelet secretory vesicle release
Binding to collagen triggers vesicle release to induce further platelet activation (ADP, serotonin, etc.) and platelet aggregation (pos. feedback loop where new platelets adhere to old ones)
Platelet activation
Local factors induce changes in local platelet shape, metabolism, and surface protein to facilitate forming platelet plug. Platelet activity also induces local vasoconstriction.
Fibrinogen binding to platelets
Platelet activation exposes fibrinogen binding sites; fibrinogen fills gaps in between platelets to seal plug
Clot retraction
Platelets have high actin+myosin content; aggregation induces interaction to compress and strengthen clot.
Platelet plug regulation
Undamaged endothelial cells secrete prostacyclin and NO; strong inhibs. of platelet aggregation, adhesion, activation, and vasodilator
Prostacyclin
Aka prostaglandin I2 (PGI2). Acts to limit platelet plug formation to damaged area and prevent unnecessary plug formation
Blood coagulation (clot formation)
Transformation of blood to solid gel clot (thrombus); chemical cleavage cascade. Dominant hemostatic defense.
Thrombus
Primarily made of fibrin polymers, occurs locally around platelet plug. Traps RBCs/other cells
Key point of clot formation
Activation of prothrombin -> thrombin; thrombin catalyzes fibrinogen -> fibrin and XIII -> XIIIa (X-linking of fibrin in clot).
Clotting also requires Ca++ (never deficient)
Thrombin-platelet activation
Thrombin activated platelets bind several clotting factors and display platelet factor (PF); cofactor for clotting cascade
2 pathways for clotting cascade, linked by collagen
- Intrinsic: everything req. is in blood
- Extrinsic: req. additional cellular element (Tissue Factor)
Clotting pathway activation
Activated sequentially (not parallel!). Extrinsic typically initiates but requires intrinsic thrombin pos. feedback for adequate sustained coag.
Role of liver in clotting
Liver produces many plasma clotting factors; also produces bile salts for Vit. K absorption. Vit. K req. for prothrombin/factor synthesis.
Anti-clotting systems
Defects -> hypercoagulability
1. Tissue Factor Pathway Inhibitor
2. Thrombomodulin
3. Antithrombin III
Tissue Factor Pathway Inhibitor
TFPI acts during initiation phase of clotting; secreted mainly by endothelial cells and limits extrinsic thrombin generation.
Thrombomodulin
Endothelial cell receptor that binds thrombin and eliminates all clot producing effects. Bound thrombin binds/activates protein C -> inactivates VIIIa, Va. Thus intact endothelium makes thrombin inactivate clotting
Antithrombin III
Inactivates thrombin/other factors, present on endothelial cell surface. Enhanced when bound to heparin (anticoagulant). Prevents clot spreading; rapid inactivat. of factors carried away by blood flow.
Fibrinolytic (thrombolytic) system
Dissolves cells after forming (not limiting formation). Principal effector of clot removal via plasmin
Plasmin
Plasminogen -> plasmin -> fibrin digestion; many plasminogen activators
tissue Plasminogen Activator
tPA secreted by endothelial cells; plasminogen + tPA bind fibrin during clotting and is incorporated throughout the clot. tPA very weak w/o fibrin
Anticlotting drugs
-Aspirin (inhib. cyclooxygenase to reduce platelet aggregation; low dose doesn’t affect endothelial COX)
-Oral anticoagulants interfere w/ clotting factors
-Thrombolytic therapy dissolves formed clots
Cyclooxygenase (COX)
Generates prostaglandins, thromboxanes
Spectrin
Long, rod shaped protein that scaffolds under RBC membrane to maintain shape/integrity.
Spherocytosis
Spectrin deficiency leading to fragile, sphere-shaped RBCs
Oxidation of hemoglobin to methemoglobin
Oxidation of Fe++ -> Fe3+ (nonfunctional); methemoglobin reductase in RBC counters. Req. NADH (glycolysis byproduct)
Oxidation of hemoglobin cysteines
Cys oxid. -> irreversible crosslinking; inactivates Hb. Prevented w/ GSH + glutathione peroxidase, NADPH cofactor (maintain by G6P DH)
Extravascular hemolysis
RBC senescence -> engulfment by splenic macrophages
Intravascular hemolysis
Hb release into blood as dimers/methemoglobin -> haptoglobin/hemopexin -> bile. Excess Hb overwhelms haptoglobin, remaining to urine
Erythroblastosis Fetalis
Hemolytic newborn disease based on Rh compatibility. Rh+ sperm + Rh- egg -> Rh+ fetus; first birth triggers Rh Ab generation in mother; future Rh+ babies trigger immune response, hemolysis -> neurotoxic bilirubin. Req. giving mothers anti-D Abs near birth for rapid removal of D Ag
Basic blood groups
ABO antigens (A/B Abs), Rh +/- (D antigen)
Activated Thromboplastin Time
aPTT test; time required for recalcified plasma to clot after adding activated partial thromboplastin; measures intrinsic clotting path
Prothrombin Time
Assesses extrinsic clotting path.; time req. for recalcified plasma to clot after adding tissue thromboplastin. No clinical assay for tissue factor deficiency exists.
