Main Ideas - Blood clotting!- The blood clotting cascade is complicated.!- Many factors are serine protease or cofactors.!- Vit K is a crucial factor for blood coagulation.!- The anti-coagulant subsystem prevents spreading of blood clotting.!- The fibrinolytic subsystem makes the clot temporary.!- Hemoglobin associated disorders!- Thalassemias (cause anemia)!- Hemoglobinopatheis (e.g. sickle cell disease, less O2 transport, but mostly vaso-occlusion)!- Heme associateed disorders!- Porphyrias: heme synthesis defects cause various problems due to toxicity of precursors!- Bilirubin: degradation product of heme, deficiency in bilirubin processing --> hyperbilirubinemia!!Learning Objectives 1) Know the important factors of the intrinsic and extrinsic blood coagulation pathway (incl. vWF, Vitamin K). - Hemostasis (w/extrinsic pathway):!- Trauma and exposure of sub-epithelium --> platelet activation and adherence to damaged site --> serine protease activation cascade --> activation of thrombin --> production of fibrin and spont. polymerization into fibrin clot --> cross-linking of fibrin at the clot --> heal/repair --> fibrinolysis!- Intrinsic coagulation pathway (not adding extra factors to make it coagulate)!- contact activation pathway!- rare trigger of hemostatis in health peeps!- inducible by: inflammation, bacterial wall contact, contact of kallikrein w/neg. charged surfaces (e.g. phospholipids of circulating lipoproteins)!- thought to be involv. in activation of clotting on artificial surfaces !- Integrated view of the clotting system - In both ex/in you have a cascade of serine protease activations (from zymogens)!- TF= tissue factor!- Factor VIII: is NOT a serine prot., it's a cofactor that helps a serine protease!- Factor XIII: involved in crosslinking fibrin monomers!- Thrombin is a serine protease that is where the ex/in pathways converge. Helps concert fibrinogen into fibrin (cuts the little arms). These monomers are crosslinked by Factor XIII and this helps form the clot.!- von Willebrand Factor - multisub protein circulating in blood!- functions: 1) anchor platelets to the subendothelial collagen (that has become free) 2) carries Factor VII (a cofactor)!- vW disease= most common inherited bleeding disorder - defective primary hemostasis: decreased adherence, defective platelet plug-->longer bleeding time, varying degrees of bleeding tendency!- Imp. of Vitamin K in blood clotting!- req. to introduce gamma=carboxylation of clotting factors: II, VII, IX, and X (on their aa side chains) --> introduces Ca2+ sensitivity !- Gla domains allow protein to interact w/phospholipids on platelet membrane!- Deficiency: bruising, bleeding gums, nose bleeds, broken blood vessels!- Antagonist: warfarin to prevent thrombosis and embolism blocks vit K epoxide reductase (which recycles Vit K) 2) Understand the mechanism of anti-coagulant systems and fibrinolysis. - Neg. controls of clot formation= you have the clot and want to get rid of it or you don't want the tissue around the injury to clot because it's fine!- Thrombomodulin present on intact epi--> binds Thrombin so it has a diff. activity --> activates Protein C--> degrates other factors of coag. cascade!- Serpins (serine protease inhibs): antithrombin (III) inhibits thrombin + factors VIIa, IXa, Xa, Xa, and XIIa!- Heparin can stimulate antithrombin activity by 1000x = a blood thinner!- Fibrinolysis: the hard fibrin clot is dissolved when the damaged epithelium is repaired !- Plasmin (serine protease) degrades fibrin!- fibrin clot integrates Plasminogen (PLG) in its inactive form (precurs to plasmin, is a ticking time bomb). tPA is also incorp. and can turn plasminogen--> plasmin. Plasmin also can be activated in the blood.!- all paths --> degrading clot 3) Understand hemoglobin- and heme- associated deficiencies and their connection to related disorders. - Hemoglobin associated:!- Thalassemia: gen. defect --> production of abnormally low amts. of 1 or more Hg chains!- Alpha thalassemia: expression of alpha-globin gene is reduced (large deletions)!- A: silent carrier!- B: both alleles deleted, alpha thalassemia minor, mild anemia!- C: both alpha genes deleted on SAME CHROM, same as B!- D: three alpha genes deleted, hemoglobin H disease, mod. severe anema!- E: all alpha genes del., Hg bart disease, mostly fatal!- Beta thalassemia: expression of B globin genes is reduced, caused by various types of muts (pt. and splice)!- B+: residual Hg B is produced!- B^o: no Hg B produced, only have HbA2 and HbF!- gamma B^o: HPFH, no Hg B or gamma is produced, only have HbF, often barely any symptoms (regulatory seqs deleted?)!- Excess alpha globin can't function and precipitates --> early RBC destruction!- Hemoglobinopathy: gen. defect --> abnormal structure of a globin chain the in Hg molecule!- Sickle cell disease: caused by a single pt. mutation on the B-globin chain: Glu6(hydrophilic) --> Val6 (hydrophobic)!- Hb [ ] in RBC= very high! 340 mg/m!- HbS (sickle) = hemoglobin S. HbS is synthesized at normal rate, with normal O affinity, BUT HbS Val6 fits perfectly into the hydrophobic pocket of another deoxy-Hb (no pocket in oxy-Hb) --> deoxy-Hb polymerizes into fibers that stiffen and deform the RBCs ---> Sickle shape!- Consequences: low oxygenation of HbS, vaso-occulusion, RBC lifetime shorter (1/10 --> anemia), resistance to malaria!- Difficult to load oxygen into this shape!- Poryphryia: a gen defect in heme biosynthesis pathway!- 8 dedicated steps, each step is considered irreversible!- Heme is synthesized from succinyl-CoA + glycine in 8 irreversible steps!- Heme is mostly produced in liver and bone marrrow (in mitochrondria and cytoplasm)!- End product heme is an allosteric inhibitor of ALA synthase (beginning of these steps) (neg feedback reg)!- rate limiting 1st step!- Diseases assoc. w/mistakes in the 8 steps in the pathway!- All of these won't completely know out your heme production... not making heme would be incompatible w/life. Also, you have build up of precursor before the step that doesn't work.!- Porphyria cutanea tarda!- most common subtype!- defect in uroporphyrinogen decarboxylase (see above) or sporadic (?)!- symptoms: skin blistering in sunlight in exposed areas, onycholysis, chronic liver problems!- vampire myths!!- Heme degradation...to bilirubin!- deficiencies in the heme degradation pathway!- macrophages dispose of old erthryocytes, degrade heme --> bilirubin!- SA: liver conjugated to form bilirubin diglucuronide !-
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