Biochemistry - Unit III - Blood clotting, Calcium metabolism

• Involves series of zymogen (inactive molecules, become active by cleavage of one or more peptide bonds) activations
• Intrinsic
• Extrinsic
• Common

• releasing of two serine proteases: kininogen and kallikrein
• they convert XII (Hageman factor) -> XIIa
• XIIa convert XI -> XIa
• XIa converts IX (Christmas factor) -> IXa
• IXa + VIIIa converts X -> Xa
• factor VIII is antihemophilic factor and its absence causes hemophilia

• Extrinsic pathway has the tissue factor, and tissue is extrinsic to the vasculature
• VII -> VIIa
• activated tissue factor + VIIa convert X -> Xa

• Xa + Va convert prothrombin (modified by Vit K) -> thrombin
• Thrombin converts fibrinogen -> fibrin, the main substance of a clot
• XIII -> XIIIa, causes covalent cross linking of fibrin -> Clot

• helps adding γ-carboxyl groups to glutamate side chains of prothrombin, VII, XI, and X.
• Negative charges attract Ca++ within platelets membrane.

Coumadin (Warfarin)

• Fibrinogen has two sets of three chains Aα, Bβ, γ
• A and B peptides (fibrino peptides) have negative charges (arginine and glycine), maintain an extended structure
• Thrombin cleaves out A and B (hydrolysis at arginine and glycine; homologous to trypsin)
• Remaining monomers 2(α, β, γ) aggregate -> globular fibrin

• Antithrombin III
• Lysis of clot

• inhibits thrombin; forms irreversible complex with it
• Also blocks: XIIa, XIa, IXa, Xa
• Enhanced by heparin

• Endogenous tissue type plasminogen activator - TPA
• contains a finger domain, a domain similar to growth hormone, a kringle domain, and a serine protease domain
• The clot binds to TPA's Kringle domain
• The serine protease domain cleaves plasminogen to plasmin
• plasmin (protease) dissolves the clot

• 10mg/dl
• 51% free ion (possibly more critical)
• 46% binds to protein (albumin)
• 3% complex to other ions

increase serum calcium by increasing the number of osteoclasts

• PTH binds to Receptors on osteoblast membrane and stimulates its synthesis of RANK ligand (osteoclast differentiating factor)
• In the presence of preosteoclasts, RANKL stimulates synthesis of osteoclasts

A new treatment for osteoporosis is RANK ligand antibody, decreases the synthesis of osteoclasts

• Inhibits phosphate resorption (proximal and distal tubule).
• Stimulates Calcium resorption (distal).

• No direct effect on intestine, no receptors
• Only indirect effect: stim synthesis of 1,25-DHD3 in kidney, eventually increase absorption of calcium

• Isolated from Lung and kidney tumors
• Responsible for the hypercalcemia of malignancy
• similar but not identical to PTH, binds to the same receptors as PTH to cause an increase in calcium
• Monoclonal antibody against PTHrP can be used to treat these cancers

• Peptide hormone synthesized and secreted from the C cells of the thyroid
• End action of calcitonin is to decrease calcium

shrink osteoclasts

increase calcium secretion, but only at supraphysiological doses

• skin, 7-dehydrocholesterol is converted to vitamin D by UV
• food

• Liver: Vitamin D -> 25-hydroxy vit D (most stable form, the best index to test for deficiency)
• 25-hydroxy-D is insoluble and is transported by the vitamin D binding protein, a plasma protein, to the kidney
• Kidney: 25-hydroxy-D3 -> 1,25-dihydroxy-D3 (active form); PTH increases the 1-hydroxylase reaction; 24,25-dihydroxy-D3 is also formed, which is the inactive form

• increase synthesis of calcium binding protein, calbindin
• increase synthesis of epithelial calcium channel, TRPV6
• increase intestinal calcium absorption
• (also increase phosphate absorption, via different mechanism)

• stimulates osteoclastic activity and bone resorption
• intracellular receptor for 1,25(OH)2D3 in osteoblasts
• binding stimulates synthesis of RANKL
• Stimulates osteoclasts in the presence of preosteoclasts

enhances the action of PTH at the distal tubule (resorption of Ca++ and inhibition of phosphate resorption)

• gastrin
• has nothing to do with Ca

• PTH raises #osteoclasts
• Calcitonin SHRINKS osteoclasts
• Vitamin D raises #osteoclasts

• PTH Inhibits phosphate reabsorption (proximal and distal tubule); Increases calcium reabsorption (distal tubule)
• Calcitonin Increases Urinary calcium excretion (only at supra-physiological concentration)
• Vitamin D Enhances action of PTH on calcium at the distal tubule

• PTH no direct effect, increase kidney produce 1,25DHD3, indirectly increase intestinal calcium absorption
• Calcitonin none
• Vitamin D increase Calcium absorption (and phosphate absorption)