Understand 2nd year medicine

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Content

Bones



Osteoarthritis (non-inflammatory arthritis)

  • Asymmetrical joint involvement
  • Main proximal joints affected (e.g. knee)
  • Joint stiffness <30minutes
  • Wear and tear of cartilage  (worse after exercise/night)
    • Less joint space because less cartilage
    • Bone meets bone → Eburnation (Osteosclerosis, an elevation in bone density - appear bright)
    • Subchondral cyst: Synovial fluid in bone
    • Bone margin: Osteophytes
      • DIP: Heberden’s nodes
      • PIP: Bouchard’s nodes

Osteoarthritis of cervical vertebrae: Cervical spondylosis
  • Osteophyte compress spinal nerve

Treatment
  • Lifestyle: Analgesic, NSAID (Non-Steroid Anti-Inflammatory Drugs), intraarticular corticosteroid injection
  • Medical: Analgesic, NSAID



Rheumatoid arthritis (inflammatory arthritis) - SYNOVITIS!!!
  • 1% of population, Female3:1Male
  • Genetics: HLADR4
  • Mainly peripheral synovial joints (finger, wrist)
  • Joint stiffness >1 hour!
  • Synovitis, Type 3 hypersensitivity (RhF [RHeumatoid factor] IgM vs serum IgG)
    • Symmetrical
    • Systemic
      • Lungs: Pulmonary fibrosis, rheumatoid nodule
      • Blood Vessel: Vasculitis
      • Eyes: Dry eye syndrome (keratoconjunctivitis sicca)
      • Heart: Pericarditis
      • Autoimmune: Anemia, leukopenia
      • Joint: Rheumatoid nodule (basically granuloma!)
      • Polyarthritis
        • MCPJ (MetaCarPophalangeal Joint) /PIPJ (Proximal InterPhalangeal joint)→ Ankle → Wrist
        • Spine
    • Inflammed synovium - villus pattern
    • Pannus formation: Granulation tissue for T cell and macrophage to adhere to and destroy cartilage and invade other structures!!!!
      • Macrophage: Make TNF-alpha which activate osteoclast, MMP (matrix metalloproteinase.g. collagenase)
    • Ulnar deviation of MCP, swan neck deformity (hyperextended PIP, flexed DIP [Distal InterPhalangeal]), Z/Boutonniere’s deformity of thumb (PIP flexion, DIP hyperextended), subluxation (partial joint dislocation)
  • Complication: Atlantoaxial joint subluxation (tear of transverse ligament → axis pushes on spinal cord → quadriplegic)


  • Serology
    • AntiCCP
    • ANA [Anti-nuclear antibody]
    • RhF (Rheumatoid factor]: Present in 80% RA (Rheumatoid arthritis) patients, present in all patients with Rheumatoid nodules
      • not so specific as it is also present in TB (Tuberculosis)

Inflammatory arthritis
  • Seropositive (RhF): RA
    • Female3:1Male
  • Seronegative
    • HLAB27 Ankylosing spondylitis
    • M3:1F
    • Spinal joint ossification from lower vertebrae to upwards

Clotting

 Blood vessel structure


Platelet
Remains in blood for 10 days
Fragments of megakaryocyte
Form platelet plug
Contain dense granules (ADP, Ca2+ - dense abbrev.) and alpha granules (vWf, Fibrinogen)

 

Clotting cascade

Importance of vWF von willebrand factor (made by endothelium)


Subendothelial Collagen is exposed by trauma. vWf binds to Subendothelial collagen. vWf then binds to gp1b on platelet and sets off sequential steps which ultimately upregulates gp2b/3a (a receptor for fibrinogen). All platelets have receptors for fibrinogen, hence, expression of gp2b/3a sticks platelets together (imagine....... gp2b/3a of platelet A x fibrinogen x gp2b/3a of platelet B x fibrinogen x gp2b/3a of platelet C etc....)

 

Stages of platelet plug formation
1. Adhesion: vWF x Platelet activates the platelet
2. Secretion: Activated platelet releases TXA2 (Thromboxane) , ADP. These granules activate gp2b/3a via Gq mechanism
3. Aggregate: ADH x ADH receptor (p2y12)-> Upregulation of gp2b/3a x Fibrinogen x gp2b/3a on another platelet. THe platelets provide a platform for clotting to take place (see "clotting cascade")

4. Clot contraction: Platelet contracts via actin to consolidate to shrink the platelet fibrin clot (actin filaments are linked to the membrane)

 Thromboxane synthesis



Normal conditions: Endothelial cells inhibit platelet activation by producing nitric oxide, endothelial-ADPase, and PGI2 (Prostacyclin), PAI (plasminogen activator inhibitor)


Prostacyclin: Non-damaged endothelium express prostacyclin  - non sticky surface  - Gs

  • Vasodilation - Less Ca2+ and more K+ and cAMP (PKA phosphorylate thus inhibit MLCK -> MLCK can't phosphorylate myosin head -> No contrxn)
  • Antithrombotic - Less TXA2 (THromboxane)

 


Clotting factors - are zymogens (inactive) -> (active) serine proteases

(except 13 - final one - transglutaminase)

Mnemonic for clotting factors: Foolish people try climbing long slopes so after Christmas some people have fallen

Fibrinogen, prothrombin, thrombplastin (tissue factor), calcium, labile factor, (NO SIX), stable factor, antihemophilic factor, christmas factor, stuart prowess factor, PTA (plasma thromboplastin antecedent), hageman’s factor, fibrin stabalizing factor


Clotting cascade

Phosphatidylserine on platelt provides negative charge

Intrinsic: Initiated by contact between blood and negatively charged surface (collagen, glass, HMWk, phosphotidylserine?)
Extrinsic: Initiated upon vascular injury -> release of tissue factor (3)
Intrinsic: TwelvE -> EleveN -> NinE (+EighT a) -> Ten (+Five a)  -> Two (+Thirteen a) -> Fibrinogen (soluble) to Fibrin (insoluble) …......

Calcium binds platelet’s phospholipid to the prothrombinase/tenase complex -> activation (Imp’t for platelet to aggregate first from vWF ->

Platelet phospholipid and calcium to activate the complexes!)

Extrinsic: Ten (+ factor 7 which is activated by factor 3 + Calcium) -> Five -> Two (+Thirteen) -> Fibrinogen (soluble) to Fibrin (insoluble)

Tenase complex
Extrinsic tenase complex: Factor 10, 7, 3, 4
Intrinsic tenase complex: Factor 10, 9, 8a, 4

Prothrombinase complex: 10, 5a and 4, 2

Cofactors: 5 and 8... Protein C and S cleaves cofactors 5a and 8a to inactivate them
Cofactor 5 activated by thrombin (2... +3)

 

Remember that the activated things are ENZYMES (E.G. thrombin!!)

 


Fibrinogen -> FIbrin monomer -> Fibrin polymer --> Cross-linked fibrin polymer

Fibrin monomers must first polymerize. The fibrin polymers later cross-link to form the final product.

Fibrin Polymerization

http://tollefsen.wustl.edu/coagulation/coagulation.html

Factor 12 deficiency does not cause excessive bleeding because this is compensated by increased activity of thrombin to activate factor 11 (which 12 activates)



The zymogen form of factor 13 is converted to an active enzyme (13a) by thrombin (Fig. 12). XIIIa catalyzes a transglutamination reaction that initially cross-links the C-terminal ends -> solidifying the clot.



Not enzymatically active but is essential

Intrinsic clotting...
- Long term
- Factors released from WITHIN bloodstream
- Endothelial damage exposes subendothelial collagen -> vWF von willebrand factor made by endothelium and platelet (alpha granules) x Collagen -> Hageman factor
- APTT (activated partial thromboplastin time - 30s) test for clotting factors 8, 9, 11, 12
Isolated high APTT (Hemophilia type A - 8)

Extrinsic clotting (ExWARF who is a PT cries 7 times a day so she needs TISSUE)
- Short term
- Factors released from OUTside bloodstream (dmged tissue releases tissue factor 3)
- Measure PT (Prothrombin) time (less letters, less time - 15s) - test for clotting factors 7
Isolated high PT: Warfarin (inhibits vit-K dep. synthesis of clotting factors - 2, 7, 9, 10) (PS: 3 [3-some prime], 7, 9, 10)
- Factor 3 (tissue factor) + 4 (Calcium) + 7  -> Activate Factor 10 (7+3)

Essentially platelets provide the negatively charged surface for tenase activation!!!

In steady state, phosphatidylserine (negatively charged) is found in the inner monoplayer of platelet membrane.

This organization is maintained by transport system that "flip" and "flop" negatively-charged phospholipids (i.e. phosphatidylserine) across the membrane.

Flipase transports them from outer to inner monolayer
Scramblase moves them in both directions

PS exposure requires flippase inhibition and activation of scramblase. This is caused by platelet activation - perhaps involving elevation of intracellular calcium, and the involvement of signal transduction molecules such as protein kinase C (PKC).

When is PS exposed on the surface, it forms a docking site for hemostatic factors such as the prothrombinase complex (10, 5, 4, 2) and tenase complex (10, 9, 8, 4)


Protein C &S
Thrombomodulin x thrombin -> protein C... + (cofactor Protein S) -> Activated Protein C cleaves cofactors 5a and 8a to inactivate them

Factor 5: Leiden mutation - mutated factor 5 -> can not be cleaved by Protein C&S -> hypercoagulation

Hemophilia
Type A : Clotting factor 8 (A) deficient
Type B: Clotting factor 9 deficient





Kallikrein
http://ethesis.helsinki.fi/julkaisut/laa/biola/vk/lassila/fig3.gif

Note that ACE (Angiotensin-converting enzyme) breaks down bradykinin so no vasodilation!


Fibrinolysis

http://rpmedia.ask.com/ts?u=/wikipedia/commons/0/0e/Fibrinolysis.png

Therefore kallikrein is involved in

- Fibrinolysis: Turning plasminogen to plasmin
- Inflammation: Turn kinongen to kinin -> vasodilation

Fibrinolysis

Plasminogen - (Plasminogen activators: tPa [made by endothelium] or Urokinase or Streptokinase-> Plasmin -> Cleaves fibrin into FDP (fibrin degradation products)

Thrombomodulin: Endothelial surface integral membrane protein
Thrombin x thrombomodulin complex activates protein C -> Activated Protein C (APC)

Protein C + cofactor Protein S cleaves cofactors 5a and 8a.



Anticoagulant
Inhibit clot formation by
- Inhibit clotting factor synthesis

 

  • TFPI (tissue factor pathway inhibitor)
- inhibit thrombin
  • Heparin
- antiplatelet drugs
  • Clopidogrel binds to P2y12 (ADH receptor)
  • gp2b/3a antagonist

Tissue factor pathway inhibitor
Inhibit 10a and 2a (same factors inhibited by antithrombin)
Tissue factor also acts as a high-affinity receptor for the coagulation factor 7. (3, 4 - 7)

tPa
Plasminogen -> Plasmin -> Turning fibrin to FDP fibrin degrading product (fibrin degradation products)

Chelating (binding) agents
e.g. EDTA, sodium citrate: Binds to calcium so no Ca2+ for platelet phospholipid x calcium x clotting factors!

http://www.mayoclinicproceedings.com/content/84/12/1079/F1.large.jpg

Warfarin

Oxidized Vitamin K  (Vitamin K epoxide) + Vitamin K -epoxide reductase in liver (VKOR) - (reduction) -> Reduced Vitamin K (Vitamin K Hydroquinone)
Vitamin K hydroquinone + Gamma-glutamyl carboxylase in liver + CO2 + O2 - (oxidation) -> Oxidized Vitamin K

In the course of the this, gamma-glutamyl carboxylase CARBOXYLATES (adds COOH) to glutamate (Gla) residues to clotting factors 2, 7, 9, 10, protein C. The zymogens only become active serine protease when Calcium/platelet phospholipid binds to its Gla residues


i.e.  The coagulation factors get produced, but have decreased functionality due to undercarboxylation;

Warfarin inhibits VKOR, therefore no reduced Vitamin K hydroquinone, therefore, gamma carboxylase enzyme not active, therefore no carboxylation of glutamate residues of clotting factors, therefore, less interaction with calcium, platelet phospholipid...

Vitamin K is also made by gut bacteria, which neonates lack.Therefore, Vitamin K supplements are given to them.

Heparin
Potentiates antithrombin 3 (made by liver) - inactivates 2a and 10a (X not V... 2+3=5.. anyways the most important ones!!!)
Negatively charged and large size -> Given paraenterally (IV - full heparin or SC - low molecular weight heparin fragment)

Dipyridamole
Vasodilator drug that blocks adenosine uptake by cells, thereby reducing the metabolism of adenosine - dipyridamole-induced vasodilation  by increasing extracellular adenosine thus for a1 (Vascular Smooth muscle) and a2 action (SinoAtrialNode/AtrioVentricularNode)
Clinical use: Wolff-Parkinson-White Syndrome (reentrant -> tachycardia)

Adenosine is a purine formed from ATP hydrolysis into ADP -> dephosphorylated to AMP.
Most ADP and AMP is rephosphorylated, requiring oxygen. If hypoxia and excess hydrolysis ATP -> ADP -> AMP -> FURTHER DEPHOSPHORYLATION by nucleotidase into adenosine.

Adenosine is rapidly deaminated by adenosine deaminase to inosine - short t1/2


Adenosine can bind to purinergic receptors (A1 and A2 depending on its location)
- VSM relax -> vasodilation
  • esp. coronary blood flow to meet metabolic demands (coronary vessel: adenosine binds to A2 receptors which are coupled with Gs -> AC stimulate -> more cAMP -> PKA (stimulate KATP channels - K+ efflux hyperpolarization, inhibit MLCK -> Less myosin phosphorylation -> less cross-bridges thus contraction)
- SAN and AVN (1 heart... 1=i)
  • A1 receptor in Gi protein less cAMP - both opening K+ channel, inhibit L-type calcium channel -> hyperpolarize cell -> inhibit pacemaker current (If) - less slopy phase 4 -> negative chronotropy and dromotropic (condxn velocity b/c of L-type calcium channels inhibited)
  • Cause heart block if toxic


Procoagulant

1. Phytomenadione: Vitamin K

2. Tranexamic acid: Antifibrinolytic by inhibiting tissue plasminogen activator (tpa) which converts plasminogen to plasmin (plasmin breaks down clots), used in trauma patients

Therapeutic index: TD50/ED50

Lethal dose of a drug for 50% of the population (LD or TD50) divided by the minimum effective dose for 50% of the population (ED50).

A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the lethal threshold than the dose taken to elicit the therapeutic effect.

Narrow therapeutic index (i.e. having little difference between lethal and therapeutic doses) e.g. WARFARIN



3. Desmopressin: ADH (antidiuretic hormone) analog
- Promote release of vWF (-> subsequent increase in factor 8 due to complexing with vWF)

vWF: A blood glycoprotein which binds to several things...
  • Factor VIII is bound to vWF while inactive in circulation; Factor VIII degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of thrombin. (Thrombin activates 5, 8, 11)
  • vWF binds to collagen, e.g., when it is exposed in endothelial cells
  • vWF binds to platelet gpIb

 

 


4. PAI Plasminogen activator inhibitors (produced by endothelium) (mechanism similar to tranexamic acid)

inhibitor of tissue plasminogen activator (tPA) and urokinase
produced by the endothelium


5. Alpha2-antiplasmin  (produced by liver)
Inactivates plasmin by forming complex with it, thus, plasmin can not degrade clot



Most pulmonary embolism stems from venous thrombus originating from DVT deep vein thrombosis

Venous thrombus: Slow RBC -> More RBC red blood cells trapped -> RED thrombus
Arterial thrombus: Fast moving RBC -> Less RBC trapped -> WHITE thrombus