10 - Clotting Issues and the Diagnosis of Disease Flashcards
(36 cards)
Gla domain
amino acids that bring coagulation cascade to the correct place
Coagulation cascade activation
- platelets activated with negative charge on surface
- binds to Ca and then binds to Gla residues located on a protein in coagulation. (Gla residues serve as Ca2+ binding site to attach polypeptide to phospholipid. Residues generated by carboxylation process with vitamin K).
- allow coagulation enzymes to bind to platelets so cascade at right place.
What are Gla domains used for?
To localised to the site of the injury
• Factors VII, VIII, IX, X and prothrombin all rely on the presence of Gla domains
Vitamin K
cofactor for Gla residues (gamma-carboxyglutamate).
- If deficient, cannot coagulate properly, Ca2+ not chelated.
- Inhibitors of this reaction if thrombosis risk e.g. Warfarin.
Gla Domains and the need for Vitamin K
- Factors VII, VIII, IX, X and prothrombin contain specialised Gla domain which contain10 y-carboxyglutamate (Gla) residues which serve as Ca2+-binding sites to attach the protein to phospholipids found on the outside of the platelets.
- This causes the above factors to localise to the site of injury where the platelet plug has formed. This is a critical process in the formation of the clot.
Thrombin
central enzyme to form fibrin clot
Prothrombin (aka FII)
• Prothrombin contains 10-12 glutamic acid (Glu) residues which in the presence of Vitamin K are carboxylated to gamma-carboxyglutamic acid residues (Gla).
- made and released when factor 10 is made after the phospholipid is activated and then binds calcium.
- Brought to the correct site by Gla domains.
- Cleaved by active factor 10.
What can go wrong?
Clotting must occur in the correct place and at the correct time.
Deficiency or excess of any component could cause pathology.
• Platelets
• Vitamin K
• Coagulation factors
Haemophilia
- Type A: most common, severe, Factor VII deficiency
- Type B: 2nd most common, moderate, Factor IX deficiency
- Type C: rare, mild, Factor XI deficiency
Haemophilia A
- most common, hereditary disease where patient has tendency to bleed, cannot coagulate properly.
- Deficiency in factor 8 - in intrinsic pathway so extrinsic and common still occur, but coagulation is not quick.
• The severity of haemophilia emphasises the importance of the intrinsic pathway
Haemophilia A transmission
Genetically transmitted as sex-linked recessive characteristic, on X chromosome.
Factor V Leiden
Risk factor for thrombosis
- single point mutation in factor V, Arg506 replaced with Gln.
- now resistant to degredation
- some present venous thrombosis
- gene frequency of 5-10%
• The mutation manifests itself in the form of abnormal blood clots in the legs (DVTs) and lungs.
Platelet adhesion
Following an injury to blood vessels, the process of primary haemostasis is initiated, involving the release of molecules such as serotonin, causing vasoconstriction. at the same time collagen is exposed, causing platelets to be attracted and attached
Stopping the coagulation cascade
plug forms, platelet activation has stopped, enzymes and cofactors are broken down due to their half life
vonWillebrand disease
coagulation is impaired
Mechanism of platelet adhesion
Activation, and the change in shape that occurs is triggered by GP1b receptors for vWF and collagen.
These are only found inside the blood vessel wall.
Therefore, they are only exposed if the vessel is damaged.
Main symptoms of a deficiency of vWF
Large bruises or bruising easily Frequent or long lasting nose bleeds Bleeding gums Heavy or long lasting bleeding from cuts Heavy periods/ parturition haemorrhage Heavy or long lasting bleeding after tooth extraction
Adhesion leads to Activation which leads to
Aggregation
- Activated platelets release granules that help coagulation, platelet activation and vasoconstriction.
- Activated platelets will express surface glycoproteins required for aggregation and fibrin attachment.
- Activated platelets are flatter and have pseudopodia
Platelet Activation and Role of Gla Domains
- Gla modules on coagulation factors interact, via Ca2+, with the activated platelets.
- This allows coagulation to happen only at the site of damage; the only place platelets are activated.
- The binding of factors Xa and Va to the platelets enhances the production of Thrombin at the site of injury
platelet number decrease
can accommodate a large drop, but if significant then clotting time rapidly increases - even if coagulation pathway is fine
thrombocytopaenia - platelet deficiency
bleeding time increases
produces faecal occult blood due to lack of clotting within the body
Laboratory Investigations
- Prothrombin Time (PT)
- Activated Partial Thromboplastin Time (aPTT)
- Thrombin Time (TT)
- Mixing Studies
Prothrombin Time (PT)
If elevated, problem in the extrinsic pathway.
Blood sample mixed with components and time measured for coagulation to occur.
- add recombinant TF, phospholipid, calcium
INR (International Normalised Ratio)
ratio of a patient’s prothrombin time to a control.
This takes account of differences between manufacturers products.
It is the preferred test of choice for patients taking vitamin K antagonists such as warfarin.
