What are the compounds secreted by thrombocytes when they are activated, and what does each of them cause?
- ADP – activate platelets further
- Serotonin – vasoconstriction
- Thromboxane A2 (TxA2) – Vasoconstriction and aggregation
- Calcium & presence of phospholipids – allows for coagulation reactions
Name compounds released by platelets that responsible for vasoconstriction during haemostasis.
- Serotonin
- Thromboxane A2
List the cells that the platelets are derived from developmentally
- Multipotent stem cells
- Myeloid precursor cells
- Megakaryocytes
What are the compounds that initiate the internal and external coagulation cascades.
- External (tissue factor) pathway – tissue factor
- Internal (contact activation) pathway – thrombin, factor XIIa, a nucleation site (eg glass in a laboratory)
What are the enzymes directly responsible for transforming fibrinogen to a clot?
•Thrombin (factor II) turns it into fibrin. Factor XIII cross-links it into a clot
What are the enzymes that are specifically part of the intrinsic (contact activation) coagulation pathway (i.e. not part of the common or extrinsic pathways)?
- Factor I – no. this is fibrinogen and part of the common pathway
- Factor II – no. this is thrombin and part of the common pathway
- Factor III – no. this is tissue factor (also known as thromboplastin) and part of the extrinsic pathway
- Factor IV – not specifically. This is calcium.
- Factor V – no. This is not an enzyme (it is a co-factor) and it is part of the common pathway
- Factor VI – no. does not exist
- Factor VII – no. Part of the extrinsic pathway.
- Factor VIII – not quite. This is a co-factor that is part of the intrinsic pathway
- Factor XI – yes
- Factor X – nearly. part of common pathway as well as intrinsic pathway
- Factor XI – yes.
- Factor XII – yes.
- Factor XIII – No. part of common pathway
What is the role of vitamin K in haemostasis?
•It is necessary for the production in the liver of Ca-dependent proteases: II, VII, IX, X
What conditions might lead a patient develop a vitamin K deficiency?
•Warfarin toxicity, poor absorption of vitK (eg lack of bile salts)
What is the aetiology (including environmental & genetic influences) of haemophilia A?
•Genetic. X-linked (recessive), factor VIII mutation
What is the aetiology (including environmental & genetic influences) of haemophilia B?
•Genetic. X-linked (recessive), factor IX mutation
Give an overview of how the body responds to an injury in a blood vessel.
- Formation of a haemostatic plug physically protects and coats the surface of injury initially; this involves platelet adhesion, activation and aggregation.
- Coagulation creates a large scale meshwork that can close off blood vessels and make a protective surface for repair.
- Vasoconstriction decreases the local flow of blood. It accelerates coagulation, as well as minimising blood loss
Explain the role platelets play in haemostasis.
- Platelets contribute to all three aspects of haemostasis.
- Platelets contribute to vasoconstriction by releasing vasoconstrictor compounds (serotonin, TxA2)
- The form the primary haemostatic plug
- And they secrete or provide compounds that encourage coagulation (including their phospholipids)
List 4 differentiated cell types that develop from the lymphoid precursor cells
- NK cells
- T cells
- B cells
- Plasma cells
List 4 differentiated cell types that develop from the myeloid precursor cells
- Megakaryocytes (thrombocytes are not cells because they do not have nuclei, so they are “formed elements”)
- Red blood cells
- Eosinophils, basophils, mast cells
- Monocytes, macrophages
- neutrophils
Explain platelet activation.
- It is when platelets change dramatically (usually in response to ADP or exposed collagen).
- A) Their shape becomes more spindly (less regular or rounded),
- B) their metabolism goes up,
- C) they exocytose many granules, and
- D) their membrane gains proteins (eg GP2b/3a).
- Many of the reactions of the clotting cascade can only take place on the membrane of an activated platelet, and Platelet aggregation requires binding proteins only present on the platelet membrane when activated.
List the formed elements of blood that are anucleate and explain why they do not need nuclei.
- Nuclei are important for making different proteins in response to environmental changes, as well as for cellular reproduction. Nuclei are not needed by cells that are produced elsewhere and that do not need to respond to environmental changes.
- Platelets act as bags of signalling molecules and also contain enzymes and binding proteins necessary for coagulation. They do not need to reproduce locally because their actions are non-specific; they are made by megakaryocytes in the marrow.
- Erythrocytes act as bags of haemoglobin. Their function to carry oxygen (and also CO2) is non-specific, and they can be made in the bone marrow, so they have no need to reproduce.
What prevents blood from clotting spontaneously and inappropriately?
- Fibrinolysis.
- Anticoagulation factors.
- Maintaining platelets in the inactivated state.
- Keeping coagulation initiation signals sequestered (eg having Factor III/Tissue factor behind the endothelium).
- Rapid blood flow
What is the difference between Factor X, Xa, and Xase?
- Factor Xa is an activated enzyme. It catalyses the conversion of prothrombin (factor II) to thrombin. Its activity is substantially increased when it combines with active factor five.
- Factor X is the inactive form of Factor Xa
- Xase is the name of two different enzyme complexes (intrinsic and extrinsic) that can convert Factor X to factor Xa (ie activate it). Intrinsic Xase is Factor IX + factor VIII, extrinsic Xase is Factor VII + tissue factor
Explain how the clotting cascade is a positive feedback loop.
- Thrombin activates many upstream coagulation factors that contribute to activating thrombin:
- Factor V & Factor VIII (both of which are co-factors, not enzymes)
- Thrombin also activates Factor XI
What is the difference between intrinsic Xase and extrinsic Xase?
•Xase is the generic name for an enzyme that activates factor X. Extrinsic Xase is made up of factor VIIa + tissue factor. Intrinsic Xase is factor VIIIa + factor IXa. Extrinsic Xase is part of the extrinsic pathway, which must begin with a factor outside the blood (tissue factor). Intrinsic Xase is part of the intrinsic pathway, in which all the necessary coagulation factors are already present in the plasma (albeit in inactivated forms).
PT becomes longer when the extrinsic pathway is compromised, while APTT becomes longer when the intrinsic pathway is compromised. Both PT and APTT become longer when the common coagulation pathway is compromised. Bleeding time becomes longer if the common pathway (or both the extrinsic pathway AND the intrinsic pathway) or total platelet activity is compromised/reduced. Given this information, fill In the following table concerning how each clinical condition will affect the timings (or platelet count) as shown below
For each unique aspect of positive feedback loops, give a specific instance of how that happens in the clotting cascade.
- Amplification: thrombin activates factors V and VIII, which contribute to activated Xase, which activates thrombin
- All-or-none: when collagen is exposed (threshold), a clot forms
- Two stages: extrinsic pathway followed by common pathway
Which of the following are enzymes, and what are the others: factor I, factor II, factor III, factor IV, factor V, Factor VII, factor VIII, factor IX, factor X, factor XI, factor XIII
- Enzymes: II, III (tissue factor), VII, IX, X, XI, XIII
- The others are co-factors, except for factor I (a structural protein), IV (calcium)
