Haemostasis Flashcards
What is haemostasis?
- haemo = blood - stasis = stop - to stop bleeding
What is haemorrhage?
- escape of blood from damaged blood vessels
What is primary haemostasis?
- platelet and endothelial interactions
- weak platlet blood clot
What is secondary haemostasis?
- coagulation cascade
- strong fibrin clot
What is thrombopoiesis?
- thrombosis = platlets forming blood clot
- formation of platelets
- part of Erythropoiesis but differentiate into platelets earlier
What is a primitive erythroid progenitor?
- early blood cells
- differentiate into megakaryocytes
What hormone produced in the kidneys and liver is thrombopoiesis (platelet formation) dependent on to differentiate into megakaryocytes?
- thrombopoietin
What is the myeloproliferative leukemia protein (MPL) receptor, also known as the thrombopoietin receptor?
- Cluster of Differentiation 110 (CD110)
- receptor on megakaryocytes
- thrombopoeitin binds and activates megakaryocytes
Once thrombopoietin is bound to the MPL receptor on megakaryocytes, what do they produce?
- platelets
What do megakaryocytes create?
- platelets
What is endomitosis in megakaryocytes?
- replication of DNA within cell
- does not undergo cytokinesis
- required to create platelets
What is a key component, structurally of the megakaryocytes that helps form platelets on the periphery of megakaryocytes?
- cytoskeleton
- specifically microtubules
- platelets then bud off including part of cytoplasm
Do platelets contain a nucleus?
- no
Do platelets contain any organelles?
- only a few
What do platelets contain on their cell surface that is crucial for adhesion to endothelial and to help cells form aggregates when required?
- glycoproteins
What are the most important glycoproteins that platelets possess?
- GP 1b = binds to Von Willdbrand factor
- GP2b3a = binds with fibrinogen
- P2Y12 = binds with ADP
What are alpha granules contained with platelets?
- granules involved in platlet blood clot formation
- granules involves in the coagulation cascade
What are some of the alpha granules?
- fibrinogen
- von Willebrand factor
- factor V (5)
- heparin antagonist
- platelet derived growth factor (PDGF)
What are dense granules found within platelets?
- further granule category
What are the most common components of dense granules found within platelets?
- nucleotides
- serotonin
- ADP and ATP
- Ca2+
Why do platelets contain dense granules with ATP, ADP and Ca2+ in them?
- important energy and co-factors for coagulation cascade
When endothelium are damaged, what is one of the first things that plasma comes into contact with that initiates platelet clotting?
- collagen fibres
Once injury to endothelial cells has been identified what do the glycoproteins of platelets help with?
- adhesion to endothelial cells
- adhesion to other platelets
What does the release of platelet derived growth factor (PDGF) initiate?
- signals smooth muscles cells
- initiate healing process
What are the 3 functions of platelets?
1 - adhesion to endothelial cells
2 - aggregation with other cells
3 - activation of alpha granule content
What is the von Willebrand factor?
- a glycoprotein
- important for binding proteins
- important for platelet adhesion
Where is von Willebrand factor produced?
- endothelial cells
- alpha granules of platelets
- megakaryocytes
Can deficiencies in the von Willebrand factor cause problems?
- yes
- inability to for blood to clot
What is the coagulation cascade?
- secondary haemostasis
- process where stable blood clots form
What are the 3 pathways involved in the coagulation cascade?
1 - Intrinsic
2 - Extrinsic
3 - Common
Why is the intrinsic pathway of the coagulation pathway called intrinsic?
- all factors required for activation are found within blood
Why is the extrinsic pathway of the coagulation pathway called extrinsic?
- it is activated by tissue factor
- tissue factor is located extrinsically to blood
How is the extrinsic factor activated?
- damage to the endothelium
- Tissue factor (factor III) is activated
- Tissue factor (factor III) activates factor VII
What is tissue factor?
- protein that acts as catalyst to start coagulation cascade
Where can tissue factor be released from, keeping in mind it is external to the blood?
- smooth muscle cells
- fibroblasts
Where is factor VII produced and found commonly?
- produced by the liver
- located in plasma in inactive form
- activated by factor III (tissue factor)
When looking at the coagulation flow, do the arrows mean the factors upstream become what is below them or the factors above are the activating the factors below?
- above factors become activated
- then become catalyst to active factor below
What is the pathway of factors in the intrinsic pathway?
- factor XII (12)
- factor XI (11)
- factor IX (9)
- factor VIII (8)
- factor X (10) (overlap between intrinsic and common pathway)
Are the intrinsic factors XII (12), XI (11), IX (9), VIII (8) and X (10) co-factors or enzymes?
- all are enzymes
When factor VII (7) is activated by factor III (tissue factor) what factor can it activate in the common pathway?
- factor X (10)
Once factor X (10) is activated what does it do downstream?
- it activates factor V (5)
Once factor X (10) has activated factor Va (5a) what does it do downstream?
- forms the prothrombinase complex factor II (2)
Once prothrombinase complex factor II (2) has become active, what does it do?
- activates thrombin
- called factor IIa (2a)
What is thrombin?
- enzyme that converts factor I (1) called fibrinogen to factor Ia (1a) called fibrin
- fibrin is like rope holding platelet clot together
In addition to converting fibrinogen into fibrin what does thrombin amplify?
- intrinsic pathway (specifically factor 8 (VIII)
- factor 5 in common pathway converting prothrombin into thrombin
- positive feedback loop
- loop stops when no further thrombin produced
Specifically what factors is thrombin able to activate that will in turn amplify the intrinsic coagulation cascade? To remember think of odd numbers 5 and above.
- factor XIII (13)
- factor XI (11)
- factor VIII (8) (exception to rule)
- factor VII (7)
- factor V (5)
How is factor XII (12) in the intrinsic pathway activated?
- when comes into contact with negative charged phosphates
- negaitvely charged phosphates on activcated platelets
- negaitvely charged phosphates on subendothelial collagen
Where can factor XII (12) bind with negatively charged phosphates to become actived?
- activated platelets
- exposed sub-endothelial collagen
What does factor XIII (13) do in the coagulation pathway, and what activates this?
- forms crosslinks between fibrins and gives stability
- activated by factor IIa (2a) called thrombin
In addition to a number of factors in the coagulation cascade, what else is thrombin able to act upon?
- an enzyme called plasmin
- plasmin is able to degrade fibrin in blood clots
What is the main purpose of the intrinsic coagulation pathway?
- amplify signalling pathway cascade
- increased fibrin production
What is the positive feedback loop that thrombin is involved in?
- ⬆️ thrombin = ⬆️ activation of factors VIII (8) and V (5)
- ⬆️ activation of factors VIII (8) and V (5) = ⬆️ thrombin
What common cation (+ charge) does the intrinsic pathway depend on, and what cells provide this?
- Ca2+
- Ca2+ located in dense granules in platelets
What are the 2 key factors that the common pathway heavily relies on?
- factors X (10) and V (5)
What is vitamin K?
- fat soluble vitamin - found in green vegetable and synthesised by bacteria
Why is vitamin K important in the coagulation cascade?
- required to activate a number of factors
- factors II (2) (prothrombin), VII (7), IX (9) and X (10)
- same factors as heparin (2+7=9…10, 11, 12)
If a patient has low vitamin K or a genetic deficiency of vitamin K, what could happen to them if they cut themselves?
- unable to effectively clot - bleed to death
Warfarin is a drug that thins the blood. How does it act on vitamin K to ensure blood remains thin?
- inhibits vitamin K reductase
- vitamin K reductase recycles vitamin K
How can liver disease affect vitamin K levels?
- reduced absorption
What is tissue factor pathway inhibitor (TFPI)?
- single-chain polypeptide
What is the role of tissue factor pathway inhibitor (TFPI)?
- inhibits tissue factor and VIIa (7a) in the extrinsic pathway
- inhibits factors Xa (10a) in the common pathway
Which cells produce tissue factor pathway inhibitor (TFPI)?
- endothelial cells - platelets - present in plasma
Once tissue factor, and factors VIIa (7a) and X (10) have been activated by the extrinsic pathway, even though they produce some thrombin, why is this not able to then produce fibrin?
- endothelium injury causes tissue factor (TF) to be released
- tissue factor pathway inhibitor (TFPI) also activated
- TFPI inhibits further expression of TF (safety mechanism)
- reason that intrinsic pathway needs amplifying
What is thrombomodulin?
- integral membrane protein
- expressed on the surface of endothelial cells
How does thrombomodulin slow down coagulation?
- thrombomodulin present on healthy epithelial cells
- excess thrombin binds to thrombomodulin
- creates thrombin/thrombomodulin complex
- ⬇️ thrombin in positive feedback loop
In addition to reduce in thrombin in the coagulation cascade 2 other proteins are able to bind with the thrombomodulin/thrombin complex, what are they?
- proteins S and C
Once proteins S and C are bound to the thrombomodulin/thrombin complex how are they able to inhibit the coagulation cascade further?
- inhibit factors thrombin accentuates, specifically 5 and 8
- inhibit cofactor V (5) in common pathway
- inhibit cofactor VIII (8) in intrinsic pathway
- significant reduction in coagulation cascade
What protein is the activation of protein C dependent on?
- protein S
What fat soluble vitamin is key for the activity of protein S?
- vitamin K
What is antithrombin III?
- small glycoprotein produced by liver
- synthesised in endothelial cells
- found in circulating plasma
What 2 factors in the common pathway is antithrombin III able to bind with and inhibit?
- factor X (10)
- thrombin (factor II (2))
- inhibits factors 2, 7, 9, 10, 11, 12
What 3 factors in the intrinsic pathway is antithrombin able to bind with and inhibit?
- factors IX (9) XI (11) and XII (12)
- lower affinity than common pathway
What medication can enhance the affinity of antithrombin III and in doing so inhibit factors VII (7), IX (9) XI (11) and XII (12)?
- heparin
What is fibrinolysis?
- gradual degradation of fibrin mesh
What plasminogen and where is it created?
- protein produced by liver
- released into blood stream
How does plasminogen degrade fibrin formed blood clots?
- tissue plasminogen activator released by endothelial cells - activated by thrombin and tissue plasminogen activator into plasmin
In coagulation disorders what can be affected in primary and secondary haemostasis?
- ⬇️ platelet function - ⬇️ coagulation cascade - ⬇️ coagulation inhibition
What is thrombocytopenia?
- thrombo = platelets - penia = lack of - low platelet count
What 3 disorders can be causing thrombocytopenia?
- bone marrow failure - autoimmune disease - hereditary disease
What is Haemophilia A?
- hereditary disease
- deficient in factor VIII (8)
- causes reduced amplification of intrinsic pathway
What is Haemophilia B?
- hereditary disease
- deficient in factor IX (9)
- causes reduced amplification of intrinsic pathway
Is it easy to determine between Haemophilia A and B?
- no - need genetic testing
What is the von Willebrand disease?
- autosomal dominant inheritance (only need 1 gene)
- deficiency in von Willebrand production
- reduced initial blood clotting
What is Ashkenazi Jewish deficiency, also commonly referred to as Haemophilia B?
- deficiency in factor XI (11) in intrinsic pathway
What is thrombosis?
- formation of a blood clot
If blood clots are not degraded, thrombosis can occur, why is this dangerous?
- they can block circulation
- myocardial infarctions and cerebrovascular disease
What is an embolus?
- thrombosis (blood clot) that has broken free into circulation
What is the factor V (5) Leiden gene mutation?
- arginine switched with glutamine
- protein C cannot effectively inhibit factor V (5)
- coagulation cannot be inhibited effectively
