Haemostasis Basics Flashcards
what type of feedback system is blood coagulation
positive feedback
Define haemostatsis
Haemostatsis is defined as the cessation of bleeding at a vascular injury site via the formation of a thrombus
what is the two primary components of a thrombus
- platelet plug
- fibrin clot
describe what a platelet plug is
- this is when the circulating platelets form a physical plus by adhering to the injury site and each other
- aggregation of platelets is termed primary haemostats
what is the difference between primary and secondary haemostatsis
- primary haemostatsis is the platelet plug
- secondary haemostats is the fibrin clot
describe what a fibrin clot is
- activation of coagulation factor proteases results in a protease thrombin
- thrombin is essential for the production of fibrin monomers
- these are cross linked and form a meshwork around the platelet plug
- this is termed secondary haemostasis
Describe the structure of platelets
- NOT CELLS, little bags of cytoplasm shed from megakaryocytic
- no nuclei
- 1-4um in diameter
- each megakaryocyte can produce over 1000 platelets
how long can platelets survive for
- there are about 1-2 platelets per 20 RBC
- survive 8.5-10 days and have a half life of 4 days
what regulates platelet production
- Megakaryocyte and platelet production is regulated by thrombopoietin, a hormone produced in the kidneys and liver.
what is a low platelet count called
what is a high platelet count called
thrombocytopenia
thrombocytosis
Describe how the platelet plug forms (primary haemostasis)
- damaged endothelium
- this means that collagen underneath the endothelium is exposed to the blood
- Von willebrand factor (VWF) binds to the exposed collagen
- platelets then bind to the VWF via the platelet GP1b receptors (platelets can also bind directly to the collagen via Gp1a and Gp6 receptors but this is very weak)
- the VWF has formed a bridge between the collagen and platelets, this is called platelet adherence
- the adherent platelets express the GP2b/3a receptor
- GP2b/3a receptors bind to fibrinogen which binds more platelets to form a meshwork this is called platelet aggregation
- the binding of platelets cause the platelets to become activated
- they change shape and become spiky and entailed together
- they release ADP and thromboxane A2 (TXA2) and serotonin (5-HT) from granules, this is called the platelet release reaction
- ADP & TXA2 attract more platelets to the site which aggregate to form a platelet plug.
- 5-HT acts on local smooth muscle to increases local vasoconstriction.
- The spiky platelets in turn release cytokines which attract even more platelets and so a positive feedback system operates until a plug large enough to stop the bleeding is formed.
what normally prevents platelet adhesion
- the endothelium which is intact continuously releases nitric oxide and prostacyclin (PG12) this prevents platelet adhesion
- this also happens adjacent to the damage endothelium to prevent the platelet plug from separating
what is van willebrand factor
- it is a glycoprotein that circulates in the blood and binds to the exposed collagen
what receptors do the platelets bind to when creating the platelet plug
- platelets then bind to the VWF via platelet GP1b receptors.
- Platelets can also bind directly to collagen via Gp1a and Gp6 receptors: However without VWF the binding is very weak and the platelets are easily dislodged).
what is platelet adherence
- when the platelets bind to the VWF via platelet GP1b receptors
- this means that the VWF has formed a bridge between the collagen and platelets this is called platelet adherence
where is Von williebrand factor stored
stored in the endothelial cells, inside granules called Weibel–Palade bodies (WPBs)
what substances are released in the platelet release reaction
- They release adenosine diphosphate (ADP), thromboxane A2 (TXA2) and serotonin (5-HT) from granules
what does ADP and TXA2 do in the platelet plug
- ADP & TXA2 attract more platelets to the site which aggregate to form a platelet plug.
what does 5HT do in the platelet plug
5-HT acts on local smooth muscle to increases local vasoconstriction which reduces the local blood flow
where is VWF made
liver
what determines the bleeding time
- the formation of the platelet plug determines the bleeding time
how long does it take for bleeding to stop
normally stops within 1-9 minutes but may be longer in children (1-13 minutes) and tends to take slightly longer in females than in males
what does the bleeding time test involve (test for platelet function)
- A lancet or scalpel blade is used to make a shallow incision 1 millimeter deep on the underside of the forearm.
- The time from when the incision is made until all bleeding has stopped is measured and is called the bleeding time
- Normal values fall between 3 – 10 minutes.
what are the three pathways in the fibrin clot
- extrinsic pathway
- intrinsic pathway
- common pathway
Describe the steps in the extrinsic pathway
- Factor VII is exposed to tissue factor (III) when the blood vessel is injured
- the tissue factor (III) converts factor VII to VIIa
- VIIa then reacts with calcium and factor X in the blood to form factor Xa
what is the clinical test for extrinsic and common pathway
PT
what type of protein is factor VII
plasma protein
where is tissue factor (III) found
- it is intracellular in the endothelium and smooth muscle
what are the substances called that convert factor X to Xa called
The enzymes and calcium which convert factor X to Xa are sometimes called the tenase complex
Describe the steps of the common pathway
- Xa and calcium from the extrinsic pathway cause prothrombin to be converted to thrombin
- thrombin turns fibrinogen to fibrin
- thrombin also creates a bit of XIII
- XIII turns into XIIIa
- XIIIa stabilises the fibrin into a stable clot
what does a stable clot consist of
- matrix of fibrin
- platelets
- trapped erythrocytes
What causes amplification of thrombin formation
- the extrinsic pathway produces a small amount of thrombin by forming a small amount of Xa
- The initially formed thrombin converts three other factors – V VIII, XI into their active forms Va VIIIa Xia
- Xia then converts factor IX to IXa
- VIIIA and Isa increases conversion of X to Xa
- Va increases effective of the increased Xa
Describe the steps of the intrinsic factor
- Factor XII is converted into XIIa
- XI is converted to XIa by XIIa
- IX is converted into Isa by XIa and calcium
- then IXa and calcium is used to convert X to Xa
when is the intrinsic factor activated
- it activates clotting when the blood is stagnant
- often happens in the atria or leg veins (deep vein thrombosis)
-
what is the clinical test for the intrinsic pathway and common pathway
is APPT (activated partial prothrombin time) – sometimes called surface activation pathway, the surface of the slide which is polar activates this surface
what test is used for assessing platelet function
bleeding time
What is the INR
- number derived from the prothrombin time
- it is used to assess the coagulability of blood in patients taking warfarin or heparin as they are at risk of abnormal clot formation such as deep vein thrombosis or pulmonary emboli
What is the ideal INR value
- in patients on warfarin or heparin 2-3 (not more than 3) is aimed for
- INR healthy range is 0.8-1.2
what are two types of haemophilia
Haemophilia A
Haemophillia B
what is the difference between haemophilia A and haemophilia B
- Hameophilia A is caused by a deficiency of factor VIII. It reduces the effectiveness of the positive feedback loop forming thrombin
- Haemophilla B is caused by a deficiency of factor IX
What are the two substances involved in getting rid of clots
- antithrombin III
- plasmin
Describe how clots are removed
- Plasmin circulates in the blood in the form of an inactive precursor plasminogen. Plasminogen binds to platelet plugs as they form, and gets incorporated into the final clot. Plasminogen is held in its inactive form by alpha-2 antiplasmin which circulates in high concentration in the plasma
- When the tissue is healed the plasminogen becomes plasmin this happens by tissue plasminogen activator (tPA)
- this causes fibrinogen to be proteolysis and turned to fibrin
what type of protein is antithrombin III
- plasma protein
what is the dominant form of antithrombin found in the blood plasma
α-antithrombin is the dominant form of antithrombin found in blood plasma.
what does tPA do
- Tissue plasminogen activator (tPA) is released from normal endothelial cells. It catalyses conversion of plasminogen to plasmin
- One of its functions is to prevent a clot extending too far along a blood vessel into healthy tissue.
name a product of fibrin breakdown
D-dimer
why is D dimer important
Measurement of D-Dimer levels is an important test performed in patients with suspected thrombotic disorders (eg DVT).
- it is an indication that thrombosis is not present
what other factors also catalyse plasminogen to plasmin
urokinase plasminogen activator, kallikrein, and factor XIIa
what factors is vitamin K important for
requires for full effectiveness of Factors VII, IX and X of the coagulation cascade.
what does vitamin K do
Vitamin K modifies the proteins to allow them to bind calcium ions.
what are the two main forms of vitamin K
Vitamin K1 and vitamin K2.
where are two main forms of vitamin K found
- Vitamin K1 is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis.
- Animals can convert it to vitamin K2.
- Bacteria in the gut flora can also convert K1 into vitamin K2
what are the risk factors for vitamin K deficiency
- Liver disease,
- poor diet (no green vegetables)
- poor absorption, antibiotics
- Deficiency of vitamin K seen as increased INR and may result in unstable clots. It may also be a factor in osteoporosis
what is used in treatment for overdose of the anticoagulant drug warfarin and rat poisoning
Vitamin K
what are the two classic anticoagulants
heparin
warfarin
what does heparin do
Heparin binds to and massively increases the activity of anti-thrombin
Activated AT inhibits thrombin and factor Xa
how is heparin given
Must be given parenterally (i.v. or subcutaneous) as not absorbed through gut
Short half-life (one hour) so give continuously or regularly
Effective instantly
what does warfarin effect
- Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors especially Factors VII, IX and X.
- It also competes with sites on these factors that bind vitamin K reducing their effectiveness
name the modern anticoagulants
Direct acting anticoagulatns DOACs
name some direct acting anticoagulants DOACs
- These agents include a direct thrombin inhibitor(dabigatran)
- factor Xa inhibitors (eg rivaroxaban, apixaban and edoxaban).
describe the positives and negatives for DOACs
Positives
- less serious side effects than traditional anticoagulants
- a rapid onset action and relatively short half-lives, therefore more effective
- don’t need monitoring like warfarin
negative
- more expensive and needed for kidney problem patients
- is no antidote for the factor Xa inhibitors, so it is difficult to stop their effects in the body in cases of emergency
