Blood: Haemostasis L3

Question 1

what is Haemostasis

Answer 1

the arrest of bleeding from a broken blood vessel
- capillaries, arterioles, venules

Question 2

what are platelets

Answer 2

cellular elements of the blood
- they are fragments of large cells from bone marrow called megakaryocytes
- have no nucleus

Question 3

what hormone regulated megakaryocytes and platelet production and where is it made

Answer 3

thrombopoietin
produced in liver and kidneys

Question 4

describe thrombopoiesis
-platelet synthesis

Answer 4

1. starts with hematopoietic stem cell
   - differentiate into megakaryoblasts
2. megakaryoblasts follow myeloid line
   - develop into megakaryocytes by undergoing repeated mitotic cycles without ever actually dividing.
   - Megakaryocytes are massive cells with multiple copies of DNA
3. thrombopoietin stimulates megakaryocyte to extend arm through bone marrow sinusoids into blood vessels
   - Break off as platelets
   Produce about 1011 a day
   1000-3000 platelets/megakaryocyte in its life span

Question 5

describe the structure of platelets

Answer 5

Exterior coat – rich in glycoproteins (adhesion, aggregation and activation)
Tubular System - site of thromboxane A2 synthesis and release
Microtubules and microfilaments – maintain shape
Granules – alpha: contain clotting mediators including von Willebrand factor, factors V, VIII and fibrinogen;
delta (dense bodies): contain ADP, Ca++ and serotonin, required for platelet activation and clotting
mitochondria

Question 6

where are platelets stored and when are they released

Answer 6

in the spleen (short life span- undergo apoptosis and phagocyted in liver and spleen)
released by contraction of the spleen activated by sympathetic nervous system

Question 7

what are the 3 main steps in Haemostasis

Answer 7

1. vascular spasm (contraction of vessel)
2. formation of platelet plug
3. blood coagulation

Question 8

describe vascular spasm

Answer 8

1. damage to vessel causing damaged cells and platelets to release potent vasoconstrictors such as serotonin and ADP at cut site
   - causes smooth muscle layer in vessel wall to constrict slowing flow of blood and limiting blood loss
2. ends of endothelial layer pushed together by the spasm becoming sticky
   - adhere to each other
   - aided by platelets that stick to exposed collagen

Question 9

describe formation of platelet plug

Answer 9

1. platelet adhesion
   - platelets stick to each other using von Willebrand’s factors (plasma protein secreted by endothelial cells and platelets
2. platelet activation
   - activation causes platelets to have irregular shape with many protruding pseudopodia
   - they are more sticky this way
   - Secrete things that cause them to stick together and attract more platelets
3. plug is formed
   - seals the break in the lining

Question 10

what is the function of the platelet plug

Answer 10

1. seal break
2. compaction/ strengthening
3. further vasoconstriction
4. stimulate clotting cascade

Question 11

what is the role of Prostacyclin (PGI2) which is released by normal vessel lining

Answer 11

inhibits platelet aggregation
limits platelet plug to the damaged region of the vessel preventing it’s spread to normal, undamaged tissue.

Question 12

describe Blood coagulation

Answer 12

aka blood clotting
-process changing liquid blood to a solid gel (clot or thrombus)
- Clot strengthens and supports the platelet plug

Question 13

what is the final step in blood coagulation

Answer 13

fibrinogen (large soluble plasma protein) converted to fibrin (insoluble thread like molecule) which RBC get trapped in

Question 14

what factors are involved in the final steps of blood clotting

Answer 14

1. thrombin (IIa- active 2)
   - turn fibrinogen (factor 1) into fibrin monomers
2. XIII (active 13) and calcium
   - turns fibrin monomer to fibrin polymer which forms the clot

Question 15

what are the three pathways of blood clotting

Answer 15

1. intrinsic
   - Initial stimulus is exposed collagen (through damage to the endothelium wall).
2. extrinsic
   - Initial stimulus is blood contact with damaged tissue outside of the blood vessel that exposes tissue factor (also known as factor III; or tissue thromboplastin).
3. common pathway
   - I and E join in the later stages of coagulation

Question 16

describe intrinsic pathway

Answer 16

1. blood vessel damaged
   - active XII (12) activates XII (11) which activates IX (9) which activates X (10) (active X is start of common pathway)

Question 17

describe extrinsic pathway

Answer 17

1. damage to tissue outside blood vessel
   - exposes tissue factor III (3)
   - tissue factor III and active VII (thromboplastin) activates IX (9) which activates X

Question 18

give 2 examples of positive feedback in the pathways

Answer 18

1. high levels of thrombin leads to more XI being activated
2. high levels of active X causes more tissue factor III and VII (thromboplastin)

Question 19

what does Anti-thrombin do in the anti clotting system

Answer 19

inhibits clotting factors including thrombin

Question 20

what does Thrombomodulin do in the anti clotting system

Answer 20

binds to thrombin stopping its clotting effects and inactivates factors Va and VIIIa

Question 21

what does tissue factor pathway inhibitors do in the anti clotting system

Answer 21

bind to factor III/VIIa complex preventing it from activiating IX and X
binds directly to Xa

Question 22

what does Thrombin do in the anti clotting system

Answer 22

binds to its receptor stimulating production of prostaglandins (PGl), nitric oxide and ADP to inhibit further platelet aggregation

Question 23

what is Fibrinolysis

Answer 23

clot break down

Question 24

describe fibrinolysis

Answer 24

Aggregated platelets secrete platelet derived growth factor β (PDGF β) that recruits fibroblasts from the surrounding tissue.
Fibroblasts form scar tissue at the site of the damage.
Simultaneous with healing - clot is dissolved by a fibrinolytic enzyme called plasmin.

Question 25

what is plasmin activated by

Answer 25

tissue plasminogen activator (t-PA), secreted by endothelial cells. t-PA needs to bind fibrin to become active, hence only works on clot.

Question 26

give summary of clotting factors

Answer 26

Clotting factors other than III, V, VIII and XIII are proteases that activate downstream factors III, V and VIII are glycoproteins XIII is a transglutaminase

Question 27

give 4 types of haemostasis disorders

Answer 27

1. excessive or inadequate clotting 2. acquired (something happens that changes physiology) or inherited 3. defects of platelets - quantitative (thrombocytopaenia) - qualitative (thrombopathy) 4. Deficiency or dysfunction of coagulation factors (coagulopathy)

Question 28

acquired disorders are more common than inherited - give examples

Answer 28

- renal disease – lack of thrombopoeitin - hepatic disease - lack of fibrinogen - vitamin K deficiency – needed for synthesis of clotting factors II, VII, IX and X (VK needed) - drug-induced disorders include effects on platelet activity e.g. aspirin and other non-steroidal anti-inflammatory drugs inhibit thromboxane A2 synthesis and secretion

Question 29

give examples of inherited disorders

Answer 29

- Structural defects to vascular system. - Thrombotic disorder: an alteration to haemostasis that impairs capacity to combat clot formation - Quantitative (thrombocytopaenia) or qualitative (thrombopathy) defects of platelets - Deficiency or dysfunction of coagulation factors (coagulopathy)

Question 30

what is Haemorrhage

Answer 30

“Black and blue” marks caused by internal bleeding. Due to degradation of haemoglobin to biliverdin, bilirubin and heamosiderin - Come from break down of heam Eventually removed by plasmin and phagocytosis

Question 31

Thrombosis - Excessive/unwanted clotting what are consequences of thrombosis

Answer 31

1. Thrombus – Blood clot within a vessel or the heart 2. Embolus – detached mass able to travel in a vessel Solid, liquid or gas 3. Embolism - the lodging of an embolus 4. Thrombo-embolism – blockage by a thrombus 5. Stenosis – abnormal narrowing of a passage in the body

Question 32

Virchow’s Triad describes three risk factors for thrombosis: what are they

Answer 32

1. Blood stasis e.g. deep vein thrombosis (DVT) - Blood not moving around body in normal way blood more likely to clot 2. Changes in the vessel wall – injury, inflammation 3. Thrombogenic changes in the blood – hypercoagulability (causes/risk factors include obesity, smoking, pregnancy, cancer, age; can be inherited)

Question 33

how does thrombosis effect blood flow - Thromboembolism

Answer 33

Need to get to high percentage of blocking before it really affects blood flow

Question 34

what treatments are there for thrombosis

Answer 34

anticoagulant drugs Warfarin: Most widely prescribed oral anticoagulant; inhibits vitamin K. Heparin: endothelial cell–derived polysaccharide. Given by injection (not absorbed through gut). Activates antithrombin III (AT) Used where the likelihood of forming clots is increased: - atrial fibrillation (an irregular heart beat where blood can pool and clot in the heart) sits in heart- more likely to clot - aortic valve replacement - recent surgery - autoimmune disease attacking fat and protein components of blood vessel walls

Question 35

what is Thrombocytopenia

Answer 35

quantitative platelet disorder that sees low platelet count caused by autoimmune disease drug induced – inhibition of platelet synthesis (eg interferon, alcohol), immunologic destruction of platelets (eg ibuprofen, tamoxifen) results in Easy bruising, petechial rash, mucous membrane bleeding or excessive bleeding after minor trauma - Petechiae

Question 36

what is Thrombotic thrombocytopenic purpura

Answer 36

platelet disorder caused by formation of small clots in the circulation; results in low platelet numbers. Spontaneous aggregation of platelets and initiation of the clotting cascade Rare but serious disorder; can be congenital, an autoimmune disease or caused by toxins

Question 37

give 3 examples of inherited coagulopathies

Answer 37

1.von Willebrand’s Disease: - Lack of von Willebrand factor ->. poor platelet aggregation. Common symptom: excessive gum bleeding. Autosomal dominant. Mild. 2. Haemophilia A: - Deficiency in factor VIII. X-linked recessive disorder. Excessive bleeding 3. Haemophilia B: - Deficiency in factor IX. Also known as ‘Christmas disease’. Less server - both associated with excessive bleeding - Severity depends on how much factor VIII or IX is present in blood. Treatment: replacement of ‘missing’ clotting factor