Haemostasis

Question 1

What are the 3 main steps of haemostasis?

Answer 1

1) Trauma/breach triggers vascular spasm/constriction to reduce blood flow and loss
2) Primary haemostasis (formation of platelet plug)
3) Secondary haemostasis (formation of blood clot)

Question 2

Describe the process of thrombopoiesis

Answer 2

1) Thrombopoietin (TPO) constantly produced by liver/kidney
2) TPO stimulates thrombopoiesis (Myeloid stem cells to Megakaryocytes)
3) Megakaryocytes fragment and shed into circulation as platelets
4) TPO removed from circulation by platelets (-ve feedback)

Question 3

What is the typical lifespan of a platelet?

Answer 3

~10 days

Question 4

Where are senescent platelets broken down?

Answer 4

Spleen

Question 5

Describe the process of primary hemostasis.

Answer 5

1) Platelet adhesion to collagen and then activation
2) Release of granules containing platelet agonists
3) Platelet aggregation to form plug and release > platelet agonists (+ve feedback)
4) Repair
5) Intact endothelial cells release NO and Prostacyclins (anticoagulation) inhibits platelet activation and aggregation

Question 6

Describe the role of Von Willebrand’s Factor (vWF) in platelet adhesion.

Answer 6

vWF binds platelets (Gp1b glycoprotein receptor) to exposed collagen
- binding activates platelets
- allows for morphological change and release of platelets agonists from granules
- promotes aggregation

Question 7

Where does Von Willebrand’s Factor come from?

Answer 7

Platelets

Question 8

What are 2 examples of platelet agonists released from granules in platelet activation?

Answer 8

ADP and Thromboxane A2 (Tbx A2)

Question 9

Describe the process of platelet adhesion.

Answer 9

1) vWF binds platelets to exposed collagen
2) Adhesion activates platelets stimulates morphological change in platelets (spiky)
3) Platelet activation triggers release of platelet agonists from granules (eg. ADP, Tbx A2)
4) Aggregation

Question 10

In platelet aggregation:
i) ADP ______________
ii) Tbx A2 ___________
iii) Fibrinogen ___________

Answer 10

i) ADP attracts and activates > platelets (+ve feedback)
ii) Tbx A2 promotes aggregation and vasoconstriction
iii) Fibrinogen links platelets via glycoprotein receptors

Question 11

Why is secondary hemostasis needed?

Answer 11

Fibrinogen links formed in platelet aggregation are weak

Question 12

Describe the common pathway of secondary hemostasis.

Answer 12

1) F10 → F10a
2) Prothrombin (zymogen) + Ca2+ +F5a → Thrombin (serine protease)
3) Thrombin cleaves Fibrinogen → Fibrin monomer (soluble)
4) Fibrin monomers polymerise → Fibrin strands
5) Thrombin activate F8 → F8a (fibrin stabilising factor) → crosslink fibrin strands

Question 13

What are 2 benefits of having blood clotting a cascade?

Answer 13

1) Rapid amplification (all enzymes → exponential activation)
2) Multiple +ve feedback loops (thrombin promotes F5,8,11)

Question 14

What are the 3 different pathways in the coagulation cascade?

Answer 14

1) Common pathway
- F10 → F10a → Prothrombin + FVa → Thrombin → Fibrinogen → Fibrin → Mesh

2) Extrinsic pathway
- Damaged tissues → F7 → F7a → F10

3) Intrinsic pathway
- Collagen fibre / foreign material exposure
→ Platelet phospholipid + conformational change
→ F12 → F11 → F9 + F8a → F10

Question 15

Describe how the extrinsic pathway aids in the coagulation cascade.

Answer 15

1) Damaged tissues release tissue factor/thromboplastin (F3)
2) F7 + tissue factor → F7a
3) F7a + Ca2+ → FX (common pathway)

Question 16

Describe how the intrinsic pathway aids in the coagulation cascade.

Answer 16

12 → 11 → 9 + 8 → 10
1) Exposure to collagen fibres/foreign surfaces
2) Platelet phospholipids and conformational change
3) F12 → F12a
4) F11 → F11a
5) F11a + Ca2+ → F9
6) F9 → F9a
7) F9a + F8a + Ca2+ → FX (common pathway)

Question 17

Which clotting factors require Ca2+ to be activated?

Answer 17

9, 10, prothrombin

Question 18

What is the effect of calcium chelators on clotting?

Answer 18

Inhibits clotting

Question 19

How does applying dressing to a wound promote clotting?

Answer 19

Dressing acts as a foreign surface, kickstarting the intrinsic pathway by inducing platelet phospholipid and conformational change

Question 20

Is Ca deficiency a significant cause of coagulopathies?

Answer 20

No

Question 21

How many coagulation factors are there?

Answer 21

12
- goes up to 13 but no F6

Question 22

What is the main source of most coagulation factors?

Answer 22

The liver

Question 23

Most clotting factors are ________ in nature, and are produced in the ______, with the exception of (i) ______ which is a ______ produced by _______ and (ii) ______ which is a ______ found in _____.

Answer 23

Most are plasma proteins produced in the liver

Exceptions: F3&4
i) Tissue factor/thromboplastin/F3:
- mixture of Glycoproteins and phospholipids
- produced by damaged tissue

ii) Ca2+ (F4):
- inorganic ion
- found in plasma

Question 24

Of the coagulation factors, Factor ________ specially require ________ for production.

Answer 24

F2, 7, 9, 10 require Vitamin K for production

Question 25

What are 3 quick diagnostic screens for coagulopathies?

Answer 25

1) FBC (platelet count) 2) Prothrombin time (PT) 3) Partial Thromboplastin Time (aPTT)

Question 26

What are 3 specific/confirmatory tests for coagulopathies?

Answer 26

1) Coagulation factor assays 2) Platelet aggregation tests 3) vWF Ag assay

Question 27

Describe the process of assessing PT in a px.

Answer 27

1) Draw blood into a Citrated tube (Ca2+ chelator) 2) Separate citrated plasma via centrifugation 3) Add thromboplastin and Ca2+ 4) Time clotting

Question 28

Describe the process of assessing aPTT in a px.

Answer 28

1) Draw blood into citrated tube (Ca2+ chelator) 2) Separate citrated plasma via centrifugation 3) Add Kaolin + Phospholipids + Ca2+ 3) Time clotting

Question 29

What does PT tell you?

Answer 29

It evaluates the extrinsic coagulation pathway. (normal time = 10sec) (normal INR = 0.8-1.2)

Question 30

What is INR?

Answer 30

International Normalised Ratio: Corrected ratio of px PT vs normal PT (normal range = 0.8-1.2)

Question 31

What is aPTT used for?

Answer 31

1) Assess intrinsic pathway (normal time = 25-35s) (screen bleeding disorders) 2) Monitor anti-coagulant therapy eg. Heparin therapy (1.5-2.5X of normal PTT)

Question 32

What is the difference between Hemophilia A and B?

Answer 32

A: F8 defiency b: F9 deficiency

Question 33

How can a haemophilia diagnosis be confirmed?

Answer 33

1) Coagulation factor assay 2) Mixing assay

Question 34

What are some possible treatment options for px with Haemophilia?

Answer 34

1) Platelet infusion 2) Fresh frozen plasma 3) Cryoprecipitates 4) Activated Prothrombin Complex Concentrates (APCC): - Cryoprecipitates + F7a 5) Recombinant Coagulation factors (eg. rvWF, rF8, rF7, etc.)

Question 35

Thrombocytopenia often presents as _______ on the skin.

Answer 35

Petechiae

Question 36

What are some common causes of thrombocytopenia?

Answer 36

1) Chemotherapy (myeloablation) 2) Leukemia 3) **Immune Thrombocytopenia (ITP) 4) Splenomegaly

Question 37

What could be a possible diagnosis for a px with: i) poor eating and drinking habits ii) Prolonged PT + INR iii) Prolonged aPTT

Answer 37

Liver dysfunction leading to coagulopathies (decreased clotting factor production)

Question 38

What could be a possible diagnosis for a px with: i) Prolonged aPTT ii) Family Hx mild affecting F of family

Answer 38

Hemophilia (XLR)

Question 39

What could be a possible diagnosis for a px with: i) Sudden onset coagulopathies + petechiae ii) Low platelet count iii) No family Hx iv) Normal PT, aPTT, Liver f(x)

Answer 39

Acute Thrombocytopenia

Question 40

What could be a possible diagnosis for a young px with: i) Combination of rashes and bruises of unknown causes ii) Similar symptoms in parent and sibling iii) Only abnormal aPTT

Answer 40

Von Willebrand Disease

Question 41

Von Willebrand Disease is a form of ___________ deficiency, leading to __________ and ____________ as vWF is essential in _________ and __________ respectively.

Answer 41

vWF deficiency i) Defective platelet adhesion ii) Prolonged aPTT (vWF also stabilises F8)

Question 42

What is the inheritance pattern of Von Willebrand Disease?

Answer 42

AD

Question 43

What biochemical test would confirm a Von Willebrand Disease diagnosis?

Answer 43

vWF Ag Assay

Question 44

What are the 3 processes of anti-coagulation?

Answer 44

1) Plug prevention (inhibit primary hemostasis) 2) Clot prevention (inhibit secondary hemostasis) 3) Clot removal (fibrinolysis)

Question 45

What are the some chemicals that are produced by intact and smooth endothelial cells to prevent aberrant clot formation?

Answer 45

1) NO and Prostacyclins 2) Tissue Factor Pathway Inhibitor (TFPI) 3) Thrombomodulin and Protein C Receptor

Question 46

How is plug prevention regulated?

Answer 46

The components are only produced/excreted by intact and smooth endothelial cells (healed/normal).

Question 47

What are the functions of NO and Prostacyclins in anti-hemostasis?

Answer 47

Inhibit platelet activation and aggregation

Question 48

What are the functions of Tissue Factor Pathway Inhibitor in anti-hemostasis?

Answer 48

Inhibits Tissue factor/F7 activation (extrinsic pathway)

Question 49

What are the functions of Thrombomodulin and Protein C receptors in anti-hemostasis?

Answer 49

1) Sequester/inactivate thrombin 2) Activate Protein C/S

Question 50

Describe the process of Protein C/S activation

Answer 50

1) Thrombomodulin sequesters Thrombin 2) Endothelial Protein C Receptor (EPCR) binds Protein C and brings to thrombin-thrombomodulin complex 3) Complex activates protein C (APC) 4) APC binds circulating Protein S 5) APC-PS complex is an active protease: - cleaves and inactivates F5a and F8a

Question 51

What is anti-thrombin?

Answer 51

A group of serine protease (thrombin) inhibitors (Serpins) that sequester thrombin leaked from clots

Question 52

Where is anti-thrombin produced?

Answer 52

Liver

Question 53

Which clotting factor(s) does anti-thrombin inhibit?

Answer 53

1) Thrombin 2) F10a 3) F9a

Question 54

What is the function of anti-thrombin?

Answer 54

To ensure clotting is localised to damaged site (via inhibition of thrombin, F10a, F9a)

Question 55

What are the 3 physiological inhibitors of the coagulation cascade and their targets?

Answer 55

1) Tissue Factor Pathway Inhibitor (IFPI): Tissue factor/thromboplastin (extrinsic pathway) 2) APC/S Complex: F7a & F5a (intrinsic and common pathway) 3) Anti-thrombin: Thrombin, F10a, F9a (intrinsic and common pathway)

Question 56

How are clots resolved/removed after healing?

Answer 56

Fibrinolysis: 1) Intact endothelial cells release Tissue Plasminogen Activator (TPA) 2) Plasminogen (Zymogen) activated by TPA in presence of fibrin 3) Plasmin mediates fibrinolysis 4) Fibrin degradation products (FDP) released

Question 57

What does ↑circulatory D-dimers indicate?

Answer 57

A thrombotic event

Question 58

Fibrin monomers are crosslinked at their __________, forming ______ when fibrinolysed.

Answer 58

D-domains, forming D-dimers

Question 59

How is fibrinolysis regulated physiologically?

Answer 59

Only occurs at right place: 1) No TPA from damaged vessels 2) Low TPA affinity to plasminogen w/o fibrin (no free-floating active plasmin) 3) Circulating Plasmin Activator Inhibitor (PAI/TPA inhibitor) and anti-plasmin (plasmin inhibitor)

Question 60

What is Virchow's triad?

Answer 60

3 main thrombosis risk factors: 1) Endothelial damage 2) Venous stasis 3) Hypercoagulability

Question 61

How does endothelial damage predispose a px to thrombosis?

Answer 61

Damaged endothelium → no intact & smooth endothelial wall → no inhibition of plug/clot formation → ↑ risk of thrombosis

Question 62

How does venous stasis predispose a px to thrombosis?

Answer 62

Slow blood flow → ↓ anti-coagulant-coagulation factor interaction (TFPI, APC/S complex, AT) → ↑ risk of thrombosis

Question 63

What are some examples of risk factors predisposing a px to endothelial damage and thus thrombosis?

Answer 63

1) Smoking (secondary to hypercoagulability) 2) High blood pressure 3) Hyperlipidemia 4) Atherosclerosis

Question 64

What are some examples of risk factors predisposing a px to venous stasis and thus thrombosis?

Answer 64

1) Surgery 2) Trauma (secondary to endothelial damage) 3) Prolonged immobilisation

Question 65

What are some examples of risk factors predisposing a px to hypercoagulability and thus thrombosis?

Answer 65

1) Genetic disorders (eg. FV Leiden, Protein C/S deficiency, Anti-thrombin 3 deficiency) 2) Cancer 3) Oral contraceptives

Question 66

What is Factor V Leiden?

Answer 66

A genetic condition prevalent in Caucasians (3-8/100) which predisposes px to thrombosis (20-25%) - Factor V Leiden resistant to degradation by APC/S complex

Question 67

What would be the most likely diagnosis in a px with: - R calf swollen and red w bulging veins after 6 hour flight - no injury - normal BP and pulse - No change in PPT +- Activated Protein C - ↑ D-dimer

Answer 67

Thrombosis + Factor V Leiden

Question 68

What is the MOA of Warfarin (anti-coagulant)?

Answer 68

Vitamin K antagonist → ↓ F7, F9, F10

Question 69

What is the MOA of Rivaroxaban (anti-coagulant)?

Answer 69

FXa inhibitor

Question 70

What is the MOA of Dabigatran (anti-coagulant)?

Answer 70

Thrombin inhibitor

Question 71

What is the MOA of Heparin (anti-coagulant)?

Answer 71

Potentiates Anti-thrombin

Question 72

What is the MOA of Clopidogrel (anti-platelet)?

Answer 72

ADP inhibitor

Question 73

What is the MOA of Aspirin (anti-platelet)?

Answer 73

COX-1 inhibition → ↓Tbx A2

Question 74

What is the MOA of Abciximab (anti-platelet)?

Answer 74

Fibrinogen and vWF inhibitor

Question 75

What are some examples of anti-coagulants?

Answer 75

1) Warfarin (Vitamin K antagonist) 2) Rivaroxaban (FXa inhibitor) 3) Dabigatran (Thrombin inhibitor) 4) Heparin (Anti-thrombin potentiator)

Question 76

What are some examples of anti-platelets?

Answer 76

1) Clopidogrel (ADP inhibitor) 2) Aspirin (COX-1/Tbx A2 inhibitior) 3) Abciximab (Fibrinogen and vWF inhibitor)