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Haematology > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What are the 3 main steps of haemostasis?

A

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)

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2
Q

Describe the process of thrombopoiesis

A

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)

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3
Q

What is the typical lifespan of a platelet?

A

~10 days

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4
Q

Where are senescent platelets broken down?

A

Spleen

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5
Q

Describe the process of primary hemostasis.

A

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

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6
Q

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

A

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

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7
Q

Where does Von Willebrand’s Factor come from?

A

Platelets

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8
Q

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

A

ADP and Thromboxane A2 (Tbx A2)

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9
Q

Describe the process of platelet adhesion.

A

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

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10
Q

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

A

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

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11
Q

Why is secondary hemostasis needed?

A

Fibrinogen links formed in platelet aggregation are weak

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12
Q

Describe the common pathway of secondary hemostasis.

A

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

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13
Q

What are 2 benefits of having blood clotting a cascade?

A

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

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14
Q

What are the 3 different pathways in the coagulation cascade?

A

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

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15
Q

Describe how the extrinsic pathway aids in the coagulation cascade.

A

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

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16
Q

Describe how the intrinsic pathway aids in the coagulation cascade.

A

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)

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17
Q

Which clotting factors require Ca2+ to be activated?

A

9, 10, prothrombin

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18
Q

What is the effect of calcium chelators on clotting?

A

Inhibits clotting

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19
Q

How does applying dressing to a wound promote clotting?

A

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

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20
Q

Is Ca deficiency a significant cause of coagulopathies?

A

No

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21
Q

How many coagulation factors are there?

A

12
- goes up to 13 but no F6

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22
Q

What is the main source of most coagulation factors?

A

The liver

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23
Q

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 _____.

A

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

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24
Q

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

A

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

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25
Q

What are 3 quick diagnostic screens for coagulopathies?

A

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

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26
Q

What are 3 specific/confirmatory tests for coagulopathies?

A

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

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27
Q

Describe the process of assessing PT in a px.

A

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

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28
Q

Describe the process of assessing aPTT in a px.

A

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

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29
Q

What does PT tell you?

A

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

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30
Q

What is INR?

A

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

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31
Q

What is aPTT used for?

A

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)

32
Q

What is the difference between Hemophilia A and B?

A

A: F8 defiency
b: F9 deficiency

33
Q

How can a haemophilia diagnosis be confirmed?

A

1) Coagulation factor assay
2) Mixing assay

34
Q

What are some possible treatment options for px with Haemophilia?

A

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.)

35
Q

Thrombocytopenia often presents as _______ on the skin.

A

Petechiae

36
Q

What are some common causes of thrombocytopenia?

A

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

37
Q

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

A

Liver dysfunction leading to coagulopathies (decreased clotting factor production)

38
Q

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

A

Hemophilia (XLR)

39
Q

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)

A

Acute Thrombocytopenia

40
Q

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

A

Von Willebrand Disease

41
Q

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

A

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

42
Q

What is the inheritance pattern of Von Willebrand Disease?

A

AD

43
Q

What biochemical test would confirm a Von Willebrand Disease diagnosis?

A

vWF Ag Assay

44
Q

What are the 3 processes of anti-coagulation?

A

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

45
Q

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

A

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

46
Q

How is plug prevention regulated?

A

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

47
Q

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

A

Inhibit platelet activation and aggregation

48
Q

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

A

Inhibits Tissue factor/F7 activation
(extrinsic pathway)

49
Q

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

A

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

50
Q

Describe the process of Protein C/S activation

A

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

51
Q

What is anti-thrombin?

A

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

52
Q

Where is anti-thrombin produced?

A

Liver

53
Q

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

A

1) Thrombin
2) F10a
3) F9a

54
Q

What is the function of anti-thrombin?

A

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

55
Q

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

A

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)

56
Q

How are clots resolved/removed after healing?

A

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

57
Q

What does ↑circulatory D-dimers indicate?

A

A thrombotic event

58
Q

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

A

D-domains, forming D-dimers

59
Q

How is fibrinolysis regulated physiologically?

A

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)

60
Q

What is Virchow’s triad?

A

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

61
Q

How does endothelial damage predispose a px to thrombosis?

A

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

62
Q

How does venous stasis predispose a px to thrombosis?

A

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

63
Q

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

A

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

64
Q

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

A

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

65
Q

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

A

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

66
Q

What is Factor V Leiden?

A

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

67
Q

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

A

Thrombosis + Factor V Leiden

68
Q

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

A

Vitamin K antagonist
→ ↓ F7, F9, F10

69
Q

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

A

FXa inhibitor

70
Q

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

A

Thrombin inhibitor

71
Q

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

A

Potentiates Anti-thrombin

72
Q

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

A

ADP inhibitor

73
Q

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

A

COX-1 inhibition → ↓Tbx A2

74
Q

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

A

Fibrinogen and vWF inhibitor

75
Q

What are some examples of anti-coagulants?

A

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

76
Q

What are some examples of anti-platelets?

A

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

Haematology (9 decks)

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