Haemostasis and Bleeding Disorders

Question 1

What are procoaguolant factors in Primary and Secondary Haemostasis?

Answer 1

Primary: platelets, endothelium, vWF
Secondary: coagulation cascade

Question 2

What are anticoagulant processes?

Answer 2

Fibrinolysis

Inhibition of thrombosis (antithrombin, Protein C/S, TFIP)

Question 3

What are the THREE simultaneous responses to vessel injury?

Answer 3

VASOCONSTRICTION - to prevent excess blood loss
PLATELET ACTIVATION - primary haemostasis
COAG CASCADE - secondary haemostasis

Question 4

What are the two key functions of endothelium?

Answer 4

BARRIER - prevent exposure of pro coag sub endothelial structures to blood

SYNTHESIS - of prostaglandins, vWF, plasminogen activators, thrombomodulin

Question 5

What occurs following endothelial injury, when subendothelial factors are exposed?

Answer 5

Platelet aggregation at site of damage occurs

Question 6

What cell do platelets derive from?

Answer 6

Megakaryocytes

Question 7

How many platelets can each megakaryocyte produce?

Answer 7

4000

Question 8

How long is the lifespan of a platelet?

Answer 8

10 days

Question 9

How soon before surgery do you need to stop someone on aspirin?

Answer 9

7-10 days prior to surgery

This is because aspirin (anti-platelet drug) has effect for about 10 days, until platelets are able to regenerate

Question 10

Explain the 5 stages of primary haemostasis

Answer 10

1. Endothelial injury
2. Exposure - damaged endothelial cells expose sub endothelial collagen and release vWF, which binds to the collagen
3. Adhesion - platelets bind to vWF through GP1b protein
4. Activation - platelet is activated, releases ADP and thromboxane A2, expresses GPIIb/IIIa to bind to other platelets
5. Aggregation - GPiib/IIIa is used to bind to other platelets

Question 11

What do damaged endothelial cells produce and release?

Answer 11

von Willenbrand Factor

Question 12

What binds to vWF?

Answer 12

PLATELETS bind to vWF through GPIb protein

Question 13

What surface glycoprotein to platelets use to aggregate?

Answer 13

GpIIb/IIIa

Question 14

What is the function of the open canalicular system on platelets?

Answer 14

To massively expand platelet SA

Question 15

What chemicals do platelets produce top attract more platelets?

Answer 15

Thromboxane A2

ADP

Question 16

What molecule other than platelets binds to GlpIIb/IIIa?

Answer 16

Fibrinogen

Question 17

How does ASPIRIN work?

Answer 17

It irreversibly inhibits COX enzyme

COX is necessary to convert Arachidonic Acid to Thromboxane A2 > platelet formation

Thereby aspirin inhibits platelet formation

Question 18

What do NSAIDS do to COX?

Answer 18

REVERSIBLY inhibit COX

Question 19

What is the rate limiting step in Secondary Haemostasis?

Answer 19

Fibrin formation

Question 20

Explain the extrinsic pathway

Answer 20

Factor 7a binds to Tissue Factor
This complex activates F10a
F10a activates F5a (COMMON PATHWAY)
F10a+F5a = prothrombinase complex 
They cleave prothrombin into thrombin (small amount)

Question 21

What are the functions of thrombin?

Answer 21

(Platelets
Co-factors
Fibrin
FXIII)

Activates Platelets
Activates co-factors FV, FVIII (and FIX) > THROMBIN BURST
Converts fibrinogen to FIBRIN
Cleaves FXIII to FXIIIa (forms cross links between fibrin clot, strengthening it=

Question 22

What occurs in the propagation stage of the clotting cascade?

Answer 22

F5,8,9 generate thrombin burst
High amount of thrombin converts fibrinogen to fibrin
This enables the formation of a fibrin clot

Question 23

What is the intrinsic pathway? Explain

Answer 23

Collagen + platelets activate FXIIa
FXIIa activates FXIa
FXIa activates FIX
FIXa + FVIIa activates F10
Then common pathway

Question 24

Where are clotting factors produced in the body?

Answer 24

in the LIVER

Question 25

What ion do some factors require?

Answer 25

CALCIUM

Question 26

Which factors require Vitamin K for production?

Answer 26

F2, 7, 9, 10

Question 27

Where / how do we make or find Vitamin K?

Answer 27

In green leafy vegetables | Produced by Gut Bacteria

Question 28

What kind of medications can reduce Vitamin K?

Answer 28

Warfarin | Antibiotics (as they alter gut flora)

Question 29

What is anticoagulation?

Answer 29

Process that occurs during primary/secondary haemostasis to regulate clot formation (keeps it from becoming too large/prevents emboli)

Question 30

What is fibrinolysis?

Answer 30

Degradation of clot mesh once endothelial injury has resolved

Question 31

Through which 3 processes does anticoagulation work?

Answer 31

1. Thrombomodulin-ProteinC-ProteinS 2. Antithrombin 3. NO, prostacyclin

Question 32

Explain Thrombomodulin-ProteinC-ProteinS action

Answer 32

Thrombomodulin is the protein found on healthy endothelial cells Thrombomodulin binds to Protein C and Protein S to form Active Protein C complex Active protein C breaks down F5/F8 to slow down coagulation

Question 33

Explain Antithrombin action

Answer 33

Antithrombin binds to thrombin OR to F10 (prevents thrombin formation)

Question 34

What drug augments antithrombin?

Answer 34

Heparin

Question 35

Explain how NO and prostacyclin cause anticoagulation

Answer 35

They decrease thromboxane A2 | Thereby there is less platelet aggregation

Question 36

Explain fibrinolysis process

Answer 36

Endothelial cell is now healthy, and produces tPA tPA converts plasminogen to plasmin Plasmin cuts up the fibrin

Question 37

Which other molecule can also convert plasminogen to plasmin?

Answer 37

UROKINASE

Question 38

What occurs in mutated F5?

Answer 38

Factor 5 leiden This means there is protein C resistance So there is a prothrombotic state

Question 39

What does tissue factor pathway inhibition block?

Answer 39

TFPI blocks F7

Question 40

When does TFPI occur?

Answer 40

Physiologically, after the activation of F7 | As F7 is only needed temporarily to activate the rest of the intrinsic pathway, then it can be switched off

Question 41

How can we split causes of excessive bleeding?

Answer 41

Genetic | Acquired

Question 42

What are genetic causes of excessive bleeding ?

Answer 42

Platelet abnormalities Endothelial wall abnormalities Clotting factor abnormalities Excessive clot breakdown

Question 43

What are acquired causes of excessive bleeding?

Answer 43

``` liver disease Vit K deficiency AI disease Trauma Anticoagulant / anti platelet ```

Question 44

What are sites of bleeding in primary haemostasis disorders?

Answer 44

``` Skin Mucous membranes (epistaxis, gum, vaginal, GI tract) ```

Question 45

What kind of bruising occurs in primary haemostasis disorders?

Answer 45

Petechiae, purpura | Small, superficial bleeding

Question 46

What is the timing of bleeding in primary haemostasis disorders?

Answer 46

Immediate

Question 47

What are the sites of bleeding in secondary haemostasis disorders?

Answer 47

Soft tissues Joints Muscles (deep) e.g. haemoarthroses

Question 48

What is the timing of bleeding in secondary haemostasis disorders?

Answer 48

Slow, delayed

Question 49

What kind of bruising occurs in secondary haemostasis disorders?

Answer 49

deep | Large bleeds

Question 50

Below what platelet count is treatment required always?

Answer 50

Below 30 x10^9

Question 51

Why must we always perform microscopy in thrombocytopenia?

Answer 51

To confirm true thrombocytopenia To exclude pseudothrombocytopoenia from ETPA To investigate rare conditions eg Grey Platelet syndrome

Question 52

What does typical anti platelet therapy comprise of?

Answer 52

DUAL therapy | e.g. aspirin + clopidogrel

Question 53

How does clopidogrel work?

Answer 53

Block ADP binding > no GLPIIb/IIIa activation > no platelet aggregation

Question 54

How are causes of thrombocytopenia categorised?

Answer 54

Immune mediated | Non-immune mediated

Question 55

Immune mediated causes of thrombocytopoena

Answer 55

``` Idiopathic Drug induced Connective tissue disease (RA, SLE) Lymphoprolif disease Sarcoidosis ```

Question 56

What are drugs that can cause thrombocytopenia?

Answer 56

Quinine (malaria) Rifampicin (TB) vancomycin

Question 57

What are non-immune mediated causes of thrombocytopoenia'

Answer 57

DIC | MAHA

Question 58

What is the pathogenesis of ITP^

Answer 58

Antiplatelet antibodies circulate in the blood Platelets become sensitised to antibodies (as antibodies tag them) Platelets get destroyed by macrophages

Question 59

What are the two types of ITP?

Answer 59

Acute vs chronic

Question 60

Who does acute ITP occur in? How long does it take to resolve?

Answer 60

Children | 2-6 weeks

Question 61

Who does chronic ITP occur in? How long does it take to resol ve?

Answer 61

Adults | Never resolves, need treatment, indolent

Question 62

How do u stratify risk and thereby tx of ITP?

Answer 62

Based on platelet count

Question 63

How do u treat ITP if platelet count <20000

Answer 63

Steroids regardless of bleeding status | If bleeding, also IVIG

Question 64

What does IVIG do?

Answer 64

It competes with anti-platelet antibodies

Question 65

What is an important feature of petechiae in ITP?

Answer 65

They DO NOT blanche

Question 66

What does Vitamin B12 deficiency present as on blood film?

Answer 66

Megaloblastic anaemia | So large RBC, as DNA synthesis is impaired and cell cycle cannot progress

Question 67

What are examples of INHERITED coagulation factors disorders? (disorders of secondary haemostasis)

Answer 67

Haemophilia A, B vWD Other factor deficiencies

Question 68

What are examples of ACQUIRED coagulation factors disorders? (disorders of secondary haemostasis)

Answer 68

Liver disease Vitamin K deficiency Warfarin DIC

Question 69

What is the cause of haemophilia?

Answer 69

congenital deficiency of F8,9

Question 70

How is haemophilia carried across generations?

Answer 70

X linked

Question 71

What clotting test will be prolonged for haemophilia?

Answer 71

APTT

Question 72

What are clinical features of haemophilia?

Answer 72

Haemarthroses Soft tissue haematoma Other sites of bleeding Prolonged bleeding following surgery

Question 73

How is vWD carried across generations?

Answer 73

Autosomal DOMINANT

Question 74

What is the classical clinical feature of vWD?

Answer 74

mucocutaneous bleeding

Question 75

How do you classify vWD?

Answer 75

Type 1,2,3

Question 76

What is T1 vWD?

Answer 76

partial qualitative deficiency = LOW vWF

Question 77

What is T2 vWD?

Answer 77

qualitative deficiency = NON-FUNCTIONING vWF

Question 78

What is T3 vWD?

Answer 78

total qualitative deficiency = NO vWF

Question 79

What are sources of vitamin K?

Answer 79

Green vegetables | Synthesis by bacterial flora

Question 80

What is vitamin K soluble in?

Answer 80

FAT soluble

Question 81

What factors and proteins is vitamin K required to synthesise?

Answer 81

Factors 2,7,9,10 | Proteins C, S, Z

Question 82

What are common causes of vitamin K deficiency?

Answer 82

Malnutrition Biliary obstruction (reduces absorption of VitK) Malabsorption Antibiotic therapy (kills gut flora)

Question 83

How do you treat Vitamin K deficiency?

Answer 83

Vitamin K replacement | FFP

Question 84

What is DIC?

Answer 84

Activation of both coagulation and fibrinolysis

Question 85

What can trigger DIC?

Answer 85

TOM VIS ``` Trauma, toxins Obstetric complications Malignancy Vascular disorder Immune disorder (allergic reaction, incompatible blood transfusion, transplant rejection) Sepsis (common in children) ```

Question 86

What two simultaneous clinical occurrences occur in DIC?

Answer 86

Thrombosis | Bleeding

Question 87

What is tx for DIC?

Answer 87

TREAT UNDERLYING DISORDER Anticoagulation with heparin Platelet transfusion FFP

Question 88

What ways does liver disease cause bleeding disorders?

Answer 88

``` Decreased clotting factor synthesis Dietary Vitamin K deficiency Dysfibrinohenaemia Enhanced haemolysis DIC Thrombocutopoenia ```

Question 89

How do you treat low fibrinogen?

Answer 89

Cryoprecipitate

Question 90

How do you monitor warfarin?

Answer 90

INR

Question 91

What is the target INR values you want

Answer 91

2. 5 if 1st episode of DVT/PE, AF | 3. 5 if recurrent DVT/PE, mechanical prosthetic valve

Question 92

What do you do in the different cases of raised INR?

Answer 92

INR 5-8, no bleeding: withhold few doses, reduce maintainance, restart when INR<5 INR 5-8, minor bleeding: stop warfarin, vit K slow IV INR > 8, no bleed/minor bleeding: stop warfarin, vit K INF >8, bleeding: stop warfarin, give PCC (or FFP if PCC unavailable) + vit K

Question 93

What components in the blood drop in pregnancy?

Answer 93

Hb, Htc Platelets F11, Prot S

Question 94

what should you be offered if you. are OVER 60 YEARS OLD and have IDIOPATHIC THROMBOEMBOLIC DISEAASE?

Answer 94

Offer. Ct scan to look for underlying cause of clotting e.g. malignancy