Abnormalities of Homeostasis

Question 1

Broadly speaking, what are the two causes of abnormal haemostasis?

Answer 1

Lack of a specific factor (quantitative problem)

Defective function of a specific factor (qualitative problem)

Question 2

State some quantitative causes of thrombocytopenia? (qualitative in another card)

Answer 2

QUANTITATIVE:
Not produced enough or removed too quickly:

Failure of production – bone marrow failure e.g. leukaemia, B12 deficiency

Accelerated clearance leading to shortened half life- e.g DIC, autoimmune thrombocytopenic purpura (ITP)

Pooling of platelets in enlarged spleen followed by destruction

Question 3

State one very common cause of thrombocytopenia.

Answer 3

ITP (immune and idiopathic are the same thing)

Question 4

What is a distinctive clinical feature of thrombocytopenia?

What is does bleeding resemble in VWD patients?

Answer 4

Petechiae

Severe VWD – haemophilia-like bleeding (because vWF is needed to stabilise factor 8. Low vWF=low factor 8=haemophilia)

Question 5

State three hereditary platelet defects leading to impaired platelet FUNCTION (qualitative) .

Answer 5

Glanzmann’s Thrombasthenia – absence of GlpIIb/IIIa (prevents platelet aggregation)

Bernard Soulier Syndrome – absence of GlpIb (prevents binding to von Willebrand factor)

Storage Pool Disease – storage granules are not able to release adequately

Question 6

Broadly speaking, state three causes of thrombocytopenia.

Answer 6

Failure of platelet production by the megakaryocytes

Shortened half-life of platelets Increased pooling of platelets in an enlarged spleen (hypersplenism)

Question 7

State a broad acquired cause of impaired platelet function. (qualitative,slide 21)

Answer 7

Drugs e.g. NSAIDs, clopidogrel

Question 8

What are the two roles of von Willebrand factor in haemostasis?

Answer 8

Binding to collagen and trapping platelets

Stabilising factor 8 (if VWF is low, factor 8 may be low)

Question 9

Von Willebrand Disease is usually hereditary. What are the three types of von Willebrand disease?State their pattern of inheritance

Answer 9

Types 1 and 3 are quantitative issues. Type 2 is qualitative.
Type 1 – partial deficiency of VWF but it functions normally (autosomal dominant)
Type 2 – VWF does not function normally (autosomal dominant)
Type 3 – VWF not made at all (autosomal recessive)

Question 10

State two inherited vessel wall conditions that cause defects in primary haemostasis.

Answer 10

Hereditary haemorrhagic telangiectasia (HHT)

Ehlers-Danlos Syndrome

Question 11

State some acquired causes of vessel wall conditions that cause defects in primary haemostasis.

Answer 11

Scurvy
Steroid therapy
Ageing (senile purpura)
Vasculitis

Question 12

Describe the pattern of bleeding in defects of primary haemostasis.

Answer 12

Primary haemo goes before secondary (sort of) and it is normally involved in haemostasis in small blood vessels. Without this, its bad….

Bleeding is immediate
Prolonged from cuts  
Epistaxes  
Gum bleeding  
Menorrhagia  
Easy bruising  
Prolonged bleeding after trauma and surgery

Question 13

How are the clotting factors affected in severe von Willebrand disease?

Answer 13

Reduced factor 8 (because VWF stabilizes factor 8)

This causes haemophilia type bleeding patterns

Question 14

What tests can be done for disorders of primary haemostasis?

Answer 14

Platelet count
Bleeding time (not used anymore, brutal)
Assays for VWF (its level and activity)
Clinical observation

Question 15

What is haemophilia caused by?

What is its pattern of inheritance?

Answer 15

Lack of Factor 8 (haemo A) or Factor 9 (haemo B)
This leads to impaired thrombin generation
In haemophilia you get failure to generate fibrin to stabilize the platelet plug
It is X-linked recessive

Question 16

Outline the different clotting factors that could be deficient as a result of a hereditary disease and their different patient outcomes

Answer 16

2(prothrombin) – lethal
8/9 (haemophilia) – severe but compatible with life, spontaneous bleeding in joints and muscles
11 – bleeding after trauma but not spontaneously
12 – no excess bleeding at all (F12 is part of intrinsic pathway which doesnt really matter)

Question 17

State some acquired causes of deficiency of coagulation factors and hence inadequate secondary haemostasis

Answer 17

Liver disease
Dilution (slide 45 for more deets)
Anti-coagulant drugs (e.g. warfarin)

Question 18

State some causes of coagulation/secondary haemostasis due to increased consumption of clotting factors

Answer 18

Disseminated intravascular coagulation (DIC)

Autoimmune thrombocytopenia

Question 19

What happens in Disseminated Intravascular Coagulation (DIC)? What is it associated with?

Answer 19

Generalised activation of coagulation
It is associated with sepsis, inflammation and tissue necrosis
It consumes and depletes coagulation factors
Platelets are consumed

Question 20

Describe the pattern of bleeding in coagulation disorders.

Answer 20

Superficial cuts DO NOT bleed (because primary haemostasis is fine)
Bruising is common
Spontaneous bleeding is DEEP, into muscles and joints
Bleeding after trauma may be delayed and prolonged
Frequently restarts after stopping

Question 21

What is the hallmark of haemophilia?

Answer 21

Haemarthrosis

Question 22

What simple medical procedure must you avoid doing to patients with haemophilia?

Answer 22

Intramuscular injection – it can cause deep bleeding patterns

Question 23

State some tests that are used for coagulation disorders.

Answer 23

PT - measures how long it takes to clot after activating extrinsic pathway
APTT - same as above but for intrinsic pathway
full blood count (look at platelets)
factor assays to look at clotting factors
tests for inhibitors

Question 24

Describe the APTT and PT results for a patient with haemophilia.

Answer 24

Prolongs APTT but normal PT

This is because the defect lies in the intrinsic pathway (factor 8 or 9)

Question 25

State some bleeding disorders that are not detected by routine clotting tests.

Answer 25

Mild factor deficiencies  
Von Willebrand Disease  
Factor 8 Deficiency (cross-linking) 
Platelet disorders  
Excessive fibrinolysis  
Vessel wall disorders  
Metabolic disorders (e.g. uraemia) 
NOTE: urea interferes with platelet function

Question 26

State a hereditary cause of fibrinolytic disorder.

State an acquired cause of a fibrinolytic disorder.

Answer 26

Hereditary: Antiplasmin deficiency
Acquired: drugs e.g tPA, disease eg DIC which uses up ingredients needed for haemostasis including fibrinolytic factors

Question 27

State two acquired disorders of fibrinolysis.

Answer 27

Drugs such as tissue plasminogen activator

Disseminated intravascular coagulation (DIC) – because everything has been used up

Question 28

What is the drug treatment that is considered for a patient whose abnormal haemostasis is caused by immune destruction of platelets?

Answer 28

Immunosuppression (e.g. prednisolone)

Question 29

What clotting factors are found in cryoprecipitate?

Answer 29

Fibrinogen
Factor VIII
Factor XIII
Von Willebrand Factor

Question 30

Factor concentrates are available for all factors except which one?

Answer 30

Factor V

Question 31

Describe the use of Desmopressin (DDAVP) in von Willebrand disease.

Answer 31

Desmopressin makes the endothelial cells release their stored VWF
vWF stabilises factor 8=good for haemophilia

Question 32

State two other drugs that are used as haemostatic treatments.

Answer 32

Tranexamic acid (inhibits fibrinolysis): 
an antifibrinolytic drug. tPA binds to plasminogen to activate it to plasmin which then breaks down clot. Tranexamic acid mimics the binding site for tPA so that it does not activate plasminogen. = less plasmin= less fibrinolysis 

Fibrin glue

Question 33

What is a hallmark of haemophilia

Answer 33

haemarthosis slide 49

Question 34

Compare the bleeding in disorders affecting primary and secondary haemostasis

Answer 34

slide 52

Question 35

give some examples of factor replacement therapies

Answer 35

1. Plasma
   - Contains all coagulation factors
2. Cryoprecipitate
   - Rich in Fibrinogen, FVIII, VWF, Factor XIII
3. Factor concentrates
   - Concentrates available for all factors except factor V.

4.Recombinant forms of FVIII and FIX are available.

Question 36

What advanced treatment can be used on patients with haemophilia? hint: haemophilia is a genetic disorder

Answer 36

gene therapy