Haem 8

Question 1

Questions to ask on history to identify blood disorder (abnormal bleeding)… these discriminate those with bleeding disorders vs normal people in which things like bruising etc is common

Answer 1

Epistaxis not stopped by 10 mins compression or requiring medical attention/transfusion.

Cutaneous haemorrhage or bruising without apparent trauma (esp. multiple/large).

Prolonged (>15 mins) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in 7 days after wound. Spontaneous GI bleeding leading to anaemia.

Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions of the uterus.

Heavy, prolonged or recurrent bleeding after surgery or dental extractions.

Question 2

2 overall cuases of abnormal haemostasis

Answer 2

Lack of a specific factor
-Failure of production:
congenital and acquired
-Increased consumption/clearance

Defective function of a specific factor

• Genetic defect
• Acquired defect – drugs, synthetic defect, inhibition

Question 3

What can go wrong in primary haemistasis

Answer 3

Platelets, VWF or vessel wall

Question 4

Platelet disorders

Answer 4

Low numbers: “thrombocytopenia”

• Bone marrow failure eg: leukaemia, B12 deficiency
• Accelerated clearance eg: immune (ITP), DIC.
• ITP=Auto-Immune Thrombocytopenic Purpura (auto-ITP)

or

Impaired function

• Hereditary absence of glycoproteins (on the surface) or storage granules
• Acquired due to drugs (e.g. aspirin/clopidogrel)

Question 5

What s autoimmune ITP

Answer 5

autoantibodies against platelets and sensitises platelet to the macrophge

Question 6

3 mechanisms of thrombocytopenia

Answer 6

1. Failure of platelet production by megakaryocytes
2. Shortened half life of platelets
3. Increased pooling of platelets in an enlarged spleen
   (hypersplenism) + shortened half life

Question 7

What is glanzamanns thrombasthenia

What is bernard soulier syndrome

Storage pool syndrome

Answer 7

GpIIb/IIIa deficiency (usually binds other platelets)

GpIb deficiency (which usually binds vWF)

Dense granules

Question 8

What drugs can cause platelet dysfunction

Answer 8

aspirin, NSAIDs, clopidogrel

Question 9

Cause of VW disease

Answer 9

Hereditary decrease of quantity +/ function (common)

Acquired due to antibody (rare)

Question 10

Function of VWF in haemostasis

Answer 10

Binding to collagen and capturing platelets

Stabilising Factor VIII
-Factor VIII may be low if VWF is very low

Question 11

Types of hereditary VWD

Answer 11

Deficiency of VWF (Type 1- deficient or 3-none)

VWF with abnormal function (Type 2)

Question 12

Causes of vessel wall disorders causing primary haemostasis

Answer 12

Inherited (rare) Hereditary haemorrhagic telangiectasia/ Ehlers-Danlos syndrome and other connective tissue disorders

Acquired: Scurvy, Steroid therapy, Ageing (age related purpura), Vasculitis

Question 13

When is petechiae seen

Answer 13

Only thrombocytopenia (not defects, only quantitative probllems with platelets)

Question 14

Tests for disorder of primary haemostasis

Answer 14

Platelet count, platelet morphology

Bleeding time (PFA100 in lab)

Assays of von Willebrand Factor

Clinical observation

Question 15

What is the role of the coagulation casade

Answer 15

The role of the coagulation cascade is to generate a burst of thrombin which will convert fibrinogen to fibrin

Question 16

Why is secondary haemostasis necessary

Answer 16

The primary platelet plug is sufficient for small vessel injury
In larger vessels it will fall apart
Fibrin formation stabilises the platelet plug

Question 17

Define haemophilia

Answer 17

failure to generate fibrin to stabilise the platelet plug

Question 18

Bleeding patterns for deficiency of:

Factor VIII and IX
Prothrombin
Factor XI and
Factor XII

Answer 18

Factor VIII and IX (Haemophilia)

• Severe but compatible with life
• Spontaneous joint and muscle bleeding

Prothrombin (Factor II)
-Lethal

Factor XI
-Bleed after trauma but not spontaneously

Factor XII
-No excess bleeding at all

Question 19

Causes of deficiency of coagulation factor production

Answer 19

Hereditary failure of production
-Factor VIII/IX: haemophilia A/B

Acquired

• Liver disease
• Dilution
• Anticoagulant drugs – warfarin

Increased consumption

• DIC
• Immune - autoantobodes

Question 20

Outline liver failure as a disorder of coagulation

Answer 20

Liver failure – decreased production

Most coagulation factors are synthesised in the liver

Question 21

Outline dilution as an anticoagulant disorder

Answer 21

Dilution

• Red cell transfusions no longer contain plasma (which is good)
• Major transfusions require plasma as well as rbc and platelets

Question 22

Outline disseimnated intravascular coagulation

Answer 22

Generalised activation of coagulation – Tissue factor

Consumes and depletes coagulation factors

Platelets consumed

Activation of fibrinolysis depletes fibrinogen

Deposition of fibrin in vessels causes organ failure

(Disseminated intravascular coagulation is a condition in which small blood clots develop throughout the bloodstream, blocking small blood vessels. The increased clotting depletes the platelets and clotting factors needed to control bleeding, causing excessive bleeding.)

Question 23

Causes of DIC

Answer 23

sepsis, major tissue damage, inflammation

Question 24

Bleeding in coagulation disorders

Answer 24

• superficial cuts do not bleed (platelets)
• bruising is common, NOSEBLEEDS ARE RARE

-spontaneous bleeding is deep, into muscles
and joints

• bleeding after trauma may be delayed and is prolonged
• frequently restarts after stopping

Question 25

What is the hallmark of haemophilia What should NOT be given to people with coagulation disorders

Answer 25

haemarthrosis- SPONTANEOUS bleeding into joints DON'T GIVE intramuscular injections in ANY coagulation disorders

Question 26

Compare bleeding in coagulation disorders with primary heamostatic bleeding

Answer 26

Primary vs secondary Superficial bleeding into skin, mucosal membranes (primary) vs Bleeding into deep tissues, muscles, joints (secondary) and ``` Bleeding immediate after injury (primary) ``` vs Delayed, but severe bleeding after injury. Bleeding often prolonged (secondary)

Question 27

How can you test for coagulation disorders

Answer 27

Screening tests (‘clotting screen’) - Prothrombin time (PT) - Activated partial thromboplastin time (APTT) - Full blood count (platelets) Factor assays (for factor VIII) Tests for inhibitors (not drug ones, ones that the patients have made)

Question 28

How does haemphilia show in tests

Answer 28

Prolonged APTT, normal PT

Question 29

Which bleeding disorders are not detected by routine clotting tests

Answer 29

``` mild factor deficiencies von Willebrand disease Factor XIII deficiency (cross linking) Platelet disorders Excessive fibrinolysis Vessel wall disorders Metabolic disorders (e.g. uraemia) (Thrombotic disorders) ```

Question 30

Differentiate hereditary vs acquired excessive fibrinolysis

Answer 30

Hereditary -antiplasmin deficiency (this acts against plasmin, which turns fibrin into FDAs (fibrin degradation products)... don't confuse antiplasmin with antithrombin) Acquired - drugs such as tPA - Disseminated intravascular coagulation

Question 31

What does the level of factor 8 in female carriers dependent on

Answer 31

relative lyonisation

Question 32

Inheritence of VWF vs haemophilia and all other coagulation factor hereditary deficiencies

Answer 32

Von Willebrand disease =Autosomal -Type 2, (Type 1) AD -Type 3 AR Haemophilia Sex linked recessive (SLR) All the rest (V, X etc.) Autosomal recessive (AR) And therefore much less common

Question 33

Treatment of abnormal haemostasis

Answer 33

For failure of production or function : - replace missing factor/platelets (prophylactic or therapeutic) - stop drugs Due to immune destruction -immune suppression, splenectomy for ITP Increased consumption - treat cause - replace as necessary

Question 34

types of treatments of haemostatic disorders

Answer 34

Factor replacement therapy (problem is that patients make inhibitors) Gene therapy (haemophilia b or a) Platelet replacement therapy Novel approaches

Question 35

Tyoes of factir replacement therapy

Answer 35

Plasma -Contains all coagulation factors Cryoprecipitate -Rich in Fibrinogen, FVIII, VWF, Factor XIII Factor concentrates: - Concentrates available for all factors except factor V. - Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X) Recombinant forms of FVIII and FIX are available.

Question 36

Other treatments for haemostatic disorders

Answer 36

DDAVP (happen to increase endothelial vWF production) Tranexamic acid (for mucosal type bleading) Fibrin glue/spray

Question 37

How does DDAVP work in blood disorders

Answer 37

2-5 fold rise in VWF-VIII (VIII>vWF) Releases endogenous stores - Hence only useful in mild disorders

Question 38

How does tranexamic acid work

Answer 38

Inhibits fibrinolysis Widely distributed – crosses placenta Low concentration in breast milk useful adjunctive therapy

Question 39

Learn a bit about PT and APTT

Answer 39

....

Question 40

Which factors require post trnalsationsal vitamin K dependnet modification

Answer 40

2, 7, 9 and 10 so common

Question 41

Which clotting factors are NOT serine proteases

Answer 41

5, 8 and 13 (which causes fibrin to become crosslinked)

Question 42

Type of bleeding seen in primary haemostasis disorders

Answer 42

``` Immediate Prolonged bleeding from cuts Epistaxes Gum bleeding Menorrhagia Easy bruising Prolonged bleeding after trauma or surgery ```

Question 43

What type of molecule is FXIII

Answer 43

transglutamidase i.e. not a serine protease