Abnormalities of haemostasis

Question 1

Appreciate how minor bleeding abnormalities are common

Answer 1

Easy bruising 				 	12%
Gum bleeding 				  	 7%
Frequent nosebleeds			  	 5%
Bleeding after tooth extraction	  		 2.5%
Post operative bleeding 		  		 1.4%
In women
Menorrhagia			            		23%
Post partum bleeding			    	 6%

Family history 44%

Question 2

When is bleeding also common

Answer 2

After removing tonsils (tonsillectomy)
e.g % of easy bruising, frequent bruising and epistaxes are increased in patients with no known bleeding disorders and comparable to statistics in those with known bleeding disorders

however the severity is not comparable (i.e the % of epistaxes lasting greater than 10 mins is very low in those with no known bleeding disorders).

This highlights how the bleeding history is the most important investigation.

Question 3

What are the key elements of a significant bleeding history

Answer 3

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 (e.g fibroids) of the uterus.
Heavy, prolonged or recurrent bleeding after surgery or dental extractions.

Question 4

When is primary haemostasis sufficient

Answer 4

In small blood vessels- bleeding is stopped without the need for a fibrin meshwork.

Question 5

Summarise the causes of abnormal haemostasis

Answer 5

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 (anti-platelet drugs or anti-coagulants), synthetic defect, inhibition

Question 6

Summarise platelet adhesion in primary haemostasis

Answer 6

Can attach to collagen indirectly via VWF- platelet binds to VWF via Glp1b
Can attach to collagen directly via Glp1a

This leads to platelet activation, leading to release of ADP and thromboxane
The platelets then aggregate, via fibrinogen and Ca2+
Platelets bind to fibrinogen via Glp2b/3a

Question 7

Describe a low number of platelets as a disorder of primary haemostasis

Answer 7

Low numbers: “thrombocytopenia”
Bone marrow failure eg: leukaemia, B12 deficiency (megaloblastic anaemia- cells grow and grow without means of synthesising new DNA- thus they cannot divide)- both of these ‘clog’ up the bone marrow and interfere with normal haemostasis.
Accelerated clearance eg: immune (ITP)- making lots of platelets- but they are destroyed in the circulation, DIC.
Pooling and destruction in an enlarged spleen

Question 8

Describe the pathogenesis of auto-ITP

Answer 8

Auto-Immune Thrombocytopenic Purpura (auto-ITP)
Purpura means bruising

Antiplatelet antibodies
Sensitised platelet
Sensitised platelets cleared by the macrophages in the reticulo-endothelial system (especially in the spleen)

Question 9

Summarise the mechanisms and causes of thrombocytopenia

Answer 9

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 10

Describe an impaired function of platelets as a cause of a disorder in primary haemostasis

Answer 10

Impaired function
Hereditary absence of glycoproteins or storage granules
Acquired due to drugs: aspirin, NSAIDs, clopidogrel
These drugs can be given to prevent strokes, but increased risk bleeding will be a major side effect.

Question 11

State three hereditary platelet defects

Answer 11

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 (no release of ADP,ATP, serotonin or Ca2+ from dense granules)

Question 12

What is a distinctive feature of thrombocytopenia

Answer 12

Petechiae

Question 13

Describe VWD as a disorder or primary haemostasis

Answer 13

Von Willebrand disease
Hereditary decrease of quantity +/ function (common)
Acquired due to antibody (rare)

Question 14

What are the two functions of VWF in primary haemostasis

Answer 14

VWF has two functions in haemostasis
Binding to collagen and capturing platelets
Stabilising Factor VIII
Factor VIII may be low if VWF is very low

Question 15

Describe the genetic defects in VWF

Answer 15

VWD is usually hereditary
Deficiency of VWF (Type 1 or 3)
VWF with abnormal function (Type 2)

Type 3 - complete absence – autosomal recessive
the other 2 are AD

Question 16

Describe problems with the vessel wall as cause of primary haemostasis

Answer 16

The vessel wall
Inherited (rare) Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disorders
Blue sclera, especially seen in females.Atypical ears: prominent “winged”, small, round, lobeless, lobe attached to face, ears with different shapes: kidney shape, “Dumbo ears”, “Mr. Spock ears”, soft ears, with bent helix.Abnormal nose: with a lump in the union of the bone and the cartilage, nasal septum deviation,

Acquired: Scurvy, Steroid therapy, Ageing (senile purpura), Vasculitis - can all thin the blood vessel and make it weak.

Question 17

Summarise the disorders of primary haemostasis

Answer 17

Platelets
Thrombocytopenia

Drugs
Von Willebrand Factor
Von Willebrand disease

The vessel wall
Hereditary vascular disorders
Scurvy, steroids, age

Question 18

What is the key function of primary haemostasis

Answer 18

Formation of the platelet plug

Question 19

Describe the pattern of bleeding in disorders of primary haemostasis

Answer 19

Typical primary haemostasis bleeding:
Immediate 
Prolonged bleeding from cuts
Epistaxes
Gum bleeding
Menorrhagia 
Easy bruising
Prolonged bleeding after trauma or surgery

The primary platelet plug isn’t strong enough to stop the bleeding

Question 20

Summarise the other key features of disorders in primary haemostasis

Answer 20

Thrombocytopenia – Petechiae
Severe VWD – haemophilia-like bleeding- due to loss of stabilisation of FVIII

Purpura and petechiae

Question 21

Summarise the different tests available for the disorders of primary haemostasis

Answer 21

Platelet count, platelet morphology
Bleeding time (PFA100 in lab)
Assays of von Willebrand Factor
Clinical observation

Question 22

Summarise the clotting cascade

Answer 22

1. Biological amplification system in which proteins are activated sequentially
2. Incredibly efficient: 1 mole XIa generates ~107 moles thrombin
3. Clotting factors numbered I - XIII
   I Fibrinogen
   II Prothrombin
   III Tissue Factor
   IV Calcium ions
   VI Activated factor V (Va)
4. Factors II, VII, IX & X require a post-translational vitamin K dependent modification
5. Most clotting factors (except V, VIII and XIII) are serine proteases
6. Factors V & VIII are co-factors/Factor XIII is a transglutamidase
7. Phospholipid derived from activated platelet membrane
   Fibrin mesh binds and stabilises platelet plug and other cells

Question 23

What is needed for the actions of FVa and FIXa

Answer 23

Ca2+ and PI

Question 24

How can we measure thrombin generation by the coagulation cascade

Answer 24

We can visualise the process of coagulation by measuring thrombin generation over time. This is often called the thrombogram and looks like this…

Normal large spike
Haemophilia- generate less thrombin ,, Haemophilia
Factor VIII <1%

Much smaller peak

Question 25

What is the role of the coagulation cascade

Answer 25

The role of the coagulation cascade is to generate a burst of thrombin which will convert fibrinogen to fibrin Deficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formation

Question 26

When is primary haemostasis sufficient

Answer 26

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

Question 27

Essentially, what happens in haemophilia

Answer 27

Haemophilia: failure to generate fibrin to stabilise platelet plug

Question 28

Describe deficiencies in coagulation factor production as a disorder of coagulation

Answer 28

Deficiency of coagulation factor production Hereditary Factor VIII/IX: haemophilia A/B

Question 29

Describe the differing consequences of the different coagulation factor deficiencies

Answer 29

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 30

State the acquired causes of deficiencies in coagulation factor production

Answer 30

Acquired Liver disease Dilution Anticoagulant drugs – warfarin

Question 31

Describe some acquired causes of deficiencies in coagulation factor production

Answer 31

Liver failure – decreased production Most coagulation factors are synthesised in the liver Dilution Red cell transfusions no longer contain plasma Major transfusions require plasma as well as rbc and platelets- i.e after a haemorrhage

Question 32

State disorders of coagulation as a result of (acquired) increased consumption of clotting factors

Answer 32

Increased consumption Acquired Disseminated intravascular coagulation (DIC) Immune - autoantibodies

Question 33

Describe DIC

Answer 33

Consumption Disseminated intravascular coagulation increased consumption Generalised activation of coagulation – Tissue factor Associated with sepsis, major tissue damage, inflammation Consumes and depletes coagulation factors Platelets consumed Activation of fibrinolysis depletes fibrinogen Deposition of fibrin in vessels causes organ failure Need to treat the cause: deliver the baby teat the sepsis

Question 34

Describe the pattern of bleeding in coagulation disorders

Answer 34

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 Superficial cuts DO NOT bleed (because primary haemostasis is fine)

Question 35

What is a hallmark of haemophilia

Answer 35

Haemarthrosis – hallmark of haemophilia Bleeding in the joints- spontaneous Intramuscular injections should be avoided

Question 36

Compare bleeding defects in primary haemostasis and secondary haemostasis

Answer 36

Platelet/Vascular Superficial bleeding into skin, mucosal membranes Bleeding immediate after injury Coagulation Bleeding into deep tissues, muscles, joints Delayed, but severe bleeding after injury. Bleeding often prolonged This is a simplistic distinction. Note that either defect can be life threatening

Question 37

Describe the tests for the different coagulation disorders

Answer 37

Screening tests (‘clotting screen’) Prothrombin time (PT) Activated partial thromboplastin time (APTT) Full blood count (platelets) ``` Factor assays (for Factor VIII etc) Tests for inhibitors ```

Question 38

Describe the APTT

Answer 38

Measures coagulation disorders in the intrinsic pathway: Factor 12 -- Factor 11 -- Factor 8 and 9 --- factor 5, 10 and 2

Question 39

Describe the PT

Answer 39

Factor 7 --- factor 5, 10 and 2

Question 40

Describe the bleeding disorders not detected by routine clotting tests

Answer 40

``` 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) ``` Urea can interfere with platelet function.

Question 41

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

Answer 41

Prolongs APTT but normal PT | This is because the defect lies in the intrinsic pathway (factor 8 or 9)

Question 42

Summarise the disorders of fibrinolysis

Answer 42

Disorders of fibrinolysis can cause abnormal bleeding but are rare Hereditary antiplasmin deficiency Acquired drugs such as tPA Disseminated intravascular coagulation

Question 43

Why is there a wide range in FVIII and FIX levels in femal carries of haemophilia

Answer 43

Wide range in carriers- depends on which X Is inactivated

Question 44

Summarise the genetics of common bleeding disorders

Answer 44

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

Question 45

Summarise the treatment for abnormal haemostasis

Answer 45

``` Failure of production/function Replace missing factor/platelets Prophylactic Therapeutic Stop drugs Immune destruction Immunosuppression (eg prednisolone) Splenectomy for ITP Increased consumption Treat cause Replace as necessary ```

Question 46

Describe factor replacement therapy

Answer 46

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- used to reverse actions of warfarin Recombinant forms of FVIII and FIX are available - but body can develop antibodies against these

Question 47

Describe some novel approaches for the treatment of haemostasis

Answer 47

``` Novel approaches In development Bispecific antibody Anti TFPI antibody Antithrombin RNAi ``` Bispeficic antibody- mimc=is FVIII- does its binding but no inhibitors form- unlike FVIII given to haemophilics- will develop antibodies against it Sc in skin once a fortnight- unlike previous daily injections Anti TFPI- risk of too much antibody RNAi- reduce antithrombin- resulting in more clotting

Question 48

Describe gene therapy

Answer 48

Haemophilia B, (Haemophiia A)

Question 49

Describe platelet replacement therapy

Answer 49

Pooled platelet concentrates available

Question 50

State some additional haemostat treatments

Answer 50

DDAVP Tranexamic acid Fibrin glue/spray

Question 51

Describe desmopressin

Answer 51

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

Question 52

Describe traneximic acid

Answer 52

Inhibits fibrinolysis Widely distributed – crosses placenta Low concentration in breast milk Competes with fibrin for binding of tPA tPA needs to bind to fibrin and plasmin for activation Staboilise the clot Useful adjuvants: Intravenous: 0.5g tds Oral: 1.5g tds Mouthwash: 1g (10ml 5%) qds

Question 53

Summarise how we can assess platelet function

Answer 53

There are three laboratory tests to monitor platelets, the platelet count, the bleeding time and platelet aggregation. The most important of these is the platelet count, as progressive reduction of platelets dramatically increases the risk of bleeding. Platelet aggregation is performed to monitor platelet dysfunction and can be used to measure von Willebrand factor activity. The bleeding time is now rarely used in clinical practice although it is sometimes required if it is necessary to assess vessel wall function.