Abnormalities of haemostasis Flashcards

1
Q

Appreciate how minor bleeding abnormalities are common

A
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%

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2
Q

When is bleeding also common

A

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.

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3
Q

What are the key elements of a significant bleeding history

A

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.

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4
Q

When is primary haemostasis sufficient

A

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

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5
Q

Summarise the causes of abnormal haemostasis

A

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

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6
Q

Summarise platelet adhesion in primary haemostasis

A

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

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7
Q

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

A

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

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8
Q

Describe the pathogenesis of auto-ITP

A

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)

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9
Q

Summarise the mechanisms and causes of thrombocytopenia

A

Failure of platelet production by megakaryocytes

  1. Shortened half life of platelets
  2. Increased pooling of platelets in an enlarged spleen
    (hypersplenism) + shortened half life
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10
Q

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

A

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.

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11
Q

State three hereditary platelet defects

A

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)

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12
Q

What is a distinctive feature of thrombocytopenia

A

Petechiae

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13
Q

Describe VWD as a disorder or primary haemostasis

A

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

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14
Q

What are the two functions of VWF in primary haemostasis

A

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

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15
Q

Describe the genetic defects in VWF

A

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

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16
Q

Describe problems with the vessel wall as cause of primary haemostasis

A

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.

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17
Q

Summarise the disorders of primary haemostasis

A

Platelets
Thrombocytopenia

Drugs
Von Willebrand Factor
Von Willebrand disease

The vessel wall
Hereditary vascular disorders
Scurvy, steroids, age

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18
Q

What is the key function of primary haemostasis

A

Formation of the platelet plug

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19
Q

Describe the pattern of bleeding in disorders of primary haemostasis

A
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

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20
Q

Summarise the other key features of disorders in primary haemostasis

A

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

Purpura and petechiae

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21
Q

Summarise the different tests available for the disorders of primary haemostasis

A

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

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22
Q

Summarise the clotting cascade

A
  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
23
Q

What is needed for the actions of FVa and FIXa

A

Ca2+ and PI

24
Q

How can we measure thrombin generation by the coagulation cascade

A

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

25
Q

What is the role of the coagulation cascade

A

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

26
Q

When is primary haemostasis sufficient

A

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

27
Q

Essentially, what happens in haemophilia

A

Haemophilia: failure to generate fibrin to stabilise platelet plug

28
Q

Describe deficiencies in coagulation factor production as a disorder of coagulation

A

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

29
Q

Describe the differing consequences of the different coagulation factor deficiencies

A

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

30
Q

State the acquired causes of deficiencies in coagulation factor production

A

Acquired
Liver disease
Dilution
Anticoagulant drugs – warfarin

31
Q

Describe some acquired causes of deficiencies in coagulation factor production

A

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

32
Q

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

A

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

33
Q

Describe DIC

A

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

34
Q

Describe the pattern of bleeding in coagulation disorders

A

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)

35
Q

What is a hallmark of haemophilia

A

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

36
Q

Compare bleeding defects in primary haemostasis and secondary haemostasis

A

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

37
Q

Describe the tests for the different coagulation disorders

A

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
38
Q

Describe the APTT

A

Measures coagulation disorders in the intrinsic pathway:

Factor 12 – Factor 11 – Factor 8 and 9 — factor 5, 10 and 2

39
Q

Describe the PT

A

Factor 7 — factor 5, 10 and 2

40
Q

Describe the bleeding disorders not detected by routine clotting tests

A
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.

41
Q
  1. Describe the APTT and PT results for a patient with haemophilia.
A

Prolongs APTT but normal PT

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

42
Q

Summarise the disorders of fibrinolysis

A

Disorders of fibrinolysis can cause abnormal bleeding but are rare
Hereditary
antiplasmin deficiency

Acquired
drugs such as tPA
Disseminated intravascular coagulation

43
Q

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

A

Wide range in carriers- depends on which X Is inactivated

44
Q

Summarise the genetics of common bleeding disorders

A
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
45
Q

Summarise the treatment for abnormal haemostasis

A
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
46
Q

Describe factor replacement therapy

A

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

47
Q

Describe some novel approaches for the treatment of haemostasis

A
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

48
Q

Describe gene therapy

A

Haemophilia B, (Haemophiia A)

49
Q

Describe platelet replacement therapy

A

Pooled platelet concentrates available

50
Q

State some additional haemostat treatments

A

DDAVP
Tranexamic acid
Fibrin glue/spray

51
Q

Describe desmopressin

A

Vasopressin derivative

2-5 fold rise in VWF-VIII (VIII>vWF)

Releases endogenous stores -
Hence only useful in mild disorders

52
Q

Describe traneximic acid

A

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

53
Q

Summarise how we can assess platelet function

A

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.