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Foundations of Pathology > L13 - Coagulation and Haemophilia > Flashcards

L13 - Coagulation and Haemophilia Flashcards

1
Q

Haemostasis

A

• A complex process involving:

  • Platelets
  • Plasma proteins
  • Endothelial cells
  • Smooth muscle cells

•Keeps the blood fluid while ensuring that blood loss is minimised at a site of vessel injury

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2
Q

Old theories of blood coagulation

A
  • Cooling
  • Blood clotted when it cooled
  • Rest
  • Motion inhibited clotting, rest encouraged it
  • Vital Force
  • Blood was alive in blood vessels and died outside them
  • Air
  • Exposure to air (either oxygen or nitrogen) caused the blood to clot
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3
Q

Prothrombin Time

A
  • Plasma (100 µL)
  • Normal (control) or patient plasma
  • Thromboplastin - 200 µL (Tissue factor, phospholipids, calcium (0.025 M))
  • Reactions proceed through extrinsic/common pathways
  • Generates fibrin (clot)
  • Record clotting time (1 decimal place)
  • Clotting factor deficiencies (VII, X, V, II, I)
  • Monitor oral anticoagulant therapy (warfarin)
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4
Q

Partial Thromboplastin Time

A
  • Plasma (100 µL)
  • Partial Thromboplastin (Phospholipid -100 µL)
  • Activator (100 µL) -negatively charged e.g. kaolin
  • Incubate for 3 minutes
  • Calcium chloride (0.025 M) (100 µL)
  • Reaction proceeds through intrinsic/common pathways
  • Generates fibrin clot -record clotting time (1 d.p.)
  • Clotting factor deficiencies (I, II, V, VIII, IX, X, XI, XII)
  • Monitor anticoagulant therapy (UF heparin)
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5
Q

Normal PT, Prolonged aPTT

A
  • Extrinsic and common pathways are normal

* Deficiency in intrinsic pathway (Factor VIII, IX, XI, or XII)

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6
Q

Prolonged PT, Normal aPTT

A
  • Intrinsic and common pathways are normal

* Deficiency in extrinsic pathway (Factor VII)

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7
Q

Prolonged PT, Prolonged aPTT

A
  • Deficiency in common pathway (Factor X, V, Prothrombin, Fibrinogen)
  • Deficiency in multiple coagulation factors
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8
Q

Pattern of inheritance of haemophilia

A
  • Males were affected by the disease

* Females were vary rarely affected, but they could pass the disease onto their offspring (carriers)

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9
Q

Those affected from haemophilia suffered from bleeding into:

A
  • Muscle/soft tissue
  • Brain

•Joints were involved (? Arthritis)

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10
Q

Haemophilia A

A

deficiency of Factor VIII

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11
Q

Haemophilia B

A

deficiency of Factor IX

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12
Q

Incidence of haemophilia in males

A

1:5000 –1:25 000 male births

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13
Q

Haemophilia as an X-linked, recessive disease

A
  • Females that carry the mutation are called ‘carriers’
  • Carriers have a 50% chance of passing the mutation onto their sons
  • Male haemophiliacs will pass the mutation to their daughters, while their sons are unaffected
  • 1980’s -Both Factor VIII and IX genes were cloned and found to reside on the long arm of the X-chromosome
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14
Q

Haemophilia in females (rare cases):

A
  • Offspring of a male haemophiliac and a female carrier
  • Occurrence of two factor VIII gene mutations
  • Extreme Lyonisation (or X-inactivation)
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15
Q

Lab diagnosis of haemophilia

A

•Mixing studies

  • Mix an equal volume of patient plasma with normal plasma
  • Perform an aPTT
  • If the patient has a factor deficiency, the missing factor is replaced by the same factor that is present in the normal plasma
  • The aPTT is corrected back to normal (i.e. normalized)

•Factor assays to determine the concentration of FVIII and FIX present in the patient plasma

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16
Q

Haemophilia Clinical Manifestations in newborns

A
  • Bleeding at the umbilical stump
  • Bleeding after circumcision
  • Bleeding with heel pricks/immunisation
  • Rarely, newborns will present with severe bleeds
  • Bleeding in infants often does not occur until they become mobile
17
Q

Development of haemophilia joint disease

A
  • An acute bleed into the joint increases pressure within the synovial cavity
  • Recurrent bleeding causes chronic synovitis and damage to the cartilage and bone, → haemarthrosis
  • Haemarthrosisoccurs in three stages
18
Q

Stages of haemoarthosis

A
  1. Acute haemarthrosis
    • Bleed into the joint
  2. Chronic synovitis
    • Iron (from lysed RBCs) promotes the production of inflammatory cytokines

• Synovium becomes vascular and inflammatory cells are recruited

  1. Degenerative arthritis • Exposure of blood and cytokines to the cartilage results in its destruction
19
Q

Pseudotumours

A
  • A clinical manifestation of haemophilia

* Large encapsulated haematomas in large muscle groups and some bones

20
Q

Intracranial haemorrhage

A
  • Can occur in the neonatal period (3-5% of haemophiliacs)

* Childhood and adult ICH usually occurs after trauma

21
Q

Treatment of haemophilia

A
  • Early “treatments”
  • Russell’s Viper Venom
  • Blood transfusion
  • Fresh Frozen Plasma (FFP)
  • Cryoprecipitate
  • Factor VIII and IX concentrates
  • Haemophilia Treatment Centres –early 1970’s
22
Q

Early “treatments”

A

• Administration of lime, O2, use of thyroid gland, bone marrow, H2O2, gelatin etc.

23
Q

Russell’s Viper Venom

A

• Used in the 1930’s for “local” applications

24
Q

Blood transfusion

A
  • First documented case for the treatment of haemophilia was in 1840
  • Not accepted as a routine treatment until the 1940’s
25
Q

Fresh Frozen Plasma (FFP)

A
  • Used for treatment in the 1950s/1960s
  • Recipient required hospitalisation
  • Required large volumes
26
Q

Cryoprecipitate

A
  • Prof Judith Pool discovers that, if FFP is allowed to slowly thaw in the cold, a precipitate forms. This can be collected by centrifugation and the remaining plasma recombined with the remaining blood
  • The precipitate, called cryoprecipitate, contains FVIII and fibrinogen and can be stored frozen
  • Allowed injection of concentrated FVII
27
Q

Factor VIII and IX concentrates

A
  • Late 1960’s –methods to purify fVIII and fIX from plasma were described
  • Allowed the production of fVIII and fIX concentrates
  • Large volumes of plasma were pooled from multiple donors to make one batch of concentrate
  • Early 1970’s –factor concentrates were available for home use
28
Q

Blood related discoveries in the late 1970s/1980s

A
  • 1984 –HIV was identified
  • 1985 –HIV testing in blood facilities implemented
  • 1989 –Hepatitis C was isolated
  • 1990 –Hepatitis C testing of blood donors began
  • Was estimated that 50% of haemophiliacs succumbed to viral infection
29
Q

Recombinant factor treatments 1980s/1990s

A
  • 1982 –factor IX was cloned
  • 1984 –factor VIII was cloned (These important discoveries allowed the production of recombinant fVIII/fIX protein)
  • 1992 –recombinant fVIII was licensed for the treatment of haemophilia A
  • 1997 –recombinant fIX was licensed for the treatment of haemophilia B
30
Q

On-demand treatment regimes

A
  • Affected individuals are treated with replacement factor only when a bleeding episode begins
  • Does not prevent bleeding episodes from starting
31
Q

Prophylactic treatment regimes

A
  • Affected individuals are treated with replacement factor 1-4 times a week
  • Achieves a basal level of factor that maintains haemostasis (~30%)
  • A significant amount of factor is used
32
Q

Life expectancy of haemophilia by the 1980’s

A
  • Before the advent of cryoprecipitate, males rarely lived to reproductive age. The average life expectancy was 11 years.
  • by 1980s this was increased to 50-60 years
  • Use of factor concentrate had a significant effect
33
Q

Life expectancy of haemophilia today

A
  • Normal life expectancy
  • Use of recombinant factor and prophylactic treatment
  • Death from other causes (i.e. cardiovascular disease etc)
34
Q

Future treatment of haemophilia

A

Gene therapy:

  • Recent studies have investigated the use of gene transfer to insert a normal VIII/IX gene into affected individuals
  • Factor IX gene is put into a vector which targets the production of factor IX protein to the liver
  • Maintains FIX at 1-6% of normal in individuals with severe haemophilia B
  • Decreases the amount of factor IX concentrate used
  • Decreases the number of bleeding episodes
35
Q

Royal family haemophilia

A
  • It was hypothesised that those affected by Haemophilia in the Royal Family had Haemophilia A
  • In 2009, it was reported that the remains of all Russian Royal Family members were found
  • They found that there was no mutation in the factor VIII gene (F8), but there was one in IX gene
  • Therefore, the Royal Family had haemophilia B

Foundations of Pathology (15 decks)

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