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CP reviewer 1 > Heritable Bleeding Disorders > Flashcards

Heritable Bleeding Disorders Flashcards

1
Q

Describe the formation of a haemostatic plug

A
  1. Normal platelets in flowing blood
  2. Damaged endothelium leads to platelets adhering to the wall (bind to collagen in sub endothelium) and becoming activated
  3. Activated platelets aggregate to form a thrombus (platelet plug)
  4. Receptors are expressed and fibrinogen binds to platelets
  5. Granules are released, stimulating further platelet activation
  6. Coagulation cascade follows – clotting factors are soluble proteins and contribute to fibrin formation.
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2
Q

Which enzyme converts fibrinogen to fibrin?

A

thrombin (serine protease)

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3
Q

How is thrombin formed?

A

Prothrombin (coagulation factor II) is cleaved to form thrombin

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4
Q

What is Von Willebrand factor?

A

Von Willebrand factor helps platelets aggregate and adhere to (collagen in) walls of blood vessels.

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5
Q

What is the most common heritable bleeding disorder?

A

Von Willebrand disease

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6
Q

What is Von Willebrand disease?

A

low or dysfunctional Von Willebrand factor –> bleeding

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7
Q

What acts as receptors on platelet surfaces?

A

Membrane glycoproteins

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8
Q

The membrane glycoproteins of platelets act as receptors that mediate 2 important functions. What are these?

A
  1. adhesion to the subendothelial matrix
  2. platelet aggregation
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9
Q

What are the 2 important membrane glycoproteins found on platelets? What is each one a receptor for?

A
  1. 2b3a –> receptor for fibrinogen
  2. 1b9 –> receptor for vWf
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10
Q

Inside the platelets are granules. What are the 3 different types of granules found?

A
  1. alpha granules
  2. dense granules
  3. lysosomal granules
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11
Q

What do alpha granules contain?

A

contain adhesion proteins and calcium (role in coagulation cascade)

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12
Q

What do dense granules contain?

A

contain ATP and ADP which are released when platelets become activated (ADP forms positive feedback loops – activates more platelets)

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13
Q

Metabolic processes are going on inside cytoplasm of platelets when they become activated. What 2 major metabolic processes are going on?

A
  1. Formation of prostaglandins
  2. Formation of thromboxane
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14
Q

How are prostaglandins formed in the cytoplasm of platelets?

A
  • Mobilisation of fatty acids from platelet membrane
  • Conversion of the fatty acid arachidonic acid to intermediate prostaglandins
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15
Q

How is thromboxane formed in the cytoplasm of platelets?

A
  • Synthesised by activated platelets from arachidonic acid (via the enzyme cyclooxygenase)
  • Released from phospholipid membrane upon platelet activation
  • Secreted into surrounding and stimulates activation of new platelets as well as platelet aggregation
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16
Q

What enzyme converts arachidonic acid to thromboxane?

A

cyclooxygenase

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17
Q

how does aspirin act as an anti-thrombotic agent?

A

Aspirin inhibits cyclooxygenase (COX) –> prevents production of thromboxane A2

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18
Q

Name 4 anti-platelet drugs

A
  1. Aspirin
  2. Clopidogrek
  3. Dipyridamole
  4. IIb and IIa anatagonists
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19
Q

How does Clopidogrel act as an anti-platelet drug?

A
  • blocks ADP receptor (P2Y12 inhibitor)
    • P2Y12 is a chemoreceptor for ADP
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20
Q

How does Dipyridamole act as an anti-platelet drug?

A

Stimulated prostacyclin to inhibit binding site for collagen, thrombin, thromboxane A2

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21
Q

How do IIb and IIa antagonist act as an anti-platelet drugs?

A

blocks GPIIb/IIIa

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22
Q

Overview of coagulation cascade

A
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23
Q

Describe the steps of the extrinsic pathway

A
  1. Coagulation is triggered by tissue factor
  2. Factor VII binds to tissue factor and becomes activated –> VIIa
  3. VIIa can directly activated X –> Xa
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24
Q

What is tissue factor? Where is it found?

A

a cellular protein found on surface of cells – damaged endothelium, inflamed blood vessels, WBCs, brain cells

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25
Q

Describe the steps of the intrinsic pathway

A

Doesn’t rely on molecules external from the blood but instead becomes activated when blood is exposed to a foreign surface:

  1. Factor 12 is activated when exposed to a foreign surface –> XIIa
  2. XIIa then activates XI –> XIa
  3. XIa then activates IX –> IXa
  4. IXa (with cofactor VIII) activates X –> Xa
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26
Q

Describe the steps of the common pathway of the coagulation cascade

A
  1. Xa (with cofactor Va) will convert prothrombin –> thrombin
  2. Thrombin converts fibrinogen to fibrin (crosslinked by Factor 13)
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27
Q

What is the ‘prothrombin time’?

A
  • Used to measure extrinsic pathway:
    • Adding a tissue factor substitute (thromboplastin) to plasma in a test tube
    • Time how long it takes blood to clot
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28
Q

What is the Activated Partial Thromboplastin Time (APTT) used to measure?

A

Intrinsic pathway

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29
Q

What is the thrombin clotting time?

A
  • Used to measure final step
    • Thrombin is added to plasma
    • Time how long it takes to clot
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30
Q

What is the thrombin clotting time dependent on?

A
  • Very dependent on level of plasma fibrinogen
  • Dependent on there being nothing in blood inhibiting formation of fibrin from fibrinogen
    • E.g. heparin
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31
Q

What is often the first line of investigation of someone with abnormal bleeding?

A

Prothrombin Time (PT)

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32
Q

What does a coagulation screen comprise?

A
  1. Prothrombin time
  2. Activated Partial Thromboplastin Time (APTT)
  3. Thrombin Clotting Time
33
Q

Why are the top parts of the intrinsic pathway is less physiologically important?

A
  • Extrinsic pathway is thought to start it off.
  • Intrinsic pathway acts as amplification system instead of initiator.
  • Thrombin has positive feedback effect

Factor 11 can therefore be activated through extrinsic pathway activating thrombin and then the thrombin activating Factor 11 through a feedback system.

34
Q

Does a patient with Factor VII deficiency have a bleeding disorder? What will the APTT be like?

A

No - this factor is less important

But will have a long APTT (instrinsic pathway time)

35
Q

Will a patient with a factor XI deficiency have a bleeding disorder?

A

Yes but only mild

36
Q

Protein C and Protein S also play a role in the coagulation cascade. What is their function?

A

Both have a role in anticoagulation:

  • Protein C plays an important role in regulating anticoagulation by inhibiting Factor V
  • Protein S has a role in the anticoagulation pathway, where it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa
37
Q

Antithrombin also has a role in the coagulation cascade. What is its function?

A

Anticoagulant effects; It inactivates several enzymes of the coagulation cascade, in particular thrombin and factor Xa

38
Q

The fibrinolytic system also has a role in the coagulation cascade. What is its function?

A

Anticoagulant: The fibrinolytic system comprises an inactive proenzyme, plasminogen, which can be converted to the active enzyme, plasmin, which in turn degrades fibrin into soluble fibrin degradation products.

39
Q

When conducting an assessment of a suspected bleeding disorder, clinical history is key.

What questions should you ask?

A
  • Date of onset
  • Previous history (longer is congenital, shorter if acquired)
  • Clinical pattern (more severe presents in childhood)
  • Response to challenges: surgery, dental extraction
  • Young children: bleeding from umbilical stump, vaccinations, circumcision
  • Requirement for medical/surgical intervention to ascertain extent of bleeding
  • Systemic illness, drug history, family history – helps to identify if congenital
40
Q

When conducting a clinical examination during an assessment of a suspected bleeding disorder, waht should you look for?

A
  • Pattern of any bruising
  • Signs of underlying disease: Joints, muscles, skin
41
Q

Exampls of blood tests done during an assessment of a suspected bleeding disorder

A
  • FBC and blood film
  • Coagulation screen
  • Clauss fibrinogen (D-dimer if suspicion of acquired disorder)
  • Mixing studies: if clotting tests are longer than expected, they can be performed with the patient’s plasma and normal plasma. Test will correct significantly if there is a lack of factors. It will not correct significantly if the patient’s blood contains an inhibitor of clotting.
  • Von Willebrand profile
  • Coagulation factor assays
  • Inhibitor assays (antiphospholipid type)
  • Platelet function tests
  • If all normal and suspicion remains: factor 13 and alpha2antiplasmin assays.
42
Q

During mixing studies, if clotting tests are longer than expected, they can be performed with the patient’s plasma and normal plasma.

  • If the clotting test corrects significantly, what does this indicate?
  • If the clotting test does not correct significantly, what does this indicate?
A
  • Lack of factors in patients blood
  • Patients blood contains an inhibitor of clotting
43
Q

If a patient has a normal coagulation screen (APTT, PT, TCT), what are other potential causes of a bleeding disorder?

A
  • Thrombocytopenia (low platelets)
  • Disorder of platelet function
  • vWD
  • Factor 13 deficiency
  • Mild coagulation factor deficiency
  • Vascular disorder
  • Disorder of fibrinolysis (rare)
  • Platelet/vessel wall defects (1ary haemostasis) –> give rise to prolonged bleeding time
44
Q

How can a factor 13 deficiency lead to bleeding? How does this bleeding present?

A
  • Factor 13 covalently crosslinks the fibrin polymer and stabilises it
  • Patients with this deficiency typically present with late bleeding (a few days after sometimes)
45
Q

How can platelet/vessel wall defects give rise to bleeding disorders?

A
  • Reduced number of platelets (thrombocytopenia)
  • Abnormal platelet function (could be iatrogenic, caused by aspirin)
  • Abnormal vessel wall
    • E.g. Ehlers-Danlos syndromes; a group of rare inherited conditions that affect connective tissue –> bleeding due to defects in collagen
  • Abnormal interaction between platelets and vessel wall
    • E.g. vWD – reduction in platelet adhering molecules to the wall.
46
Q

What is Ehlers-Danlos syndromes?

A

Ehlers-Danlos syndromes; a group of rare inherited conditions that affect connective tissue –> bleeding due to defects in collagen

47
Q

Difference in presentation between vascular/platelet defects and coagulation defects

A
48
Q

What is this? What would it indicate?

A

Petechiae

  • Little red spots often around hair follicles
  • Don’t blanch with pressure
  • Not palpable (flush against skin)
  • Think about; thrombocytopenia, meningitis, vascular/platelet defects
49
Q

There are 3 types of Von Willebrand Disease. How does each type differ?

A
  • Type 1:
    • Reduced production of normal vWf, tend to have normal/slightly reduced Factor VIII
    • Common, mild; especially in blood group O
    • Variable penetrance in a family with all the same genetic defect.
  • Type 2:
    • Patient is producing enough vWf but often is structurally abnormal so is dysfunctional (low molecular weight polymers)
    • Slightly more severe than type 1
  • Type 3:
    • vWf is absent altogether and Factor VIII tends to be greatly reduced too
    • Severe and spontaneous;
      • ​bleeding into joints and vessels as well as mucosal surfaces
50
Q

Why can vWd often present with reduced Factor VIII levels?

A

Vwf is a carrier protein for factor VIII (carries it around circulation)

51
Q

Inheritance pattern of vWf (remember different types)?

A
  • Mainly autosomal dominant inheritance.
  • Type 3 is autosomal recessive.
52
Q

Which blood group is often associated with low vWf levels?

A

Blood group O (this is not vWd)

53
Q

Symptoms of vWd?

A
  • Postoperative/post-partum bleeding
  • Mucocutaneous bleeding
  • Menorrhagia
54
Q

vWf has 2 functions. What are these?

A
  1. binds to protein 1b9 on the platelet surface and helps it bind to the vessel wall (collagen)
  2. forms a complex with factor 8 (carrier protein) to activate factor 10
55
Q

What factors are deficient in vWd?

A

In vWD, there is less 8a, F10a and fibrin and so bleeding is more likely

56
Q

Treatment options for vWd:

A
  • Anti-fibrinolytics –> tranexamic acid
  • DDAVP
  • Factor concentrates containing vWF (pool plasma derived)
  • Vaccination again hepatitis
  • Combined OCP for menorrhagia (or Mirena coil)
57
Q

What is tranexamic acid? What is it useful in treating?

A

Anti-fibrinolytic - good for bleeding of the mouth, periods and nosebleeds.

58
Q

What is DDAVP? What is it used to treat?

A
  • DDAVP is an analogue of vasopressin
  • Analogue of vasopressin
  • Side effect of promoting secretion of vWf from where it is stored inside endothelial cells inside lining of blood vessels –> short term solution
59
Q

What is Factor I?

A

Fibrinogen

60
Q

What is Factor II?

A

Prothrombin

61
Q

Haemophilia A is a defect in what?

A

Factor VIII

62
Q

Haemophilia B is a defect in what? What is this also known as?

A

Factor IX - Christmas disease

63
Q

Summary of Heritable Coagulation Factor Deficiencies

A
64
Q

Inheritance of haemophilias?

A

X-linked recessive

65
Q

How does haemophilia affect men vs women? Why?

A
  • Typically expressed in males and carried by females.
  • In females, the normal X chromosome will compensate for the faulty X chromosome so tend to be carriers only
66
Q

Is haemophilia A or B more common?

A

Haemophilia A: 1 in 5000 males

Haemophilia B: 1 in 30,000 males

67
Q

Which part of the coagulation cascade is affected in haemophilia A/B?

A

8 and 9 are intrinsic pathway factors and contribute to the common clotting cascade.

68
Q

Factor VIII or IX levels determine if haemophilia is mild, moderate or severe. What are the Factor VIII or IX levels for each of these?

A
  • Normal: Factor VIII or IX level between 50-150%
  • Mild: Factor VIII or IX level between 6-50%
  • Moderate: Factor VIII or IX level between 1-5%
  • Severe: Factor VIII or IX level less than 1%
69
Q

How does mild haemophilia present?

A
  • Bleeding only with moderate trauma or surgery.
  • Diagnosis often due to family history or later in childhood
70
Q

How does moderate haemophilia present?

A

Variable, occasional spontaneous bleeds, often proceeding trauma

71
Q

How does severe haemophilia present?

A

Frequent bleeds into muscle and joints

72
Q

Types of bleeding - reflect the severity of haemophilia

A
  • Spontaneous/post traumatic
    • Can be diagnosed after surgery, trauma, dental procedure etc
  • Joint bleeding = haemarthrosis, sets of synovitis and causes abnormal, damaged joints
  • Muscle haemorrhage – hallmark of severe haemophilia, leading to contractures, compartment syndrome, shortening, MSK disability
  • Soft tissue – bleeds into tongue, pharynx, primary teeth eruption, can threaten the airways (life threatening).
  • Life threatening bleeding – intracranial bleeding in severe/moderate
73
Q

Treatment of haemophilia;

A
  • Replacement of missing clotting protein (daily): on demand or prophylaxis.
  • Using factor concentrates; recombinant are products of choice, no longer blood derived
  • DDAVP (only for mild/moderate haemophilia A)
  • Antifibrinolytic agents – for mucosal bleeding, GI bleeding
  • Vaccination against hepatitis A and B
  • Supportive measures: icing, immobilisation, rest
74
Q

What are the supportive measures for haemophilia?

A

icing, immobilisation, rest

75
Q

Which haemophilia does DDAVP treat?

A

A

76
Q

One complication of treatment of haemophilia is the potential development of inhibitors. What are these?

A

Antibodies formed against Factor VIII or IX that stop the factor concentrates from working due to immune response:

  • More common in haemophilia A (25%)
  • Genetic predisposition
77
Q

Presentation of development of inhibitors during haemophilia treatment?

A
  • Poor recovery, bleeding difficult to manage, muscle/joint damage.
  • Poor clinical response to treatment, factor ineffective or less effective
  • Occurring early in course of condition, around 10 exposure days
78
Q

Emicizumab is a treatment used for Haemophilia. Mechanism?

A

Used for haemophilia A only, with and without inhibitors

  • Is a “monoclonal antibody”
    • Monoclonal antibodies are proteins that are designed to bind to a specific target in the body
    • They can be used to treat diseases or conditions
  • Emicizumab:
    • Mimics the action of the missing FVIII in the clotting pathway
    • The cue for its action is FIXa, which appears after an injury
    • Emicizumab binds to FIXa and FX, forming a link between these two clotting factors
    • FIXa can then activate FX, allowing the pathway to continue and the blood to clot
79
Q

Factor VIII Prophylaxis can also be used in haemophilia A treatment. How does this work?

A
  • FVIII concentrate replaces missing or low levels of FVIII
  • Prophylaxis is the regular administration of FVIII concentrate, to try and prevent bleeds
  • FVIII rises quickly after infusion and then decreases over a number of hours

CP reviewer 1 (59 decks)

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