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Y2 Clinical Pathology > Heritable Bleeding Disorders > Flashcards

Heritable Bleeding Disorders Flashcards

1
Q

What is meant by the hemostatic balance?

A

a delicate balance of procoagulant and anticoagulant components

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2
Q

What is involved in hemostatic plug formation?

A

aggregation of platelets formed during early stages of haemostasis in response to blood vessel wall injury

platelets are recruited and begin to accumulate around the breakage

they adhere to each other to form a platelet plug that prevents more blood from leaving the vessel and any contaminants from getting in

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3
Q

how is fibrin involved in haemostatic clot formation?

A

thrombin acts on fibrinogen to convert it to fibrin through polymerisation

polymerised fibrin, together with platelets, forms a haemostatic plug / clot over a wound site

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4
Q

What is involved in formation of a platelet thrombus?

A

platelets adhere to the subendothelial space when an endothelium is damaged and undergo activation

platelets aggregate into a thrombus

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5
Q
A
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6
Q

What is contained within the alpha granules of platelets?

A

fibrinogen and von Willebrand factor (vWF)

these are adhesive proteins which mediate platelet-platelet and paltelet-endothelial interactions

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7
Q

What is contained within the dense granules of platelets?

A
  • adensoine diphosphate (ADP)
  • adenosine triphosphate (ATP)
  • ionized calcium
  • serotonin
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8
Q

What is contained within lysosomal granules of platelets?

A

mainly digestive enzymes

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9
Q

What is the mechanism of action of clopidogrel?

A

it selectively inhibits the binding of ADP to its platelet P2Y12 receptor

this prevents the ADP-mediated activation of the glycoprotein IIb/IIIa complex

this inhibits platelet aggregation

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10
Q

What is the mechanism of action of dipyridamole?

A

it inhibits the cellular reuptake of adenosine into platelets

it stimulates prostacyclin production by increasing intracellular levels of cAMP

prostacyclin is an endogenous inhibitor of platelet activation and aggregation

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11
Q

What is the mechanism of action of aspirin?

A

it inhibits the activity of the enzyme cyclooxygenase (COX)

this irreversibly blocks the formation of thromboxane A2 in platelets

this produces an inhibitory effect on platelet aggregation

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12
Q

How do IIb/IIIa antagonists work?

A

they prevent platelet aggregation and thrombus formation

they inhibit the GP IIb/IIIa receptor on the surface of platelets

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13
Q

Which clotting assays are used to measure the different components of the coagulation cascade?

A

activated partial thromboplastin time:

  • measures the intrinsic pathway

prothrombin time:

  • measures the extrinsic pathway

thrombin time:

  • measures fibrin formation from thrombin
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14
Q

What activates the clotting cascade?

A

exposure of underlying collagen to circulating platelets when a blood vessel is damaged

platelets bind directly to collagen to form a “platelet plug”

adhesion is strengthened further by vWF that forms additional bonds between platelets and collagen

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15
Q

What is the difference in the ways the intrinsic and extrinsic pathways are activated?

A

intrinsic:

  • activated by damage directly to the blood vessel
  • collagen is exposed to circulating platelets

extrinsic:

  • activated by tissue factor
  • released in response to many things including tissue damage outside the blood vessel, sepsis, malignancy, inflammtion
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16
Q

What pathway is activated by thrombin?

A

it activates the intrinsic pathway through activation of factor 8 and 11

it also activates factors 5, 7 and 13 to increase the coagulation effects of the extrinsic and common pathways

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17
Q

What is produced by both the intrinsic and extrinsic pathways?

A

a prothrombin activator

this triggers the common pathway

prothrombin becomes thrombin, which then converts fibrinogen into fibrin

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18
Q

Which factors are involved in the intrinsic and extrinsic pathways?

A

intrinsic:

  • XII
  • XI
  • IX
  • VIII and IX form a complex

extrinsic:

  • III
  • VII
  • VIII and III form a complex

common:

  • the complexes from both pathways activate X
  • X combines with V to activate thrombin
  • fibrinogen is converted to fibrin
  • XIII cross-links fibrin
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19
Q

What are the procoagulant and anticoagulant factors involved in hemostatic balance?

A

procoagulant:

  • platelets
  • clotting factors

anti-coagulant:

  • protein c
  • protein s
  • anti-thrombin III
  • fibrinolytic system
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20
Q

What is the role of plasmin?

A

it is a serine protease enzyme that degrades many blood plasma proteins, including fibrin clots

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21
Q

What is involved in the conversion of plasminogen to plasmin?

A
  • tissue plasminogen activator (tPA)
  • urokinase plasminogen activator (uPA)
  • factor XII

fibrin is a cofactor for plasminogen activation by tPA

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22
Q

What is the role of TAFI?

A

when activated to TAFIa, it suppresses fibrinolysis by the removal of lysine residues from the fibrin clot

these would be exposed as fibrin is degraded by plasmin

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23
Q
A
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24
Q

What are the 4 different types of bleeding disorders?

A
  • congenital (usually a single defect)
  • acquired (often multiple defects)
  • platelet / vessel wall bleeding - mucosal and skin
  • coagulation defect - deep muscular and joint bleeding, often following trauma
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25
Q

What is involved in appropriate investigation of a possible bleeding disorder?

A
  • full blood count and blood film
  • coagulation screen and Clauss fibrinogen
  • mixing studies if abnormal results
  • von willebrand profile
  • FVIII / FIX +/- other appropriate coagulation factor assays
  • platelet function tests
  • inhibitor assays in some cases (antiphospholipid type and/or specific coagulation factor inhibitors)
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26
Q

What should be done if all test results are normal and suspicion still remains?

A

FXIII assay and assay of alpha2antiplasmin

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27
Q

When should D dimer be performed when investigating a bleeding disorder?

A

if there is a suspicion of acquired disorder

28
Q

What can be detected on a bleeding / normal coagulation screen?

A
  • thrombocytopenia
  • disorder of platelet function
  • vWD
  • factor XIII deficiency
  • mild coagulation factor deficiency
  • vascular disorder
  • disorder of fibrinolysis
29
Q

What do all platelet / vessel wall defects give rise to?

A

a prolonged bleeding time

30
Q

What are the 4 causes of a platelet / vessel wall defect?

A
  1. reduced number of platelets
  2. abnormal platelet function (drugs / aspirin)
  3. abnormal vessel wall
  4. abnormal interaction between platelets and vessel wall (von willebrand disease)
31
Q

What are the signs of a vascular/platelet defect?

A
  • petechiae and superficial bruises
  • affects skin and mucous membranes
  • spontaneous bleeding
  • bleeding is immediate, prolonged and non-recurrent
32
Q
A
33
Q

What are the signs and properties of a coagulation defect?

A
  • deep spreading haematoma
  • haemarthrosis (haemorrhage into a joint space)
  • retroperitoneal bleeding
  • bleeding is prolonged and often recurrent
34
Q

What are petechiae?

A

tiny purple, red or brown spots on the skin

they do not blanch with pressure

they are not palpable

35
Q

What is von Willebrand disease?

A

genetic disorder caused by missing or defective von Willebrand factor (vWF)

this is a clotting protein that binds to FVIII and platelets

it helps to form a platelet plug during the clotting process

36
Q

What causes severe and less severe von Willebrand disease?

A

severe:

  • von willebrand factor is completely absent

less severe:

  • reduced production of vWF
  • low molecular weight polymer produced
37
Q

What is the role of vWF in the clotting cascade?

A

it binds to FVIII and acts as a FVIII carrier protein

FVIIIa involved in FIXa converting X to Xa

this then leads to fibrin production

38
Q

What type of inheritance is seen in von willebrand disease?

A

autosomal dominant inheritance

39
Q

What is von willebrand disease associated with?

A
  • defective primary haemostasis
  • variable reduction in factor VIII levels
  • mucocutaneous bleeding including menorrhagia
  • postoperative and post-partum bleeding
40
Q

Why is it difficult ot diagnose mild vWD?

A

it is difficult to diagnose due to confounding factors

there is variable penetrance for mild types

blood group O has lower levels of vWF

41
Q

What is meant by defective primary haemostasis?

A

platelet plug formation is inadequate

this manifests as haemorrhage from small blood vessels subjected to daily minor trauma

i.e. those supplying mucosa

42
Q

What is involved in the treatment of von willebrand disease?

A
  • antifibrinolytics - tranexamic acid
  • DDAVP (type 1 vWD)
  • factor concentrates containing vWF (plasma derived)
  • vaccination against hepatitis
  • COCP for menorrhagia
43
Q

What are the 2 most common hereditary coagulation factor deficiencies?

A

factor XII deficiency - autosomal inheritance

factor VIII vWD - autosomal recessive

44
Q

What are the 2 sex linked recessive coagulation factor deficiencies?

A
  • IX haemophilia B
  • VIII haemophilia A

these are both uncommon

45
Q

What type of defect is FXI deficiency?

A

it is a rare autosomal disease

46
Q

What are the autosomal recessive hereditary deficiencies?

A
  • factor VII
  • factors X, V, II, I and XIII

these are all very rare

47
Q

What coagulation factor deficiencies are characterised by abnormal aPTT ONLY?

A
  • XII
  • XI
  • IX (christmas disease)
  • VIII (haemophilia)
  • VIII (von willebrand disease)
48
Q

What clotting factor deficiencies are characterised by abnormal PT ONLY?

A
  • factor VII
49
Q

What clotting factor deficiencies are characterised by abnormal aPTT and PT?

A
  • factor X
  • factor V
  • factor II (prothrombin)
50
Q

What clotting deficiencies are associated with abnormal aPTT, PT & TCT?

A

factor I (fibrinogen)

51
Q
A
52
Q

What clotting factor deficiency is associated with normal aPTT, PT & TCT?

A

factor XIII

53
Q

What are the 2 different types of haemophilias?

A

they are X-linked recessive disorders

haemophilia a:

  • factor VIII deficiency
  • affects 1 in 5,000 males

haemophilia b:

  • factor IX deficiency
  • affects 1 in 30,000 males
54
Q

Which pathways are affected by haemophilia?

A

intrinsic and common

extrinsic:

  • tissue factor (thromboplastin)
  • Ca2+
  • factor VII

intrinsic:

  • factor XII
  • factor XI
  • factor IX
  • factor VIII
  • platelet phospholipid
  • Ca3+
55
Q
A
56
Q

How many cases of haemophilia are new mutations?

In which gender does it tend to be seen?

A

30% of cases of haemophilia are new mutations

it is typically expressed in males and carried by females

severity level is consistent between family members

57
Q

What levels of factor VIII / IX characterise mild, moderate and severe haemophilia?

A

normal factor VIII or IX level is 50 - 150%

mild haemophilia:

  • factor VIII or IX level = 6 - 50%

moderate haemophilia:

  • factor VIII or IX level = 1 - 5%

severe haemophilia:

  • factor VIII or IX level < 1%
58
Q

What are the 5 different types of bleed?

A
  1. spontaneous / post traumatic
  2. joint bleeding = haemarthrosis
  3. muscle haemorrhage
  4. soft tissue
  5. life threatening bleeding
59
Q

What is meant by haemophilic arthropathy?

A

permanent joint disease occurring in haemophilia sufferers as a long-term consequence of repeated haemarthrosis

60
Q

What treatments are available for haemophilia?

A
  • replacement of missing clotting protein - on demand or prophylaxis
  • DDAVP (mild / moderate haemophilia a)
  • factor concentrates (recombinants are products of choice)
  • antifibrinolytic agents
  • vaccination against hepatitis A and B
  • supportive measures such as immobilisation and rest
61
Q

What are the transfusion transmitted infections that come with treatment of haemophilia?

A
  • hepatitis A, B, C . ……. …….. …….. G
  • HIV
  • parvovirus
  • vCJD ??
62
Q
A
63
Q

What is the incidence of inhibitor development after treatment of haemophilia?

What are the consequences?

A

incidence is 25% in haemophilia A

it is more common in haemophilia A than B

it results in poor recovery and/or shortened half life of factor replacement therapy

there is a poor clinical response to treatment

64
Q

When does inhibitor development tend to occur?

What is required when this happens?

A

most occur early in course of condition (within 10 exposure days)

specialised management of bleeds is required and eradication of inhibitor (immune tolerance)

65
Q
A

Y2 Clinical Pathology (76 decks)

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