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MCD Haematology > Abnormalities of haemostasis > Flashcards

Abnormalities of haemostasis Flashcards

1
Q

what are some examples of minor bleeding?

A

bruising
gum bleed
menorrhagia

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2
Q

name for nose bleed

A

epistaxes

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3
Q

what are examples of abnormal bleeding?

A

o Epistaxes not stopped by 10 minutes of compression.
o Cutaneous haemorrhage/bruise without apparent trauma.
o Prolonged (>15m) bleeding from trivial wounds.
o Menorrhagia requiring treatment or leading to anaemia.
o Heavy, prolonged or recurrent bleeding after surgery.

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4
Q

what are the 2 main causes of abnormal bleeding

A
  • lack of a specific factor (production failure can be genetic or acquired, increases consumption/clearance)
  • defective factor function (genetic or acquired), can be a defect of a drug
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5
Q

which components of primary haemostasis can have defects?

A

platelets
VWF
collagen

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6
Q

what are some causes of thrombocytopenia?

A
  • low number platelets
  • BM failure e.g. leukaemia, B12 deficiency.
  • accelerated clearance e.g. ITP –> reduces lifespan
  • pooling and destruction in splenomegaly
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7
Q

what are two causes of impaired function of platelets?

A

o Hereditary absence of glycoproteins/storage-granules.
o Acquired from drugs
– e.g. aspirin (NSAIDs), Clopidogrel.

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8
Q

what drugs cause platelet defects?

A

aspirin, other NSAIDs, Clopidogrel.
(anti-platelets)

aspirin impairs platelet aggregation by preventing TXA2 synthesis via COX-1 inhibition

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9
Q

what is ITP?
how does it increase platelet clearance?
what does this cause?

A

Immune Thrombocytopenia

Anti-platelet antibodies attack platelets that get engulfed by splenic macrophages.

Very common cause of thrombocytopenia.

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10
Q

what are the consequences for platelets due to thrombocytopenia

A

o Failure of platelet production by megakaryocytes.
o Shortened half-life of platelets.
o Increased pooling and decreased half-life of platelets in spleen.

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11
Q

hereditary diseases affecting platelets

A

Glanzmann’s thrombasthenia
Bernard Souiler syndrome
Storage Pool disease

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12
Q

hereditary VW disease

what are the types of VWD?

A

common form of vWD.
vWF two functions – bind collagen (to catch platelets) and stabilise F8.

  • Type 1, 3 – deficiency of vWF.
  • Type 2 – abnormal function of vWF.
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13
Q

types of hereditary VWD

A
  • Type 1, 3 – deficiency of vWF.

* Type 2 – abnormal function of vWF

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14
Q

what causes the rare acquired form of VWD

A

an antibody

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15
Q

abnormal haemostasis diseases

A

thrombocytopenia (platelets)
VWD (VWF)
Ehlers-Danlos syndrome (collagen)

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16
Q

inherited conditions of collagen defect

A

Hereditary haemorrhagic telangiectasia

Ehlers-Danlos syndrome [excessively stretchy skin]

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17
Q

acquired collagen defect

A

scurvy
steroid therapy
ageing (senile purpura)
vasculitis

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18
Q

typical bleeding patterns

A 
o	Immediate.
o	Prolonged from cuts and after trauma/surgery.
o	Epistaxes.
o	Gum bleeding.
o	Menorrhagia.
o	Easy bruising.
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19
Q

what is characteristic in thrombocytopenia?

A

petechiae bruising (characteristic of low platelets)

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20
Q

tests for abnormal bleeding investigation

A

o Platelet count.
o Bleeding time (PFA100 lab test).
o Assays of vWF.
o Clinical observation.

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21
Q

where do the defects lie in secondary haemostasis

A
  • in coagulation factors

- in the crosslinked fibrin

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22
Q

what occurs in the haemophilia type 8?

A

failure of generation of thrombin burst due to defects in F8
(thrombin provides +feedback to F8)

Thrombin converts fibrinogen to fibrin)

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23
Q

what is the importance of fibrin in larger vessels?

A

The primary platelet plug is sufficient for small vessel injury but in the larger vessels, the plug will break apart unless it is stabilised by fibrin.

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24
Q

what can cause the decrease in cross-linked fibrin

A
  • deficiency in factor 13 production

- increase consumption of factors

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25
Q

hereditary deficiencies in factor production

A

 F8/9 – Haemophilia A/B,
Haemarthrosis is hallmark (the bleeding into joint spaces)
 F2 (thrombin) – lethal.

 F11 – bleed after trauma but not spontaneously.
 F12 – no excess bleeding at all.

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26
Q

acquired (more common) deficiencies in factor production

A

1) Liver disease (production site)
2) Dilution – e.g. transfusions.
- RBC transfusions don’t contain plasma unless they’re major.
3) Anticoagulant drugs – e.g. Warfarin.

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27
Q

what are 2 acquired increased consumptions causes?

A

1) DIC – Disseminated Intravascular Coagulation.
• Generalised activation of coagulation via TF.
• Associated with sepsis, major tissue damage and inflammation.
• Consumes and depletes coagulation factors, platelets and fibrinogen.
• Deposition of fibrin in vessels causes organ failure.

2) Immune – auto-antibodies.

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28
Q

typical bleeding patterns in secondary haemostasis

A

o Superficial cuts DO NOT bleed.
o Bruising is common, nosebleeds are rare.
o Spontaneous bleeding is deep, into muscles and joints (haemarthrosis)
o Bleeding after trauma may be delayed but is prolonged.
o Bleeding frequently restarts after stopping.

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29
Q

what precaution must be taken with haemophiliacs considering deep bleeding

A

intramuscular injections must be avoided due to deep tissue bleeds possible

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30
Q

tests for defective secondary haemostasis

A

o Screening tests (‘clotting screen’):
- PT – Prothrombin Time.
(Extrinsic & Common pathway defects)
- APTT – Activated Partial Thromboplastin Time.
(Intrinsic & Common pathway defects)
- FBC – Full Blood Count (for platelets).

o Factor assays – e.g. for F8 etc.

o Tests for inhibitors.

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31
Q

PT and TT and APTT resulst in haemophilia

A
  • Prothrombin time =normal
  • Thrombin time =normal
  • Activated partial thromboplastin time = abnormal
    (due to defective intrinsic pathway)

remember Prothrombin time does not include F8
(1,2,5,7,10) therefore remains normal

APTT is best to measure for haemophilia

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32
Q

bleeding disorders not detected by routine clotting tests

A 
	Mild factor deficiencies.
	vWD.
	F13 deficiency (to cross-link the fibrin) – common pathway is measured in BOTH APTT and PT.
	Platelet disorders.
	Excessive fibrinolysis.
	Vessel wall disorders.
	Metabolic disorders – e.g. uraemia.
	Thrombotic disorders.
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33
Q

hereditary cause of excessive fibrinolysis

A

anti-plasmin deficiency therefore less plasmin deactivation

plasmin causes fibrinolysis

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34
Q

what are the acquired causes of poor fibrinolysis?

A

1) Drugs – e.g. affecting tPA and bacterial streptokinase.
tPA activates plasmin

2) Disseminated Intravascular Coagulation (DIC)

35
Q

what are some genetic bleeding disorders?

A

1) Haemophilia : Sex-linked recessive.
2) Von Williebrand disease: Autosomal dominant usually
- -> Dominant – Type 1, 2.
- -> Recessive – Type 3.
- 3) Factor V Leiden: autosomal recessive

these are usually treated with replacement therapy

36
Q

treatment of production/function failure

A

o Replace missing factors/platelets – prophylactically or therapeutically.
o Stop drugs causing it.

37
Q

treatment of immune destruction

A

o Immunosuppression – e.g. prednisolone.

o Splenectomy for ITP.

38
Q

treatment of increased consumption

A

treat cause or replace

39
Q

factor replacement therapy

A

o Plasma – contains ALL coagulation factors.
o Cryoprecipitate – rich in fibrinogen, F8, vWF, F13.
o Factor concentrates – concentrates available for all factors except F5.
o Recombinant forms of F8 and F9 are available.

40
Q

platelet replacement therapy

A

o Pooled platelet concentrates available.

41
Q

DDAVP (Desmopressin- vasopressin alternative/derivative)

A

only when you don’t have enough (not for intrinsic dysfunctions):

  • use in VWD and Haemophilia A (mild to moderate cases only i.e. not absolute deficiencies)
  • Results in a 2-5x rise in vWF and F8 (more F8 rise) by stimulating endothelial cells to release internal stores.

Only really good for mild disorders.

42
Q

what is the effect tranexamic acid on haemostasis?

A

slows down the breakdown of clots and therefore prevents excessive blood loss:

  • inhibits fibrinolysis – competes with tPA.
  • It is widely distributed in the body and can cross the placenta.
  • However, it does have a low concentration in breast milk.
  • Delivered by IV, oral or mouthwash.
43
Q

what are the causes of thrombocytopenia?

A

-Bone marrow failure e.g. Leukaemia

  • Accelerated clearance of platelets
    e.g. Disseminated intravascular coagulation (DIC)
    uses up clotting factors and platelets
  • Pooling and destruction in splenomegaly
44
Q

what are some hereditary conditions causing defects in primary haemostasis?

A

1) Glanzmann’s thomboasthenia
(no GlpIIb/IIIa–> no platelet activation)

2) Bernard Soullier syndrome (no GlpIb –>no vWF binding )
3) Von Willebrand Disease (low or abnormal vWF)

45
Q

what are the causes of deficiency in coagulation factors?

A
  • Liver failure (production site of factors)

- Haemophilia (8 and 9)

46
Q

which haemophilia is more prevalent?

A

A x5 than B

47
Q

what causes the excess consumption of coagulation factors?

A
  • Autoimmune diseases
  • DIC (disseminated intravascular coagulation)

use up clotting factors

48
Q

what are the defects in primary haemostasis?

A

1) thrombocytopenia (low platelets)

2) hereditary conditions

49
Q

what are the defects in secondary haemostasis?

A

1) coagulation factor deficiency e.g. haemophilia

2) overconsumption of coagulation factors

50
Q

what is the presentation of primary haemostasis defect?

A
  • Immediate
  • Prolonged bleeding from superficial cuts

Epistaxes
Gum bleeding
Menorrhagia
Easy bruising (seen in thrombocytopenia)

51
Q

what is the presentation of secondary haemostasis defect?

A

Spontaneous bleeding is deep, into muscles and joints (haemarthrosis) –> typical in haemophiliacs

  • Bleeding after trauma may be delayed and is prolonged
  • Superficial cuts do not bleed
52
Q

what is a key characteristics in presentation of thrombocytopenia?

A

Petechiae 1-2mm

purpura up to 1cm

53
Q

what are 3 causes of prolonged APTT?

A
  • heparin
  • Haemophilia A
  • Haemophilia B
  • Vitamin K deficiency

APTT is a measure of intrinsic pathway
F8 and F9 are intrinsic pathway factors
F8 and F9 are involved in haemophilia

54
Q

what are the 3 physiological inhibitors of the clotting cascade?

A

protein C
protein S
anti thrombin

55
Q

what is the MoA of warfarin?

A

Vitamin K inhibitor

action of gamma-glutamyl carboxylase in activation of factors 2,7,9,10
inhibits the post translational Gla modifications of certain clotting proteinases, thus reducing their activities

56
Q

what does heparin act on so have its anticoagulant effect?

A

anti thrombin

accelerates the inhibition of thrombin and other clotting proteinases by antithrombin

57
Q

what pathway does prothrombin time measure?

A

extrinsic pathway and common

58
Q

what pathway does Activated Partial Thromboplastin Time measure?

A

intrinsic pathway and common pathway

59
Q

what is haemoarthrosis?

A

bleeding into joint cavity

60
Q

what factors are involved in the intrinsic pathway?

what measures it?

A

F8,9,
F10, 11, 12

12–> not significant in symptoms
11–> rare
8 and 9–> haemophilia

measure with Activated Partial Thromboplastin Time

61
Q

what factors are involved in the extrinsic pathway?

what measures it?

A

TF (3) and F7

Prothrombin Time

62
Q

what factors are involved in the common pathway?

what measures it?

A

F5
thrombin (2)
fibrin (1)
F13 (cross linker)

Thrombin time :
measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added

63
Q

how is haemophilia treated?

A

with recombinant F8/9

64
Q

what does normal fibrinogen production suggest in a jaundiced patient?

A

functional liver so not hepatic jaundice

key: liver is the production site of fibrinogen therefore a healthy liver is needed for fibrin clot formation

65
Q

which factors are Vitamin K dependent?

A

2,7,9,10

Warfarin inhibited

66
Q

how can jaundice cause malabsorption of vitamin K?

A

bile is used to emulsify vitamin K so can be absorbed

obstructive jaundice (gall stones or tumour) would reduce vitamin K absorption

67
Q

what pathways would Vitamin K deficiency/malabsorption affect? why?

A

both extrinsic and intrinsic as well as common

factors dependent on Vit K are 2,7,9,10

68
Q

how is vitamin K def treated?

A

IV Vitamin K

or replace factors in emergency

69
Q

what are 2 acquired platelet disorders?

A

1) thrombocytopenia

2) drug-induced

70
Q

what are the 3 mechanisms leading to thrombocytopenia?

A

1) failure of platelet production e.g. aplastic anaemia, leukaemia, vitamin b12/folate def
2) shortened platelet half life e.g. AI thrombocytopenia, thrombotic thrombocytopenia, infections, drugs
3) increased pooling of platelets in enlarged spleen

71
Q

what are the 3 tests to monitor platelets?

A

1) platelet count
2) bleeding time
3) platelet aggregation e.g vWF activity

platelet count is the most important (as a massive decrease increases risk of bleeding)

72
Q

what is the role of F13a?

A

cross linkage of fibrin

activated by thrombin

73
Q

which of the pathways plays the minimal role in haemostasis?

A

intrinsic (started by factor 12)

Tissue factor is main, framing complex with F7a

74
Q

what do factors 7,9,10 and prothrombin need to do to activate their substrate?

A

bind to phospholipid

this requires Vitamin K dependent post translational modification of certain amino acids (“Gla” residues) and is mediated by Ca2+ ions.

75
Q

what occurs on the platelet membrane phospholipid surface to cause activating of thrombin?

A 
11--> 11a
- 11a complexes with 8a enables:
10--> 10a
- 10a complexes with 5a enables:
prothrombin--> thrombin
76
Q

what are the main tests for coagulation?

A

1) activated partial thromboplastin time (APTT)
- monitors the function of the intrinsic and common pathways and is used to control the level of heparin in patients.

2) prothrombin time (PT)
- monitors the extrinsic and common pathways and is used to control levels of oral anticoagulant (warfarin) in patients.

77
Q

what drug is monitored by APTT?

A

heparin

78
Q

what drug is monitored by PT?

A

warfarin

79
Q

what test can detect haemophilia?

A

APTT (F8 and F9 def)

80
Q

what can both the PT and APTT test identify?

A

acquired disorders such as disseminated intravascular coagulation (increased coagulation factor consumption)

81
Q

what converts plasminogen to plasmin?

plasmin will lyse the fibrin clot

A

tissue plasminogen activator (tPa)

Alteplase drug

82
Q

how can bleeding due to platelet-vWF (primary haemostasis) be distinguished from defects in coagulation (secondary haemostasis)?

A

1) Defect in platlet-vWF:
- characterised by SUPERFICIAL bleeding into the skin and mucosal membranes
- bleeding immediately following injury.

2) Defect in coagulation (deficiencies):
- tends to be into DEEP tissues, muscles and joint
- Often delayed after injury
- prolonged and can be severe

83
Q

characteristics of Von Williebrand Disease

A
  • nosebleeds, menorrhagia and prolonged bleeding from superficial cuts
  • due to its importance of vWF in the platelet-vessel wall interaction

remember that defects in primary haemostasis leads to a lot of superficial bleeds

MCD Haematology (11 decks)

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