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Year 5 path SW > Haematology 3: Haemostasis And Bleeding Disorders > Flashcards

Haematology 3: Haemostasis And Bleeding Disorders Flashcards

1
Q

List 4 Pro-coagulant factors in the body?

A

Platelets
vWF
Endothelium
Coagulation cascade

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2
Q

List 4 Anti-coagulant factors in the body ?

A

AT (antithrombin)
Protein S + Protein C
TFPI (Tissue factor pathway inhibitor)
Fibrinolysis

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3
Q

List 2 thrombopoietic factors ?

A

Thrombopoietin
IL-6
IL-12

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4
Q

Which Surface glycoprotein do platelets use to bind to vWF ?

A

GpIb (more important route)

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5
Q

Which glycoprotein do platelets use to bind directly to collagen ?

A

GpIa

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6
Q

Which glycoproteins do platelets use to bind to other platelets when aggregating ?

A

GpIIb/IIIa (fibrinogen receptor)

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7
Q

Which 2 mediators do platelets release when they bind to subendothelial structures (vWF or collagen) to cause platelet aggregation ?

A

ADP

Thromboxane A2

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8
Q

How does Aspirin inhibit platelet aggregation?

A

aspiring irreversibly Inhibits Cyclo-oxygenase (COX)
This prevents Arachidonic acid being converted to cyclic endoperoxides
This prevents formation of thromboxane A2
Less Thromboxane A2 means less platelet aggregation

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9
Q

List 2 drug targets for inhibiting platelet aggregation ?

A

Thromboxane A2 production - Aspirin

ADP receptors - Clopidogrel

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10
Q

Which pathway is more important for coagulation in the human body ?

A) Intrinsic pathway
B) Extrinsic pathway
C) Contact activation pathway

A

B) extrinsic pathway

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11
Q

Describe the sequence of events in the Initiation phase of the Clotting cascade ?

A

1) Damage to endothelium causes TF to be exposed
2) Factor 7 binds to TF and becomes activated to F7a
3) F7a/TF complex activate F9 and F10 to F9a and F10a
4) F10a binds to F5a –> first step in the coagulation cascade

TF7a - 9a + 10a - 10a+5a

note: people with factor V leiden cannot beind factor 5a to factor 10a

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12
Q

Describe the sequence of events in the amplification phase of the clotting cascade ?

A

1) activated factors 10 + 5 results in formation of a small amount of thrombin
2) thrombin will activate platelets
3) also activates factor 11 which activates factor 9. activated factor 8 and recruits more factor 5a
4) factors 5a, 8a, 9a bind to the activated platelet - last phase of clotting cascade

thrombin - F11a -9a, 8a, 5a - 5a,8a,9a –

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13
Q

Describe the sequence of events in the propagation phase of the clotting cascade ?

A

1) the activated platelet with factors 5,8+9 recruit factor 10a
2) results in generation of large amounts of thrombin (thrombin burst)
3) converts fibrinogen to fibrin
4) enables formation of a stable fibrin clot

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14
Q

Which 4 clotting factors are vitamin K dependent ?

A

10
9
7
2

Think 1972
made in the liver
vitamin K required as a coenzyme for gamma carboxylation of the clotting factors

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15
Q

What is the role of tPA (tissue plasminogen activator) ?

A
  • Converts plasminogen to plasmin
  • Plasmin cleaves The fibrin clot

tPA is produced by the endothelium

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16
Q

Which of these molecules does not promote Plasminogen conversion to Plasmin ?

A) tPA
B) Urokinase 
C) FXIIa
D) FXIa 
E) PAI 1
A

E) PAI1

Plasminogen activator inhibitor inhibits Plasminogen conversion to Plasmin by inhibiting Urokinase and tPA

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17
Q

What does TAFI do ?

A

TAFI (thrombin Activated Fibrinolysis inhibitor) is a Thrombin dependent inhibitor of Fibrin breakdown

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18
Q

Deficiency of which component is the most Thrombogenic ?

A) TAFI
B) FVIIIa
C) AT3
D) vWF 
E) Protein S
A

C) AT3

Deficiency of Antithrombin (AT) is very rare but is the most thrombogenic

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19
Q

What is the role of Protein C and protein S ?

A

Inhibit FVIIIa and FVa

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20
Q

What is the role of Thrombomodulin ?

A

Thrombomodulin is an endothelial receptor for Protein C
It first needs to be activated by Thrombin.
EPCR is another receptor which helps Thrombomodulin bind to protein C

When Thrombomodulin binds to Thrombin and Protein C the complex is called APC (activated protein C)

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21
Q

What is the role of APC (activated protein C) ?

A

APC inactivates FVa and FVIIIa

Requires protein S as cofactor

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22
Q

What is different in the interaction between APC and FVa in people with Factor V Leiden ?

A

People with Factor V Leiden have APC resistance.

This means activated factor V is not inactivated by APC.

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23
Q

What is the physiological role of TFPI as an anticoagulant ?

A

TFPI neutralises the TF/FVIIa complex.

TFPI is produced as a result of TF/FVIIa complex formation in order to stop activation by the extrinsic pathway. (TF/FVIIa is only required for a very short time to activate FX and FIX)

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24
Q

What disease is associated with large platelets ?

A

grey platelet syndrome

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25
Q

What is ITP (immune thrombocytopenia purpura) ?

A

Autoantibodies against platelets

This causes the platelets to b e removed and destroyed by the immune system

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26
Q

List 2 common inherited disorders of coagulation (bleeding disorders) ?

A

Haemophilia A / B

Von willibrand disease

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27
Q

Which coagulation factors are deficient in:

Haemophilia A
Haemophilia B

A

Haemophilia A - Factor 8

Haemophilia B - Factor 9

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28
Q

What is the inheritance pattern of haemophilia A /B ?

A

X-linked

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29
Q

What happens to APTT and PT in Haemophilia A/B ?

A

APTT - INCREASED
PT- normal

APTT Is a measure of the intrinsic pathway

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30
Q

List 3 clinical features of haemophilia A/B ?

A

Haemarthroses (bleeding into joints)
Prolonged bleeding after surgery
Ecchymoses

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31
Q

How is vWD inherited ?

A

Autosomal dominant

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32
Q

What are the differences in type1, type 2 and type 3 vWD ?

A

Type 1- partial quantitative defficiency in vWF
Type 2- Partial Qualitative decency in vWF
Type 3- Complete quantitative deficiency in vWF

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33
Q

How does most of vWF circulate in the blood ?

A

Most of it is bound to factor 8

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34
Q

What happens to APTT, PT, TT and fibrinogen in DIC ?

A

APTT- prolonged
PT- prolonged
TT- prolonged
Fibrinogen- decreased

35
Q

What are 3 treatments of Vitamin K deficiency ?

A

I.V Vitamin K
FFP
PCC (Prothrombin complex concentrate) Vit K dependent coagulation factors

36
Q

List 3 differences in clinical presentation of Coagulation and platelet disorders ?

A

Platelet disorders

  • Superficial bleeding (petechia)
  • mucous membrane bleeding - epistaxis, gym, vaginal, GI
  • bleeding immediately after surgery
  • small, superficial ecchymoses

Coagulation disorders

  • Deep bleeding into Joints (haemarthroses)/muscles
  • delayed bleeding after surgery/trauma
  • no prolonged bleeding after cuts
37
Q

List 2 congenital causes of Vascular defects of coagulation ?

A

Older-Weber-rendu syndrome

Ehler’s danlos syndrome

38
Q

List 3 acquired vascular defects of coagulation ?

A

Dengue haemorrhagic fever
Scurvy
Meningococcal infection

39
Q

What is the treatment of Haemophilia A / B ?

A

Factor 8 / 9 concentrates replacement therapy

40
Q

Which drug is used in the treatment of Haemophilia A ?

A

Desmopressin (causers increased vWF release from the endothelium. vWF is a factor VIII carrier)

41
Q

Name 1 carrier protein of Factor VIII ?

A

vWF

42
Q

Describe how you can used Ristocetin to test for vWD ?

A

Add Ristocetin to the patients vWF and platelets in a test tube. Ristocetin normally causes vWF to find to Gp1b on platelets causing platelet aggregation. If there is no platelet aggregation then this means there is a qualitative defect in vWF or Gp1b (Bernard soulier syndrome).

43
Q

what 3 responses does vessel injury stimulate

A

vasoconstruction
platelet activation
activation of the coagulation cascade

44
Q

what is the role of the endothelium in coagulation

A 
barrier
produce:
- prostaglandins
- vWF 
- plasminogen activators
- thrombomodulin
45
Q

where do platelets originate from

A

bone marrow
made by megakaryocytes
life span of 10 days
production regulated by thrombopoietic factors (thrombopoietin, IL-6, 1L-12)

46
Q

describe the structure of platelets

A

glycoproteins - cell surface proteins use dto interact with the endothelium, vWF and other platelets
dense granules - contain energy stores (ATP, ADP)
open canalicular system, microtubules, actomyosis - pl can expand their surface area

47
Q

how are aspirin and NSAIDs different

A

NSAIDs reversibly inhibit COX

aspirin reversibly blocks COX

48
Q

role of prostaglacyclin PGI2 in platelet function

A

inhibits platelet aggregation

49
Q

what other receptor is also important for platelet aggregation

A

ADP receptors

inhibitors = clopidogrel, ticagrelor

50
Q

what is the rate limiting step for fibrin formation

A

factor Xa

51
Q

what are the 5 main effects of thrombin

A 
activates fibrinogen 
activates platelets 
activates pro-cofactors (5 and 8)
activates zymogens (7,11,13)
all link together to form a prothrombinase complex - activates prothrombin to thrombin
52
Q

what is the role of the prothrombinase complex

A

made up of factor 10a and factor 5a

converts prothrombin - thrombin

53
Q

what are some causes of vitamin K deficiency

A

most common = warfarin
antibiotics
obstruction of biliary tree

54
Q

describe the process of fibrinolysis

A

plasminogen - plasmin - fibrin –> fibrin degradation products
tPA - made by endothelium and converts plasminogen to plasmin
urokinase can also activate plasminogen to plasmin
tPA and urokinase are inhibited by plasminogen activator inhibitor 1+2
plasmin is inhibited by alpha 2 antiplasmin + alpha 2 microglobulin
TAFI (thrombin-activatable fibrinolysis inhibitor) is an important inhibitor of fibrin breakdown

55
Q

describe the action of physiological anticoagulants

A

ANTITHROMBINS:

  • bind thrombin 1:1 then excreted in the urine
  • most active = AT III
  • lack or deficiency = the most thrombogenic condition

PROTEIN C+S:
- to stop thrombin generation, f 5 and 8 need to be inactivated
- trace amounts of thrombin generated at the start of the cascade activate thrombomodulin
opens up the receptor for thrombomodulin to bind protein C through EPCR
- forms APC
- APC, in the presence of protein S fully activates protein C
- inactivates factor 5a and 8a

TISSUE FACTOR PATHWAY INHIBITOR:
- as soon as tissue factor and factor 7 released in the first step of the coagulation cascade - TFPI is activates to neutralise the TF-F7a complex

56
Q

what are two causes of APC resistance

A

mutated factor 5 (eg factor V leiden) - factor 5a resistant to breakdown by APC –> prothrombotic state
high levels of factor 8

57
Q

list some genetic causes of excessive bleeding

A

platelet abnormalities
vessel wall abnormalities
clotting deficiencies
excess clot breakdown

58
Q

list some inherited causes of excessive bleeding

A 
liver disease
vitamin K deficiency 
AI disease
trauma 
anticoagulants/antiplatelets
59
Q

what causes pseudothrombocytopaenia

A

platelets clump together

60
Q

list different platelet disorders

A

decreased number (thrombocytopaenia):

  • decreased production
  • decreased survival (ITP)
  • increased consumption (DIC)
  • dilution

defective platelet function:

  • acquired (aspirin, end-stage renal failure)
  • congenital (thrombasthenia)
  • cardiopulmonary bypass
61
Q

list things that can cause thrombocytopaenia

A

IMMUNE:
drug induced -quinine, rifampicin, vancomycin
rheumatoid arthritis, SLE
sarcoidosis

NON-IMMUNE :
DIC
MAHA

IDIOPATHIC THROMBOCYTOPAENIC PURPURA

62
Q

describe features of ITP

A

autoantibodies generated against platelets
platelets then destroyed in the reticuloendothelial system (spleen, liver, bone marrow - anywhere with macrophages)
childhood ITP - acute following illness, self-limiting
adult - chronic and indolent
hematomas and subconjunctival haemorrhages

63
Q

how can we treat ITP

A

depends on platelet count and symptoms
steroids
IVIG - cometes with anti-platelet antibodies

64
Q

list inherited and acquired coagulation factor disorders

A

inherited:

  • haemophilia A dn b
  • vWD

acquired:

  • liver disease
  • vitamin K deficiency/warfarin
  • DIC
65
Q

what is haemophilia

A

congenital deficiency of factor 8 or 9
deep bleeding into joints and muscles
x-linked recessive
abnormality of intrinsic pw so get PROLONGED APTT , NORMAL PT
need clotting factor replacement for life
haemophilia A - factor 8 deficiency, B - factor 9 deficiency

66
Q

clinical features of haemophilia

A

haemarthroses (most common)
soft tissue haematomas
prolonged bleeding after surgery or dental extractions

67
Q

describe features of VWD

A

most common coagulation disorder
autosomal dominant
mucocutaneous bleeding
measure vwf antigen/ vwf activity/multimer

68
Q

classification of VWD

A

type 1 - partial quantitative deficiency
2 - qualitative deficiency
3 - total quantitative deficiency

69
Q

describe vitamin K deficiency `

A

sources: green veg and intestinal flora
factors 1972 and protein C,S,Z need vit K
causes: malnutrition, biliary obstruction, malabsorption, antibiotic therapy
treat: vit K and FFP

70
Q

features of DIC

A 
emergency 
activation of coagulation and fibrinolysis triggered by:
- sepsis
- trauma
- obstetric complications
- malignancy 
- vascular disorders 
- reaction to toxins eg snake venom

systemic activation of coagulation - deposition of fibrin in small vessels - kidney damage, brain damage, damage to extremities

71
Q

clotting study results in DIC

A 
prolonged APTT 
prolonged PT 
prolonged TT 
decreased fibrinogen 
decreased FDP 
decreased platelets 
schistocytes
72
Q

treatment of DIC

A 
treat underlying disorder 
anticoagulation with hepatin 
platelet transfusion
FFP 
coagulation inhibitor concentrate (APC concentrate)
73
Q

why does liver disease lead to bleeding disorders

A 
decreased synthesis of 2,7,9,10,11 and fibrinogen 
dietary vitamin K deficiency 
dysfibrinogenaemia
enhanced haemolysis 
DIC 
thrombocytopenia due to hypersplenism
74
Q

describe treatment for prolonged PT/PTT

A

vitamin K 10mg od

FFP

75
Q

treatment for low fibrinogen

A

cryoprecipitate

76
Q

list some new anticoagulants

A 
tissue factor pathway inhibitors 
factor 9a inhibitors 
protein C activators
factor 10a inhibitors - fondaparinux, rivaraxaban, apixaban 
thrombin inhibitors
77
Q

key features of the intrinsic pathway

A

APTT
monitor heparin therapy
starts with factor 12 ( - 11 - 9 - 8 - 10 )

78
Q

key features of the extrinsic pathway

A

PT
monitor warfarin therapy (INR)
starts with factor 7

79
Q

key features of the common pathway

A

TT

starts with activated factor 5

80
Q

diagnosis and treatment of haemophilia A

A

high APTT, normal PT, low factor VIII assay

avoid NSAIDs and IM injections, factor VIII concentrate replacement life-long

81
Q

diagnosis and treatment of haemophilia B

A

clinically similar to haemophilia A

treat with factor IX concentrates

82
Q

diagnosis of vWD

A

low platelet function
low factor VIII (vWF faces factor VIII in the circulation)
mainly AD
high APTT, high bleeding time, low factor VIII, low vWF, normal INR and platelets

83
Q

diagnosis of DIC

A

low platelets, low fibrinogen, high FDP/D-dimer, long PT/INR

Year 5 path SW (106 decks)

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