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8. CP - Core Haematology > (38) Acquired bleeding disorders > Flashcards

(38) Acquired bleeding disorders Flashcards

1
Q

Name the 6 main types of acquired bleeding disorders

A
  • vitamin K deficiency
  • liver disease-associated
  • massive transfusion syndrome
  • DIC
  • iatrogenic (drugs)
  • acquired inhibitors eg. in haemophilia
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2
Q

What in the clinical history is particularly important in diagnosing acquired bleeding disorders?

A
  • date of onset
  • previous history of bleeding episodes
  • other systemic illnesses
  • drug history
  • signs of underlying disease
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3
Q

When you have a prolonged APTT, how do you distinguish between a clotting factor deficiency or inhibitor against a clotting factor?

A
  • repeat APTT with 50:50 mix of patient to normal plasma
  • if there is a significant correction of clotting time = deficiency
  • no correction = inhibitor
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4
Q

What abnormal coagulation results do you get in liver disease?

A
  • normal thrombin time
  • low platelet count
  • prolonged PT time
  • prolonged APTT
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5
Q

Why do you get a prolonged PT time in liver disease?

A

Factor 7 falls early in the disease

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6
Q

Why do you get a low platelet count in liver disease?

A

Liver disease = abnormal vessels in liver = portal hypertension = congestion in spleen

Third of platelets in spleen, more platelets in spleen in liver disease so low platelet count

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7
Q

Why do you get a prolonged APTT and PT time, and low platelet count in massive transfusion?

A

Transfusing lots of pure red cells, not whole blood. So there is dilution effect on the clotting factors

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8
Q

What are the abnormal coagulation screen results in other causes of acquired bleeding disorder?

A

(look at slide 6 of lecture)

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9
Q

Which coagulation factors are vitamin K-dependent?

A

2, 7, 9, and 10

7 = extrinsic
2, 10 = common
9 = intrinsic

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10
Q

Where are clotting factors synthesised?

A

They are all synthesised in the hepatocytes of the liver apart from factor 8 which is also synthesised in the liver but in the Kupffer cells

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11
Q

Why are factors 2, 7, 9 and 10 vitamin K-dependent?

A

These clotting factors need to be gamma glutanyl carboxylated before they can be active (modification step). Vitamin K is a cofactor in this process. Vitamin K is oxidised to vitamin K epoxide in the process.

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12
Q

Why does vitamin K epoxide need to be reduced back to vitamin K?

A

Vitamin K epoxide cannot act as a cofactor - it needs to be recycle back to vitamin K

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13
Q

Which enzyme reduces vitamin K epoxide back to vitamin K?

A

Vitamin K reductase (VKORC1)

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14
Q

How does warfarin act as an anticoagulant?

A

It is a vitamin K antagonist. It blocks the activity of VKORC1 so vitamin K cannot be recycled so the clotting factors cannot become activated

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15
Q

Vitamin K deficiency has the same clinical features of which drug use?

A

Warfarin - functional deficiency of coagulation factors 2, 7, 9 and 10

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16
Q

Give 4 causes of vitamin K deficiency?

A
  • obstructive jaundice
  • prolonged nutritional deficiency
  • broad spectrum antibiotics
  • neonates (classical 1-7 days)
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17
Q

Why is obstructive jaundice a cause of vitamin K deficiency?

A

As vitamin K is a fat-soluble vitamin so you bile to be able to absorb fat so you can absorb vitamin K

no bile = vitamin K deficiency

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18
Q

Why does nutritional deficiency have to be prolonged to cause vitamin K deficiency?

A

Vitamin K is stored in the body for quite a long time

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19
Q

Why are broad spectrum antibiotics are cause of vitamin K deficiency?

A

A source of vitamin K is gut flora - kill off these flora = vitamin K deficiency

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20
Q

What is haemorrhagic disease of the new born?

A

Coagulation disturbance in newborns due to vitamin K deficiency

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21
Q

What is done nowadays to prevent haemorrhagic disease of the newborn?

A

Vitamin K is given to neonates

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22
Q

What are the bleeding patterns in cirrhotic coagulopathy?

A

Increased risk of severe bleeding from invasive procedures or surgery - cirrhotic coagulopathy is a major source of morbidity and mortality in patients with liver disease

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23
Q

Why is treated cirrhotic coagulopathy difficult?

A

Conventional methods for treatment and prevention of bleeding are limited

Conventional treatments eg. FFP, platelet transfusions are limited because they may not effectively increased factors to a good level - require volume for transfusion may be too large = risk of viral transmission

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24
Q

What types of impaired haemostasis do you get in liver disease?

A
  • thrombocytopenia
  • platelet dysfunction
  • reduced plasma concentration of all coagulation factors except factor VIII
  • delayed fibrin monomer polymerisation
  • excessive plasmin activity
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25
Q

Why do you get thrombocytopenia in liver disease?

A

Due to splenic congestion because of portal hypertension (also in alcoholic liver disease, alcohol has toxic effect on platelet production in bone marrow)

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26
Q

In what way might platelets be dysfunctional in liver disease?

A

Can get plasmin-induced cleavage of surface glycoproteins on platelets

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27
Q

Why do you not get reduced factor VIII in liver disease?

A

It is the hepatocytes that are damaged in liver disease; the Kupffer cells are well-preserved

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28
Q

Why do you get delayed fibrin monomer polymerisation in liver disease?

A

Due to altered fibrinogen glycosylation (excess sialic acid)

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29
Q

What do excessive plasmin activity in liver disease cause?

A

Excessive fibrinolytic activity

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30
Q

What is the definition of ‘massive transfusion’?

A

Transfusion of a volume equal to the patient’s total blood volume in less than 24 hours

OR

50% blood volume loss within 3 hours (more practical definition)

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31
Q

The haemostatic abnormalities in massive transfusion are due to what?

A

The dilution depletion of platelets and coagulation factors

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32
Q

The haemostatic abnormalities in massive transfusion may be due to underlying problems such as what?

A
  • DIC (risk factors = extensive trauma, head injury, prolonged hypotension)
  • underlying disease eg. liver or renal drug treatment or surgery
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33
Q

How much blood needs to be transfused before thrombocytopenia is likely?

A

At least 7-8 litres in adults usually transfused before problems are likely

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34
Q

In coagulation factor depletion due to dilution, which factors are most affected?

A

Mainly factors V, VIII and fibrinogen

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35
Q

Why might you get citrate toxicity in massive transfuse syndrome?

A

As the blood from the blood bank has been treated with citrate-containing anticoagulants

36
Q

What might you get low levels of due to citrate toxicity in blood transfusion?

A

Hypocalcaemia - low levels of serum calcium - but this has no clinically significant effect on coagulation

37
Q

Why might you get hypothermia in blood transfusion?

A

As the blood is kept cold - hypothermia is not uncommon unless measures are taken to keep the patient warm

38
Q

Describe how DIC leads to organ ischaemia

A
  • inappropriate activation of coagulation system
  • intravascular coagulation
  • fibrin deposition
  • thrombosis of small vessels
  • organ dysfunction
39
Q

Describe 2 ways how DIC leads to bleeding

A
  • intravascular coagulation
  • consumption of clotting factors and platelets
  • bleeding
  • intravascular coagulation
  • fibrin deposition
  • secondary activation of fibrinolytic system
  • fibrinolysis through plasmin generation
  • FDPs
  • bleeding
40
Q

Why do fibrin degrations products (FDPs) lead to bleeding?

A

They interfere with fibrin polymerisation

41
Q

What does plasmin generation in DIC lead to?

A

Fibrinolysis and also plasmin digests other clotting factors such as fibrinogen and factor V which leads to bleeding

42
Q

In general, what is DIC?

A

A disruption in the physiological balance of procoagulant and anticoagulant mechanisms

43
Q

Microvascular thrombosis in DIC leads to what?

A

Tissue ischaemia and organ damage

44
Q

In DIC, there is microangiopathy haemolysis. What does this mean?

A

Haemolysis in the small blood vessels

45
Q

What are the causes of acute DIC?

A
  • sepsis
  • obstetric complications
  • trauma/tissue necrosis
  • acute intravascular haemolysis eg. ABO incompatible blood transfusion
  • fulminant liver disease (rapid onset and progressing)
46
Q

What is the most common cause of DIC?

A

Severe sepsis - often due to Gram negative organisms

47
Q

Why does tissue damage cause DIC?

A

Tissue factor exposed on white cells

48
Q

What type of obstetric complications may cause DIC?

A

Placental damage - placenta rich in tissue factor and procoagulant - these can cause systemic problems in mother

49
Q

What are the causes of chronic DIC?

A
  • malignancy
  • end-stage liver disease
  • severe localised intravascular coagulation
  • obstetric: retained dead foetus
50
Q

What is the most common cause of chronic DIC?

A

Malignancy

51
Q

What are the lab test results in DIC?

A
  • FBC and blood film
  • PT = 70% prolonged
  • APTT = 50% prolonged
  • TCT = usually prolonged
  • fibrinogen concentration falling
  • FDP or D-dimer = elevated in 85%
  • low blood platelet count

There is not one single diagnostic test, scoring systems sometimes used

52
Q

What are the 2 general treatment principles in management of DIC?

A
  • treat underlying cause

- supportive treatment

53
Q

In what ways would you treat the underlying cause in DIC?

A
  • antibiotics (sepsis)
  • obstetric intervention eg. deliver baby or remove retained placenta)
  • chemotherapy/ATRA/tumour resection (malignancy)
54
Q

What types of supportive treatment would you give in DIC?

A
  • maintain tissue perfusion (avoid ischaemia)
  • coordinate invasive procedures
  • folic acid and vitamin K to support recovery period especially if illness prolonged
55
Q

When would you give platelet transfusion in DIC?

A

If platelets are below 50

56
Q

When would give FFP in DIC?

A

If PT or APTT ratio is more than 1.5, give FFP 15ml/kg

57
Q

What would give as a source of fibrinogen in DIC?

A

Cryoprecipitate of fibrinogen concentrate. When fibrinogen is less than 1g/l

58
Q

Name 3 new novel oral anticoagulant drugs (NOACs)

A
  • rivaroxaban
  • apixaban
  • dabigatran
59
Q

What do rivaroxaban and apixaban do?

A

They target factor 10a - bind to the activate site and inhibit - so reduces thrombin generation and therefore clot formation

60
Q

What does dabigatran do?

A

Direct inhibitor of thrombin (factor 2a) = binds to active site in vivo and prevents it cleaving fibrinogen

61
Q

What is Fondaparinux?

A

An anticoagulant drug, chemically similar to low molecular weight heparins. Has anti-Xa and anti-thrombin activity.

62
Q

What are the 2 most commonly used NOACs?

A

Rivaroxaban and apixaban (factor 10a inhibitors)

63
Q

What effect do NOACs have on the coagulation screen?

A

Very small effects, may well cause no change at all - so important to take a drug history as this may not be picked upon lab tests

64
Q

What effects does warfarin however have on the coagulation screen?

A

Prolongs PT time and also prolongs APTT a little bit since there is reduced factor 9

65
Q

What are the risks of NOACs vs warfarin?

A

Risks are fairly similar although there may be a reduced risk of intracranial bleeding on NOACs

66
Q

What is the INR?

A

International normalised ratio. A derivate of the prothrombin time (PT)

(should be 1 ideally - aim for 2-3 for someone on warfarin for AF)

67
Q

You dose NOACs according to what?

A

Renal function

INR

68
Q

There has only recently been an antidote to anticoagulants developed to manage bleeding. What is the antidote to dabigatran?

A

Idarucizumab

69
Q

What is adarucizumab?

A

An antibody - an antidote to dabigatran which is used in the case of bleeding

Very specific to Dabigatran

70
Q

What might be the cause of a painful shoulder in an elderly lady on warfarin and erythromycin?

A

Haemarthrosis - antibiotic interfered with warfarin metabolism in liver - slowed down warfarin metabolism = become grossly over-anticoagulated = bleeding

71
Q

What would be the coagulation screen results in a patient with haemarthrosis due to warfarin over-anticoagulation?

A
  • grossly prolonged PT and INR
  • prolonged APTT
  • normal TCT
72
Q

What would be the correct treatment for somebody with bleeding due to warfarin-overanticoagulation?

A

Give vitamin K to reverse the effects of warfarin (give intravenously)

73
Q

Prothrombin ratio (PR or INR) =

A

Patient’s prothrombin time divided by the mean normal prothrombin time

74
Q

INR = (prothrombin ratio)ISI. What does ISI mean?

A

Correction factor to account for sensitivity of thromboplastin compared with the international reference preparation (IRP)

75
Q

Name some drugs which potentiate the effect of Warfarin

A
  • cimetidine
  • amiodarone
  • sulphinpyrazone
  • cotrimoxazole
  • erythromycin
  • cephalosporins
  • ampicillin (oral
  • NSAIDs
  • chlorpromazine
  • sulphonylureas
  • corticosteroids
76
Q

Name some drugs which antagonise the effect of Warfarin

A
  • cholestyramine
  • spironolactone
  • rifampicin
  • carbamazepine
  • vitamin K
77
Q

How would you reverse oral anticoagulant treatment in life threatening haemorrhage?

A
  • 5mg-10mg vitamin K (IV)

- four factor concentrate (PCC) eg. Octaplex or Beriplex

78
Q

How would you reverse oral anticoagulant treatment in non-major bleeding?

A
  • withhold warfarin

- vitamin K 1-3mg (IV)

79
Q

How would you reverse oral anticoagulant treatment in INR of more than 8 without haemorrhage?

A
  • withhold warfarin

- vitamin K 1-5mg (orally)

80
Q

How would you reverse oral anticoagulant between INR 5-8 without haemorrhage?

A
  • withhold warfarin

- consider oral vitamin K if high risk of bleeding

81
Q

What would you do in unexpected bleeding at therapeutic levels?

A
  • reverse warfarin appropriately

- investigate underlying cause eg. unsuspected renal or alimentary tract disease

82
Q

What is a D-dimer?

A

A fibrin-degradation product. It contains two crosslinked D fragments of the fibrin protein.

83
Q

How is heparin monitored?

A
  • anticoagulant effects of UFH can be monitored by tests sensitive to the anti-thrombin/anti-Xa effects of heparin
  • for purposed of full anticoagulation with UFH, the APTT is most commonly used assay
84
Q

What are the alternative methods of monitoring heparin?

A
  • heparin level by protamine titration
  • heparin level by anti-Xa assay
  • calcium thrombin time
  • anti-Xa assay used when desirable to monitor effect of LMWH
  • APTT not sensitive to LMWH
85
Q

How do you manage bleeding/over-anticoagulation due to heparin?

A
  • stop infusion
  • consider protamine administration (1mg neutralises 100IU of heparin, maximum 40mg)
  • effects of protamine on LMWH are less predictable and more complex
86
Q

What are the properties of LMWH compared to UFH?

A

LMWH =

  • higher ratio of anti-Xa to anti-IIa activity
  • improved bioavailability
  • longer half life allowing once daily administration
  • more predictable anticoagulant response = minoring is not routinely required

8. CP - Core Haematology (11 decks)

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