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

(38) Acquired bleeding disorders Flashcards

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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
Why do you get thrombocytopenia in liver disease?
Due to splenic congestion because of portal hypertension (also in alcoholic liver disease, alcohol has toxic effect on platelet production in bone marrow)
26
In what way might platelets be dysfunctional in liver disease?
Can get plasmin-induced cleavage of surface glycoproteins on platelets
27
Why do you not get reduced factor VIII in liver disease?
It is the hepatocytes that are damaged in liver disease; the Kupffer cells are well-preserved
28
Why do you get delayed fibrin monomer polymerisation in liver disease?
Due to altered fibrinogen glycosylation (excess sialic acid)
29
What do excessive plasmin activity in liver disease cause?
Excessive fibrinolytic activity
30
What is the definition of 'massive transfusion'?
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)
31
The haemostatic abnormalities in massive transfusion are due to what?
The dilution depletion of platelets and coagulation factors
32
The haemostatic abnormalities in massive transfusion may be due to underlying problems such as what?
- DIC (risk factors = extensive trauma, head injury, prolonged hypotension) - underlying disease eg. liver or renal drug treatment or surgery
33
How much blood needs to be transfused before thrombocytopenia is likely?
At least 7-8 litres in adults usually transfused before problems are likely
34
In coagulation factor depletion due to dilution, which factors are most affected?
Mainly factors V, VIII and fibrinogen
35
Why might you get citrate toxicity in massive transfuse syndrome?
As the blood from the blood bank has been treated with citrate-containing anticoagulants
36
What might you get low levels of due to citrate toxicity in blood transfusion?
Hypocalcaemia - low levels of serum calcium - but this has no clinically significant effect on coagulation
37
Why might you get hypothermia in blood transfusion?
As the blood is kept cold - hypothermia is not uncommon unless measures are taken to keep the patient warm
38
Describe how DIC leads to organ ischaemia
- inappropriate activation of coagulation system - intravascular coagulation - fibrin deposition - thrombosis of small vessels - organ dysfunction
39
Describe 2 ways how DIC leads to bleeding
- 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
Why do fibrin degrations products (FDPs) lead to bleeding?
They interfere with fibrin polymerisation
41
What does plasmin generation in DIC lead to?
Fibrinolysis and also plasmin digests other clotting factors such as fibrinogen and factor V which leads to bleeding
42
In general, what is DIC?
A disruption in the physiological balance of procoagulant and anticoagulant mechanisms
43
Microvascular thrombosis in DIC leads to what?
Tissue ischaemia and organ damage
44
In DIC, there is microangiopathy haemolysis. What does this mean?
Haemolysis in the small blood vessels
45
What are the causes of acute DIC?
- sepsis - obstetric complications - trauma/tissue necrosis - acute intravascular haemolysis eg. ABO incompatible blood transfusion - fulminant liver disease (rapid onset and progressing)
46
What is the most common cause of DIC?
Severe sepsis - often due to Gram negative organisms
47
Why does tissue damage cause DIC?
Tissue factor exposed on white cells
48
What type of obstetric complications may cause DIC?
Placental damage - placenta rich in tissue factor and procoagulant - these can cause systemic problems in mother
49
What are the causes of chronic DIC?
- malignancy - end-stage liver disease - severe localised intravascular coagulation - obstetric: retained dead foetus
50
What is the most common cause of chronic DIC?
Malignancy
51
What are the lab test results in DIC?
- 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
What are the 2 general treatment principles in management of DIC?
- treat underlying cause | - supportive treatment
53
In what ways would you treat the underlying cause in DIC?
- antibiotics (sepsis) - obstetric intervention eg. deliver baby or remove retained placenta) - chemotherapy/ATRA/tumour resection (malignancy)
54
What types of supportive treatment would you give in DIC?
- maintain tissue perfusion (avoid ischaemia) - coordinate invasive procedures - folic acid and vitamin K to support recovery period especially if illness prolonged
55
When would you give platelet transfusion in DIC?
If platelets are below 50
56
When would give FFP in DIC?
If PT or APTT ratio is more than 1.5, give FFP 15ml/kg
57
What would give as a source of fibrinogen in DIC?
Cryoprecipitate of fibrinogen concentrate. When fibrinogen is less than 1g/l
58
Name 3 new novel oral anticoagulant drugs (NOACs)
- rivaroxaban - apixaban - dabigatran
59
What do rivaroxaban and apixaban do?
They target factor 10a - bind to the activate site and inhibit - so reduces thrombin generation and therefore clot formation
60
What does dabigatran do?
Direct inhibitor of thrombin (factor 2a) = binds to active site in vivo and prevents it cleaving fibrinogen
61
What is Fondaparinux?
An anticoagulant drug, chemically similar to low molecular weight heparins. Has anti-Xa and anti-thrombin activity.
62
What are the 2 most commonly used NOACs?
Rivaroxaban and apixaban (factor 10a inhibitors)
63
What effect do NOACs have on the coagulation screen?
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
What effects does warfarin however have on the coagulation screen?
Prolongs PT time and also prolongs APTT a little bit since there is reduced factor 9
65
What are the risks of NOACs vs warfarin?
Risks are fairly similar although there may be a reduced risk of intracranial bleeding on NOACs
66
What is the INR?
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
You dose NOACs according to what?
Renal function INR
68
There has only recently been an antidote to anticoagulants developed to manage bleeding. What is the antidote to dabigatran?
Idarucizumab
69
What is adarucizumab?
An antibody - an antidote to dabigatran which is used in the case of bleeding Very specific to Dabigatran
70
What might be the cause of a painful shoulder in an elderly lady on warfarin and erythromycin?
Haemarthrosis - antibiotic interfered with warfarin metabolism in liver - slowed down warfarin metabolism = become grossly over-anticoagulated = bleeding
71
What would be the coagulation screen results in a patient with haemarthrosis due to warfarin over-anticoagulation?
- grossly prolonged PT and INR - prolonged APTT - normal TCT
72
What would be the correct treatment for somebody with bleeding due to warfarin-overanticoagulation?
Give vitamin K to reverse the effects of warfarin (give intravenously)
73
Prothrombin ratio (PR or INR) =
Patient's prothrombin time divided by the mean normal prothrombin time
74
INR = (prothrombin ratio)ISI. What does ISI mean?
Correction factor to account for sensitivity of thromboplastin compared with the international reference preparation (IRP)
75
Name some drugs which potentiate the effect of Warfarin
- cimetidine - amiodarone - sulphinpyrazone - cotrimoxazole - erythromycin - cephalosporins - ampicillin (oral - NSAIDs - chlorpromazine - sulphonylureas - corticosteroids
76
Name some drugs which antagonise the effect of Warfarin
- cholestyramine - spironolactone - rifampicin - carbamazepine - vitamin K
77
How would you reverse oral anticoagulant treatment in life threatening haemorrhage?
- 5mg-10mg vitamin K (IV) | - four factor concentrate (PCC) eg. Octaplex or Beriplex
78
How would you reverse oral anticoagulant treatment in non-major bleeding?
- withhold warfarin | - vitamin K 1-3mg (IV)
79
How would you reverse oral anticoagulant treatment in INR of more than 8 without haemorrhage?
- withhold warfarin | - vitamin K 1-5mg (orally)
80
How would you reverse oral anticoagulant between INR 5-8 without haemorrhage?
- withhold warfarin | - consider oral vitamin K if high risk of bleeding
81
What would you do in unexpected bleeding at therapeutic levels?
- reverse warfarin appropriately | - investigate underlying cause eg. unsuspected renal or alimentary tract disease
82
What is a D-dimer?
A fibrin-degradation product. It contains two crosslinked D fragments of the fibrin protein.
83
How is heparin monitored?
- 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
What are the alternative methods of monitoring heparin?
- 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
How do you manage bleeding/over-anticoagulation due to heparin?
- stop infusion - consider protamine administration (1mg neutralises 100IU of heparin, maximum 40mg) - effects of protamine on LMWH are less predictable and more complex
86
What are the properties of LMWH compared to UFH?
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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