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Case 1045: Coagulopathy reversal
Authors and Affiliations
Dr Mark Plummer
University of Adelaide
Case Overview
This case presents the relatively common clinical scenario of a warfarin drug interaction resulting in
coagulopathy with clinically significant bleeding. It is important to understand the difference in
management of mild, moderate and severe warfarin induced coagulopathy and the different reversal
agents available.
Learning Objectives
Understand the common drug interactions with warfarin
Ability to assess severity of hypovolemia in the shocked patient
Understanding the indications, dose and mechanism of the common agents used to reverse warfarin.
Question 1 : SC
Question Information:
You are the medical resident at a small peripheral hospital and are called by the nursing staff to review
a patient who has had a †˜ large amount of PR blood loss†™.
The patient, Mr Morris, is a 75 year old man who was admitted to the medical ward 6 days ago for the
management of aspiration pneumonia that has been treated with a course of benzylpenicillin and
metronidazole. Mr Morris has a past medical history of hypertension controlled with enalapril and
hydrochlorothiazide, atrial fibrillation for which he takes warfarin and digoxin, epilepsy controlled with
phenytoin and depression managed with sertraline and St. John†™s wort from a naturopathist.
Question:
Which of the following medications may potentiate the therapeutic effect of warfarin?
Choice 1: Benzylpenicillin Score : 0
Choice Feedback:
While antibiotics commonly interact with warfarin, benzylpenicillin does not alter warfarin metabolism.
Choice 2: Metronidazole Score : 1
Choice Feedback:
Metronidazole is a hepatic cytochrome enzyme inhibitor and will decrease the metabolism of warfarin,
potentiating the anti-coagulant effect.
Choice 3: Enalapril Score : 0
Choice Feedback:
Enalapril does not commonly interact with warfarin.
Choice 4: Digoxin Score : 0
Choice Feedback:
Digoxin does not commonly interact with warfarin.
Choice 5: Phenytoin Score : -1
Choice Feedback:
Phenytoin is a hepatic cytochrome enzyme inducer and will increase the metabolism of warfarin and
decrease the therapeutic efficacy.
Choice 6: St John's Wort Score : -1
Choice Feedback:
St. John†™s wort is a common over the counter herbal medication advocated by naturopathists for the
treatment of depression. It is a potent CYP3A4 hepatic enzyme inducer and will increase the
metabolism of a number of drugs including warfarin.
Question 2 : MS
Question Information:
You arrive on the ward and see Mr Morris sitting up in bed. He looks worried but is otherwise
comfortable. A commode is being wheeled away by the nursing staff containing a large plum coloured
stool. The last set of observations taken 5 minutes ago are HR 110 irregular, BP 135/100, SaO2 97%
resp rate 20, temp 36.8C.
Question:
As a rough guide, how much blood loss could account for these observations?
Choice 1: 0-15% (0-750ml) Score : 0
Choice Feedback:
Incorrect †“ this is usually well tolerated and would not result in a sinus tachycardia or tachypnea.
Choice 2: 15-30% (750-1500ml) Score : 1
Choice Feedback:
Correct. This is so called stage 2 hypovolemic shock. While the systolic blood pressure is usually
maintained, diastolic blood pressure is often increased resulting in a narrow pulse pressure. Heart rate
increases to maintain cardiac output and there is an associated tachypnea. It is important to remember
that these numbers should only be used as a guide. In elderly patients on multiple chronotropic and
vasoactive medications physiological parameters should be used with caution.
Choice 3: 30-40% (1500-2000ml) Score : 0
Choice Feedback:
Incorrect. This degree of hypovolemia would result in a dramatic decrease in the systolic blood pressure
and a more rapid tachycardia.
Choice 4: >40% (>2000ml) Score : -1
Choice Feedback:
Incorrect. This would result in significant decompensated hypovolemia with marked hypotension,
probable confusion and lethargy and marked tachycardia.
Question 3 : MS
Question Information:
You suspect that Mr Morris has lost approximately 1 liter of blood into his gastrointestinal tract. On
examination he is cool and clammy with poor capillary refill. His chest is clear, heart sounds are dual
with no murmurs and his abdomen is soft and non-tender with active bowel sounds. You insert two
large bore intravenous cannulae and take bloods for a full blood count, group and hold, coagulation
profile and biochemistry.
His last blood tests taken four days ago reveal a haemoglobin concentration of 150 g/L and an INR of
3.0.
Question:
Which of the following would be an appropriate fluid order for resuscitation while awaiting the blood
results?
Choice 1: 2 units of O negative blood Score : 0
Choice Feedback:
Incorrect. While Mr Morris may need a blood transfusion, he is currently in stage 1 shock (suspected
~1L blood loss). As his starting hemoglobin was in the high normal range it would be reasonable to wait
for the repeat haemoglobin before using this valuable resource.
Choice 2: 500ml 5% dextrose Score : -1
Choice Feedback:
Incorrect. 5% dextrose is not a resuscitation fluid
Choice 3: 500ml 4% albumin Score : 0
Choice Feedback:
Incorrect. There are no data to suggest that colloids are better than crystalloids for the resuscitation of
hypovolemic shock. Albumin is presented in a glass bottle which abdicates the use of a pressure bag to
increase the infusion rate.
Choice 4: 250ml gelofusine Score : 0
Choice Feedback:
Incorrect. While there are no data to suggest that colloids are better than crystalloids in the
management of hypovolemic shock, this volume is inadequate for the degree of suspected blood loss.
Choice 5: 1000ml 0.9% normal saline Score : 1
Choice Feedback:
Correct. There are no data to suggest that crystalloids are inferior to colloids in the management of
hypovolemic shock. Mr Morris is showing signs of class 2 shock and infusing 1000ml of crystalloid in a
patient with no history of symptomatic heart failure would not be unreasonable.
Question 4 : MS
Question Information:
Mr Morris†™ heart rate decreases to 90 bpm following one liter of normal saline. His blood pressure
remains stable at 140/95 and his respiratory parameters are unchanged. The nurses report he has
passed a further large plum coloured bowel motion. The lab calls you with his blood results which are
as follows:
Hb 105 g/L
WCC 9 x 10^9/L
Plt 160 x 10^9/L
INR: 11
APTT: 35 sec
Question:
You call the gastroenterology team at the tertiary referral hospital and arrange for medical evacuation.
The gastroenterologist requests that you 'reverse the warfarin immediately'. Which of the following
would be appropriate management for warfarin reversal?
Choice 1: 5mg of oral vitamin K Score : -1
Choice Feedback:
Incorrect. Mr Morris has clinically significant bleeding in the setting of a supratherapeutic INR. This
requires immediate reversal. The onset of oral vitamin K is too slow to be used in this setting.
Choice 2: 1 unit of platelets Score : -1
Choice Feedback:
Incorrect. Mr Morris has a normal platelet count and is not taking any anti-platelet agents. Platelet
deficiency or dysfunction will not be contributing to the coagulopathy.
Choice 3: 10mg of IV Vitamin K Score : 1
Choice Feedback:
Correct. However the onset of IV vitamin K is 6-12 hours. Intravenous vitamin K should be given in
combination with more rapid acting reversal agents.
Choice 4: Prothrombinex 25 units/kg Score : 2
Choice Feedback:
Correct. This is an appropriate dose of prothrombinex to use in this setting. Note that prothrombinex is
presented as a freeze dried powder (500IU/vial). If Mr Morris weighs 80kg he will require at least 4 vials
of prothrombinex. In this setting prothrombinex should be given in combination with vitamin K and FFP.
Choice 5: 2 units of Fresh Frozen Plasma Score : 2
Choice Feedback:
Correct. Note that fresh frozen plasma requires thawing and so call early when you suspect that it will
be required. In this setting FFP should be given in conjunction with prothrombinex and vitamin K.
Choice 6: 1 unit of whole blood Score : -1
Choice Feedback:
While Mr Morris is likely to require a blood transfusion at some point this will not correct the
coagulopathy (and in fact will make it worse). Stored whole blood becomes deficient in clotting factors
(particularly V and VIII) over time.
Question 5 : SC
Question Information:
The nurse assisting you is concerned about giving fresh frozen plasma when the cross matching is not
yet back.
Question:
Can FFP be given to Mr Morris without cross matching?
Choice 1: Yes Score : 1
Choice Feedback:
FFP needs to be group specific but does not require cross matching. If Mr Morris' blood group is known
then he can be given FFP.
Choice 2: No Score : 0
Choice Feedback:
FFP needs to be group specific but does not require cross matching. If Mr Morris' blood group is known
then he can be given FFP.
Question 6 : MS
Question Information:
The nurse asks what Fresh Frozen Plasma is made of.
Question:
Which of the following are present in FFP?
Choice 1: Factor VII Score : 1
Choice Feedback:
Fresh frozen plasma is prepared from donated blood. It contains all coagulation factors and
anticoagulants.
Choice 2: Factor II Score : 1
Choice Feedback:
Fresh frozen plasma is prepared from donated blood. It contains all coagulation factors and
anticoagulants.
Choice 3: Factor IX Score : 1
Choice Feedback:
Fresh frozen plasma is prepared from donated blood. It contains all coagulation factors and
anticoagulants.
Choice 4: Factor X Score : 1
Choice Feedback:
Fresh frozen plasma is prepared from donated blood. It contains all coagulation factors and
anticoagulants.
Choice 5: Protein C Score : 1
Choice Feedback:
Fresh frozen plasma is prepared from donated blood. It contains all coagulation factors and
anticoagulants.
Choice 6: Protein S Score : 1
Choice Feedback:
Fresh frozen plasma is prepared from donated blood. It contains all coagulation factors and
anticoagulants.
Choice 7: Antithrombin Score : 1
Choice Feedback:
Fresh frozen plasma is prepared from donated blood. It contains all coagulation factors and
anticoagulants.
Choice 8: Leukocytes Score : -1
Choice Feedback:
Incorrect. FFP does not contain red cells, leukocytes or platelets.
Question 7 : FT
Question Information:
You start preparing the 4 vials of prothrombinex and the junior medical student asks "How does that
white dust make the blood clot?"
Question:
Explain to the medical student the composition and mechanism of action of prothrombinex.
Choice 1: null Score : 0
Choice Feedback:
Prothrombinex is lyophilized (freeze dried) powder prepared from human plasma. Each vial contains
500IU of factor II, 500IU of factor IX, 500IU of factor X and a small amount of factor VII. This makes it
well suited to reverse the actions of warfarin (which you will recall inhibits the action of factors II, VII, IX
and X). Prothrombinex also contains a small amount of antithrombin and heparin to prevent clotting in
the vein on delivery.
Synopsis
Mr Morris receives 25 units/kg of prothrombinex, 300ml of FFP, 10mg of IV vitamin K and a further
500ml of normal saline. He has no further episodes of melena. His repeat bloods reveal a haemoblobin
of 87 g/L and an INR of 5.0. The medical retrieval team arrives to transfer the patient under the care to
the gastroenterology team at the tertiary referral centre.
Warfarin drug interactions are one of the more common pharmacological dilemmas that a junior medico
will have to manage. Common drugs that inhibit hepatic metabolism of warfarin and increase
therapeutic efficacy include metronidazole, macrolides (erythromycin), antidepressants (sertraline,
citalopram), omeprazole and amiodarone (important to remember for the warfarinized patient with atrial
fibrillation).
The management of a supratherapeutic INR will be determined by the INR level and whether the patient
is a low or high bleeding risk or actively bleeding. For patients with an INR
Higher INR levels or active bleeding requires more immediate reversal as outlined in this case.
For further information see
Baker RI, Coughlin PB, Gallus AS et al. The Warfarin Reversal Consensus Group. Warfarin reversal:
consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. MJA
2004; 181(9):492-492