1. Strategies for Reversing Warfarin Anticoagulation
W. Cederquist, MD, Anesthesiology PGY-V
Mentor: Paul Picton, MD
Case Discussion – Practical Updates in Anesthesiology 2014
Tues, February 4th, 2014

2. Disclosures
No conflicts of interest to report

3. Case Presentation (1)
HPI: 70 y.o. ASA 3 man presenting to ED with 12 hours of vomiting, loose stools and RLQ abdominal pain.
PMH: HTN and atrial fibrillation on warfarin
VS: T 39°C; BP 108/63; HR 74 regular; RR 16; SpO2 96% RA.
Exam: 72 in, 100kg, BMI 30. Neurologic, HEENT, cardiopulmonary, GU, MSK and skin wnl. Tenderness at McBurney’s point, Rosving’s sign.
Septic but not in shock.

4. Case Presentation (2) Labs: WBC 14.3 (4-10 K/mm3) 80% PMNs
Hct (40-50 %)
Plt ( K/mm3)
COMP Within normal limits
aPTT 31.6   (  s)
PT   (  s)
INR 2.8 4

5. Case Presentation (3) CT abdomen/pelvis with IV/PO contrast
So a 70 yo ASA 3 man on warfarin for afib presents for a lap appy. How do you proceed?
Surgical plan: Laparoscopic appendectomy 5

6. Case Presentation (4)
Surgery Note: “The patient will be transfused 3 units of FFP to correct his INR to less than 1.5. The patient will have immediate INR check and will be continued to be transfused with FFP should he remain therapeutic... Once his INR is reversed, the patient will be taken to the operating room...” 6

7. Perioperative Course (1)
1349 Arrival to ED
1425 INR 2.8
1624 CT abdomen/pelvis
1745 Ciprofloxacin/Metronidazole Administered
st FFP
nd FFP
2136 Arrived in Pre-Op Area
2212 INR 2.2
rd FFP and 4th FFP
0146 INR 1.7
th FFP
0300 Facial edema and urticaria noted
Here’s what happened… Blood bank was consulted for an allergic reaction to FFP 7

8. Perioperative Course (2)
0412 Patient In Room
0421 Anesthesia Induction End
0431 Urology Consult for Difficult Foley Placement
0502 Surgical Incision
0545 Converted to Open Ileocecetomy
0611 INR 1.7
0845 EBL 300cc
0851 Surgical Dressing Complete
0858 Extubated Awake
0901 Transported to PACU
0942 INR 1.8
1325 Admitted to Surgical Ward
Time from arrival in ED to arrival on the surgical ward was 24 hours, Time from FFP ordered to given was 2 hours, Time from starting FFP to surgical incision was over 8 hours, INR drawn 5 times in 24 hours 8

9. Perioperative Course (3)
Post Op Course
- complicated by paroxysmal atrial fibrillation
Outcome
- warfarin restarted at discharge to home on postoperative day #4
The post operative course was complicated by brief periods of afib. Warfarin was restarted at discharge on POD#4. The patient ultimately did well, so why am I presenting this case? Well, it brings up a number of interesting points regarding anticoagulation and the appropriate use of blood products.
In addition, with more than 60,000 emergency room visits per year for hemorrhagic complications of warfarin therapy, this is a scenario you have seen or will see in your future practice. 9

10. Goals and Objectives
Identify the hemostatic defect in warfarin therapy
Evaluate the safety and efficacy of three methods to correct warfarin anticoagulation
Critically appraise the association between an elevated prothrombin time and bleeding risk
Introduce prothrombin complex concentrate as an alternative to FFP for warfarin reversal 10

11. Classical Coagulation Pathway
aPTT
PT/INR
Let’s start with a brief review. This is the classic model of the coagulation and its really best suited to explain the two most common tests of coagulation we have available. The activated partial thromboplastin time (which is a measure of the intrinsic pathway “click”) and the prothrombin time (which is a measure of the extrinsic pathway “click”). The international normalized ratio or INR is derived from the prothrombin time and that’s the side of this diagram that ill be focusing on today. 11

12. Differential Diagnosis
Anticoagulants
warfarin, argatroban, heparin
Liver disease
multiple etiologies
Vitamin K deficiency
malnutrition, antibiotic use
Factor deficiency
hemophilia, autoimmune disease, coagulation factor inhibitors
In treating a patient with abnormal coags, one must cast a broad differential. The causes of an abnormal prothrombin time fall into one of four categories. These are the presence of anticoagulants, as was the case here. But also one may consider liver disease which has multiple etiologies, vitamin K deficiency (either through malnutrition or the depletion of gut flora) and finally, inherited or acquired coagulation factor deficiency. Today, we’ll focus primarily on warfarin-induced coagulopathy. 12

13. Warfarin Factors II VII IX X ACCP Guidelines 8th Edition (2008)
So how does warfarin exert its effect on the coagulation system? Wafarin inhibits vitamin K oxide reductase, a key player in the regeneration of active (that is to say the reduced form of) vitamin K. Vitamin K is an essential cofactor in the final step of production of several coagulation factors. Before these coagulation factors are released into the blood by the liver, they are carboxylated allowing them to be functional in the clotting cascade. In the presence of warfarin, the reduced form of vitamin K is depleted and the functional release of factors II, VII, IX and X is impaired.
ACCP Guidelines 8th Edition (2008) 13

14. Coagulation Factor Activity vs INR
But what does that mean in terms of factor activity in the plasma? As you can see here in this pseudo dose-response curve for warfarin, increasing doses of the drug lead to a marked decline in activity level of the vitamin K dependent factors. A preop INR of 2.8 (which our patient arrived with) suggests factor activity levels in the 20% range.
Gulati et al. Archives of Pathology & Laboratory Medicine ( 2011) 14

15. Classical Coagulation Pathway
And what does a factor activity level of 20% of normal do to the patient’s ability to form clot? Well as you can see here warfarin affects the cascade at multiple levels. It impairs that critical initial step where endothelial trauma exposes tissue factor to factor VII. It decreases the level of IX and X which from the tenase complex, the enzyme complex responsible for the thrombin burst. And of course, the production of thrombin is impaired, that’s that crucial enzyme which will eventually convert fibrinogen into a blood clot. 15

16. Question - supplement vitamin K (12 - 24 hours)
What three general strategies are available for the correction of warfarin-induced coagulopathy?
- discontinue warfarin (days)
- supplement vitamin K ( hours)
- replace clotting factors (immediate)
So when faced with a patient taking warfarin but now needing an emergent procedure, I pose to you the following question: What three general strategies are available for the correction of warfarin-induced coagulopathy?
The first strategy is to discontinue warfarin but that will take several days and was clearly not appropriate in this case. The second strategy is to supplement vitamin K and I’ll show you that that can be effective within hours. The third strategy is to replace clotting factors, which has the most immediate effect. Let’s talk about vitamin K first. 16

17. Vitamin K Supplementation
Vitamin K is a fat soluble vitamin obtained from the diet or produced by gut flora. The recommended dose of vitamin K is usually between 1 and 10mg. Effects are more rapid of course when given IV, and oral administration is not appropriate for the reversal of warfarin in the patient who is actively bleeding. Vitamin K should essentially never be given subcutaneously, as this route is associated with a higher risk of anaphylaxis. (click) So how does vitamin K work? By replacing reduced vitamin K stores, it allows for the carboxylation and release of active clotting factors.
Phytonadione
ACCP Guidelines 8th Ed 17

18. Intravenous Vitamin K - 178 patients on warfarin - vitamin K 3 mg IV
- PT/PTT checked on day of procedure
Several studies have examined the use of vitamin K for surgical patients taking warfarin. This study by Burbury et al. claims that vitamin K is “safe, reliable and convenient.” In this elegant study, 178 patients taking warfarin (mostly for afib like our patient) came to the anesthesia preop clinic in the afternoon before elective surgery. Warfarin was stopped and they received a 3 mg vitamin K infusion. The next morning coags were checked in the preop area.
Burbury et al. Br J Haematology (2011) 18

19. Intravenous Vitamin K Burbury et al. Br J Haematology (2011)
Normal Range
The results are really quite remarkable. The median starting INR was 2.4 and the median post vitamin K INR was 1.3.
94% of patients reached an INR of <1.5 and 100% of patients < No surgery was cancelled. There were no reported adverse reactions to vitamin K, median time to full anticoagulation after surgery was 4 days, indicating that no patient developed “warfarin resistance.”
The authors concluded that vit K is safe (no adverse events), reliable (94% of patients had an INR <1.5) and convenient (perhaps it is more convenient than stopping warfarin 5 days before and bridging with another anticoagulant).
Burbury et al. Br J Haematology (2011) 19

20. Added to Chest Guidelines
Recommendations: “Anticoagulation reversal for non-major bleeding should be with 1-3 mg intravenous vitamin K (Grade 1B).”
In fact, the evidence supporting the use of vitamin K is so compelling that all professional societies include it in their guidelines for management of warfarin overdose with or without bleeding. Here is one from the British Committee for Standards in Hematology which recommends that anticoagulation reversal for non-major bleeding should be with 1-3 mg of intravenous vitamin K.
How is this relevant to our case? Of course, we could not have predicted that the patient was going to develop acute appendicitis, so bringing him in the day before for a vitamin K infusion would be impossible. However, for urgent surgery that can be delayed 12 hours, IV vitamin K is a valid option for warfarin reversal. 20

21. Question - supplement vitamin K (12 - 24 hours)
What three general strategies are available for the correction of warfarin-induced coagulopathy?
- discontinue warfarin (days)
- supplement vitamin K ( hours)
- replace clotting factors (immediate)
Say for example a more urgent procedure is required or the patient presents with life threatening hemorrhage. “click” In this case, immediate replacement of clotting factors is the only option. 21

22. Replacement of clotting factors
Blood Product
(FFP)
Multiple factor replacement (Prothrombin Complex Concentrate)
There are three ways to replace clotting factors: 1) By transfusing blood product i.e. FFP. 2) By replacing multiple clotting factors, for example, what if you could give the patient concentrated factors II, VII, IX and X without the hazards of FFP? 3) By administering a massive overdose of a single factor to overwhelm the coagulation cascade (Of course, here I am referring to the use of recombinant factor VII which is prohibitively expensive and not well supported by evidence so I won’t discuss it further). Lets start with FFP.
Single factor replacement (Recombinant Factor VIIa) 22

23. What’s in it? Stanworth. Hematology (2007)
What is FFP? Plasma left over from one unit of whole blood when all cellular elements removed. It contains by definition around 1 U/ml of each of the coagulation factors. One unit of FFP is approximately 250cc in volume and it must be ABO compatible.
Stanworth. Hematology (2007) 23

24. Professional Guidelines
ASA Practice Guideline for Perioperative Blood Transfusion (2006):
“FFP should be given … to achieve a minimum of 30% plasma factor concentration (usually achieved with administration of ml/kg FFP), except for urgent reversal of warfarin anticoagulation, for which 5-8 ml/kg FFP usually will suffice.”
FFP has only a handful of indications but as you can see here the ASA Practice Guideline for Perioperative Blood Transfusion from 2006 states that: (read slide)
Our patient received a final dose of 12 ml/kg of FFP but in a stepwise fashion not as a single dose.
You’ll note that there is no mention here of titrating FFP to a particular INR, yet that’s exactly what was done in our case.
American Society of Anesthesiology. Anesthesiology (2006) 24

25. Making Assumptions
Surgery Note: “The patient will be transfused 3 units of FFP to correct his INR to less than 1.5…and will be continued to be transfused with FFP should he remain therapeutic... ”
Assumptions:
1) FFP will decrease the bleeding risk
As you’ll remember the plan was to transfuse to an INR of less than 1.5. There two assumptions inherent in that plan. “click” The first assumption is that FFP when given to a patient with an elevated prothrombin time will decrease the bleeding risk. Well, I’m sure you will agree patients taking warfarin are probably at higher risk overall for bleeding and that correcting the factor deficiency will decrease that risk. But where’s the evidence? 25

26. Will FFP decrease the bleeding risk?
- review of FFP
- multiple clinical endpoints
- evidence supporting FFP is weak
Of course, there will never be a study of warfarinized patients having surgery randomized to either FFP or placebo. The best available evidence for the effectiveness of FFP comes from a systematic review in A wide variety of clinical scenarios were represented – GI bleeding, liver biopsy, CABG, warfarin-related ICH, and so on. (click) This review found significant methodological defects and insufficient evidence for the effectiveness of FFP across multiple clinical endpoints (including estimated blood loss). In particular, the evidence to support the prophylactic use of FFP was lacking. So, despite the broad use of FFP in clinical practice, the authors showed that evidence supporting its use is weak. This is not to say that FFP is not effective in certain patients, just that adequate scientific studies do not exist to support its use.
Stanworth. Hematology (2007) 26

27. Making Assumptions
Surgery Note: “The patient will be transfused 3 units of FFP to correct his INR to less than 1.5…and will be continued to be transfused with FFP should he remain therapeutic... ”
Assumptions:
1) FFP will decrease the bleeding risk
2) FFP will correct the INR to < 1.5
The second assumption is that FFP will correct the INR to less than 1.5. “click” I’ll show you now that this is difficult to do with FFP alone. 27

28. Change in INR per unit FFP
Holland et al. reviewed 103 patients who received FFP for a median INR of Based on lab results taken pre and post transfusion, the authors developed a mathematical model to predict the effect of FFP on the INR. That is shown here. If your starting INR is high say 8 to 10, then FFP will result in a significant change perhaps 2 or 3 points. However, if your INR is only mildly elevated (like those patients near the lefthand end of this line), a dramatic improvement is unlikely. In fact, only 50% of patients with an INR of 1.7 will have a significant decrease in the INR with FFP transfusion.
Holland LL, Brooks JP. Am J Clin Path (2006) 28

29. Will FFP decrease the INR to 1.5?
Starting INR
Median INR change = 0.07
Less than 1% achieve normalization of the INR.
Here’s another study to emphasize the point. These authors prospectively audited the use of FFP at their hospital in They studied patients with an INR of who received FFP. The cohort included patients with and without active bleeding and those transfused prophylactically prior to a procedure.
The median change in INR was 0.07 per unit of FFP. Less than 1% achieve normalization of the INR. Only 15% of patients achieved an INR of halfway to normal. Explain figure.
Clearly, FFP is unlikely to change the INR significantly in patients with mild elevations say up to 1.8. One can think of any number of reasons why this might be the case. Each unit of FFP given is diluted out by the patient’s blood which is factor deficient, so one will never reach 100% coagulation factor activity, irrespective of the volume given. In addition, the coagulation factors in FFP each have a half life. They are cleared from plasma by protein uptake into cells or by consumption from clotting. Factor VII has the shortest half life of all coagulation factors - 4 hours. So a unit of FFP given four hours ago, now has only half the factor VII activity it did when it was administered. So in real world practice, where FFP administration takes hours, it is nearly impossible to achieve total normalization of the INR.
Abdel-Wahab et al. Transfusion (2006). 29

30. Where did that number come from?
So you can see titrating FFP to an INR number cannot be recommended based on the available evidence. But at many institutions an INR of 1.5 is considered the cutoff for invasive procedures. Where then did that number come from? “click” I’m not really sure. The cutoff probably comes from several studies mostly concerning trauma patients undergoing massive transfusion. In these studies, microvascular bleeding (or oozing as our surgical colleagues will report to us) occurred at factor levels less than 30% of normal which is around INR of But there are some obvious limitations to these studies. Most of these studies are over 30 years old, there are methodological issues, microvascular bleeding was determined subjectively, etc. 30

31. Where did that number come from?
But despite these limitations the majority of professional societies recommend transfusion of FFP for patient in whom bleeding is anticipated if the INR is >1.5. Why 1.5 when the studies suggested 1.8? I can only guess that that is a conservative interpretation of the data.
Holland LL, Brooks JP. Am J Clin Path (2006) 31

32. Replacement of clotting factors
Blood Product
(FFP, whole blood)
Multiple factor replacement (Prothrombin Complex Concentrate)
So we’ve talked about reversing the hemostatic defect of warfarin therapy with FFP. Despite its broad clinical use, FFP can only lower the INR to a certain point. I’ve tried to convince you that FFP should not be given solely to correct an abnormal lab test and probably the titration of FFP towards a certain INR cutoff is futile. In retrospect, in the case of our patient, we probably should have administered a dose of say 8 ml/kg of FFP and proceeded to surgery with more FFP available in the event of microvascular bleeding.
In terms of its safety, the blood supply today has never been safer but it still has risks. Could our patient’s allergic reaction to FFP have been avoided? (click)
Perhaps it could have with multiple factor replacement.
Single factor replacement (Recombinant Factor VIIa) 32

33. Prothrombin Complex ConcentrateII
VII IX X
PCC
Prothrombin complex concentrate (or PCC for short) was developed for the treatment of factor IX deficiency, hemophilia B. The term “prothrombin complex” refers to those factors immediately upstream of thrombin in the classical model of coagulation - VII, IX and X. So PCC is the vitamin K dependent factors in a bottle.
Hemophilia B 33

34. How is it made? II Ion exchange chromatography Pasteurize
VII IX X
A large pool of FFP is subject to ion exchange chromatography to isolate the vitamin K dependent factors. Next, it is pasteurized to remove infectious diseases such as hepatitis, HIV, etc and then it’s bottled it as a powder. Prior to administration it is reconstituted in sterile water to a volume of just 20 mls, with a clotting factor concentration of 25 times that of plasma. The dose is typically U/kg for the bleeding patient.
Pasteurize
Adult dose: U/kg 34

35. Effect of PCC on clotting factors
What effect does PCC have the coagulation system? Well, this data from 2008 shows what PCC does in patients who present with hemorrhage while taking warfarin. Factors II, IX and X are normalized immediately. Factor VII reaches only 50% of normal but this is presumably sufficient for clotting.
And regarding the lab tests? PCC drops the INR to less than 1.4 in 100% of patients. A powerful hemostatic agent for sure.
Pabinger et al. J. Thromb Haemost (2008). 35

36. PCC vs FFP PCC FFP Onset immediate
limited by acquisition time and infusion rate
Duration
~ 3-6 hours
Volume
↓↓↓
↑↑↑
Risks
thrombosis
allergic rxn, TRALI, TACO, infection
Cost
+++ +
So how does PCC line up against FFP? (Talk about each line). 36

37. Added to Chest Guidelines
Recommendation: “For patients with warfarin-associated major bleeding, we suggest rapid reversal of anticoagulation with four-factor PCC rather than with plasma (Grade 2C).”
Seems like PCC is the obvious choice right? The ACCP felt that the evidence was compelling enough to make the following recommendation in the 2012 guidelines for the Evidence-Based Management of Anticoagulant Therapy: read slide
ACCP Guidelines 9th Edition (2012) 37

38. Coming soon to a pharmacy near youII IX X
PCC
3 factor PCC
When I originally prepared this talk in January last year, there was actually no such drug available. All preparations approved by the FDA up to that point contained little or no factor VII and were therefore called three factor PCCs. (click)
However, this year I can report that there is one newly approved preparation of prothrombin complex concentrate which contains all four vitamin K dependent factors along with small amounts of protein C and S. It is supplied in 500 unit vials and the recommend dose is again IU/kg. II IX X
PCC
3 factor PCC 38

39. Clinical Trials - 202 patients taking warfarin
- equal in terms of “effective hemostasis”
- possibly fewer adverse events
So is it time to toss out all the FFP and replace it with PCC instead? Well, there are only a handful of studies comparing the two directly. The largest of these studies was published this year in Circulation. (click) 202 patients taking warfarin who presented with major bleeding (most GI bleeding) were randomized to FFP vs PCC. The studied results were mixed. The primary endpoint was “Effective hemostasis” as judged by blinded expert chart reviewers. There was no difference between the treatment and control arms in effective hemostasis. So PCC was shown only to be non-inferior to FFP in that regard.
It may be that PCC is associated with fewer adverse events than plasma transfusion, in particular, the number of patients with volume overload was smaller in the PCC group. However, the authors readily admit that the sample size was too small to make final conclusions regarding safety.
All in all, it appears that more research is needed to determine the patient population who will definitively benefit from this newer therapy and thus justify the increased cost.
Sarode et al. Circulation (2013) 39

40. New Oral Anticoagulants
- direct thrombin inhibitors (dabigatran)
- factor Xa inhibitors (-xabans)
- consider PCC if all else fails
One developing story in the field of anticoagulation deserves mention here. While a full discussion is outside of the scope of this lecture, new oral anticoagulants with novel mechanisms of action are now available. “click” These are the direct thrombin inhibitors and factor Xa inhibitors and they have the potential to make warfarin obsolete. While these medications have a short half life, there is currently no effective way to immediately reverse their anticoagulant effect. If local hemostatic measures, volume resuscitation and hemodialysis are ineffective, some professional societies are suggesting that PCC be considered.
In the case of dabigatran, there is an effort underway to produce a monoclonal antibody to serve as an antidote. But this may be several years in the future.
Heidbuchel et al. Europace (2013) 40

41. Conclusions
Identify the hemostatic defect in the coagulopathic patient presenting for emergency surgery.
Use vitamin K for procedures that can be delayed 12 hours, otherwise use FFP.
Minor elevations in INR are unlikely to be corrected by plasma transfusion.
Prothrombin complex concentrate is a promising alternative but further studies are needed.
In conclusion, one must first identify the hemostatic defect in the coagulopathic patient presenting for emergency surgery so that the treatment can be tailored.
For patients on warfarin, use vitamin K if the procedure can be delayed 12 hours, otherwise use FFP with a recommended dose of 5-8 ml/kg.
Minor elevations in INR are not clearly associated with an increased bleeding risk and are unlikely to be corrected by plasma transfusion.
Prothrombin complex concentrate is a promising alternative to FFP but further studies are needed to confirm a benefit over FFP in terms of clinically relevant endpoints. 41