Additionally, INR levels may be influenced by multiple factors. Most commonly, elevated hematocrit has a proportionally reduced volume of plasma, and therefore the ratio of anticoagulant to plasma is increased, resulting in a prolonged bleeding time and spurious elevation in the INR [8]. It is important to recognize the limitations of the INR. INR is validated for patients who are stably Coumadin anticoagulated, but not for patients with coagulopathy of liver disease or isolated factor VII deficiency.
In the latter settings the interlaboratory agreement may be poor and the bleeding risks poorly correlated with INR. The purpose of FFP transfusion is to lower the risk of bleeding in patients with coagulopathy. However, studies have found no difference in bleeding events in patients receiving FFP compared to those not. In a retrospective study of patients, 44 critically-ill, non-bleeding patients received FFP. Results showed no statistically significant decrease in INR or bleeding episodes, hospital deaths or length of stay in ICU [9].
Which begs the question, what are the risks of FFP, especially when the benefits are seemingly slim to none? While infection is a well-known but rare risk of blood product transfusion, other risks of plasma therapy include severe allergic reaction, transfusion-associated volume overload which is the most common, and transfusion-related acute lung injury 2.
TRALI represents the acute pulmonary pathology occurring within six hours of transfusion and presenting with tachypnea, cyanosis, hypoxemia, and decreased pulmonary compliance [11].
There is a large proportion of inappropriate FFP use in medical institutions, a glaring example of which is the reversal of Coumadin anticoagulant effect in patients undergoing elective procedures or surgery due to scheduling constraints. Usage of FFP in non-bleeding patients with acquired coagulation deficits is more often dictated by convention rather than rationally based approaches. However, awareness of the harmful consequences of FFP usage must be underscored among healthcare providers.
What is the take home message? Furthermore, elevation of INR does not predict bleeding in the setting of a procedure nor does prophylactic FFP transfusions result in fewer bleeding events. Guidelines for the administration of plasma, The duration of effect is 2—5 days. The elimination of warfarin is almost entirely by metabolism, with very little excreted unchanged in the urine and bile. Metabolism occurs mainly in the liver, involving the cytochrome P, and in particular the CYP2C9, isoenzyme.
Understanding the difference between the antithrombotic and anticoagulant effects of warfarin is useful in clinical practice. Initial increases in international normalised ratio INR are typically noted 24—36 hours after giving the first dose of warfarin.
This early effect is related to the clearance of coagulation factor VII, which has a short half-life in vivo of 6 hours. However, the initial elevation of the INR is not thought to be associated with a clinically important antithrombotic effect, as warfarin is thought to exert its antithrombotic effect mostly through reductions in factor II prothrombin and factor X levels.
If the ability of warfarin to curb existing clot growth and prevent further clot formation depends largely on the clearance of prothrombin with its half-life of 60—72 hours, then it should take a minimum of two prothrombin half-lives, or up to 5 days, to fully express the antithrombotic effect in patients. These observations form the basis of the current recommendations that, unless there is reason to believe that the patient will be unusually sensitive, warfarin therapy is best initiated with a daily dose of 5 mg about the usual maintenance dose rather than by using a loading regimen.
Much higher loading doses may expose patients to an increased risk of bleeding, and increase the required frequency of monitoring. Drug interactions can critically interfere with warfarin control. Common examples of drugs that can influence the absorption or metabolic clearance of warfarin include antibiotics, amiodarone, statins and anticonvulsants. The INR should be tested more frequently after starting, stopping or changing the dose of concomitant medication.
It takes several days for enzyme induction or other drug effects to take place, so that an INR measured about one week after a change in medication should reflect clinically significant interactions. Alcohol in small to moderate amounts probably has little effect on warfarin metabolism.
In heavy drinkers, however, factors such as increased falls, alcohol-induced gastritis, poor diet and poor compliance increase the risk of bleeding. The amount of vitamin K in the diet partly determines the sensitivity to warfarin.
This is important to consider in situations when diet changes, such as during illness, travel, fad diets, hospitalisation and postoperatively. Dark green vegetables such as spinach and broccoli are typically high in vitamin K. Rather than restricting vegetable intake, it is better to recommend a balanced and consistent diet. The most common complication of warfarin therapy is bleeding.
A major determinant is the INR. In one study, the bleeding rate was doubled as the INR increased from 2. Observational studies suggest that the risk of bleeding is also related to age, history of past bleeding and specific comorbid conditions. Generally, elderly people have increased sensitivity to the anticoagulant effect of warfarin and require a lower mean daily dose than younger patients. Box 1 lists the patient-related risk factors. Bleeding during the early months of therapy, particularly from the gastrointestinal or renal tracts, often indicates an underlying lesion and should be thoroughly investigated.
Many bleeding episodes are not clinically significant although many patients are unlikely to view their bleeds in these terms. Such episodes include nosebleeds, bruising and excessive bleeding after minor injury, such as shaving.
Patients should be made aware of these problems, and simultaneously reassured that, although common, they are not serious. Risk factors can be additive. Patients with two or three risk factors have a much higher incidence of warfarin-associated bleeding than those with none or one. Warfarin is a highly effective medication. Bleeding because of an excessive INR is minimised by therapeutic monitoring and when other precautionary measures are adopted.
Avoid high loading doses of warfarin, as they are not warranted and may result in bleeding episodes. An example would be the use of a 10 mg starting dose in a frail elderly individual.
In general it is preferable to start treatment using an initial daily dose of 5 mg, or one that is closer to the usual maintenance dose of about 4—6 mg per day, as there is normally no immediate time constraint for achieving a target level of INR. Aim for an INR level that balances the therapeutic goal with the risk factors of bleeding on an individual basis. This will minimise haemorrhagic complications and maximise antithrombotic effect.
The desirable target INR for most clinical indications is 2. The optimal INR for people with mechanical heart valves is still being debated, with the American College of Chest Physicians guidelines suggesting a reduced target of 2. A reduced target INR range 1. Avoid frequent dose adjustments. A change in warfarin dose will take several days to influence the INR, so testing the INR within 24 or 48 hours of a dose change may not truly reflect the steady-state response to the dose adjustment.
Effective patient education can minimise compliance problems. Box 2 lists the key components of patient education. There is a close relationship between the INR and risk of bleeding. The risk of bleeding increases noticeably once the INR exceeds 4, and the risk rises sharply with values greater than 5.
The management options for warfarin reversal are outlined in Box 3 and depend on the INR level and whether or not bleeding is present. In addition to stopping warfarin when the effect is excessive, vitamin K 1 can be given, and coagulation factors replaced by infusing a prothrombin complex concentrate PCC and fresh frozen plasma FFP. The choice of approach is based largely on clinical judgement, because no randomised trials have compared these strategies in terms of clinical outcomes.
Vitamin K 1 is available as oral tablets or as ampoules for intravenous IV or oral administration. The ampoules are not recommended for intramuscular or subcutaneous use. Furthermore, intramuscular injection in patients on anticoagulation therapy particularly when over-anticoagulated poses a significant risk of causing a haematoma to form.
Ideally, unless the patient is actively bleeding, vitamin K 1 should be administered in a dose that will quickly lower the INR into a safe, but not subtherapeutic, range without causing resistance once warfarin is reinstated. Oral vitamin K 1 is the treatment of choice unless very rapid reversal of anticoagulation is required. If the INR is particularly high, 5 mg orally may be required. Although IV injection produces a more rapid response, it may be associated with anaphylactic reactions.
There is no evidence that this rare, but serious, complication can be avoided by using low doses. The optimal IV dose of vitamin K 1 for partial reversal of over-anticoagulation with warfarin is 0.
If correction of the INR rather than just return to the usual therapeutic range is desired, larger doses of vitamin K 1 are needed see Box 3. Large doses of vitamin K 1 may produce some resistance to re-anticoagulation with warfarin, and this can be avoided by giving smaller doses. Larger doses are appropriate if a clinical decision has been made to discontinue further warfarin treatment. Box 4 presents the recommended dose ranges of vitamin K 1 preparations available in Australasia for anticoagulation reversal.
The full effect of vitamin K 1 in reducing the INR takes up to 24 hours to develop, even when given in larger doses with the intention of complete reversal. For immediate reversal of clinically significant bleeding, the combination of prothrombin complex concentrate PCC and fresh frozen plasma FFP covers the period before vitamin K 1 has reached its full effect.
Box 3 summarises the consensus reached on the management of an elevated INR in different clinical settings. Note, however, that expert advice on management should be sought whenever there is bleeding in patients taking warfarin who have a high risk of a disabling thromboembolic event in the absence of anticoagulation therapy as with prosthetic heart valves or a recent pulmonary embolism or extensive venous thrombosis.
Opinion varies about how to manage anticoagulation in patients who have been taking warfarin long-term and who need to undergo surgery, as the evidence is mainly anecdotal. For most patients, warfarin can be withheld 5 days before elective surgery; the INR usually falls to below 1. There are some procedures, however, which entail a low risk of bleeding, and so do not require interruption to warfarin therapy if the INR is within the therapeutic range.
Examples include simple dental procedures, periodontal therapy, and minor dermatological procedures where pressure can be applied if required. If withholding warfarin preoperatively is necessary, a number of issues need to be considered. These include:. Prolonged immobility during surgery and afterward increases the risk of venous thromboembolism. The potential risk of thrombosis should be assessed. The need for bridging therapy is very much dependent on the risk of the thrombosis recurring during the period that patients are not receiving anticoagulation therapy.
Unfractionated heparin offers some advantages as an anticoagulant in the 24 hours preceding surgery because of its faster onset and offset of action. There is significant disagreement about who should and should not receive such bridging therapy, principally because there is a lack of randomised controlled trial data.
In some situations, clinical experience suggests that bridging anticoagulation is not required. Patients who take anticoagulants because of atrial fibrillation, or in whom the index event requiring anticoagulation occurred more than 3 months ago, can be safely managed without bridging anticoagulation. These patients are at relatively low risk of thromboembolism. Box 6 lists an appropriate approach for these patients. Patients with prosthetic valves and those who have suffered an acute thrombosis within the preceding 3 months should receive bridging anticoagulation in the perioperative and postoperative period.
This should be done in consultation with the relevant experts in this area. Box 6 lists the recommended plan of management for these patients who are at relatively high risk of thromboembolism. History of gastrointestinal haemorrhage, active peptic ulcer, hepatic insufficiency. Lower the dose or omit the next dose of warfarin.
Resume therapy at a lower dose when the INR approaches therapeutic range. In the absence of a device for bedside testing, this time delay can be very deleterious in cases of life-threatening haemorrhage. Calculation of prothrombin complex concentrate dose for anticoagulant reversal in bleeding patients [ 2 ]. The proposed 'calculation of dose' method is difficult to manage in an emergency situation when immediate normalisation of the international normalised ratio INR is required to stop life-threatening bleeding.
Reproduced with permission from Massachusetts Medical Society. The dose-response between coagulation time and PCC dose is not proven and studies remain ambivalent about this. For example, an in vitro study measuring changes in prothrombin time following administration of different doses of PCCs at a range of different INRs 2.
The balance between coagulant and anticoagulant factors in a patient after perfusion of PCC with pro- and anti-coagulant factors for example, Proteins C and S may provide some answers to this issue. Factor II is likely to have been mainly responsible for previous thrombogenic events associated with PCCs [ 26 ] and, due to its long half-life, would accumulate after repeated administration.
Therefore, avoidance of repeated administration is recommended to minimise the risk of thrombogenic events. It is strongly recommended that PCCs should be rapidly available to critical care physicians. Many PCCs have a short preparation time since they are stored at room temperature in the emergency department. Several clinical studies have demonstrated reversal within 3 to 10 minutes [ 12 , 33 ].
When considering major haemorrhage, it is important to fix a goal for reversal. INR recommendations for coagulation control in case of traumatic haemorrhagic shock, where the coagulation capacity is considered efficient, is equal to or less than 1.
For the moment, an INR of 1. Since normalisation of coagulation should be as rapid as possible, treatment with a 'probabilistic dose' of PCC may be considered as soon as the diagnosis of haemorrhage is confirmed Figure 3 [ 19 ]. This avoids time delays in determining the dose, which arise through waiting for test results such as INR or complicated calculations recommended in some reports [ 2 ].
Probabilistic dosing may be controversial because most PCC dosing recommendations are calculated using additional parameters such as INR; it is therefore possible that INR might not be completely normalised using this approach. However, this has never been reported, and an immediate probabilistic dose minimises haemorrhagic risk. Algorithm for anticoagulant reversal with prothrombin complex concentrates. After anticoagulant reversal with PCCs, other haemostatic treatments surgery or artery embolism should not be delayed by waiting for normalisation of INR.
Information on the INR at arrival may not be essential for reversal, given the option of probabilistic dosing. However, PCC dosing may often be determined by INR and it can also provide interesting information on the reasons for the haemorrhage, which may influence future treatments.
In general, therefore, it is preferable to take a blood sample before attempting to reverse anticoagulation. The most interesting INR is that taken after treatment to assess the success of the reversal.
The time for distribution of factors in the extracellular space is not well-known but pharmacokinetic studies in healthy volunteers are in favour of an ultra-rapid dispersion with a steady-state observed at the first point sampled, 5 minutes after perfusion [ 59 ].
Therefore, it can be assumed that control of INR is achieved within 5 to 30 minutes after injection. An INR measurement taken 6 hours after reversal demonstrates control of the capacity of endogenous hepatic production of factors.
At this point there may be an added thrombotic risk from further administration of PCC at higher INR ranges because of the long half-life of factor II and its possible accumulation.
This approach provides a further 5 hours of control before vitamin K increases production of endogenous coagulation factors.
A final assessment at 24 hours can be useful to discuss the treatment after the haemorrhagic event and examine the thrombotic and haemorrhagic risk for the patient. The development of new point-of-care devices for INR testing could change attitudes towards INR testing as it is useful to determine whether doses related to INR are related to clinical reality. For the moment, INR testing at point-of-care and the bedside has been investigated in patients receiving oral anticoagulants, with conflicting reports of the accuracy of this method [ 75 — 77 ].
Further improvements in bedside INR monitoring will improve diagnosis, and achieve more rapid and accurate tailored treatment. Severe vitamin K antagonist-related haemorrhages are being encountered more frequently by critical care clinicians and, in line with the increasing use of oral anticoagulant therapy, the need for rapid reversal of anticoagulation before emergency surgery is more common.
These situations must be treated rapidly to stop bleeding and improve patient outcomes. Supplementation of coagulation factors via the administration of PCCs provides effective correction of coagulation more rapidly than the alternative treatment options. Moreover, PCCs are associated with a reduced risk of pathogen transmission and volume overload compared with human plasma.
Although PCCs are widely recommended in current guidelines, their use remains limited due to a lack of understanding of their clinical benefits. PCCs are an effective treatment for the cessation of severe bleeding and for rapid normalisation of INR in patients receiving vitamin K antagonists, and their use should be considered immediately at the time of presentation or diagnosis in emergency situations.
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