PT/INR and Anticoagulation Status
For the vast majority of patients , monitoring is done using the prothrombin time with international normalized ratio (PT/INR), which reflects the degree of anticoagulation due to depletion of vitamin K-dependent coagulation. However, attention must be paid that the PT/INR in a patient on warfarin may note reflect the total anticoagulation status of the patient in certain settings:
- First few day of warfarin initiation
The initial prolongation of the PT/INR during the first one to three days of warfarin initiation does not reflect full anticoagulation, because only the factor with the shortest half-life is initially depleted; other functional vitamin K-dependent factors with longer half-lives (e.g., prothrombin) continues to circulate. The full anticoagulation effect of a VKA generally occurs within approximately one week after the initiation of therapy and results in equilibrium levels of functional factors II, IX, and X at approximately 10 to 35 percent of normal.
- Liver disease
Individuals with liver disease frequently have abnormalities in routine laboratory tests of coagulation, including prolongation of the PT, INR, and aPTT, along with mild thrombocytopenia, elevated D-dimer, especially when liver synthetic function is more significantly impaired and portal pressures are increased. However, these tests are very poor at predicting the risk of bleeding in individuals with liver disease because they only reflect changes in procoagulant factors.
- Baseline prolonged PT/INR
Some patients with the antiphospholipid antibody syndrome (APS) have marked fluctuations in the INR that make monitoring of the degree of anticoagulation difficult.
Time in the Therapeutic Range (TTR)
For patients who are stably anticoagulated with a VKA, the percentage of time in the therapeutic range (TTR) is often used as a measure of the quality of anticoagulation control. TTR can be calculated using a variety of methods. The TTR reported depends on the method of calculation as well as the INR range considered “therapeutic.” A TTR of 65 to 70 percent is considered to be a reasonable and achievable degree of INR control in most settings.
Factors Affecting the Dose-Response Relationship Between Warfarin and INR
- Nutritional status, including vitamin K intake
- Medication Adherence
- Genetic variation
- Drug interactions
- Smoking and alcohol use
- Renal, hepatic, and cardiac function
- Hypermetabolic states
In addition, female sex, increased age, and previous INR instability or hemorrhage have been associated with a greater sensitivity to warfarin and/or an increased risk of bleeding.
Vitamin K intake – Individuals anti coagulated with warfarin generally are sensitive to fluctuations in vitamin K intake, and adequate INR control requires close attention to the amount of vitamin K ingested from dietary and other sources. The goal of monitoring vitamin K intake is to maintain a moderate, constant level of intake rather than to eliminate vitamin K from the diet. Specific guidance from anticoagulation clinics may vary, but a general principle is that maintaining a consistent level of vitamin K intake should not interfere with a nutritious diet. Patients taking warfarin may wish to be familiar with possible sources of vitamin K (in order to avoid inconsistency).
Of note, intestinal microflora produce vitamin K2, and one of the ways antibiotics contribute to variability in the prothrombin time/INR is by reducing intestinal vitamin K synthesis.
Cranberry juice and grapefruit juice have very low vitamin K content but have been reported to affect VKA anticoagulation in some studies, and some anticoagulation clinics advise patients to limit their intake to one or two servings (or less) per day.
Medication adherence for vitamin K antagonists can be challenging due to the need for frequent monitoring and dose adjustments, dietary restrictions, medication interactions, and, in some cases, use of different medication doses on different days to achieve the optimal weekly intake. Reducing the number of medications prescribed may be helpful, if this can be done safely.
A large number of drugs interact with vitamin K antagonists by a variety of mechanisms, and additional interacting drugs continue to be introduced. Determine clinically important drug interactions is challenging because the evidence substantiating claims for some drug is very limited; in other cases, the evidence is strong but the magnitude of effect is small. Patients should be advised to discuss any new medication or over-the-counter supplement with the clinician managing their anticoagulation, and clinicians are advised to confirm whether a clinically important drug-drug interaction has been reported when introducing a new medication in a patient anticoagulated with a VKA.
Smoking and Excess Alcohol
The effect of chronic cigarette smoking on warfarin metabolism was evaluated in a systematic review and that included 13 studies involving over 3000 patients. A meta-analysis of the studies that evaluated warfarin dose requirement found that smoking increased the dose requirement by 12 percent, corresponding to a requirement of 2.26 additional mg of warfarin per week. However, two studies that evaluated the effect of chronic smoking on INR control found equivalent control in smokers and non-smokers.
The mechanisms by which cigarette smoking interacts with warfarin metabolism is by causing enhanced drug clearance through induction of hepatic cytochrome P-450 activity by polycyclic aromatic hydrocarbons in cigarette smoke. Nicotine itself is not thought to alter warfarin metabolism.
The interaction between excess alcohol use and warfarin anticoagulation was evaluated in a case-control study that compared alcohol use in 265 individuals receiving warfarin who had major bleeding with 305 controls from the same cohort receiving warfarin who did not have major bleeding. The risk of major bleeding was increased with moderate to severe alcohol use and with heavy episodic drinking.
Mechanism by which alcohol use interacts with warfarin anticoagulation are many, and the contribution of various factors depends greatly on the amount of intake and the severity of associated liver disease. Excess alcohol consumption may interfere with warfarin metabolism. Severe liver disease may also be associated with coagulopathy, thrombocytopenia, and/or gastrointestinal varices, all of which increase bleeding risk independent of effects on warfarin metabolism.
The major comorbidities that affect anticoagulation control are hepatic disease, renal dysfunction, and heart failure. In addition, other comorbidities such as metastatic cancer, diabetes, or uncontrolled hyperthyroidism may also play a role.
The liver is the predominant site of warfarin metabolism. It is also the source of the majority of coagulation factors. Thus, liver disease can affect warfarin dosage, INR control, and coagulation in general. Importantly, individuals with severe liver disease are not “auto-anticoagulated,” because they often have a combination of abnormalities that both impair hemostasis and increase thrombotic risk.
Warfarin undergoes partial excretion in the kidney. Patients with kidney disease can receive warfarin, and management is generally similar to the population without renal impairment; however, dose requirement may be lower.
Heart failure has been shown to interfere with INR stabilization.
Acute illnesses may alter anticoagulation through effects on vitamin K intake, VKA metabolism, and medication interactions, especially infections and gastrointestinal illnesses.
Genetic polymorphisms have been implicated in altered sensitivity to warfarin and other vitamin K antagonists.