| Abstract|| |
Antagonists of vitamin K dependant clotting factors are commonly used as treatment/prophylaxis for anticoagulation. Due to their narrow therapeutic window, a wide range of complications including death may occur. International normalized ratio (INR) is monitored to measure adequacy/excess of anticoagulation. There is a plethora of risk factors that may contribute to the uncontrollably high INR values. We describe our experience of a case of deep venous thrombosis wherein the patient had an overshoot of INR during anticoagulation therapy. We review the literature and discuss management in such scenarios.
Keywords: Anticoagulation, Bleeding, International normalized ratio
|How to cite this article:|
Gude D, Abbas A, Mohiuddin H. When blood is thinner than water. Ann Card Anaesth 2013;16:63-5
| Introduction|| |
Encountering high international normalized ratio (INR) values during anticoagulation therapy is not uncommon in clinical practice. The clinicians must be abreast of guidelines in managing complications of over/under correction of INR. We share our experience of managing a patient with formidably high INR and review the literature.
A seventy year old female, a known diabetic, hypertensive and asthmatic, presented with worsening swelling of left lower limb for 4 days. The swelling was associated with pain, fever and nausea. There was no shortness of breath. She gave a history of air-travel (lasting >14 hours) 5 days ago. Her body mass index was 42.3. Her blood pressure was 110/70 mmHg. Her heart rate was regular and 82/minute. Respiratory rate was 16/minute. On examination the left lower limb was swollen with pitting edema extending above knee. Deep venous thrombosis was suspected and was confirmed on duplex ultrasonography which showed an acute hypo-echoic thrombosis in the left common femoral vein extending up to popliteal vein. Additionally, the D-dimer level were increased to 2 μg/ml. Extension of thrombosis in to great saphenous vein was also noted. Total WBC count was 15,300 with 83% neutrophils. Serum homocysteine was 17.21 μmol/L (normal 5-15 μmol/L). Serum antinuclear antibody test was negative. ECG showed normal sinus rhythm. Echocardiography was normal with left ventricular ejection fraction of 62%. Her prothrombin time was 14.5 seconds and INR-1.19. She was started on anticoagulation therapy with acenocoumarol 4 mg/day and unfractionated heparin (5000 units intravenous bolus followed by 1000 units/hour for 24 hours). The next day heparin was changed to enoxaparin (60 mg subcutaneous twice daily) and antibiotics (piperacillin and tazobactam 4.5 g sixth hourly) were also started. Vitamins B 12 , B 6 and folic acid were also started (owing to her elevated homocysteine) along with adequate hydration. INR measured daily over the next three days rose to 3.24 at this point acenocoumarol was cut down to 2 mg/day, however, INR continued to increase and climbed to 3.69, 7.27, 9.96 and 10. Acenocoumarol was stopped at an INR of 7.27 and oral vitamin K 1 (phylloquinone 5 mg once daily) was started along with fresh frozen plasma (3 units/day) for 6 days. The repeat INR subsided to 3.64 and then to 1.99 during this time warfarin 2 mg (alternate day was added). Repeat duplex venous scan after 2 weeks showed partial resolution of popliteal thrombus with persisting common femoral vein thrombus. She was put on close follow-up and during the follow-up visit after 2 months of initial presentation she was doing well with the INR being 2.2.
Our patient most probably developed DVT secondary to her travel history. Travel lasting longer than 6 hours is known to significantly heighten risk for DVT (>14 hours in our case).  Our patient had high probability of DVT as per Well's scoring system, the positive factors being calf swelling >3 cm compared to the other leg, collateral (non-varicose) superficial veins, presence of swelling of entire leg, localized tenderness and pitting edema greater in the symptomatic leg. Throughout the course of hospital stay she did not develop features of pulmonary embolism (PE) with low probability for PE on Well's score. Apart from travel history, old age, obesity and moderate hyperhomocysteinemia were the risk factors for DVT in our case. The various other risk factors mentioned in literature act synergistically and compound the risk of DVT and PE.
The unusually high INR noted after starting coumarin derivatives is attributed to factors like diarrhea, malnutrition, malignancy, worsening heart failure, infection/fever, impaired liver function, other serious comorbid conditions and use of acenocoumarol rather than phenprocoumon. , Although our patient lacked fever, there was evidence of infection as evidenced by leucocytosis and neutrophilia (probably from the evolving cellulitis). Another risk factor for high INR in our case was the use of acenocoumarol. Older patients are believed to have less stores of vitamin K and exhibit an increased sensitivity and hence an exaggerated response to warfarin. Other known risk factors for high INR are higher target INR (in patients with mechanical valves) and use of drugs that can influence the absorption or metabolic clearance of warfarin such as antibiotics (especially co-trimoxazole, erythromycin, fluconazole, isoniazid, metronidazole and miconazole), amiodarone, statins, acetaminophen, anticonvulsants and herbal medications, such as St John's wort. , Alcohol especially in heavy drinkers may augment bleeding tendencies secondary to accidental falls, alcohol-induced gastritis, poor diet and poor compliance. Genetic polymorphisms in cytochrome CYP2C9 producing altered catalytic properties have been identified which explains the unusual warfarin sensitivity in certain genotypes.  Warfarin-associated bleeding is more common in those with two or three risk factors than those with none or one. On the other hand a diet rich in brassicaceae family vegetables is often rich in vitamin K, which may decrease the therapeutic effects of warfarin.
Many bleeding episodes are not clinically significant (nosebleeds, bruising and excessive bleeding after minor injury, such as shaving etc) and may need only reassurance. Asymptomatic patients with INR above 6.0 are known to be at a substantial risk of major hemorrhage in the next fourteen days.  In moribund patients the spontaneous rise in INR might suggest higher risk of death. The annual risk of bleeding in patients on warfarin is 5 times as compared to those not on warfarin and ranges from 0.6%-9.6% (10 times more common in the first month as opposed to that after first year). The rate of bleed doubles as the INR rises from 2.0-2.9 to 3.0-4.4, and quadruples when it reaches 4.5-6.0. Each increase in INR by 0.5 multiplies the absolute risk of major bleeding (mostly intracranial) by 1.43 times.  Studies have highlighted the necessity of narrower therapeutic range with INR close to 2.2-2.3 irrespective of the indication for anticoagulant treatment.  In conditions demanding higher target INR (recurrent venous thromboembolism despite treatment with warfarin and an INR >2.0, mechanical heart valves, and thrombosis in association with the antiphospholipid antibody syndrome) a combination treatment of dipyridamole, aspirin, and a fixed low daily dose of warfarin can curb the bleeding complications. In patients with INR <5 without bleeding the next dose of warfarin should be omitted and/or the maintenance dose of warfarin is reduced. If the INR is 5-9 without bleeding, warfarin is stopped temporarily and a small dose of oral vitamin K daily (2.5-5 mg) is advocated.  In case of life threatening bleed 10 mg of intravenous vitamin K supplemented with fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa are recommended. ,,
| Conclusion|| |
We highlight an important aspect of management of patients needing chronic anticoagulation. Minimizing the risk factors that cause high INR, assessment of the severity of underlying disease and vigilance of complications comprise the cornerstone of managing patients with unusually high INR values.
| Acknowledgments|| |
We thank our colleagues and staff of the department of Internal medicine for their perpetual support.
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Department of Internal Medicine, Princess Durru Shehvar Children's and General Hospital, Purani Haveli, Hyderabad
Source of Support: Princess Durru Shehvar Children’s and General Hospital Hyderabad, Andhra Pradesh, India, Conflict of Interest: None