The Case

A 61-year-old woman presented to her primary care physician with uncontrolled high blood pressure and a complaint of leg pain. She was referred to the emergency department (ED) for urgent computed tomography (CT) imaging of the right leg to rule out an arterial clot. Her past medical history was notable for having had an aortic valve replaced with a titanium valve and chronic management at a therapeutic level of anticoagulation with warfarin, based on the International Normalized Ratio (INR).

CT imaging revealed two arterial thromboses in the right lower extremity. Echocardiography revealed a thrombus near the prosthetic heart valve. The attending physician was notified and ordered discontinuation of warfarin and initiation of a heparin drip for at least 5 days. The hospital’s usual protocol for adjusting the drip rate was followed. By hospital day 3, the right leg became discolored and cold, leaving the patient in extreme discomfort. She was told to “be patient” and not to worry about the discoloration, because she was being treated appropriately. Two days later, she complained of excruciating pain and more discoloration covering the entire right leg. Her leg was cold and pulseless; her toes appeared to be turning black. The surgical consultant arrived and told the patient that amputation of the limb might be needed. The surgeon expressed regret that they were not informed earlier of the patient’s discoloration and discomfort, as they would have intervened earlier. The patient was taken to the Operating Room (OR) to extirpate the arterial thrombus, but the surgeon also needed to split the calf muscle with a fasciotomy to reduce pressure in the calf and restore arterial blood flow. The surgeon later reported that it was the best he could do under the circumstances and apologized for miscommunication.

The Commentary

By Nasim Hedayati, MD, and Richard White, MD

Background

This case involves a patient who developed thrombosis on a mechanical aortic valve during ongoing chronic warfarin therapy, which manifested as two symptomatic arterial emboli to her right lower extremity. The patient safety issues center on confirming the aortic valve-associated thrombosis, providing appropriate anticoagulant treatment, and properly managing both the valve-associated thrombosis and the arterial emboli in the right leg, which presumably originated from the cardiac valvular thrombus.

It is important to recognize at the start that the differential diagnosis of peripheral arterial emboli in a patient with a mechanical valve should include infective endocarditis. Although this complication occurs more commonly on a mechanical mitral valve than on a mechanical aortic valve, the latter has a cumulative incidence of infective endocarditis of about 7% during a 15-year follow-up period.¹ Absent fever and other symptoms of endocarditis, we assume that infective endocarditis was ruled out in this case.¹

Long-term anticoagulation treatment using warfarin is necessary for all patients who have a mechanical aortic valve to reduce the risk of valvular thrombosis and systemic thromboembolism. The new direct-acting anticoagulants either do not prevent valve thrombosis or have not been adequately studied for this indication; therefore, use of these drugs (apixaban, rivaroxaban, edoxaban and dabigatran) is not recommended for patients with mechanical aortic valve(s).² 

Unfortunately, details about the type and age of the patient’s titanium valve are not included in this case. American College of Chest Physicians (ACCP) guidelines note that patients with a bi-leaflet aortic valve and no other risk factors for stroke are in the lowest risk category for cardiac valve-related thromboembolism, which represents a rate of less than 4% per year.³ This risk of thromboembolism is similar to that for patients with atrial fibrillation and a CHA₂DS₂-VASc score of 4 or less.⁴ The highest risk group (>10% risk per year) includes patients with either a mechanical mitral valve, an early first-generation mechanical aortic valve prosthesis (e.g., caged-ball, single-disk), or a history of stroke or transient ischemic attack (TIA) within the preceding 6 months. Patients in the intermediate risk group (4-10% per year) include those with a bi-leaflet aortic valve plus at least one additional risk factor for thrombosis such as atrial fibrillation, history of a stroke or TIA, or risk factor(s) for stroke, such as hypertension, diabetes, congestive heart failure, or age >75 years. Current guidelines³ recommend a target INR of 2.5, with an acceptable range between 2.0 and 3.0, for patients with a bi-leaflet mechanical aortic valve, and a higher target INR of 3.0, with a range between 2.5 and 3.5, if the patient’s aortic valve is either an older tilt disc or ball valve, or if the patient has one or more additional specific risk factors for thrombosis: prior thromboembolism, atrial fibrillation, rheumatic mitral stenosis, or ejection fraction <35%.  

The risk of thrombosis increases exponentially as the INR falls from 2.0 down to 1.0.⁵ However, patients with a mechanical aortic valve may survive months and even years off warfarin anticoagulation treatment.⁶ Anderson et al.⁷ followed 43 patients who had first-generation aortic valve replacement surgery between 1972 and 1982, and who received anticoagulation treatment for only approximately 1 year (mean = 13 months, range 4-35 months) thereafter, for an average of 7.25 years. After 5 and 10 years, 70% and 59% of these patients, respectively, had no clinical thromboembolic events and 65% and 55%, respectively, had no valve-related events whatsoever. The take-home point from this study is that adequate anticoagulation treatment is not compulsory for patients with mechanical aortic valves, and that transiently low or even normal INR values do not invariably lead to valve-related thrombosis. Instead, some other “trigger event” is probably necessary to cause a valve thrombosis (with or without systemic thromboembolism), such as an infection (e.g., cellulitis, COVID-19) that activates the coagulation cascade. Conversely, most valve-related thromboembolism events occur in patients with INR values between 2.0 and 4.0. Thus, it is common for patients with mechanical valve-related thrombosis to present with an INR in their target range.

In this case, we are not told what the INR value was when the patient was evaluated in the emergency department (ED), only that she was chronically anticoagulated using warfarin “with a therapeutic INR.” In most patients, INR values vary significantly over time and more INR values register below the desired target range than above the target range. Maintaining the INR within the target range for a patient more than 70% of the time is considered “good control.” If the INR value falls below a value of 1.8, and especially if the INR is <1.5, prompt addition of subcutaneously administered low molecular weight heparin (enoxaparin, 1 mg/kg given every 12 hours) is recommended until the INR rises above 2.0.³

In a patient with acute mechanical valve thrombosis, with or without arterial thromboembolism, intravenous therapeutic heparin coupled with discontinuation or reversal of warfarin is recommended, in part because intravenous heparin therapy can be rapidly reversed with protamine if bleeding occurs or if urgent/emergent surgery is necessary. If there is no active bleeding and if the patient is not at high risk for bleeding, a bolus of 2500 IU of heparin should be given, followed by an intravenous heparin drip of 18 units/kg/hr. Without administering such a bolus, it may take 12-24 hours to reach a therapeutic heparin level. Intravenously administered heparin is managed using either a calibrated activated partial thromboplastin test, aiming for a value approximately 1.5-2.0 times the laboratory control value, or a heparin-calibrated anti-Xa level assay, targeting a value between 0.3 and 0.7 units per milliliter. Unless urgent surgery is needed, warfarin can be simply reversed by giving 2 mg of vitamin K intravenously over 10 minutes in 5% dextrose.

However, heparin does not, by itself, lyse a thrombus. Hence, the patient in this case, who was experiencing both valve thrombosis and arterial thromboembolism, needed to be urgently assessed by an experienced cardiovascular surgeon and vascular specialist to determine whether a better option than intravenous heparinization, such as thrombolysis, urgent valve surgery or peripheral vascular surgery, should be pursued. If the hospital that this patient was admitted to did not have a skilled vascular specialist available, she should have been transferred to a tertiary hospital that did have a vascular specialist on call.  

Acute limb ischemia results from a rapid decrease in blood flow in an extremity due to occlusion of an artery secondary to an embolism or thrombosis. In a lower extremity, this can occur in a bypass graft or in native vessels. The symptoms of acute limb ischemia are typically pain, numbness, coldness of the extremity, paresthesia, and discoloration, which may worsen with the exacerbation of the ischemia. Stages of acute limb ischemia in the lower extremity have been established and depend on the extent of loss of sensory and motor function and arterial signals in the foot. The viability and prognosis of the extremity is determined based on those findings.

Diagnosis of acute limb ischemia in a lower extremity is based on the patient’s medical history, visual and physical examination, and a Doppler examination if pulses are not palpable in the patient’s feet. An important component of the medical history is whether the patient has a prior history of claudication or lower extremity arterial interventions. Contrast-enhanced CT of the aorta with lower extremity run-off has become a useful tool in the ED to gather important information about aneurysms, arterial calcification, and sources of thrombosis/embolism. If CT angiography is contraindicated or unavailable, arterial duplex ultrasound is a low-cost, non-invasive imaging modality that can be used to assess the lower extremity for the location of arterial occlusion, the presence of plaque or thrombus, and the extent of arterial occlusive disease. Electrocardiography and echocardiography are also used to determine if an irregular heart rhythm or a cardiac thrombus may be predisposing to peripheral arterial emboli.

If there are no contraindications, treatment of acute limb ischemia starts with intravenous heparin anticoagulation with a heparin bolus followed by a continuous infusion. If symptoms worsen while the patient is on this heparin drip, images should be retaken while emergent consultation is being sought. CT aortogram with run-off is a good imaging option for evaluating for propagation of a thrombus or development of a new thrombus. Definitive treatment of acute limb ischemia includes operations such as thrombectomy and bypass if needed, or endovascular management, including catheter-directed thrombolysis, percutaneous thrombectomy and stent placement, or a combination of both. Depending on the severity of symptoms, surgery may be the best option available for the patient. In severe cases of acute limb ischemia in which irreversible damage has occurred and the extremity is non-viable, amputation is the only option.

Approach to Improving Safety and Patient Safety Target

Although we do not know this patient’s INR value at the time she was first evaluated, the initial choice of intravenous heparinization for treating this patient with arterial thrombosis was appropriate and consistent with current standards of care. However, without specifics about the heparin dose, how frequently heparin monitoring was ordered, and the timing of subsequent adjustments, it is impossible to completely evaluate the execution of the heparin treatment in terms of patient safety.

Because a thrombus “in proximity” to the valve was documented on echocardiography, associated with peripheral arterial embolization, a cardiac surgeon should have been urgently consulted. If the hospital could not provide this consultation, emergent transfer to a tertiary care center should have been arranged. Specialty consultation could have determined if more imaging was needed and recommended the optimal frequency of ultrasound monitoring to mitigate the risk of progressive valvular dysfunction. To this end, transesophageal ultrasound is generally preferred over transthoracic ultrasound, particularly for mitral valve thrombosis.  

Similarly, because arterial thromboembolism had been documented by CT examination with contrast of the lower extremity and the patient was complaining of leg pain, emergent vascular surgical consultation should have been obtained. In hospitals where vascular surgical consultations are not available due to staffing issues, ED physicians can seek phone consultations and ask for transfer if a higher level of care is recommended. With or without specialty consultation, a detailed physical examination should have been performed on the painful leg to determine limb viability. Viable limbs have minimal pain, no loss of sensation in the toes and feet, normal muscle strength, and audible doppler signals for both arteries and veins.

Take-Home Points

• Acute limb ischemia is a medical emergency requiring urgent evaluation and treatment.
• Appropriate consultation to vascular surgery, interventional radiology or interventional cardiology should be undertaken when an arterial thrombosis is diagnosed to help guide decision-making regarding the best treatment option.
• When patient symptoms worsen while on heparin drip, images should be retaken while emergent consultation is being sought. CT aortogram with run-off is an appropriate imaging option for evaluating for propagation of a thrombus or development of a new thrombus.

Nasim Hedayati, MD
Professor, Department of Surgery
Medical Director, UC Davis Vein Center
UC Davis Health

Richard White, MD
Professor, Department of Internal Medicine
UC Davis Health

References

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