Poor Frostbite Outcome Highlights Importance of Early Disease ID

Frostbite with cold agglutinin disease (CAD) in an elderly woman in France led to the patient’s death after an amputation failed to resolve the condition, a case study reported.

This case highlights the importance of early identification and treatment of CAD to improve patient outcomes in the presence of frostbite, the researchers said.

Titled “Frostbite and Cold Agglutinin Disease: Coexistence of Two Entities Leading to Poor Clinical Outcomes,” the case study was published in the journal Medicina.

CAD is caused by a misdirected immune response in which self-reactive antibodies, known as cold agglutinins, bind to red blood cells at low temperatures. This causes red blood cells to disintegrate (lyse), resulting in hemolytic anemia and a lack of oxygen throughout the body.

In 90% of patients, CAD symptoms are associated with issues in blood circulation. These may range from the mild dark purple discoloration of the fingertips, toes, nose, and ears that’s known as acrocyanosis, to Raynaud’s phenomenon, a cold-induced condition in which fingertips and toes become bluish and numb due to blood vessel constriction.

In some cases, patients can experience an irregular heartbeat (arrhythmia) or have an enlarged heart, as it works to compensate for the lack of red blood cells.

Frostbite is a skin injury resulting from tissue damage from extended exposure to temperatures below 0 degrees C (32 F). In severe cases, the skin can turn white or bluish-grey, forming blisters that become black and hard as the tissue dies.

The coexistence of both CAD and frostbite may have severe consequences for patients, and even lead to death, as illustrated by the case of an 83-year-old woman treated at Strasbourg University Hospital in France. Her case was described by researchers in a recent report.

The woman was admitted to the hospital after experiencing fatigue for seven days, along with progressive acrocyanosis — a persistent, painless, bluish discoloration — in both her hands and feet.  She also had blisters of dead skin tissue (necrotic lesions).

These symptoms developed after she had been exposed to temperatures of around -10 C (14 F) for about one hour, despite wearing protective clothing. She reported no improvements after warming at home.

The patient did not have fever, chills, or weight loss, but developed progressive shortness of breath two days before being admitted. She had a history of Raynaud’s, heart arrhythmia, and Graves disease — an autoimmune disorder that targets the thyroid gland, resulting in symptoms that include muscle weakness, sleeping problems, a fast heart rate, and low heat tolerance.

She had been taking medications for high blood pressure, heart arrhythmia, and a fast heartbeat. She lived alone, had no known food allergies, and no history of smoking, or alcohol or substance abuse.

A physical examination showed the patient had an elevated heart rate of 130 beats per minute (normal 60–100 beats/min), but her blood pressure, breathing rate, and blood oxygen levels were in the normal range.

The bluish discoloration was noted in the feet, from the toes to the ankles, and in both hands, from the fingers to the wrist. She also had necrotic lesions on her hands, fingers, and toes. Additionally, the woman displayed mild jaundice — a symptom of CAD — evidenced by yellowish skin, and her heart sounds were irregular.

Blood tests showed she had elevated white blood cell counts and C-reactive protein levels, an inflammation marker. Her hemoglobin level (7.6 g/dL) was below the normal range of 12–16 g/dL, and her haptoglobin was undetectable, a sign of hemolytic anemia. Of note, hemoglobin is the protein in red blood cells that transports oxygen, while haptoglobin is a protein that binds hemoglobin circulating freely in the bloodstream, preventing it from being eliminated through the kidneys.

The patient also had high levels of bilirubin, a marker of liver disease. An electrocardiogram showed she had an irregular and often rapid heart rate (atrial fibrillation). She was transfused with two units of blood, reaching a hemoglobin level of 9 g/dL.

Given the signs of hemolytic anemia, a Coombs test was ordered, which ended up revealing the presence of cold agglutinins. Based on this test, she was diagnosed with CAD.

Meanwhile, her skin manifestations worsened, especially in the hands, which became a reddish-purple color up to the wrist and yellowish-brown up to the elbows.

To salvage as much tissue as possible, the patient was treated with aspirin, as well as iloprost infused directly into the bloodstream. Iloprost is a vasodilator medicine that helps open up blood vessels.

Even after two more units of blood were transfused, her hemoglobin dropped from 9 to 7.2 g/dL.

All tests for viruses, which can trigger CAD, were negative. Further blood tests showed the presence of the antibody immunoglobulin M. This prompted an examination of immune cells, which was suggestive of lymphoplasmacytic lymphoma — a rare slow-growing blood cancer that affects antibody-producing B-cells.

After three days of treatment, her necrotic lesions continued to spread to the level of frostbite. Five days after treatment began, there were no signs of response, and attending physicians decided to discontinue treatment. After discussions with dermatologists, orthopedic and vascular surgeons, the decision was made to amputate the affected tissue areas.

She underwent plasma exchange to remove the disease-causing antibodies. She then was prescribed the anti-lymphoma medicine bendamustine, and rituximab, a therapy that lowers the levels of immune B-cells.

Regardless of these efforts, the necrosis progressed, which prompted discussions of additional amputations. However, due to the high risk and a refusal by the patient, she instead was given only supportive treatment. The patient died one month after hospital admission.

“Frostbite and CAD require early identification and treatment to improve outcomes,” the researchers wrote.

“Regarding the management of CAD patients, early diagnosis of CAD and prevention of CAD attacks such as acrocyanosis and subsequent hemoglobinuria [hemoglobin in the urine] are crucial in avoiding critical complications,” they concluded.