Introduction

Cold antibodies are antierythrocytic auto-antibodies which bind red blood cells at cold temperature (28 to 31⁰C, even 37⁰C or more) and produce hemolysis. They are usually IgM but can be IgG antibodies which arise due to infections, malignancies or idiopathic.¹

Case Report

A 21-year-old female presented with pain abdomen, fever, and burning micturition in the Outpatient Department of our hospital. On admission, she was diagnosed with bilateral renal calculi, and bilateral percutaneous nephrostomy was done under USG guidance. Pyelolithotomy was deferred due to severe anemia with hemoglobin of 6 gm%, and the unavailability of suitable blood donors. She was discharged with hematinics, surgery having been postponed until her hemoglobin improved.

The patient came back after one month with fever, dehydration, hematuria, drowsiness, and pus draining through both percutaneous nephrostomy. She was immediately shifted to the ICU. On investigation, her coagulation profile was normal, hemoglobin – 5 gm%, and serum creatinine – 7.9 mg/dL. Blood culture showed growth of Klebsiella pneumoniae, sensitive to Imipenem. Urine culture from right nephrostomy tube showed Klebsiella pneumoniae, and Enterobacter species, both sensitive to Imipenem. Urine from left nephrostomy tube showed growth of Enterobacter species, also sensitive to Imipenem. Urine per urethra showed growth of Enterobacter species, sensitive to Imipenem, and Escherichia Coli which showed resistance to all antibiotics tested.

The urethral and nephrostomy tubings were regularly flushed with normal saline. Injection Meropenem was started based on sensitivity and creatinine clearance, at a once daily dose of 1 gram. Dehydration and electrolyte imbalance was corrected. Due to persistent hematuria and low hemoglobin, decision was made to transfuse blood to the patient. Blood group and cross matching samples from the patient showed the presence of cold antibodies, which caused hemolysis at temperatures greater than 37°C. The blood bank refused to release blood after repeatedly confirming the finding with repeat samples from different sites.

Management of the patient was immediately directed at reducing hemolysis by maintaining patient’s body temperature above 37.5°C with prewarmed intravenous fluid infusions, and Injection Hydrocortisone 100 mg IV qid. Within 24 hours, hematuria had decreased. However, repeat blood samples still showed presence of cold antibodies, which prevented any decision on transfusing blood. Hence, other measures to improve hemoglobin level such as injectable Iron and Erythropoetin, was undertaken. Gradually, the patient improved with cessation of hematuria and pus discharge, and reduced serum creatinine level of 3.7 mg/dL.

On the 11^th ICU day, the patient suddenly deteriorated with the development of pulmonary edema and severe anemia (Hb – 2.9 gm%), and she died subsequently.

Discussion

Landsteiner first described cold antibodies in 1903. In 1904, the connection between cold antibodies and red cell destruction was made. In 1950s, Schubilhe coined the term, cold agglutinin disease (CAD), which consists of primary CAD, secondary CAD, and paroxysmal cold hemoglobinuria (PCH).

Primary CAD: Occurs in older population around age 70, more in females, and is usually associated with monoclonal IgM antibodies. This antibody targets the adult RBCs (antigen I) and is seen in B-cell neoplasm and non B-cell tumors.

Secondary CAD: Occurs in young adults, is associated with monoclonal/polyclonal IgM immunoglobins, and targets both adult RBCs (antigen I) and infant RBCs (antigen i), seen following infections which last for 2-3 weeks.

Paroxysmal cold hemoglobinemia (PCH): It was common in the preantibiotic era, and now an exceptional condition which is historically a variant of syphilis². It occurs more in children around 5 years, and is associated with polyclonal IgG, also called Donath Landsteiner antibody. It targets both adult and infant RBCs (antigen p) because of protease sensitivity, and is seen after viral and bacterial infections.

Figure 1

TABLE-1: TYPES OF COLD AGGLUTININ DISEASE

(PCH - paroxysmal cold hemoglobinuria, DAT- direct antiglobulin test, C3 - complement third component, RBC -Red blood cell)

Figure 2

TABLE – 2: CAUSES OF COLD AGGLUTININ DISEASE (CAD)

In pathophysiology, the cold antibodies bind to erythrocytes in the cold peripheral circulation (nose, feet and hands), and rapidly dissociate at higher visceral circulation. This binding time is sufficient to activate the complement cascade to stage C3b. Many C3b RBCs escape the macrophages in hepatic circulation, but are inactivated by the C3b inactivator of the systemic circulation. If the C3b inactivator protein is impaired, the complement system gets completed and causes RBC destruction⁴. ^{In PCH, the cold biphasic IgG antibody (Donath Landsteiner antibody) binds to the RBCs in the cold peripheral circulation, but activates complement and causes hemolysis on rewarming to 37°C (core body temperature) 5.}

The typical patient presents with mild to severe hemolytic anemia, pallor, and jaundice. Some have intermittent bursts of hemolysis with hemoglobinemia and hemoglobinuria. Acrocyanosis (cold, stiff, painful) occurs in cold peripheries such as hands, ears, nose, and feet, which is reversible on warming. Some have mild hepatomegaly, but enlarged spleen and lymph nodes warrant the search for neoplasm⁶. ^{On exposure to cold, patients with PCH present with symptoms like fever, rigor, leg pain, back pain and abdominal pain followed by hemoglobinuria, anemia and eventually renal failure7.}

Cold agglutinin disease is suspected when there is difficulty obtaining red cell count and indices, due to agglutination of RBCs. Agglutinates visible in the specimen tube and dissolution on warming indicates the presence of cold antibodies. Typing and cross-matching becomes difficult due to clumping of RBCs at room temperature in cases of high thermal amplitude cold antibodies. Therefore, all cross-matching should be performed at 37^°C with the use of IgG-specific antiglobulin reagent. Thus, misleading results are avoided due to cold antibodies in the serum or RBC bound C3d. In primary and secondary CAD, the direct antiglobulin test is positive with titers from 1:10,000 to 1: 1,000,000 measured at 4°C, but lower levels are significant if measured at 37C. In PCH, Donath Lansteiner test is positive⁸.

Majority of patients require no specific treatment other than avoiding temperature below which hemolysis occurs, bed rest, and oxygen therapy. Secondary CAD and PCH require no therapy due to transient nature of the antibody. Treating the underlying disease is of prime importance. It is best to avoid blood transfusion due to risk of agglutination, which poses significant difficulty in blood grouping. However, in circumstances of cardiovascular compromise such as heart failure and ischemic conditions, the least incompatible unit or washed RBC concentrate is given with caution through an inline blood warmer at a temperature of 37^°C, or a temperature at which hemolysis does not occur. Transfusion should be attempted at a slow rate initially and discontinued if hemolysis is imminent. Transfused RBCs have increased susceptibility to lysis by cold antibodies in comparison to autologous RBCs, which lack proteolytically cleaved complement on their surface and inhibit complement-mediated lysis⁹. Steroid is beneficial in low titre antibody with high thermal amplitude. Plasmapheresis is effective only temporarily, because new antibodies are constantly formed.

Immunosuppressive therapy (cyclophosphamide and chlorambucil) suppress the production of pathologic antibody. Splenectomy, is not beneficial because most red cell destruction occurs in the liver¹. ^{Recently, rituximab (anti-CD20 monoclonal antibody) has been used in a number of centers to treat cold agglutinin disease 10.}

In conclusion, although cold antibodies are not commonly seen, yet the knowledge of cold antibodies and management of associated disorders are of particular importance to the anesthesiologist and intensivist, who deal a lot with blood and blood products.