Paroxysmal cold hemoglobinuria constitutes a disorder that causes sudden-onset anemia, hemoglobinuria, and a variety of other systemic manifestations, following exposure to cold temperature. It is classified under the wider category of autoimmune hemolytic anemias.
Paroxysmal cold hemoglobinuria (PCH) has been a recognized medical entity for more than 150 years. It more commonly affects pediatric patients and is nowadays associated with prior infections, mainly pertaining to the respiratory tract. Cold temperatures act as a stimulus for a cascade of symptoms and signs to appear; the condition may lapse into chronicity with multiple episodes occurring in an individual's life, even though this is a rare phenomenon [1] [2].
Clinically significant symptoms and signs typically appear minutes after the patient has been exposed to cold, but the reaction may be delayed even to after a few hours following exposure. Hemolysis is severe to the extent that urine may appear brown-colored, with no or, rarely, minimal presence of blood. Fever with rigor is common, alongside abdominal cramping, pallor, nausea, vomiting, diarrhea, cephalalgia, and muscle spasms in the lower extremities. Should the kidneys be affected as well, the condition may progress to the renal dysfunction that presents with oliguria or even anuria in extreme circumstances; jaundice and urticarial rash may also develop [3].
Patients may report a history of prior infection localized in the respiratory tract during the past 1 to 2 weeks, although other types of infections have been linked to paroxysmal cold hemoglobinuria as well [4]. Hepatosplenomegaly may complete the clinical picture, as can microthrombosis which is an uncommon manifestation [5]. PCH is usually a self-limited, spontaneously resolving disorder that subsides over a period of a few days to some weeks after an episode [6].
PCH requires an extensive workup for an accurate diagnosis to be achieved. A thorough medical history should reveal symptoms compatible with this type of hemolytic anemia such as pallor, abdominal pain, muscle cramps, diarrhea, vomiting, and other manifestations, following exposure to a cold temperature. Patients often report a preceding respiratory tract or other infection.
Following the medical history, blood cell studies, biochemical blood studies, urinalysis, direct antiglobulin testing, and the Donath-Landsteiner test should all be performed. Blood analysis will reveal anemia of varying severity that is expected to be normocytic and normochromic or even macrocytic. Reticulocytopenia is a common finding, especially in cases where profound symptomatology is involved. Other morphological abnormalities may be observed in the red blood cells such as poikilocytosis, polychromasia, spherocytosis, and nucleated erythrocytes. Erythrophagocytosis by neutrophils may also be present and strongly indicates the presence of paroxysmal cold hemoglobinuria [7] [8] [9].
Free hemoglobin or methemoglobin and hemosiderin are usually detected via urinalysis, especially early in the course of a PCH episode. Erythrocytes are not a frequent finding but may also be observed. A complete serum biochemical profile is useful, as it will illustrate pathologically increased values of lactate dehydrogenase (LDH) and unconjugated bilirubin, decreased haptoglobin levels, and the existence of free plasma hemoglobin. During the acute phase of paroxysmal cold hemoglobinuria, complement concentration, namely, C2, C3, and C4, are found to be low.
A direct antiglobulin test with monoclonal C3 antisera is usually positive in the acute phase [10]. Lastly, the Donath-Landsteiner antibody test is considered diagnostic of PCH and is also expected to be positive in such a case.