Paroxysmal Cold Hemoglobinuria Clinical Presentation

Updated: Mar 13, 2018
  • Author: Neetu Radhakrishnan, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Presentation

History

The initial inciting event to the predisposition of Donath-Landsteiner (D-L) antibody synthesis remains unknown. However, paroxysmal cold hemoglobinuria can occur soon after developing upper respiratory and gastrointestinal symptoms. [20]

Once strongly linked with syphilis, paroxysmal cold hemoglobinuria is now associated with numerous infectious agents. Identified pathogens have included the following: measles, mumps, influenza, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, parvovirus B19, Coxsackie A9, Haemophilus influenzae, Mycoplasma pneumoniae, and Klebsiella pneumoniae. [6, 8, 9, 21] The development of the D-L antibody has also been reported following measles immunization. Other associations include solid organ and hematopoietic neoplasms . [12]

Within minutes to a few hours of exposure to cold temperatures, the patient develops a combination of the following: sudden onset of back and abdominal pain, headache, leg cramps, fever, rigors, chills, nausea, vomiting, diarrhea, and esophageal spasms. The hemoglobinuria can be severe enough to alter the urine to a dark red-brown color, although hematuria is generally minimal or absent. Oliguria or anuria can develop upon renal dysfunction. Cold urticaria and jaundice may also occur. [22] These generalized symptoms are likely attributed to the release of large quantities of hemoglobin from lysed RBCs, which then act as an irritant to various tissues.

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Physical

Patients who present with paroxysmal cold hemoglobinuria are in acute distress, with obvious pain and elevation of body temperature.

Symptoms associated with respiratory infection are the most common initial presentation.

Physical signs of massive RBC hemolysis include pallor, icterus, and urticarial dermal eruption. Severe hemoglobinuria is commonly detected during the acute event, resulting in a red-brown discoloration to the urine.

Hepatosplenomegaly can be attributed to an underlying lymphoproliferative or other neoplastic process, but it has also been observed as a reactive process in 25% of paroxysmal cold hemoglobinuria cases. A clinical examination (to rule out lymphadenopathy and/or splenomegaly) is obligatory.

Another feature can be sequelae of microthrombosis, but generally it is rare. [23]

Other constitutional symptoms are likely related to an underlying secondary pathologic process.

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Causes

Known risk factors for paroxysmal cold hemoglobinuria are attributed to underlying pathogenic states, including infectious diseases and neoplasms (see History).In the adult population, infections and neoplasms have been associated with the development of D-L antibody. [24]

Reported neoplasms include solid organ carcinomas as seen with pulmonary small cell carcinoma and hematopoietic disorders such as non-Hodgkin lymphoma (NHL), chronic lymphocytic lymphoma (CLL), primary myelofibrosis with myeloid metaplasia, myelodysplastic syndrome, and in the presence of a monoclonal protein with Bence Jones proteinuria. [7, 12, 25, 26, 27, 28, 29]

In most cases, the P antigen must be present on the RBCs for paroxysmal cold hemoglobinuria to develop. As most people express P antigen on their erythrocytes, nearly the entire population is susceptible to reactivity by the D-L antibody.

The degree and duration of hypothermia that is required to precipitate hemolysis depends on the temperature requirement of the antibody-RBC reaction and on the concentration availability of complement.

Male sex appears to be a risk factor in at least 1 study. [15]

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