A Case of Paroxysmal Cold Hemoglobinuria with Subsequent Progression to Acute Myelogenous Leukemia

Case Report

Ann Hematol Oncol. 2016; 3(10): 1118.

A Case of Paroxysmal Cold Hemoglobinuria with Subsequent Progression to Acute Myelogenous Leukemia

Ibrahim M*, Ogunleye F, Stender M, Jaiyesimi I and Huben M

Department of Hematology and Oncology, Oakland University William Beaumont School of Medicine, USA

*Corresponding author: Mohammed Ibrahim, Department of Hematology and Oncology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan 48073, USA

Received: September 19, 2016; Accepted: October 18, 2016; Published: October 21, 2016


Paroxysmal cold hemoglobinuria is a rare hematologic condition that causes autoimmune complement-mediated hemolysis on exposure to cold temperatures. The spectrum of presentation can range from a self-limited postviral hemolysis to a life-threatening acute hemolytic anemia. Timely recognition of this condition is critical, given the associated morbidity and mortality. We report a case of a 65 year-old male who presented to the hematology clinic with anemia and fatigue. Laboratory investigations revealed macrocytic anemia with elevated lactate dehydrogenase level, low haptoglobin and the presence of urine hemosiderin, raising concern for intravascular hemolysis. Testing for Donath Landsteiner antibody was positive, confirming the diagnosis of paroxysmal cold hemoglobinuria. Supportive care measures were instituted and the patient was told to avoid cold exposure. The patient eventually developed acute myelogenous leukemia and succumbed to the disease. It is important for physicians to be vigilant to the possibility of coexisting or subsequent malignancies in patients diagnosed with paroxysmal cold hemoglobinuria.

Keywords: Paroxysmal cold hemoglobinuria; PCH; Hemolysis; Anemia; Acute myelogenous leukemia; AML


Paroxysmal Cold Hemoglobinuria (PCH) is a rare cause of autoimmune complement-mediated hemolytic anemia. In 1872, a syndrome with the occurrence of red colored urine after exposure to cold temperature was described. The antibody causing PCH was first reported by Donath and Landsteiner in 1904 [1]. PCH causes a hemolytic anemia due to a cold-reacting polyclonal IgG antibody that binds to “P” antigen on the surface of the Red Blood Cell (RBC) in cold temperature and fixes complement. When the RBCs are subsequently warmed to 37°C, the complement cascade is activated, causing intravascular hemolysis, hemoglobinuria and hemosiderinuria [2].

Most cases of PCH are seen in children, where it accounts for 1-5% of childhood Autoimmune Hemolytic Anemia (AIHA) cases. In one review of 52 cases of PCH, the age range was 1 to 82 years with a median age of 5 years of age. Sokol, et al. [3] have estimated that the annual incidence of PCH is 0.4 cases per 100,000 people. The most common origins of PCH are post-infectious (eg., measles, mumps, Epstein-Barr virus (EBV), influenza, Mycoplasma pneumoniae) and autoimmune (related to lymphomas, Chronic lymphocytic leukemia (CLL), myelofibrosis, myelodysplastic syndrome and small cell lung cancer) [4-8]. Association with tertiary syphilis has been well described, as a syphilis antigen generates a cross-reacting antibody that causes this syndrome.

The adult form of PCH is usually chronic, lasting several years. Clinical features include presence of dark colored urine (hemoglobinuria) beginning several minutes to hours after exposure to cold, as well as Raynaud’s phenomenon, back pain, leg pains, abdominal pain, chills and fever, and general malaise related to the release of large quantities of hemoglobin from lysed RBCs, which then act as an irritant to various tissues. Laboratory investigations demonstrate evidence of intravascular hemolysis with jaundice, reticulocytosis, hemosiderinuria, elevated indirect bilirubin, elevated lactate dehydrogenase (LDH) level, low haptoglobin and low complement. The hemolysis can be acute and massive. Spherocytes and erthrophagocytes may be seen on the peripheral smear [9,10]. Direct Antiglobulin Test (DAT) can be positive for anti C3 and negative for IgG during the hemolytic episode.

Diagnosis is made using the Donath Landsteiner test. The patient’s serum is incubated with normal RBCs and pooled human serum (as a source for complement) at 40C, which allows the antibody and the early components of complement to be fixed, and then at 37°C for later components of complement to be activated [1,11]. Hemolysis occurs if the antibody is present.

Treatment of PCH includes supportive care to keep patient warm and avoiding exposure to cold. If life-threatening anemia occurs, transfusion of packed RBCs through a blood-warming device is needed. Most patients develop iron deficiency and require iron replacement. In general, the prognosis of PCH is good with most patients responding to supportive measures and treatment of any underlying condition [3]. There has been one case report of an 18-yearold female who was diagnosed with PCH during pregnancy. With supportive measures alone, hemolysis resolved within 6 weeks and she had a successful pregnancy outcome with no evidence of hemolysis or anemia in the newborn [12]. Anecdotal reports have indicated the use of steroids (oral prednisone at a dose of 1 mg/kg) to be beneficial if symptoms are severe and/or life-threatening. For chronic episodes, immunosuppression with prednisone, cyclophosphamide and/or azathioprine have been tried [11]. Koppel, et al. [13] described a case of a 64 year old female with steroid-refractory PCH who was treated with rituximab 375 mg/m2 weekly for 4 doses and had a normalization of her hemoglobin and cessation of hemolysis. When the hemolytic anemia recurred after 9 months, this patient was re-challenged with the same regimen of rituximab and again had a cessation of hemolysis and normalization of her hemoglobin. She remained in remission at 19 month follow-up. Eculizumab has been tried in 1 patient with PCH associated with multiple myeloma, but the patient did not have a response [14]. Given the rarity of this condition, it is unlikely that prospective clinical trials will ever be conducted. There is no role for splenectomy as hemolysis is intravascular.

The main differential diagnosis of PCH is cold agglutinin disease. This is associated with agglutination of red blood cells on the peripheral smear, elevated titers of Ig M cold agglutinin, but the Donath Landsteiner test is negative (Table 1).