Case of Donath-Landsteiner haemolytic anaemia in an adult female

Abstract

Donath-Landsteiner haemolytic anaemia (DLHA), also known as paroxysmal cold haemoglobinuria, is a very rare and difficult condition to diagnose as well as treat. Here, we present a case of a 55-year-old Hispanic woman who presented with severe intravascular haemolytic anaemia in the setting of a viral illness 2 weeks prior to presentation. Direct antiglobulin testing revealed mixed results: positive for either complement, IgG or both on various occasions which led to a battery of tests including the Donath-Landsteiner antibody testing which turned out positive establishing the diagnosis of DLHA. She was initially treated unsuccessfully with supportive care in the form of packed red blood cell transfusions and steroids as well as rituximab for about 4 weeks but her condition improved on cyclophosphamide, and she is on the road to recovery after 10 weeks of hospital stay.

Background

Donath-Landsteiner haemolytic anaemia (DLHA) is a form of acquired haemolytic anaemia caused by a complement fixing cold reacting IgG antibody directed against the P antigen which causes intravascular haemolysis on rewarming. It is usually seen in children following an episode of a viral illness and is responsible for one-third of the cases of autoimmune haemolytic anaemia (AIHA), whereas it is a very rare diagnosis in adults. It used to be associated with a diagnosis of congenital syphilis in adults which is very uncommon nowadays. Here, we present a case of DLHA in an adult woman following a viral prodrome which is an example of an atypical presentation of a rare condition since the clinical manifestations are non-specific and overlapping with other similar conditions. Also, the Donath-Landsteiner (D-L) test which is a pathognomonic marker for this condition is known to have low sensitivity. Her treatment has been very challenging since she did not respond to traditional treatments such as supportive care, warm environment and steroids but started improving on intravenous cyclophosphamide.

Case presentation

A 55-year-old woman with a medical history significant for diabetes, hypertension and obesity presented with a 1-week history of progressive crampy epigastric and right upper quadrant abdominal pain and an episode of influenza like illness about 2 weeks before hospital admission. Her vital signs were remarkable for tachycardia of 103 beats/min. Physical examination revealed an obese abdomen, normal bowel sounds and tenderness in the epigastrium and right upper quadrant without rebound tenderness or hepatosplenomegaly. After about 3 weeks of hospital stay, she developed dry gangrene of her right second and third toes (figure 1).

Figure 1.

Dry gangrene on right second and third toes in a patient with Donath-Landsteiner haemolytic anaemia.

Investigations

Laboratory studies revealed white cell count of 16×10⁹/L, haemoglobin 5.1 g/dL (baseline Hb >12.0), absolute reticulocyte count 0.468×10⁹/L, MCV 79.8, indirect bilirubin 5.8 mg/dL, lactate dehydrogenase (LDH) 2338 units/L, lactate 2.2, haptoglobin <8.0 and direct antiglobulin test (DAT) was initially positive for complement (C3). Viral studies were negative for mononucleosis, mycoplasma serology, rapid plasma reagin as well as respiratory viral multiplex panel. Cold agglutinin titre and antibody screen were negative. Peripheral smear revealed spherocytes, nucleated red blood cells (RBCs) and polychromasia, erythrophagocytosis was not noted. Her initial urinalysis on the day of admission did not reveal any haemoglobinuria and a subsequent urinalysis was difficult to interpret due to a urinary tract infection. Bone marrow biopsy did not reveal any clonal B cell proliferation or erythrophagocytosis. A repeat DAT was positive for both IgG and C3. A third DAT was performed which was positive for C3 only. Eventually, due to the mixed results of the DAT, we performed testing for the D-L antibody, a test specific for paroxysmal cold haemoglobinuria (PCH).

The test was performed at the New York Blood Center. P antigen is a common polysaccharide present on the RBC surface. D-L antibody is a biphasic IgG antibody that binds to the P antigen in the cold by fixing the early components of complement and causes complement mediated haemolysis as the temperature increases to 37°C. The antibody dissociates from the RBC’s at 37°C but the complement mediated haemolysis continues.¹ In the D-L test, the patient’s serum is cooled down to 4°C to allow fixing of complement to the P antigen, followed by warming of the sample to 37°C. If the sample shows haemolysis, the D-L test is positive. In her case normal human serum was used as the source of complement and the test result came out positive making the diagnosis of DLHA or PCH. The patient was transfused with packed red blood cells (pRBCs) prior to D-L testing but some data from case series show that it does not seem to impact the results of D-L testing.¹ Syphilis testing was negative.

Differential diagnosis

Cold agglutinin disease, mixed type AIHA, warm antibody AIHA and delayed haemolytic transfusion reaction.

Treatment

Patient was initially treated with supportive care in the form of pRBC transfusions through a blood warmer, warm environment and methylprednisolone pulse dosing for 5 days followed by a prednisone taper due to the mixed results of the testing. Due to minimal improvement and increasing pRBC transfusion requirements as well as ischaemic changes in the lower extremities, next she was treated with four cycles of weekly rituximab 375 mg/m² intravenous, also with minimal response and no change in pRBC transfusion requirements. Ultimately, the D-L antibody result came back positive and cyclophosphamide 750 mg/m² intravenous was added to the fourth cycle of rituximab and continued for two additional cycles biweekly for a total of three cycles in conjunction with steroid taper. She was hospitalised for 10 weeks and received a total of 30 units of pRBCs during her hospital stay which included 5 units of P antigen negative blood given after the diagnosis of DLHA was established.

Outcome and follow-up

A graph highlighting the trend of LDH, haemoglobin and indirect bilirubin is provided (figure 2).

Figure 2.

Graph highlighting the response to treatment with cyclophosphamide via lactate dehydrogenase (LDH), haemoglobin and indirect bilirubin trend.

Her haemolysis labs have improved, most recent LDH is 437 units/L and indirect bilirubin 0.6 mg/dL. Her most recent DAT is negative and repeat D-L antibody is negative after 12 weeks. Her haemoglobin is improving with every visit, the most recent value being 11.7 g/dL, and she has not required a pRBC transfusion in the past 5 months. Her reticulocytosis has also resolved, all signs of resolving haemolysis. She follows-up in our outpatient haematology clinic biweekly at this time for haemoglobin and haemolysis lab checks.

Discussion

AIHA can either be warm or cold, and the cold AIHA is further divided into two major categories: cold agglutinin disease and PCH or DLHA.

Cold agglutinin disease was ruled out in her condition due to a negative titre. Testing for paroxysmal nocturnal haemoglobinuria (PNH) was not pursued on account of a positive DAT, since PNH is DAT negative. The antibody screen was negative and the patient had labs significant for reticulocytosis as well as haemolysis on admission without any pRBC transfusions making delayed haemolytic transfusion reaction a low probability. The DAT being positive only for Complement only on two occasions combined with no response to steroids makes warm AIHA a low probability as well. The patient was not taking any medical drugs (despite having medical conditions) prior to her hospital admission and had labs significant for haemolysis on admission, ruling out drug induced haemolysis.

DLHA is a haemolytic anaemia caused by the presence of the D-L antibody, a specific cold-reacting immunoglobulin against the P or I antigen on the red blood cell surface.¹ DLHA can either be idiopathic or secondary to infections, autoimmune conditions or malignancy. It occurs almost exclusively in children (1%–5% of AIHA).² The male to female ratio for this disease is approximately 2:1 to 5:1.³ It presents with very non-specific symptoms including but not limited to abdominal pain, back pain, headaches, dark urine and so on. Laboratory testing showing severe haemolysis (increased indirect bilirubin, increased LDH and decreased haptoglobin) and the presence of D-L antibody are essential for diagnosing DLHA. Peripheral blood smear findings may include the presence of spherocytes and erythrophagoctosis but is non-diagnostic. The DAT is often positive for complement during and after an attack, however in some cases it can be positive for both IgG and C3 as seen in our case.¹

Gangrene is a very rare feature associated with this condition but it has been described in one other case report.⁴ The mechanism of gangrene is unclear but in her case, we propose that an ischaemic injury occurred due to decreased perfusion secondary to drop in haemoglobin to 4.3 g/dL on the day the complication developed which could have been made worse by underlying cardiovascular and peripheral vascular disease.

DLHA cases typically involve severe intravascular haemolysis and to date there are no established treatments for this condition. Severe cases may require hospitalisation and traditional treatments including avoiding cold exposure, warm clothing and blankets, transfusions using a blood warmer and if possible P antigen negative blood in refractory cases, folic acid supplementation, steroids, rituximab and cyclophosphamide.⁵ It is very important to note that haemolysis in these patients may continue for long periods of time from weeks to months.

There have been case reports describing supportive care with warm environment and transfusions as primary treatment of DLHA.⁶ There is also another case report describing rituximab as a primary treatment of refractory DLHA.⁷ Eculizumab, which is an antibody against the C5 component of the complement cascade could theoretically be a potential treatment for the condition but data are lacking in this regard.⁸ In our case, the patient was unresponsive to the conventional treatments described in the literature but improved on intravenous cyclophosphamide.

Patient’s perspective.

I am very glad that the rare condition I have was diagnosed and is being treated at this hospital. I am very thankful to all my doctors and the care provided that has led to an improvement in my condition. I feel much better than what I came into the hospital with. I am very happy to be discharged from the hospital and be able to go home. I am delighted to see that my haemoglobin numbers are improving and that I don’t require transfusions anymore. I will be very glad if other doctors can learn from my rare case and apply this knowledge for their patients.

Learning points.

• Donath-Landsteiner haemolytic anaemia or paroxysmal cold haemoglobinuria is a very rare form of cold autoimmune haemolytic anaemia in adult patients.

• Aetiology usually involves a preceding viral illness in children or an autoimmune or lymphoproliferative phenomenon in adults.

• Severe intravascular haemolysis and positive Donath-Landsteiner antibody are required for this diagnosis.

• Haemolysis can be chronic and may continue for weeks to months after diagnosis especially in the adult population.

• Supportive care, warm environment, packed red blood cell transfusions followed by immunosuppressive agents are the mainstay of treatment.