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CASE REPORT
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Donath-Landsteiner hemolytic anemia with erythrophagocytosis and platelet phagocytosis in peripheral smear: Rare findings


1 Consultant Pathologist, Department of Laboratory Medicine, Yashoda Hospitals, Hyderabad, Telangana, India
2 Consultant Biochemist Department of Laboratory Medicine, Yashoda Hospitals, Hyderabad, Telangana, India
3 Consultant Transfusion Medicine, Department of Transfusion Medicine, Yashoda Hospitals, Hyderabad, Telangana, India

Date of Submission04-Jul-2020
Date of Decision27-Nov-2020
Date of Acceptance14-Dec-2020

Correspondence Address:
Majed Abdul Basit Momin,
Department of Laboratory Medicine, Yashoda Hospital, Malakpet, Nalgonda X-Roads, Hyderabad - 500 036, Telangana
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_373_20

  Abstract 


The Donath-Landsteiner (DL) hemolytic anemia or paroxysmal cold hemoglobinuria (PCH) is a rare subtype of autoimmune hemolytic anemia (AIHA). We report here a case of a 22-year-old young female who presented with acute onset shortness of breath. Routine hematological investigation revealed erythrophagocytosis and platelet phagocytosis by monocytes in peripheral blood smear, which are rarely reported in AIHA, especially the DL. The unusual blood smear findings directed the pathologists to initiate workup for hemolytic anemia that yielded positive results in direct Coombs test C3d (Complement) and direct DL test. The findings confirmed the case as DL hemolytic anemia. To the best of our knowledge, this is the first report of both erythrophagocytosis and platelet phagocytosis in peripheral blood smear in PCH.

Keywords: Autoimmune hemolytic anemia, Donath-Landsteiner test, erythrocyte and platelet phagocytosis, paroxysmal cold hemoglobinuria



How to cite this URL:
Basit Momin MA, Aluri A, Bala Bhaskar P M. Donath-Landsteiner hemolytic anemia with erythrophagocytosis and platelet phagocytosis in peripheral smear: Rare findings. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Dec 6]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=319301




  Introduction Top


Paroxysmal cold hemoglobinuria (PCH) is a self-limited, rare form of autoimmune hemolytic anemia (AIHA), occurring mostly in children and young adults, usually triggered by a viral infection. PCH is characterized by intravascular hemolysis due to the involvement of Donath-Landsteiner (DL) antibody. This is cold reacting antibody with unique features to bind P antigen on red blood cells (RBCs) at cooler temperature (optimally at 4°C), but when the temperature is shifted to 37°C, lysis of red cells takes place in the presence of complement resulting in intravascular hemolysis and hemoglobinuria.[1],[2] Erythrophagocytosis by monocytes and neutrophils has been reported rarely in cold agglutinin disease,[2] hematological malignancies,[3] viral infections[4], and spider bite.[5] Platelet phagocytosis by monocytes in peripheral blood smears is extremely rare and seen in hemophagocytic lymphohistiocytosis and dengue viral infection.[6] To the best of our knowledge, this is the first reported case of such coexistent peripheral smear findings in PCH.


  Case Report Top


A 22-year-old young, female patient was presented to the emergency department of our hospital with a history of fever, shortness of breath, cough, and vomiting for 7 days. She was passing redbrown colored urine for the past 3 days and had a history of reduced appetite, generalized weakness, and dizziness. On clinical examination, the patient was found febrile, pale, and had icterus. She had tachycardia of 110/beats per min, blood pressure 90/60 mm of Hg with a respiratory rate of 30 breathes/min. Systemic examination was unremarkable except for the bilateral crackles that were heard in both the lungs more at base.

The initial laboratory investigations revealed [Table 1] severe anemia and high RBCs indices, neutrophilic leukocytosis, and moderate thrombocytopenia [Table 1]. Peripheral blood smear showed normocytic and macrocytic RBCs with polychromasia, and eight nucleated RBCs were recorded for every100 white blood cells.
Table 1: Laboratory findings

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At places, phagocytosis of erythrocytes by monocytes (erythrophagocytosis) [[Figure 1] upper circle inlet] and phagocytosis of platelet by monocyte [[Figure 1] lower circle inlet] seen.
Figure 1: Photomicrograph of peripheral blood smear (Leishman stained original magnification × 1000) showing polychromasia and nucleated red blood cells (blue and red arrow, respectively) along with phagocytosis of erythrocytes (upper inner circle inlet) and platelet by the monocytes (lower inner circle inlet)

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A few immature myeloid precursors were seen that were suggestive of leukoerythroblastic picture secondary to acute hemolytic anemia. Reticulocytosis was present with a reticulocyte percentage as high as 64%. During blood grouping, there was discrepancy between cell and serum grouping at room temperature, which was, however, resolved when the tests were performed at 37°C using the tube technique. Direct Coombs test specific for complement C3 was positive. Indirect Coombs test was also positive and there was panagglutination in the screen cell panel with uniform strength of reactivity. The sample was positive in the direct DL test. The autoantibody titers, when performed at cold temperature, were found to be high (>256). Incompatibilities during random crossmatch with packed RBCs were also found (probably due to the autoantibody interference) and the least incompatible units were issued for transfusions. The blood coagulation studies, including tests for prothrombin time, activated partial thromboplastin time, and fibrinogen, were normal. Serological tests for hepatitis B virus, hepatitis C virus, HIV, and syphilis were negative. Complete urine examination showed few RBCs and proteinuria (1+, 50 mg/dl, respectively). Biochemical investigations revealed indirect bilirubinemia and elevated lactate dehydrogenase [Table 1]. Based on the results of these hematological and biochemical parameters, the diagnosis of DL positive hemolytic anemia was made.

Radiological imaging, X-ray chest (anteroposterior view) showed nonhomogenous opacity in the right lower zone and few parenchymal infiltrates in the left lower zone. Computed tomography scan of the chest revealed consolidation with ground glass opacities noted in bilateral lung fields with the central distribution involving all the lobes with mild basal interstitial septal thickening. Mild bilateral pleural effusion (right >left) was also noted. The patient was finally treated as DL hemolytic anemia with bilateral pneumonia.

During her stay in the intensive care unit, the patient was transfused with three units of packed red cells and all the transfusion episodes were uneventful. Both steroids and antibiotics were initiated to control pneumonia. The overall treatment was directed toward keeping the patient as warm as possible, with strict avoidance of even minimal exposure to cold. After 48 h of initiating the treatment, her shortness of breath subsided and hemoglobin level improved. There was no evidence of erythrophagocytosis and platelet phagocytosis by monocytes in the peripheral blood smear. Before being discharge from the hospital, her hemoglobin level increased to 9.0 g/dl, and liver function tests were normal with improvement in imaging findings.


  Discussion Top


PCH was first described in medical literature as a distinct disorder in 1872. The unique serological, specific antibody associated with the disorder (DL autoantibody) was first described by Drs. Donath and Landsteiner in 1904. PCH accounts for at most 2%–10% of AIHA.[1] The disease is most often acute and occurs secondary to an infection, mainly respiratory. Although the causative agent is often undetected, PCH has been linked with chickenpox,[4] measles, mumps, respiratory tract infection, and Hemophilus influenza.[7] Earlier, secondary PCH has been reported in latent syphilis or congenital syphilis. However, the incidence of such association is now rare because of the availability of effective therapy for syphilis.

Acute cases of PCH are characterized by symptoms related to intravascular hemolysis, including high fever, weakness, and body pain. Hemolysis can be severe and life-threatening following exposure to cold. Chronic forms of PCH are characterized by recurrent episodes of hemolysis precipitated by cold exposure.

Laboratory diagnosis of PCH presents a picture corroborating an episode of hemolysis with evidence of anemia, jaundice, reticulocytosis, and increased LDH. Apart from polychromasia and nucleated RBCs, there is evidence of erythrophagocytosis and erythrocyte neutrophils rosetting. The exact pathogenesis of phagocytosis is not clear, but it is an important indicator of AIHA and alerts the pathologist for diagnosis of PCH.[8] Although our findings are in general agreement with these reports, the observed coexistent erythrophagocytosis and platelet phagocytosis by monocytes in peripheral blood smears are unique as they have not been reported earlier.

The DL test detects the presence of a biphasic hemolysin, a complement-binding immunoglobulin G (IgG) autoantibody that gets attached to the RBCs when the blood is chilled. Hemolysin usually has anti-P blood group specificity. Interestingly, when the blood is warmed to 37°C the hemolysin-sensitized RBCs are hemolyzed by the complement factor. Accordingly, the DL test is considered a gold standard for the diagnosis of this type of hemoglobinuria. Other diagnostic confirmation includes evidence of anti-P specificity of the IgG autoantibodies and the presence of hemoglobin in urine.[9]

The main differential diagnosis for PCH is acute cold AIHA secondary to mycoplasma or EpsteinBarr virus. This is due to the presence of IgM autoantibodies, which are cold agglutinin. Peripheral smear shows significant RBC agglutination in cold agglutinin syndrome.[1] However, acute onset of severe anemia in a young patient following infection seems unlikely. Moreover, a positive DL test is seen in PCH. In our case, there was acute presentation of severe anemia following respiratory tract infection with erythrophagocytosis in the peripheral smear, reticulocytosis, and positive direct DL test favoring the diagnosis of PCH.

Milder forms of PCH are mostly self-limiting and resolve spontaneously. In severe forms, packed cell transfusion[10] along with corticosteroids, plasmapheresis, and rituximab are considered.[11],[12] Strict avoidance of cold temperature is recommended and blood warmers are recommended to be used during transfusions. In case of severe and prolonged bleeding, transfusions of P-negative blood are useful.


  Conclusion Top


PCH is a rare form of AIHA. Coexistence of erythrophagocytosis and platelet phagocytosis by monocytes, as observed in this case, are unique and interesting findings that have not been reported earlier in DL hemolytic anemia cases. These findings can alert the pathologists to suspect PCH and order a DL test for confirmation. Thus, the findings may help early diagnosis and prompt treatment, necessary to avoid morbidity and mortality.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Radonjić Z, Andrić B, Šerbić O, Mićić D, Kuzmanović M, Jovanović-Srzentić S, et al. A rare case report of autoimmune haemolytic anemia in a female child due to a donath-landsteiner antibody. Transfus Clin Biol 2020;27:83-6.  Back to cited text no. 1
    
2.
Lichtman MA, Beutler E, Kipps TJ. Williams Hematology. 7th ed.. New York, NY: McGraw-Hill Companies; 2006. p. 729-45.  Back to cited text no. 2
    
3.
Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev 2008;22:1-5.  Back to cited text no. 3
    
4.
Yeh SP, Wang Y, Su J, Hsueh E, Yu M, Wu H. Near-tetraploid minimally differentiated acute myeloid leukemia with extensive erythrophagocytosis by leukemic blasts. Ann Hematol 2000;79:36-9.  Back to cited text no. 4
    
5.
Weerakkody RM, Ranasinghe NN, Sivagnanam FG. A case of paroxysmal cold haemoglobinuria following chickenpox. Ceylon Med J 2010;55:96.  Back to cited text no. 5
    
6.
Eichner ER. Spider bite hemolytic anemia: Positive coombs test, erythrophagocytosis and leukoerythroblastic smear. Am J Clin Pathol 1984;81:683-7.  Back to cited text no. 6
    
7.
Ganesan N, Gunasekaran I, Padhi S, Ramdas A, Ganeshan MP. Platelet phagocytosis in peripheral blood during acute phase of dengue virus infection. J Curr Res Sci Med 2015;1:51-3.  Back to cited text no. 7
  [Full text]  
8.
Ziman A, Hsi R, Goldfinger D. Transfusion medicine illustrated: Donath-Landsteiner antibody-associated hemolytic anaemia after Haemophilus influenzae infection in a child. Transfusion 2004;44:1127-8.  Back to cited text no. 8
    
9.
Chandrashekar V, Soni M. Florid erythrophagocytosis on the peripheral smear. J Lab Physicians 2012;4:59-61.  Back to cited text no. 9
[PUBMED]  [Full text]  
10.
Sokol RJ, Booker DJ, Stamps R. Paroxysmal cold haemoglobinuria: a clinic-pathological study of patients with a positive Donath-Landsteiner test. Hematology 1999;4:137-64.  Back to cited text no. 10
    
11.
Jeffereies LC. Transfusion therapy in autoimmune hemolytic anemia. Hematol Oncol Clin North Am 1994;8:1087-104.  Back to cited text no. 11
    
12.
Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion 2007;47:1902-4.  Back to cited text no. 12
    


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