Elevated red cell distribution width in the diagnosis of thrombotic thrombocytopenic purpura in patients presenting with anemia and thrombocytopenia.

Objective: To determine if red cell distribution width (RDW) is elevated in thrombotic thrombocytopenic purpura (TTP) and to evaluate the sensitivity and specificity of such elevation in the diagnosis of TTP.

Methods: We retrospectively studied red cell distribution width at presentation in 25 consecutive patients with newly diagnosed TTP who were treated with plasmapheresis in our institution between 1997 to 2005. Control patients consisted of 20 consecutive patients without TTP who presented to the emergency room (ER) with anemia and thrombocytopenia.

Results: Patients with TTP had significantly elevated RDW compared with the controls (23.1% versus 17.2% respectively, P = 0.0001). An RDW >18% had a 95% sensitivity and 70% specificity in the diagnosis of TTP, whereas RDW >19% had 80% sensitivity and 85% specificity.

Conclusions: TTP should be suspected in patients presenting with unexplained anemia and thrombocytopenia with an RDW [greater than or equal to]18%.

Key Words: red cell distribution width, thrombotic thrombocytopenic purpura

**********

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia with considerable morbidity and mortality. (1) The pentad of microangiopathic hemolytic anemia, thrombocytopenia, renal insufficiency, neurologic symptoms and fever is diagnostic. (1) TTP is due to accumulation of von Willebrand multimers, resulting from congenital or acquired deficiency of ADAMST13 serum metalloproteinase which cleaves the multimers. (2,3) But since assays for these molecules have not yet been clinically validated in TTP, the diagnosis is still based on classic clinical and hematologic criteria. (2,3) As most TTP patients do not display all five criteria at presentation, the combination of thrombocytopenia, anemia, and the presence of schistocytes on the blood smear must often be presumed to be due to TTP if other causes of such findings, such as DIC or the HELLP syndrome, can be clinically excluded. (1,4) Because aggressive plasmapheresis can avert rapid damage to the brain and kidneys and death characteristic of TTP, prompt diagnosis is essential. (1,4,5)

The red cell distribution width (RDW) is an indicator of the degree of variation in RBC size, determined as part of the routine complete blood count. (6) Mathematically, it is a coefficient of variation, ie, RDW = (standard deviation of red cell volume / mean cell volume) X 100. A normal RDW (11.5-14.5%) indicates that the RBCs are homogeneous with respect to size. (7) Elevations of the RDW occur in a variety of anemias, but are usually <18%. More marked elevations are found in few conditions, easily diagnosed clinically, such as sickle cell (in which thrombocytopenia is rare) or megaloblastic anemias. (6-9) We noted RDWs >20% in some TTP patients, presumably because of their schistocytosis and reticulocytosis. Since an RDW in this range might help to corroborate clinical suspicion of TTP, we retrospectively determined the RDWs at presentation of 25 patients diagnosed and treated for TTP. The RDWs of 20 patients with anemia and thrombocytopenia from other causes were also determined.

Methods

Approval for the study was obtained from the institutional review board. Twenty-two patients with newly diagnosed TTP treated at the Kings County Hospital and Down-state Medical Center from 1997 to 2005 were retrospectively identified by review of plasmapheresis records and ICD-9 codes. All patients were treated with plasmapheresis. Patients with a past history of TTP whose initial episode was treated at another institution were excluded from the study. Hemoglobin, hematocrit, RDW, platelet count, reticulocyte count, BUN, creatinine and lactate dehydrogenase (LDH) at presentation were recorded. Schistocytosis was described on the peripheral blood smears of all patients.

The control group was 20 consecutive patients without TTP who presented to the hospital during the same period with anemia (hemoglobin <10 g/dL) and thrombocytopenia (platelet count <100,000/[mm.sup.3]). Patients with sickle cell anemia, pancytopenia, iron deficiency anemia, and those on medications that commonly cause anemia and thrombocytopenia were excluded.

Statistical analysis was performed using two sided t test to calculate P-value. Sensitivity and specificity was calculated using Bayesian analysis.

Results

The results of various hematological and biochemical parameters for the TTP and control group are summarized in Tables 1 & 2. The majority of the patients in the control group had immune thrombocytopenia (ITP). There was no difference in the mean hemoglobin (7.9 g/dL versus 7.6 g/dL, P = 0.32) and platelet count (31,900/[mm.sup.3] versus 24,600/[mm.sup.3], P = 0.14) in the TTP and control groups, respectively. However, patients with TTP had significantly elevated RDW compared with the controls (23.1% versus 17.2%, respectively, P = 0.0001). The only TTP patient with an RDW <18.4% (14.8%) had only minimal anemia (hemoglobin 11.3 g/dL) at presentation. An RDW >18% had a 95% sensitivity and 70% specificity in the diagnosis of TTP whereas RDW >19% had 80% sensitivity and 85% specificity.

Discussion

Mild (<18%) RDW elevation is nonspecific and common but in only a few hematological disorders is the RDW [greater than or equal to]18%. Sickle cell anemia, pernicious anemia and rarely, iron deficiency anemia, are associated with such RDW levels, but are usually readily distinguished from TTP. (6-10) Hence, elevation in RDW in a patient presenting with unexplained anemia and thrombocytopenia should raise the suspicion of TTP. Elevation in RDW has been shown to correlate with the degree of schistocytosis in patients with liver transplant, but such a correlation has not been reported in TTP and other microangiopathies. (11) Our results suggest that an RDW >18% may be a useful adjunct to the current clinical criteria for the diagnosis of TTP, and may facilitate therapeutic intervention.

References

1. Allford SL, Hunt BJ, Rose P, et al. Guidelines on the diagnosis and management of the thrombotic microangiopathic hemolytic anemias. Br J Haematol 2003;120:556-573.

2. Furlan M, Robles R, Galbusera M, et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome. N Engl J Med 1998;339:1578-1584.

3. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585-1594.

4. George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood 2000;96:1223-1229.

5. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347:589-600.

6. Roberts GT, El Badawi SB. Red blood cell distribution width index in some hematologic diseases. Am J Clin Pathol 1985;83:222-226.

7. Saxena S, Weiner JM, Carmel R, et al. Red blood cell distribution width in untreated pernicious anemia. Am J Clin Pathol 1988;89:660-663.

8. Qrtom HA, al-Saleh QA, Lubani MM, et al. The value of red cell distribution width in the diagnosis of anemia in children. Eur J Pediatr 1989;148:745-748.

9. Schweiger DJ. Red cell distribution width in sickle cell anemia. Am J Med Technol 1981;47:231-233.

10. Aslan D, Gumruk F, Gurgey A, et al. Importance of RDW value in differential diagnosis of hypochromic anemias. Am J Hematol 2002;69:31-33.

11. Banno S, Ito Y, Tanaka C, et al. Quantification of red blood cell fragmentation by the automated hematology analyzer XE-2100 in patients with living donor liver transplantation. Clin Lab Haematol 2005;27:292-296.

Nagaprasad Nagajothi, MD, and Albert Braverman, MD

From the Department of Hematology/Oncology, State University of New York Downstate Medical Center, Brooklyn, NY.

Reprint requests to Dr. Albert Braverman, Department of Hematology/Oncology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Box 55, Brooklyn, NY 11203. Email: [e-mail]

Accepted July 18, 2006.

RELATED ARTICLE: Key Points

* Red cell distribution width (RDW) is frequently elevated in thrombotic thrombocytopenic purpura (TTP).

* Suspect TTP in patients presenting with unexplained anemia and thrombocytopenia with elevated RDW.

Table 1. Hematologic and biochemical parameters in the TTP group

             Plts
ID   Hb      (cells/      RDW   LDH     Bili     BUN      Creat    Retic
no.  (g/dL)  [mm.sup.3])  (%)   (IU/L)  (mg/dL)  (mg/dL)  (mg/dL)  (%)

 1   11.3     11000       14.8   462    2.4      12        0.8      2.6
 2    6.6     15000       29    1420    1.6      15        0.6     22.6
 3    6.2     55000       24.5                   32        1.5      3.7
 4    7       57000       27.7          2.3      14        1.1     12.1
 5    7.1     11000       21    1214    3.3      18        0.9      7.7
 6    7.9     29000       23.2          2.3      26        1.2      7
 7    8       22000       20.2          1.5      10        0.8     13.9
 8    5.4     59000       41.8  3552    7.6      25        1.5     16.6
 9    5.3     23000       30.2  2047    3.6      22        0.9     11.8
10    8.4     28000       21.4          2.7      18        1.2
11    7.4     36000       18.4   839    1.3       9        1        3.8
12    6.1     18000       28.7  2451    4.1      19        0.9     19.7
13    8.4     14000       21.1  1908             21        1.2      7.2
14   10.1     17000       18.3  2492    5.3      30        1        3.2
15   11       35000       20.3  1864    1.2      37       11.3      0.9
16    4.2     10000       20.7   351    0.4      13        0.8      1.6
17    7.5     50000       19.9   892    1.2      23        1.3      1.63
18    7.7     61000       23.6   969    1.8      23        1        3.38
19    6.5     23000       25.7   817    1.1      28        1.6      3.65
20    7.4     19000       19.6  1418    1.7      31        1.5      3.25
21    5        7000       19.8  1469    0.3      37        3.8      6.9
22   10.6     24000       18.4  3316    2.3      36        1.5      3.1
23   10       11000       28.9  1326    2.5      30        1.5
24   10.8    113000       19.7  5005    7        56        2.9
25   11       50000       18.5  1416    0.9      12        1.4

TTP, thrombotic thrombocytopenic purpura; Hb, hemoglobin; Pits,
platelets; RDW, red blood cell distribution width; LDH, serum lactic
dehydrogenase; Bili, serum bilirubin; BUN, serum blood urea nitrogen;
Creat, serum creatinine; Retic, reticulocyte count.

Table 2. Hematological and biochemical parameters in the control group

ID   Hb      Plts                RDW
no.  (g/dL)  (cells/[mm.sup.3])  (%)   Diagnosis

 1   5.3     26000               16.4  ITP with GI bleed
 2   9.8      5000               15.2  ITP with mixed connective tissue
                                         disease
 3   8.7     11000               15.8  Etiology unclear. bone marrow
                                         biopsy nonspecific
 4   8       28000               13.8  Etiology unclear
 5   8.9      8000               14.3  ITP with menorrhagia
 6   5.3      9000               16.3  ITP with chronic renal
                                         insufficiency
 7   9       21000               18.7  Alcoholic liver disease with
                                         splenomegaly
 8   9.9     17000               18.2  Acute myelogenous leukemia (M5)
 9   7.9      2000               12.3  ITP with bleeding
10   5.7      7000               14.5  ITP with menorrhagia
11   8       10000               14.4  ITP with bleeding
12   8.2      6000               14.6  ITP with bleeding
13   8.4     42000               16    B-cell lymphoma with bone marrow
                                         involvement
14   7.4     39000               18.2  Myelofibrosis
15   9.2     34000               14.7  Acquired immunodeficiency
                                         syndrome
16   8.3     12000               15    ITP with bleeding
17   9.2     31000               16.1  Aplastic anemia
18   3.8     25000               23.4  Acute myelogenous leukemia
19   7.1     85000               27.4  Pernicious anemia
20   4       74000               27.8  Pernicious anemia

Hb, hemoglobin; Plts, platelets; RDW, red blood cell distribution width;
ITP, idiopathic thrombocytopenic purpura; GI, gastroenterology.