Ann Hematol (2013) 92:509–515 DOI 10.1007/s00277-012-1647-3

ORIGINAL ARTICLE

Thrombotic microangiopathy in sickle cell disease crisis Durjoy K. Shome & Prabha Ramadorai & Abdulla Al-Ajmi & Fakhriya Ali & Neelam Malik

Received: 8 September 2012 / Accepted: 26 November 2012 / Published online: 7 December 2012 # Springer-Verlag Berlin Heidelberg 2012

Abstract Thrombotic microangiopathy (TMA) in patients with sickle cell disease (SCD) is a rare complication. These patients manifest microangiopathic hemolytic anemia (MAHA) with laboratory evidence of hemolytic anemia, schistocytosis, and thrombocytopenia. This is the first report of the syndrome in a group of these patients. A retrospective chart analysis of 10 consecutively diagnosed patients in SCD crisis who were referred for therapeutic plasma exchange (TPE) after developing MAHA was done. Patients had chest pain, respiratory distress, fever, pulmonary infiltrates, jaundice, and neurological dysfunction with abnormal liver function and coagulation tests. MAHA was diagnosed after a median hospital stay of 5 days. Nine patients recovered completely following TPE with fluid replacement by fresh frozen plasma with or without cryo-poor plasma. Incomplete response to TPE in one case was due to the development of fresh complications. During a median follow-up period of 77 months, there was one recurrent episode and one death in SCD crisis but without evidence of MAHA. TMA is not a very rare complication among Bahraini SCD patients in crisis. Characteristic features of this disorder are acute chest syndrome, organ failure, leuco-erythroblastosis, and a combination of thrombocytopenia, LDH level >1,000 U/l, and D. K. Shome (*) Department of Pathology, College of Medicine and Medical Sciences, Arabian Gulf University, P.O. Box 26671, Manama, Bahrain e-mail: [email protected] P. Ramadorai : A. Al-Ajmi Department of Hematology and Oncology, Salmaniya Medical Complex, Manama, Bahrain F. Ali Department of Pathology, Salmaniya Medical Complex, Manama, Bahrain N. Malik Department of Radiology, Salmaniya Medical Complex, Manama, Bahrain

schistocytes in blood smears. Management with TPE usually leads to complete recovery with little chance of short-term recurrence. Multiple pathogenetic mechanisms leading to increased von Willebrand factor and its multimers may form the basis of this syndrome. Keywords Sickle cell crisis . Microangiopathic hemolytic anemia . Thrombotic thrombocytopenic purpura . Schistocytes . Acute chest syndrome . Therapeutic plasma exchange

Introduction Microangiopathic hemolytic anemia (MAHA) refers to small-vessel disease associated with the presence of platelet–fibrin thrombi. Hemolysis occurs due to mechanical disruption of eythrocytes negotiating these vessels leading to the formation of fragmented cells (schistocytes) in peripheral blood [1]. The term thrombotic microangiopathy (TMA) describes a group of disorders that are characterized by the presence of MAHA, thrombocytopenia, and ischemic organ failure [2, 3]. Whereas the classical forms of TMA are thrombotic thrombocytopenic purpura (TTP/idiopathic TTP) and the hemolytic uremic syndrome, there are a large variety of disorders or conditions that manifest TMA as a complication. These are referred to as secondary TMA, and its causes include malignancies, infections, disseminated intravascular coagulation (DIC), autoimmunity, transplantation (stem cell and solid organ), liver disease, and drugs including chemotherapeutic agents, [4–7]. TTP is usually caused by autoantibodymediated deficiency of the plasma metalloprotease ADAMTS13 that normally cleaves ultra-large von Willebrand factor (ULVWF) multimers in the plasma. On the other hand, secondary TMAs are associated with multiple pathogenetic mechanisms but usually without severe ADAMTS13 deficiency [5, 6]. Historically, therapeutic

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plasma exchange (TPE) is the treatment of choice for idiopathic TTP but is mostly ineffective in the secondary TMAs [5]. Secondary TMA has been reported rarely in patients with sickle cell disease (SCD) during crisis [8–12]. In our hospital experience, this complication is not rare but forms a small and distinctive subset in patients with crises, prompting the present study of a group of these patients.

above the upper reference value, (b) total bilirubin level more than fivefold or direct bilirubin more than twice the upper limit of the reference range, and (c) abnormal prothrombin time with International Normalized Ratio (INR) ≥1.5. (3) Pulmonary insufficiency was defined as acute pulmonary infiltrates with hypoxia requiring more than 3 l of oxygen. Multi-organ failure was defined when dysfunction of at least two of the three organs was documented.

Materials and methods

Results

SCD patients in crises with TMA who were consecutively diagnosed at the Salmaniya Medical Complex (SMC) in Bahrain during the period 1 January 2002 to 31 May 2006 were included in the study. Eleven cases were identified from the TPE case records of the blood bank at SMC. One case was excluded from this report due to insufficient data. Since all cases with this complication are referred for TPE at SMC, this represents the total number of cases diagnosed during this time period. Clinical and laboratory data were documented from case files and the hospital information system. A preliminary report of six of these cases was presented at the 9th Congress of the European Hematology Association [13]. The diagnosis of TMA was based on the presence of MAHA evidenced by anemia, elevated indirect bilirubin, lactate dehydrogenase (LDH), negative Coombs’ test, and the presence of significant schistocytosis in peripheral smears associated with thrombocytopenia (platelet count < 100×109/l) and organ failure. The criteria for organ insufficiency and multi-organ failure syndrome were similar to those published earlier [10]. These included the following criteria: (1) Renal insufficiency was defined as acute elevation of serum creatinine more than 177 μmol/l, and oliguria was defined as urine output less than 479 ml/24 h. (2) Hepatic insufficiency was documented when at least two of the following laboratory criteria were met: (a) greater than fivefold elevation of alanine aminotransferase

All patients were Bahraini; eight patients were males and two were females. The mean age at presentation was 30.8 years (median 29 years) with a range of 18 to 51 years. Nine patients were homozygous sickle cell anemia cases, and one was sickle cell-beta-thalassemia.

Table 1 Symptoms and signs in patients with sickle cell disease associated with microangiopathic hemolytic anemia at presentation

Other symptoms/signs: case no. 5, melena; case no. 7, ileus a

Pain not relieved with usual analgesia

b CNS, central nervous system: signs included drowsiness, seizures, restlessness, and neck stiffness

Symptom/sign

Chest paina Respiratory distress Jaundice Fever CNSb Oliguria Hepatomegaly Splenomegaly

Clinical signs and laboratory investigations Table 1 shows the main clinical symptoms and signs in these cases. All patients presented with pain that was not relieved with common analgesics and were febrile and icteric. All of them also had chest pain, respiratory distress and hypoxemia and, with the exception of one patient, required ventilator support. Chest radiographs showed extensive pulmonary infiltrates in all cases with or without pleural effusion. Central nervous system (CNS) manifestations were seen in nine patients of whom two had generalized seizures and loss of consciousness. The latter were found to have cerebral infarction by radiologic studies. Other patients showed variable CNS alterations including restlessness and confusion; four were drowsy but arousable and one had neck stiffness with normal cerebrospinal fluid. Four patients had oliguria. The duration of hospital stay from the time of admission until the diagnosis of MAHA varied from 1 to 20 days (median 5). The results of laboratory investigations when MAHA was diagnosed are shown in Table 2. All patients were moderately anemic. Thrombocytopenia was documented at the

Case

Total

1

2

3

4

5

6

7

8

9

10

No.

%

+ + + + + + + −

+ + + − + − − −

+ + + + + + + −

+ + + + + + + −

+ + + + − − − −

+ + + + + − − −

+ + + + + − − −

+ + + + + + + −

+ + + + + − − +

+ + + + + − − +

10 10 10 9 9 4 4 2

100 100 100 90 90 40 40 20

70 28 55 592 1.0 29

14.1 200 + 17.2 127 1,983

8.1 15

2

111 85 246 370 1.3 35

11 50 + 35.2 545 5,150

6.4 39

3

116 80 166 102 1.5 26

12.2 40 + 10.8 71 5,760

7.2 29

4

35 17 47 621 1.1 28

8.6 120 + 23.2 101 3,280

7.2 46

5

38 3 91 28 0.9 25

17.5 20 + 6.7 77 3,975

7.0 34

6

73 32 62 590 1.3 35

14.2 10 + 8.1 91 3,745

6.2 32

7

220 191 145 456 1.5 47

25.5 90 + 31.7 498 1,229

7.2 62

8

33 18 1,044 456 1.3 22

6.8 24 + 10.6 86 2,235

9 20

9

365 310 178 149 1.5 52

36.5 8 + 6 84 2,103

7.4 44

10

110±106 79±98 235±297 389±220 1.31±0.25 32.1±10.3

15.8±8.9 70±65 + 17.4±10.7 210±194 3,274±1,442

7.3±0.8 34.6±13.8

Mean ± SD

WBC white blood cells, NRBC nucleated red blood cells, LDH lactate dehydrogenase, ALT alanine aminotransferase, Alk Phos alkaline phosphatase, PT prothrombin time, INR International Normalized Ratio, APTT activated partial thromboplastin time

38 26 311 529 1.7 22

<18 <18 25–41 50–135 0.82–1.18 24.7–30.3

3.6–9.6

WBC (×109/l) NRBC (/100 WBC) Schistocytes Urea (mmol/l) Creatinine (μmol/l) LDH (U/l) Bilirubin (μmol/l) Total Direct ALT (U/l) Alk Phos (U/l) PT (INR) APTT (s)

7.1 25

3–7 62–140 135–225

13–15.5 140–440

Hemoglobin (g/dl) Platelets (×109/l)

1

Case

12 140 + 24.7 417 3,281

Reference range

Laboratory parameter (unit)

Table 2 Results of laboratory investigations in sickle cell disease with thrombotic microangiopathy

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time of presentation in six cases, developed fairly rapidly within 2–7 days in the other four patients, and was seen before transfusion intervention in nine patients. In all cases, nadir platelet counts (Table 2) were reached when the red cell fragmentation syndrome was obvious and the decision to start TPE was taken. Leucocytosis was present in eight cases. Corrected reticulocyte counts were available in six cases and was increased in four (median 2.9 %, range 1.5–7.3 %). The blood smears of these patients typically showed a leuco-erythroblastic picture with variable numbers of erythroblasts. Marked erythroblastosis (≥50/100 leucocytes) was observed in half of these cases. The presence of significant numbers of schistocytes supported the diagnosis of MAHA in all cases (Figs. 1, 2, and 3). Sickle cells and dense cells were rarely seen (Fig. 2). Significant numbers of atypical lymphocytes, up to 16 % in the leukocyte differential count, were present in the blood smear of case no. 3. All patients had markedly elevated serum LDH values (greater than five times the upper limit of the reference range) and hyperbilirubinemia. The direct Coombs’ test was negative in all cases. Prothrombin time (INR) was significantly prolonged in seven cases, was associated with abnormal liver function tests in all cases, and with prolonged activated thromboplastin time in four cases. Fibrinogen and semi-quantitative Ddimer assay results were available in eight and seven cases, respectively. However, in some cases, these tests were done after TPE was started and therefore are not shown in the table. Levels of fibrinogen were normal to elevated (range 292–748 mg/dl, reference range 200–400 mg/dl). D-dimer was elevated in all cases. At the time of presentation, cultures of blood, sputum, and urine of nine patients were negative. The blood culture of one patient (no. 10) was positive for Escherichia coli. There was no history of diarrhea and no evidence of renal failure in this case. Serological tests showed evidence of recent Epstein–

Fig. 1 Typical blood smear morphology in a patient with sickle cell disease with secondary thrombotic microangiopathy. Note the presence of fragmented cells (arrows), Howell-Jolly bodies (arrow heads), nucleated red cells, and microspherocytes (magnification×400)

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Fig. 2 Blood smear from a patient of sickle cell disease showing a rare dense cell (arrow), thrombocytopenia, and fragmented cells (magnification×1,000)

Barr virus infection in case no. 3. Five cases had evidence of multi-organ failure according to the above-mentioned criteria with three patients manifesting simultaneous pulmonary, hepatic, and renal insufficiency. In addition to supportive treatment with appropriate analgesics and antibiotics, all patients had received blood transfusion and/or red cell exchange transfusion before MAHA was diagnosed. The aim of the latter was the reduction of hemoglobin S (HbS) level to less than 30 % as per the hospital protocol for the treatment of acute chest syndrome. Therefore, HbS was less than 30 % prior to the diagnosis of MAHA and institution of TPE in seven patients and ranged from 40 to 44 % in the other three cases. The evidence of MAHA and lack of improvement in the clinical scenario with red cell transfusions despite significantly reduced HbS levels prompted the decision to initiate plasma exchange for these patients.

Fig. 3 Characteristic fragmented cells (arrows) with nucleated red cells, target cells, and burr cells in sickle cell disease with secondary thrombotic microangiopathy and multiorgan failure (magnification× 1,000)

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Plasma exchange TPE was done with the COBE Spectra Apheresis System. An average of 1.5 times plasma volume was exchanged in each session using fresh frozen plasma (FFP) as the replacement fluid initially. Daily TPE sessions were continued until two consecutive platelet counts were greater than 100×109/ l. In six patients whose initial response was delayed, the replacement fluid was changed to cryo-poor plasma (CPP) instead of FFP. A median number of ten sessions was required for adequate recovery (range 5–17 sessions). Nine patients recovered completely with normalization of sensoria, correction of hypoxemia, and reversal of the abnormal laboratory parameters. Patient no. 5 showed initial improvement with near normalization of abnormal biochemical indices but with persistent thrombocytopenia. Thereafter, his hemoglobin dropped from 12.2 to 8.6 g/dl, and he manifested pancytopenia, reticulocytopenia, and further increase of erythroblastosis with rising bilirubin and alkaline phosphatase levels. A presumptive diagnosis of bone marrow necrosis was made, and a decision to stop TPE was taken after 11 sessions. This patient subsequently developed multiple complications including pseudomembranous enterocolitis. He was successfully managed with surgical intervention and total parenteral nutrition and was discharged after a hospital stay of 51 days. Follow-up Patients were followed up for a median duration of 77 months (range 3–100 months). Recurrence was documented in one case only. This event occurred 46 months after the first episode, and the patient recovered after six sessions of TPE. One patient died 3 months after discharge from the hospital. He had been re-admitted with a diagnosis of sickle cell crisis but without any recorded evidence of MAHA. The other nine patients were alive at the time of writing this report.

Discussion In Bahrain, an archipelago just off the eastern coast of Saudi Arabia, there is a high prevalence of the sickle cell gene. The prevalence rates of the trait and homozygous disease reported from a school screening program were 13.8 and 1.2 %, respectively [14]. During the period of this study, the annual average of adult SCD admissions at SMC was 1,870/ year. Therefore the frequency of secondary TMA in these cases was 1.4/1,000 SCD hospital admissions. Respiratory distress and MAHA associated with variable organ insufficiency characterized the clinical picture in all patients. The syndrome is similar to that described in some

513

published case reports [8–10] and may be associated with sickle cell–hemoglobin C disease [11, 12]. These patients were also successfully treated by TPE. Lack of response to red cell transfusion/exchange was mentioned in some reports [9, 10]. Acute chest syndrome is one of the leading causes of death in adult SCD patients [15], and the present study serves to emphasize that a thorough and continuous search for secondary TMA should be made in all SCD patients who show signs of respiratory distress. In SCD, hemolysis and vasculopathy are inherent pathologic features. These lead to typical baseline biochemical and hematological alterations increasing further in crisis. To highlight the extent of changes in laboratory parameters in crisis with TMA compared to other patients who had acute chest syndrome (ACS) but no evidence of MAHA, the data from a group of ten consecutively selected ACS cases are shown in Table 3. Compared to this group, patients with TMA had significantly lower platelets and hemoglobin, higher LDH, circulating nucleated red cells in blood smears, and other biochemical indicators of hepatic and renal impairments. The combination of thrombocytopenia and an LDH level greater than 1,000 U/l characterized all cases with TMA but was not seen in the other group. Only one case in the non-TMA group had markedly elevated LDH but showed thrombocytosis. Thrombocytopenia was present in one case. Therefore the triad of thrombocytopenia, schistocytosis, and markedly elevated LDH levels (>1,000 U/l) is sufficient to suggest TMA in these cases. Several potential causes of anemia and thrombocytopenia of acute onset are possible in these cases. Conditions

Table 3 Laboratory features of ten sickle cell patients with acute chest syndrome without TMA compared to cases with TMA (Mann–Whitney test) Parameter

Mean ± SD

Range

P value

Hemoglobin (g/dl) Platelets (×109/l) Leucocytes (×109/l) NRBC/100 leucocytes Urea (mmol/l) Creatinine (μmol/l) LDH (U/l) Total bilirubin (μmol/l) Direct bilirubin (μmol/l)

8.04±0.9 239±132 16.9±7.5 8.2±16.8 4.2±2.2 56.5±20 726±931 64.4±48.2 14.2±10.3

6.5–9.6 95–494 7.5–30.6 0–55 2.4–8.7 27–86 258–3350 23–186 3–37

.045 .000 NS .001 .001 .001 .001 NS .019

ALT (U/l) Alk Phos (U/l) PT (INR) APTT (s)

46.2±14.2 178±206 1.17±0.16 29.8±5.3

30–70 62–713 1.0–1.5 23–40

.002 .045 NS NS

NRBC nucleated red blood cells, LDH lactate dehydrogenase, ALT alanine aminotransferase, Alk Phos alkaline phosphatase, PT prothrombin time, APTT activated thromboplastin time, NS not significant

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associated with MAHA may have overlapping clinicopathological features, and in many cases, the diagnosis is made clinically with supportive laboratory evidence [16, 17]. The clinical setting of these SCD cases together with lack of an underlying condition typically associated with DIC (sepsis, malignancy, etc.) should rule out this complication [17]. Splenic sequestration crises may be excluded since mild splenomegaly was present in only two patients and was non-progressive. The pathogenetic mechanism(s) underlying the common association of pulmonary vasculopathy with MAHA in these patients are uncertain. The presence of fever in the majority of cases raises the suspicion of infection as the initiating event. With the exception of one case with E. coli and another with EBV infection, there was no evidence to suggest an infection as the initiating event in the majority of these cases. A major study of acute chest syndrome observed that fat embolism, infection, and probably infarction were causative factors in a little over half of all cases [18]. However, these causes can only be established with extensive investigations that are usually not undertaken routinely. Boga et al. [19] described seven patients with SCD and multi-organ failure who received TPE because of lack of response to red cell apheresis. Platelet counts and presence of fragmented cells in these patients were not mentioned. With the exception of one death, all other patients recovered. SCD patients with multi-organ failure who recovered following aggressive red cell transfusion have also been reported although there was no reference to association with MAHA [20, 21]. It is likely that abnormal alteration(s) of one or more plasma components underlie the pathogenesis of MAHA and explains the success of TPE in these cases. It has been observed that in other disorders associated with secondary TMA, ADAMTS13 levels are usually not severely reduced, and response to plasma exchange is unlikely [5, 22, 23]. In the absence of evidencebased recommendations on the use of TPE in secondary TMA, there is currently growing interest in identifying subsets of patients who may benefit from this measure [2]. SCD associated with MAHA may therefore be identified as a sub-type of secondary TMA in which response to TPE is as good as in idiopathic TTP. Follow-up of SCD patients after recovery postTPE has not been previously reported in the literature, but we found that recurrent episodes are rare. Few studies report ADAMTS13 levels in SCD. Schnog et al. [24] found no severe ADAMTS13 deficiency in SCD patients (asymptomatic and in crisis). Normal ADAMTS13 level was also reported in a case of SCD associated with TTP [25]. It is clear that more studies are required to confirm these preliminary data and to clarify the roles of ADAMTS13 and ULVWF in this syndrome for the following reasons: (1) Plasma level of VWF regulates ADAMTS13, and there is an inverse relationship between the plasma levels of these factors

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[26]. (2) ADAMTS13 is synthesized in the liver, and sickle cell hepatopathy could affect plasma levels of this factor. (3) The VWF-cleaving activity of ADAMTS13 is competitively inhibited by hemoglobin binding to VWF with accumulation of ULVWF multimers [27]. Hence, intravascular hemolysis in SCD could lead to inactivation of the protease. (4) In DIC with sepsis, moderately severe deficiency of ADAMTS13 (<20 %) has been documented with the presence of lower molecular weight forms of the metalloprotease in plasma suggesting cleavage of the molecule by proteases [28]. An analogous situation may be present in some SCD patients who have an inflammatory condition, higher leukocyte counts, and/or crisis associated with infections. Abnormalities in coagulation tests (prolonged PT, APTT, and elevated D-dimer) have been noted previously [29, 30]. SCD is a well-recognized hypercoagulable state that is more pronounced in vaso-occlusive crisis. This is characterized by increased thrombin generation, platelet and endothelial cell activation, elevated VWF levels, presence of ULVWF, and significantly reduced ADAMTS13/VWF antigen ratio [22, 31, 32]. Indeed, plasma VWF was assayed in two of our cases and was markedly elevated in both (200 and 264 %, respectively; data not shown). In a hypothetical scenario, endothelial activation in SCD would lead to increased release of ULVWF from these cells. Inhibition or reduction of ADAMTS13 activity (e.g., by hyperhemolysis, proteolysis, and/or reduced synthesis) may maintain this high level through reduced cleavage of ULVWF thereby precipitating platelet aggregation and formation of platelet–fibrin thrombi. Therefore, as in idiopathic TTP, induction of microvascular thrombosis by ULVWF is a likely pathogenetic mechanism leading to secondary TMA in SCD. Both these conditions improve with TPE. This could also explain the beneficial effect of fluid replacement with CPP in some cases because cryo-precipitable VWF is removed from this plasma component.

Conclusion The present report has the limitations of a retrospective study. Several issues related to the true incidence, pathogenesis, temporal progression, and management of these cases can be clarified only by prospective studies. Increased awareness of this condition in SCD patients manifesting acute chest syndrome, organ failure, and MAHA with LDH >1,000 U/l is required for timely diagnosis and institution of life-saving TPE. After recovery, recurrence of TMA in these patients is rarely seen. Acknowledgments The contribution of Transfusion Medicine technologists Abdulla Ebrahim and Ahmed Al Sekri to the data retrieval of these cases is gratefully acknowledged.

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Conflict of interest The authors declare that they have no conflict of interest. 17.

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