Cytopenias after Solid Organ Transplantation

Authors: Charulata Ramaprasad, M.D. MPH, Kenneth Pursell, M.D.

LEUKOPENIA AFTER ORGAN TRANSPLANTATION

Introduction

Leukopenia is broadly defined as having a total white blood cell (WBC) count of less than 3,000-4,000 cells/μL. Leukopenia is a common occurrence following organ transplantation, however few specifics addressing incidence, significance, and/or management exist in the published literature. The published data to date does not implicate the development of leukopenia with episodes of rejection, however there is data detailing significant infectious complications occurring during episodes of severe leukopenia. For this reason, leukopenia warrants prompt evaluation and treatment. The major etiologic considerations, diagnostic evaluation, and general management will be touched upon in this section.

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Epidemiologic Considerations

Etiology: Non-Infectious

Immunosuppressive Medications: Leukopenia of varying degrees is a reported toxicity of several immunosuppressive medications. The most predictable medication to result in leukopenia is azathioprine (Imuran), with 50% of renal transplant recipients developing some degree of depressed WBC count and severe leukopenia (<2500 cells/ μL) reported in 16% of recipients (product insert). The incidence of leukopenia due to azathioprine is dependent on dose and duration and may occur late in the course of therapy. Leukopenia due to azathioprine is most often reversible with decrease or discontinuation of the drug. Co-administration of allopurinol with azathioprine can potentiate marrow toxicity. Patients with low or absent thioprine S-methyl transferase (TPMT) activity which metabolizes 6-mercaptopurine are predictably at increased risk for myelotoxicity due to azathioprine. Leukopenia does not correlate with immunosuppressive therapeutic effect of azathioprine.

T-cell depleting antibody therapies (Thymoglobulin, Atgam, alemtuzumab, basiliximab) can result in some degree of leukopenia by eliminating targeted lymphocytes. Leukopenia is seen in 10-14% of patients treated with these agents (1).

Mycophenolate mofetil (MMF) appears to have superior anti-rejection effects compared to azathioprine. Leukopenia due to MMF use is seen in 13-35% of patients. The marrow effects of MMF are also dose dependent and correlate with trough levels of the active metabolite, mycophenolic acid (MPA). Co-administered agents with myelosuppressive effects, especially valganciclovir, have been shown to increase the risk of leukopenia (2). MMF-induced leukopenia is reversible, however there have been episodes of rejection in patients who have had MMF dosing interrupted for as short as 7 days.

Hematologic toxicities are also reported, albeit less frequently, with the calcineurin inhibitors (cyclosporine, tacrolimus, sirolimus). Again, co-administration of medications with myelotoxic side-effects tends to potentiate this manifestation. Mild leukopenia due to sirolimus that spontaneously reverses has been described from a single institution (3).

Antimicrobials: The anti- CMV medicines ganciclovir (GCV) and valganciclovir (vGCV), used for prophylaxis (universal or pre-emptive) and treatment, are well associated with hematologic toxicities which are the major dose limiting side-effects. Hematologic adverse events are reported in up to 50% of transplant patients receiving GCV or vGCV (4). The incidence of leukopenia induced by GCV/vGCV is dose-dependent. Pre-emptive prophylaxis strategies have statistically less leukopenia compared to universal prophylaxis approaches due to overall less drug exposure. In high-risk (CMV D+/R-) patients where universal prophylaxis is employed, greater than 85% of these patients develop leukopenia with 41% of these patients requiring G-CSF support (5). As mentioned, the hematologic toxicities are more pronounced with co-administration of other myelotoxic medications, particularly MMF2. GCV dosing is calculated based on ideal body mass index (BMI) and creatinine clearance. Oral vGCV (available as 450mg tablet) can lead to increased GCV exposure and toxicity in patients with lower BMI (6).

Several commonly used antibiotics can be associated with lowered WBC. Trimethoprim-sulfamethoxazole, which is routinely used for Pneumocystis jirovecii (PCP) prophylaxis in transplant recipients who are not sensitive to sulfa products, is frequently implicated as a possible etiology for leukopenia. Beta-lactam antibiotics can also cause bone marrow suppression. Piperacillin is probably the most reported agent in this class to cause this adverse drug event.   

Other: Nutritional deficiencies can rarely lead to leukopenia. Some of these essential nutrients include folic acid, vitamin B12, zinc, and copper deficiencies.

Malignancies occur approximately four times more frequently in the transplant recipient compared to the general population. This is thought to be due to complex interactions between long-term immunosuppression and viral infectious triggers. EBV-driven post-transplant lymphoproliferative syndrome (PTLD), which is in the spectrum of lymphoma, can present with leukopenia.

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Etiology: Infectious

Cytomegalovirus ( CMV) infection is probably the single most important infectious impediment to successful organ transplantation (7). As mentioned above, the treatments and strategies to prevent and manage CMV infection are frequently complicated by leukopenia. CMV infection itself has marked direct effects on the hematopoietic environment. Leukopenia is a presenting laboratory abnormality in upwards of 20% of patients with active CMV infection (8). CMV causes myelosuppression by either directly infecting hematopoietic progenitor cells or interfering with the supportive microenvironment by infecting these stromal elements (9).

Leukopenia or leucocytosis can be laboratory indicators of sepsis and/or the systemic inflammatory response syndrome (SIRS). Leukopenia as a presenting finding of the sepsis syndrome is an ominous prognostic sign. Endotoxin effects can lead to leukopenia in early sepsis.

A wide variety of miscellaneous and emerging infections have been reported to have leukopenia as a manifestation, including influenza, ehrlichiosis (10), and parvovirus B19 (11). Mention should be made of human herpesvirus-6 (HHV-6), which can cause a non-specific viral syndrome in transplant recipients. HHV-6 infection (reactivation) after transplant has been reported in up to 80% of solid organ recipients, however the range is quite wide depending on the study population and attributing end-organ disease to HHV-6 has been problematic (12, 13). HHV-6 has been reported to be the most common cause of virally-mediated febrile syndrome in liver transplant recipients (14). Most cases of HHV-6 infection are associated with leukopenia. The decision as to whether to treat HHV-6 can be complicated, as many infections are not associated with clinical syndromes. HHV-6 is inhibited in vitro by ganciclocir, foscarnet, and cidofovir. Acyclovir has little activity against this virus in vitro.

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Approach to Diagnosis/Management

The evaluation of leukopenia following transplantation involves clinical judgment and a thorough assessment to rule-out infectious etiologies. If the diagnosis leads most strongly to medication(s) as the etiologic agent, then a decision needs to be arrived at for a reasonable substitution. Resolution of leukopenia following discontinuing of the most likely offending agent is the obvious diagnostic strategy, however this frequently is accompanied by some clinical risk. As noted above, interrupting MMF immunosuppression for as few as 7 days has led to episodes of rejection. GCV/vGCV therapy is a frequent etiology of leukopenia. Dose interruptions of prophylactic GCV/vGCV coupled with close monitoring of CMV PCR (weekly) testing is a strategy that has been utilized (pre-emptive CMV strategy). Dose reductions during treatment of active infection leading to sub-inhibitory antiviral levels should be avoided. Leukopenia caused by GCV/vGCV can frequently (~80%) and safely managed with granulocyte colony-stimulating factor (G-CSF) so that full doses of GCV/vGCV can be continued (15).

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Anemia after Organ Transplantation

Introduction

Anemia after solid organ and hematopoietic transplantation is common and can be infectious or non-infectious. Most data about anemia after solid-organ transplantation is from the renal transplant population.

Epidemiologic Considerations

Frequency

The frequency of anemia varies by type of transplant and time from transplant. In renal transplant recipients the overall prevalence of anemia is approximately 40% at one year after transplantation. Severe anemia is present in 8.5% of patients six months to five years post transplant (16) (anemia is broadly defined as a hemoglobin of less than 13g/dL for males and 12 g/dL for females). Post-transplant anemia can persist into the late post-transplant period in the renal transplant population, with over 25% of patients having a hematocrit of less than 33% after 5 years (17). Importantly, post transplant anemia predicts worse renal graft function and graft loss (18).

Heart transplant recipients are affected by anemia at similar rates (about 40% of patients) (19). Those with anemia often have significantly impaired renal function. Pre-transplant anemia, present in over a quarter of heart transplant patients, affects one year survival adversely (20).

Timeline

In renal transplant recipients, anemia frequently exists pre-transplant, as hemoglobin targets are 11 or 12 g/dL in patients on dialysis. Immediately post-transplant, the hemoglobin level often rises but then falls as allograft dysfunction progresses.

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Risk Factors

One year post renal transplantation, serum carbon dioxide (CO2), blood urea nitrogen, and creatinine correlate with anemia. At 5 years post-transplant, only CO2 correlates with anemia (17). Women are also more anemic after renal transplantation (21, 22). Certain medications, used frequently after numerous types of organ transplant, are also associated with anemia (see below).

Etiology

Anemia is poorly worked up post-transplant. For example, renal transplant patients with hematocrit values of <30% have iron studies performed less than 40% of the time (21). Early post-transplant, consider surgical losses and frequent phlebotomy as causes of iron deficiency anemia, as well as residual pre-transplant anemia. Half of renal transplant recipients with anemia have iron deficiency anemia (23). Anemia of chronic disease can also cause anemia due to abnormal erythropoietin production from allograft nephropathy after renal transplantation. ACE inhibitors, frequently used in chronic renal disease, are also associated with anemia after kidney transplant (16).

Hemolytic anemia can be caused by numerous drugs. Primaquine (used for PCP treatment) causes hemolytic anemia in G6PD deficient patients. Dapsone (also used for PCP prophylaxis) causes hemolytic anemia in G6PD deficiency, but can also cause anemia in patients despite normal G6PD levels who have the risk factors of renal failure and low ideal body weight (24). Ribavirin causes hemolytic anemia, as can rifampin (25).

Bone marrow suppression can also be seen in with ribavirin, for example in liver transplant recipients being treated for recurrent hepatitis C virus (HCV) (26). In such instances, recombinant erythropoietin has been shown to improve health related quality of life and allows more patients to receive ribavirin, although concerns about its safety (for example, its association with thrombotic disease) continue to be raised (27). Ribavirin has also been used for the treatment of respiratory syncytial virus after transplant in the oral and inhaled form. The inhaled form can also lead to bone marrow suppression if it is systemically absorbed (28). For human immunodeficiency virus/HCV coinfected patients, AZT is myelosuppressive, and aggravated anemia with co-administration of AZT and ribavirin has been seen (27). Other anti-infectives, such as trimethoprim-sulfamethoxazole, can cause anemia through marrow suppression, and dapsone can cause methemoglobinemia (in addition to the aforementioned hemolytic anemia) (29, 30).   vGCV can cause hematotoxicity, especially in the setting of renal failure. There is a report of severe bone marrow failure in four renal transplant patients who received cytomegalovirus prophylaxis at 900 mg/day despite renal failure (31).

Immunosuppressive medications such as MMF and tacrolimus are associated with lower hematocrits in renal transplant patients (22). MMF (an antimetabolite) can cause marrow suppression. Twelve month post-transplant anemia is associated with lower survival and higher cardiovascular death in kidney transplant patients on MMF (32). Other immunosupressants, such as sirolimus may be more myelosuppressive than MMF (33). Additionally, sirolimus and calcineurin inhibitors cause hemolytic anemia, thrombotic thrombocytopenia purpura, and hemolytic uremic syndrome in renal transplant and lung transplant recipients (34-36). Thrombotic microangiopathy is also reported after an ABO incompatible living donor liver transplant. It responded to decreased tacrolimus dose, plasma exchange, and intravenous immune globulin (37).

Infection due to parvovirus B19 is a well described cause pure red cell aplasia (38, 39). In three lung transplant patients with otherwise unexplained anemia, circulating parvovirus was detected by polymerase chain reaction (PCR) testing (11). CMV also classically causes bone marrow suppression, as do the common first line treatments (GCV and vGCV). Other bone marrow infections, such as disseminated tuberculosis and histoplasmosis, are also possible.

Hemophagocytic syndrome, which is associated with numerous viral infections including CMV, Epstein-Barr virus, and HHV-6 and 8, should be considered in patients with pancytopenia (40). PTLD should also be considered in patients with pancytopenia.

Finally, passenger lymphocyte syndrome can cause hemolytic anemia (40).

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Approach to Diagnosis

Differential Diagnosis

Anemia is diagnosed by laboratory parameters. Medications, infection, iron loss, and erythropoietin deficiency should be considered as major causes.

Laboratory Diagnosis

The typical work up for anemia should first ascertain what type of anemia is present. The workup can include a peripheral blood smear (diagnosis of microangiopathy), red blood cell indices, reticulocyte count, iron, total iron binding capacity, ferritin, B12, and folate. Note that ferritin levels may not accurately reflect the cause of anemia since it is acute phase reactant and may go up with infection or rejection.

Lactate dehydrogenase, haptoglobin, and a Coombs test should be sent if hemolysis is suspected. In hemolytic anemia, indirect bilirubin elevation may be a diagnostic clue. If intravascular hemolysis is present it will lead to hemoglobinuria and hemosiderinuria.

For the diagnosis of methemoglobimemia, fresh blood should be sent for absorption spectrum analysis. If hemolytic anemia is present, check warm and cold agglutinins.

Infectious workup should include cytomegalovirus and parvovirus PCR tests.

If no explanation is found, bone marrow biopsy (with pathology and cultures for bacteria, viruses, fungi and mycobacteria) should be performed. Biopsy in search of PTLD may also be necessary.

 

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Approach to Management

Empiric Therapy

The etiology of anemia should be determined if possible. Transfusion should be performed is acutely indicated. This will alter the results of iron studies.

Actual Therapy

Iron deficiency anemia typically is treated with oral iron, which can cause gastrointestinal distress (41). B12 and folate deficiency can be treated with supplementation, although the cause (malabsorption or dietary) should be determined.

Autoimmune hemolytic anemia has been treated with rituximab (42-45).

The routine use of erythropoietin has been called into question due to increased mortality and vascular risk. New data about its safety is constantly emerging and should be considered before use (46, 47).

Other Issues

Outcome/Prognosis

Anemia is associated with decreased graft function.

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Thrombocytopenia after Organ Transplantation

Introduction

Causes of thrombocytopenia after transplantation include medications, infection, and anti-platelet antibodies. There is some overlap with the causes of anemia and leukopenia, in particular microangiopathy and bone marrow suppression due to medications.

Epidemiologic Considerations

Etiology

Microangipathy has been reported as a cause of thrombocytopenia after numerous types of solid organ transplant, often in the setting of sirolimus and calcineurin inhibitor use (34-37).

Other medications that cause thrombocytopenia include rabbit antithymocyte globulin (more so than other antibody preparations) (48), vGCV and GCV (4, 31), linezolid, and heparin (49).

Alloimmune thrombocytopenia from liver transplant donors with immune thrombocytopenia is also reported (50).

Infection, particularly CMV, can cause thrombocytopenia. Hemophagocytic syndrome, which can be seen in association with CMV and Epstein-Barr virus, is also reported (51).

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Approach to Diagnosis

Differential Diagnosis

Thrombocytopenia is diagnosed in the laboratory. Causes include medications, microangiopathic processes, auto and allo-immune processes, and infection.

Laboratory Diagnosis

A peripheral blood smear should be obtained to ascertain platelet morphology, clumping, and to determine if a microangiopathic process is present.

Anti-platelet antibody testing should be ordered in conjunction with hematology consultation.

CMV PCR testing should be obtained.

Bone marrow biopsy may be necessary for diagnosis.

 

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Approach to Management

Empiric Therapy

Microangipathic processes are worsened by platelet transfusion. This should be considered prior to platelet administration.

Actual Therapy

For patients with transplant associated thrombotic microangiopathy, rituximab, daclizumab and other new antibody preparations may be effective but are still being studied (52).

In heparin induced thrombocytopenia, heparin alternatives (such as bilvarudin) have been used (53). Rechallenging these patients with heparin has also been studied (54).

Thrombopoietic growth factors are also under evaluation. First generation recombinant thrombopoietin product development was halted when antibodies developed against one of the recombinant proteins, but second generation thrombopoietin drugs (romiplostim and eltrombopag) are approved for second line therapy of immune thrombocytopenia and have been used in hematopoietic stem cell transplant patients, although long term safety data is lacking (55, 56).

Other Issues

Outcome/Prognosis

Risk from bleeding may adversely affect survival.

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REFERENCES

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Table 1:  Common etiologies of Leukopenia, Anemia, and Thrombocytopenia after Solid Organ Transplant table

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