Hematologic Complications After Liver Transplant

Introduction

Solid organ transplants can be associated with a variety of hematologic abnormalities ranging from minor to life-threatening. When they occur, they may lead to prolonged admissions, reduced physical capacity, infectious complications, risk of bleeding, and overall impact the child’s return to normal life. Some of the common and earliest hematologic complications after liver transplantation are single- or multilineage cytopenias of different etiologies, including infectious, inflammatory, immune-mediated, or drug related. Other, less frequent hematologic complications, such as thrombotic microangiopathy, hemophagocytic lymphohistiocytosis (HLH), graft-versus-host disease (GVHD), venous thromboembolism, and immune-mediated hematologic abnormalities, may occur during the first few months after solid organ transplant and lead to significant morbidity and, rarely, mortality. Along this continuum, posttransplant lymphoproliferative disorder (PTLD) frequently occurs within the first year after transplant (discussed in Chapter 28 ), whereas chronic anemia secondary to nutritional deficiencies, immune-mediated processes, or infections may appear later throughout the recipient’s life.

These complications are overall infrequent and not well described. The information on the incidence and characterization of these conditions is limited to case reports, small case series, and observational studies. Future larger cohorts and insight into the pathophysiology of hematologic disorders after liver transplantation will enhance our understanding and the clinical approach to this unique group of diseases.

This chapter focuses on early hematologic complications after liver transplant, with a specific emphasis on the different etiologies and the mechanisms associated with the development of single- or multilineage cytopenias post-transplant, including autoimmune hemolytic anemia (AIHA), passenger lymphocyte syndrome (PLS), aplastic anemia, and other autoimmune cytopenias. Finally, we will discuss HLH, a rare but life-threatening complication after liver transplantation.

Early Anemia

Anemia is one of the most common hematologic disorders after liver transplant. Anemia is frequently asymptomatic, and findings can be limited to the observed low hemoglobin. However, signs and symptoms can also be related to the etiology of anemia and present with a more diverse clinical picture. In many cases, etiology is multifactorial and not related to a single cause. Beyond the known causes of anemia in healthy children, the specific post-transplant causes for anemia are time dependent and may appear early or late posttransplant. Table 23.1 and Fig. 23.1 summarize the potential etiologies of anemia during the early post-transplant period (< 2 weeks), first few weeks (2–6 weeks), and long term after transplantation. The diagnostic approach to anemia posttransplant should take into account these time frames, with early and timely investigations focusing on the previously mentioned etiologies. The workup should also include thorough nutritional and infectious studies. A bone marrow biopsy early in the investigative pathway may be needed to assess the presence of potentially life-threatening complications, such as GVHD, PTLD, HLH, aplastic anemia, or severe opportunistic infections. Early diagnosis and specific treatment of these conditions determine their prognosis.

Table 23.1

Causes of anemia after liver transplantation

Time after transplant	Etiology	When to suspect
0–2 weeks	Blood loss	Evidence of bleeding, GI pathology on endoscopy
	Infection	Fever, positive cultures, abnormal imaging
	Hypersplenism	Splenomegaly, leucopenia, and thrombocytopenia
	Medications	Use of common medications: MMF, tacrolimus, ganciclovir, trimethoprim/sulfamethoxazole, etc.; improvement when changing dose or medication
	Passenger lymphocyte syndrome	Early DAT positive hemolysis in patients with nonidentical ABO- or Rh-compatible group
2–6 weeks	Viral infections (CMV, EBV, parvovirus B19)	Virus specific serology, antigenemia, and PCR
	Medications	Use of common medications: MMF, tacrolimus, ganciclovir, trimethoprim/sulfamethoxazole, etc.; improvement when changing dose or medication
	Aplastic anemia	Pancytopenia in patient with acute liver failure
	GVHD	Cytopenias associated with development of skin and/or GI symptoms
	HLH	Fever, cytopenias, splenomegaly, hyperferritinemia
After 6 weeks	Viral infections (CMV, EBV, parvovirus B19)	Viral serology, antigenemia, and PCR
	Medications	Use of common medications: MMF, tacrolimus, ganciclovir, trimethoprim/sulfamethoxazole, etc.; improvement when changing dose or medication
	Aplastic anemia	Pancytopenia in patient with acute liver failure
	Autoimmune hemolytic anemia	Late-onset hemolysis ± other cytopenias
	Eosinophilic gastroenteritis or colitis	Peripheral eosinophilia with GI symptoms
	Nutritional deficiencies	Microcytic anemia, confirmed by iron studies; Macrocytic anemia confirmed by B12 deficiency
	Renal insufficiency	Hypertension, increase in creatinine or urea
	PTLD	EBV seroconversion, fever, lymphadenopathy, diarrhea, and/or hepatitis
	Multifactorial	No single etiology identified

CMV, Cytomegalovirus; EBV, Epstein Barr virus; GI, gastrointestinal; GVHD, graft-versus-host disease; HLH, hemophagocytic lymphohistiocytosis; MMF, mycophenolate mofetil; PCR, polymerase chain reaction; PTLD; post-transplant lymphoproliferative disorder.

Data on the incidence of anemia after liver transplant is limited. A study of 175 children who underwent liver transplant showed that 56 children (32%) presented with late-onset anemia at a mean of 48.8 months post-transplant (range: 6–132 months). More than half of the patients had anemia of unknown etiology (57%) with low or normal erythropoietin levels and an inappropriate erythropoietin response for the degree of anemia. Fifteen (27%) had spontaneous recovery of their anemia. The etiology in the remainder of cases was attributed most frequently to iron deficiency (7.1%) and less frequently to post-transplant lymphoproliferative disease (3.6%), human immunodeficiency virus (HIV) infection (1.8%), parvovirus B-19 infection (1.8%), and hypersplenism (1.8%). A more recent study on 97 adults with orthotropic liver transplant showed that 50% and 53% presented with anemia at 6 and 12 months after transplant, respectively.

Iron deficiency is a common cause of anemia after solid organ transplant, with a prevalence of 20% in long-term adult renal transplant recipients and 70% (14/20) in a small cohort of heart transplant children 4 to 6 months after transplant. The anemia in these cohorts was attributed to inadequate iron stores at the time of transplant, blood losses, frequent post-transplant blood extraction for routine laboratory studies, and low iron and erythropoietin levels with normal ferritin levels post-transplant. There are limited data on the prevalence of iron deficiency anemia after liver transplant. In a study of 56 children with anemia post liver transplant, 4 (7.1%) presented with iron deficiency potentially attributed to poor iron intake or malabsorption. All children had microcytosis and hypochromia. In adults, iron deficiency has been related to gastrointestinal blood losses. Larger studies are needed to establish the prevalence of iron deficiency anemia in liver transplant recipients.

Medication-related cytopenias post-transplant are common early after liver transplantation. Some of the immunosuppressive drugs currently in routine use can induce anemia and other cytopenias through a variety of mechanisms, including drug-induced hemolysis, bone marrow suppression, and perturbation of T-cell subsets, leading to immune dysregulation and autoimmunity. The US FK506 liver study group found that anemia was present in 47% of patients treated with tacrolimus ( n = 263), compared with 38% of patients treated with cyclosporine ( n = 266). In addition to bone marrow suppression, there are other mechanisms by which calcineurin inhibitors (CNIs) can induce anemia. Tacrolimus and cyclosporine both have been associated with thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. More recent publications suggested a potential role for tacrolimus in the development of immune hemolytic anemia in isolation and in combination with thrombocytopenia in pediatric liver transplant recipients. Mycophenolate mofetil (MMF) may have a direct antiproliferative effect on bone marrow cells and can also result in anemia and leucopenia. Anemia after liver transplant was reported as an adverse effect of MMF in 43% of patients. Sirolimus, another immunosuppressive drug less commonly used after pediatric liver transplant, has been related to the development of thrombocytopenia. These pathologies are commonly dose dependent and may improve with adjustment of the MMF or sirolimus dose.

Antiviral drugs, such as ganciclovir and valganciclovir, which are commonly used for the prophylaxis and treatment of cytomegalovirus (CMV) and Epstein Barr virus (EBV) infections, have been found to cause reversible leukopenia, but can also lead to multilineage cytopenias or severe pancytopenia. Thrombocytopenia occurred in 41 patients (30.6%), and leukopenia occurred in 36 adult patients (28.6%) who received ganciclovir. The process is reversible with a dose reduction or discontinuation of the drug.

Concomitant infectious diseases can cause anemia or other cytopenias after liver transplant through bone marrow suppression or aplastic anemia. Both EBV and CMV can cause bone marrow suppression through infection of bone marrow progenitor cells (EBV) or infection of marrow stromal cells (CMV), which may reduce the ability of stromal layers to support the proliferation of the primitive myeloid progenitor cells. In addition, EBV DNA was reported in bone marrow cells of 1 out of 40 (5%) adult patients with aplastic anemia and is also associated with the development of PTLD and HLH. Parvovirus B19 has been found to induce pure red cell aplasia after liver transplantation through lysis of erythroid precursor cells. The prevalence of parvovirus-induced anemia as a cause for anemia is low, with 1 patient out of 56 (1.8%) developing anemia related to parvovirus B19 infection after liver transplant in a pediatric cohort. More rarely, HIV infection and hepatitis B or hepatitis C virus–induced bone marrow suppression and anemia post-transplant have been described in adults. Aplastic anemia and severe cold agglutinin hemolysis are known complications of Mycoplasma pneumoniae infection and may occur in transplant recipients. Viral infections and a variety of opportunistic infections can also precipitate acquired HLH, a life-threatening systemic inflammatory disorder.

Finally, eosinophilic gastroenteritis and/or colitis may be a significant long-term complication after pediatric liver transplantation and can lead to anemia caused by chronic low-grade gastrointestinal bleeding and malabsorption. Younger age at transplant, frequency of rejection episodes, tacrolimus-based immunosuppression, high eosinophil counts post-transplant, and EBV viral load may be associated with the development of this condition. A retrospective analysis of 159 children who received deceased donor liver transplant reported an incidence of eosinophilic esophagitis of 3% (4 patients) in the 130 children who survived. A more recent pediatric study found a prevalence of 7% of eosinophilic gastrointestinal disorders among 111 liver transplant recipients. The exact pathogenesis for this high prevalence is unknown, but it is thought to be associated with an imbalance in the Th1/Th2 immune response or abnormal number and function of T-regulatory cells, potentially driven by tacrolimus.

Passenger Lymphocyte Syndrome

With the increasing demand for solid organ transplants and limited availability of donors, ABO-compatible but nonidentical organ transplants are often performed, especially in urgent situations such as acute liver failure (ALF). In the context of nonidentical ABO-compatible transplants, donor lymphocytes present within the graft (known as passenger lymphocytes) are transferred to the recipient and can produce antibodies against the recipient red blood cells (RBCs). Passenger lymphocyte syndrome (PLS) refers to the alloimmune hemolysis of recipient RBCs by donor passenger B lymphocytes. Early and accurate identification of PLS avoids unnecessary extensive workup, enhances the appropriate anemia treatment, and prevents further worsening of the anemia if the condition is misdiagnosed and incorrect blood transfusion strategy is used.

PLS is a rare hematologic complication associated with different types of solid organ transplants. A high frequency of PLS is seen in lung-heart transplants followed by liver transplants and is lowest in kidney transplants. The hemolysis induced by PLS is often a mild, transient, and self-limited process that occurs between 3 and 24 days after the transplant and peaks at 1 to 3 weeks post-transplant. It should be suspected in patients with minor ABO or Rh group incompatibility who present with acute hemolytic anemia and occasionally jaundice during the first weeks posttransplant. The diagnosis is established through the typical clinical scenario and laboratory findings including sudden onset anemia, decreased haptoglobin, elevated reticulocyte count, and indirect hyperbilirubinemia. Because PLS is an alloimmune antibody–mediated anemia, the direct antiglobulin test (DAT) is positive in all cases, and a positive result is required to establish the diagnosis. Table 23.2 summarizes immune-mediated hematologic complications after liver transplant, including PLS.

Table 23.2

Immune-mediated hematologic complications after liver transplantation

	Mechanism	Laboratory findings	Treatment
PLS	In nonidentical ABO- or Rh-compatible transplants, passenger donor lymphocytes from the graft are transferred to the recipient and produce antibodies against the recipient RBCs.	– Hemolytic anemia – High reticulocyte count – Positive DAT – Elevated unconjugated bilirubin – Elevated LDH – Low haptoglobin	First line: Transfusion of donor type ABO RBCs. Refractory cases: High-dose corticosteroids and/or IVIG.
Aplastic Anemia	– Antigen-specific T-cell reaction against hematopoietic cells – Th1-activating cytokines (INF-gamma, IL-17, and IL-27). – B-cell activation with autoantibodies against hematopoietic cells – Increase in Fas antigen on bone marrow CD34 + cells mediate signals for apoptosis	– Pancytopenia – Absolute reticulocytopenia – Bone marrow biopsy shows hypocellularity in all cell lines, with normal morphology cells	Supportive treatment: Blood products transfusions, broad-spectrum antibiotics, and antifungal agents. Definite treatment: Change in immunosuppression, ATG, and/or HSCT.
AIHA	Immune dysregulation potentially attributed to immunosuppressive therapy. Calcineurin inhibitor–mediated impaired thymus function and impaired function of regulatory T cells	– Hemolytic anemia – High reticulocyte count – Positive DAT (warm, cold, and mixed antibodies) – Elevated unconjugated bilirubin – Elevated LDH – Low haptoglobin	First line: RBC transfusions; high-dose corticosteroids; IVIG and keeping body temperature > 37° C (if cold agglutinins). Refractory cases: rituximab; plasmapheresis; splenectomy Alemtuzumab or changing tacrolimus to sirolimus.
HLH	Strong dysregulation of the immune system with disorder of T-cell function, activity of NK cells and cytotoxic T cells Can be familial (genetic background) or secondary (e.g., infection or malignancy)	– Cytopenias – Hypertriglyceridemia – Hypofibrinogenemia – Hyperferritinemia – Elevated transaminases – Hemophagocytosis in bone marrow, spleen, liver, or lymph nodes – Low/absent NK-cell activity – High levels of sIL-2r	First line: High-dose corticosteroids, Cyclosporine or Etoposide. Refractory cases: ATG; alemtuzumab, or HSCT.