com/article/198759-treatment
Updated: Apr 04, 2017 Sameer Bakhshi, MD; Chief Editor: Emmanuel C Besa, MD
Practice Essentials
Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral
pancytopenia and marrow hypoplasia (see the image below). Although the anemia is
often normocytic, mild macrocytosis can also be observed in association with stress
erythropoiesis and elevated fetal hemoglobin levels.
Low power, H and E showing a hypocellular bone marrow with increased adipose
tissue and decreased hematopoietic cells
The clinical presentation of patients with aplastic anemia includes symptoms related to the
decrease in bone marrow production of hematopoietic cells. The onset is insidious, and the
initial symptom is frequently related to anemia or bleeding, although fever or infections may
be noted at presentation.
Pallor
Headache
Palpitations, dyspnea
Fatigue
Foot swelling
Gingival bleeding, petechial rashes
Overt and/or recurrent infections
Oropharyngeal ulcerations
A subset of patients with aplastic anemia present with jaundice and evidence of clinical
hepatitis. [1, 2]
Diagnosis
Testing
Procedures
Management
Severe or very severe aplastic anemia is a hematologic emergency, and care should be
instituted promptly. Clinicians must stress the need for patient compliance with therapy. The
specific medications administered depend on the choice of therapy and whether it is
supportive care only, immunosuppressive therapy, or hematopoietic cell transplantation. [3]
Pharmacotherapy
Nonpharmacotherapy
Supportive care
Blood transfusions with blood products that have undergone leukocyte reduction and
irradiation
Hematopoietic cell transplantation
Surgical option
Central venous catheter placement is required before the administration of hematopoietic cell
transplantation.
Background
Paul Ehrlich introduced the concept of aplastic anemia in 1888 when he reported the case of a
pregnant woman who died of bone marrow failure. However, it was not until 1904 that
Anatole Chauffard named this disorder aplastic anemia. (See Etiology.)
The British Society for Standards in Haematology has issued guidelines on diagnosis and
management of aplastic anemia in adults. [5] The Pediatric Haemato-Oncology Italian
Association has issued guidelines on diagnosis and management of acquired aplastic anemia
in childhood. [6]
Anemia
Chronic Anemia
Megaloblastic Anemia
Myelophthisic Anemia
Hemolytic Anemia
Sideroblastic Anemias
Etiology
The theoretical basis for marrow failure includes primary defects in or damage to the stem
cell or the marrow microenvironment. [7, 8, 9] The distinction between acquired and inherited
disease may present a clinical challenge, but more than 80% of cases are acquired. Clinical
and laboratory observations suggest that acquired aplastic anemia is an autoimmune disease.
On morphologic evaluation, the hematopoietic elements in the bone marrow are less than
25%, and they are largely replaced with fat cells. Flow cytometry shows that the CD34 cell
population, which contains the stem cells and the early committed progenitors, is
substantially reduced. [8, 10] Data from in vitro colony-culture assays suggest profound
functional loss of the hematopoietic progenitors, so much so that they are unresponsive even
to high levels of hematopoietic growth factors.
Previously, it had been hypothesized that aplastic anemia may be due to a defect at various
levels, such as an intrinsic defect of hematopoietic cells; external injury to hematopoietic
cells; and defective stroma, which is critical for normal proliferation and functioning of
hematopoietic cells. Theoretically, all of these mechanisms could be responsible for aplastic
anemia. This theory was the basis of many in vitro stem cell culture experiments using a
crossover design in which stem cells from patients with aplastic anemia were cultured with
normal stroma and vice versa. The conclusions from these studies led to the understanding
that stem cell defect is the central mechanism in the majority of patients with aplastic anemia.
[11, 12]
In patients with severe aplastic anemia, stromal cells have normal function, including growth
factor production. Adequate stromal function is implicit in the success of hematopoietic cell
transplantation (HCT) in aplastic anemia, because the stromal elements are almost entirely
(frequently) of host origin.
The role of an immune dysfunction was suggested in 1970, when autologous recovery was
documented in a patient with aplastic anemia who failed to engraft after HCT. Mathe
proposed that the immunosuppressive regimen used for conditioning promoted the return of
normal marrow function. Since then, numerous studies have shown that, in approximately
70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow
function. [9, 13, 14, 15, 16]
Immunity is genetically regulated (by immune response genes), and it is also influenced by
environment (eg, nutrition, aging, previous exposure). [17, 18] Although the inciting antigens
that breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte
antigen (HLA)-DR2 is overrepresented among European and United States patients with
aplastic anemia, and its presence is predictive of a better response to cyclosporine.
In addition, such cytokines induce nitric oxide synthase and nitric oxide production by
marrow cells, which contributes to immune-mediated cytotoxicity and the elimination of
hematopoietic cells. Hirano et al reported that CD8+ cytotoxic T cells raised against kinectin-
derived peptides suppress colony forming units (CFUs) in an HLA class I–restricted fashion,
findings that suggest kinectin may be a candidate autoantigen in the pathophysiology of
aplastic anemia. [19]
The transcription factors FOXP3 and NFAT1 have key roles in regulatory T-cell (Treg)
development and function, and Tregs play a role in autoimmunity. Tregs are decreased at
presentation in almost all patients with aplastic anemia; FOXP3 protein and mRNA levels
also are significantly lower in patients with this condition, whereas NFAT1 protein levels are
decreased or absent. [21]
Variations in telomere length have been reported in severe aplastic anemia, but their clinical
significance is unknown. However, although telomere length was unrelated to response, it
was associated with the risk of relapse, clonal evolution, and overall survival in patients with
severe aplastic anemia. [22]
Congenital or inherited causes of aplastic anemia are responsible for at least 25% of children
with this condition and for perhaps up to 10% of adults. [23] Patients may have dysmorphic
features or physical stigmata, but marrow failure may be the initial presenting feature.
Several loci have been identified that are associated not only with increased susceptibility to
aplastic anemia but also with other physical findings.
Fanconi anemia
Dyskeratosis congenita
This is an isolated aplastic anemia. Mutations have been found in the TERC and TERT genes
and are thought to confer a susceptibility to aplastic anemia. These genes encode proteins that
are part of the telomerase apparatus that restores repeated regions in the telomere. [24]
Cartilage-hair hypoplasia
Pearson syndrome
Pearson syndrome causes sideroblastic anemia and exocrine pancreatic dysfunction. This
condition results from mitochondrial deoxyribonucleic acid (DNA) deletions.
Shwachman-Diamond syndrome
Dubowitz syndrome
Diamond-Blackfan anemia
Acquired causes
Idiopathic factors
Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), parvovirus, and mycobacteria
Exposure to ionizing radiation
Exposure to toxic chemicals, such as benzene or pesticides [27]
Transfusional graft versus host disease (GVHD)
Orthotopic liver transplantation for fulminant hepatitis
Pregnancy
Eosinophilic fasciitis
Anorexia
Severe nutritional deficiencies (B12, folate)
Paroxysmal nocturnal hemoglobinuria (PNH)
MDS
Acute lymphoblastic leukemia (ALL)(rarely)
Drugs and elements (eg, chloramphenicol, phenylbutazone, gold) may cause aplasia of the
marrow. The immune mechanism does not account for the marrow failure in idiosyncratic
drug reactions. In such cases, direct toxicity may occur, perhaps due to genetically
determined differences in metabolic detoxification pathways. For example, the null
phenotype of certain glutathione transferases is overrepresented among patients with aplastic
anemia.
PNH is caused by an acquired genetic defect affecting the PIGA gene and limited to the stem
cell compartment. Mutations in the PIGA gene render cells of hematopoietic origin sensitive
to increased complement lysis. Approximately one third of patients with aplastic anemia have
evidence of PNH at presentation, as detected by means of flow cytometry. [28] Furthermore,
patients whose disease responds after immunosuppressive therapy may recover with clonal
hematopoiesis and PNH.
Epidemiology
United States statistics
No accurate prospective data are available regarding the incidence of aplastic anemia in the
United States. Findings from several retrospective studies usually overlap those from Europe
and suggest that the incidence is 0.6-6.1 cases per million population; this rate is largely
based on data from retrospective reviews of death registries.
International statistics
The annual incidence of aplastic anemia in Europe, as detailed in large, formal epidemiologic
studies, is 2 cases per million population. [29] Aplastic anemia is thought to be more common
in Asia than in the West. The incidence was accurately determined to be 4 cases per million
population in Bangkok, [30] but based on prospective studies, it may actually be closer to 6
cases per million population in the rural areas of Thailand. This increased incidence may be
related to environmental factors, such as increased exposure to toxic chemicals, rather than to
genetic factors, because this increase is not observed in people of Asian ancestry who are
living in the United States.
Although no racial predisposition for aplastic anemia is reported in the United States, the
prevalence is increased in the Far East. The male-to-female ratio for acquired aplastic anemia
is approximately 1:1, although there are data to suggest that a male preponderance may be
observed in the Far East.
Although aplastic anemia occurs in all age groups, a small peak in the incidence is observed
in childhood because of the inclusion of inherited marrow-failure syndromes. A second peak
is observed in people aged 20-25 years.
Prognosis
The outcome of patients with aplastic anemia has substantially improved because of
improved supportive care. The natural history of aplastic anemia suggests that a small
number of patients may spontaneously recover with supportive care [31] ; however,
observational and/or supportive care therapy alone is rarely indicated.
The estimated 10-year survival rate for the typical patient receiving immunosuppression is
68%, compared with 73% for hematopoietic cell transplantation (HCT). [32] However, there is
a significantly improved outcome for HCT over time, for matched sibling and alternative
donors, and with younger age. [32] In cases of immunosuppression, relapse and late clonal
disease are risks.
The major causes of morbidity and mortality from aplastic anemia include infection and
bleeding. Patients who undergo HCT have additional issues related to acute and chronic
toxicity from the conditioning regimen and graft versus host disease (GVHD), as well as a
potential for graft failure. [18, 33, 34, 35, 36, 37] In approximately 25-30% of patients with aplastic
anemia, the condition does not respond to immunosuppression. In cases with a treatment
response, relapse and late-onset clonal disease, such as paroxysmal nocturnal hemoglobinuria
(PNH), myelodysplastic syndrome (MDS), and leukemia, are risks—regardless of the
treatment response or degree of response. [14, 38, 39, 40, 41]
Kulasekararaj and colleagues reported that the presence of somatic mutations (including
ASXL1, DNMT3A, and BCOR) in patients with aplastic anemia for more than 6 months was
associated with 40% risk of transformation to MDS. Nearly a fifth of patients with aplastic
anemia have mutations in genes typically seen in myeloid malignancies that predicted for
later transformation to MDS. [42]
In a Japanese study of 427 patients (16-72 years old) with aplastic anemia who underwent
unrelated-donor bone marrow transplantation, outcome was significantly inferior in patients
whose donors were 40 years of age or older than in those with younger donors. In the older
donor group, overall survival was significantly inferior (adjusted hazard ratio, 1.64), the
incidence of fatal infection was significantly higher (13.7% vs. 7.5%), and primary
engraftment failure and acute GVHD occurred significantly more often (9.7% vs. 5.0% and
27.1% vs. 19.7%, respectively). [43]
Blood Transfusion
Patients with aplastic anemia require transfusion support until the diagnosis is established and
specific therapy can be instituted. The British Committee for Standards in Haematology
recommends prophylactic transfusions in patients whose platelet counts fall below 10 × 109/L
(or <20 × 109/L in febrile patients). [5] However, it is important that transfusions be guided by
the patient’s clinical status and not by numbers alone. Avoiding transfusions from family
members is important because of possible sensitization against non-HLA (human leukocyte
antigen) tissue antigens of potential donors.
The British Committee for Standards in Haematology also recommends irradiated blood
products for all patients receiving antithymocyte globulin (ATG) therapy. In patients with
life-threatening neutropenic sepsis, the committee suggests consideration of irradiated
granulocyte transfusions. [5]
Treatment of Infections
Infections are a major cause of mortality in patients with aplastic anemia. [51, 52] Risk factors
include prolonged neutropenia and the indwelling catheters used for specific therapy. Fungal
infections, especially those due to Aspergillus species, pose a major risk. Patients should
maintain hygiene to reduce infection risk.
However, the strategy of empiric antibiotic use has also resulted in the development of
resistant organisms and thus is not favored by some clinicians. [53]
Human leukocyte antigen (HLA)-matched sibling-donor HCT is the treatment of choice for a
young patient with severe or very severe aplastic anemia (SAA or VSAA, respectively),
being generally accepted for patients younger than 40 years. [5] Persons undergoing this
procedure do not require irradiation-based conditioning regimens. [5]
A study of 692 German patients with SAA who received transplants from HLA-matched
siblings, noted that bone-marrow grafts were preferable to peripheral blood progenitor cell
(PBPC) grafts in patients younger than 20 years. [57] A multinational study of patients with
SAA who received HCT from an HLA-matched sibling donor concluded that although bone
marrow should definitely be the preferred graft source for these patients, PBPCs may be an
acceptable alternative in countries with limited resources where patients present later in their
disease course and risks of graft failure and infective complications are high. [58]
Although evidence suggests that stem cells from bone marrow afford better outcomes
compared with PBPCs, an additional consideration is the perspective of the donor, who must
be informed of the difference between the methods of harvesting. Bone marrow harvesting is
usually performed with the donor under general anesthesia, while with PBPC harvesting the
donor is awake and connected via large-bore intravenous catheters to an apheresis machine,
which separates out the stem cells (for descriptions of the two methods, see Bone Marrow
Donor Procedure).
Along with the risks associated with anesthesia, bone marrow donors typically experience
moderate pain for several days following the procedure. PBPC donors usually experience
bone pain, which may be severe, from the filgrastim-induced bone marrow stimulation used
to mobilize stem cells in advance of the procedure.
One of the major problems of HCT in aplastic anemia is the high rate of rejection (10%;
range, 5-50%). This is positively correlated with the number of transfusions the patient
received and the duration of his or her disease, prior to transplantation.
Previously, a higher stem cell dose, as well as the addition of total body irradiation to
cyclophosphamide conditioning, was tried. Although it was associated with a reduced
incidence of graft rejection, the benefit was negated by high transplant-related mortality
(TRM) due to an increase in graft versus host disease (GVHD).
Immunosuppressive Therapy
Immunosuppressive therapy using antithymocyte globulin (ATG) and cyclosporine is
associated with an overall response rate of 60-80% and a 5-year survival rate of 75% in most
reports, but event-free survival rates are in the range of 35-50%.
Immunosuppressive therapy using ATG plus cyclosporine is being administered as first-line
therapy [73] for patients with severe or very severe aplastic anemia (SAA or VSAA,
respectively) who are older than 40 years and as second-line therapy in younger patients with
SAA or VSAA if a human leukocyte antigen (HLA)–matched sibling donor is not available.
Immunosuppressive therapy is also recommended in patients with nonsevere aplastic anemia
who are transfusion dependent. [5]
Scheinberg et al reported that a large difference was observed in patients with aplastic anemia
in the rate of hematologic response at 6 months in favor of horse ATG (68%), as compared
with rabbit ATG (37%). [74] Overall survival at 3 years also differed, with a survival rate of
96% in the horse-ATG group, compared with 76% in the rabbit-ATG group when data were
censored at the time of stem-cell transplantation, and 94% versus 70% in the respective
groups when stem-cell–transplantation events were not censored. [74]
A review by Risitano also demonstrated that immunosuppression with rabbit ATG, as well as
cyclophosphamide and alemtuzumab, in patients with aplastic anemia or immune-mediated
bone marrow failure syndromes had an inferior outcome relative to horse ATG. [75] Therefore,
rabbit ATG, cyclophosphamide, and alemtuzumab are not recommended as first-line therapy
in these patients. [75]
In other studies of ATG, responses have been defined as complete responses (CRs) when all
blood counts return to normal, and as partial responses (PRs) when there is an improvement
in blood counts with transfusion independence. In these analyses, response to ATG is slow,
usually taking 10-12 weeks for a response to occur; and the response may also continue to
improve or occur later. If the patient has not responded to a first course of ATG, then a
second course may be given, using either the same preparation or another one.
Approximately 30-60% of patients may respond to a second course of ATG. [76, 77, 78, 79, 80, 81,
82]
In one study, response rates to cyclosporine alone were 45% overall, 16% for VSSA, 47% for
SAA, and 85% for moderate aplastic anemia. [83] Therefore, the only predictor of response to
cyclosporine was an absolute neutrophil count (ANC) of less than 200/mm3. Adding
granulocyte colony-stimulating factor (G-CSF) to ATG and cyclosporine in patients with an
ANC of over 200/mm3 does not provide any additional advantage in reducing the infection
rate or in increasing survival or therapeutic responses.
A meta-analysis by Hayakawa et al of 13 studies comparing horse ATG with rabbit ATG for
immunosuppressive therapy in severe aplastic anemia concluded that horse ATG results in a
higher respnse rate (p=0.015); further, a sensitivity analysis showed that there was higher
early mortality with rabbit ATG. [84] Hence, horse ATG is the preferred choice in this setting.
Time to response and relapse
The treatment response in aplastic anemia, unlike in other autoimmune diseases, is slow. At
least 4-12 weeks is usually needed to observe early improvement, and the patient may
continue to improve slowly thereafter. About 50% of patients respond by 3 months after ATG
administration, and about 75% respond by 6 months. Most patients improve and become
transfusion independent, but many still have evidence of hypoproliferative bone marrow.
Although the initial response rate is good, durable responses with no relapse or clonal
evolution are observed in 50% of the patients. [85] To reduce the risk of relapse, continue
cyclosporine for a minimum of 12 months after achieving maximal hematologic response,
with a very slow tapering thereafter. [5] Approximately one third of patients have a relapse,
most of whom have a relapse at the time of cyclosporine taper. About one third of responders
are cyclosporine dependent. Of patients without a response or who relapse, 40-50% respond
to a second course of immunosuppressive therapy.
In rare cases, full hematologic recovery is observed, but most patients improve to a functional
hematologic recovery that obviates further transfusion support. Furthermore, the risk of some
form of clonal disease other than paroxysmal nocturnal hemoglobinuria (PNH) is 15-30% and
may be due to the inability of these therapies to completely correct bone marrow function, a
missed diagnosis of myelodysplastic syndrome (MDS), or the fact that the stem cells under
proliferative stress may be more prone than other cells to mutation.
At present, the use of high-dose cyclophosphamide should be limited to clinical trials. [85]
Preliminary data have suggested that high-dose cyclophosphamide may result in durable
remissions in some patients with aplastic anemia. However, some of these patients develop
PNH and cytogenetic abnormalities on follow-up. When investigators conducted a
prospective, randomized study based on the above preliminary report by using
cyclophosphamide versus ATG plus CSA, the study was terminated early because of very
high mortality and fungal infections in the cyclophosphamide arm. [86, 87]
Up to 50% of patients with aplastic anemia demonstrate small PNH clones in the absence of
evidence of hemolysis. [5] In patients with a history of PNH-associated thrombosis, use of
ATG is not recommended. In addition, because abnormal cytogenetic clones can occur in up
to 12% of patients with aplastic anemia, the presence of some clones in otherwise typical
cases of aplastic anemia does not necessarily signify a diagnosis of myelodysplastic
syndrome (MDS) or acute myeloid leukemia (AML). [5] However, an exception is when the
monosomy 7 clone is present, in which case there is a high risk of transformation to MDS or
AML. [5]
Except in the setting of prospective clinical trials, hematopoietic growth factors (eg,
recombinant human erythropoietin [rHuEPO], granulocyte colony-stimulating factor [G-
CSF]) is not recommended for routine long-term use following ATG and CSA therapy. [5]
Diet and Activity
The diet for the patient with aplastic anemia who has neutropenia or who is receiving
immunosuppressive therapy should be tailored carefully to exclude raw meats, dairy
products, or fruits and vegetables that are likely to be colonized by bacteria, fungus, or molds.
Furthermore, a salt-limited diet is recommended during therapy with steroids or cyclosporin-
A (CSA).
The patient should avoid any activity that increases the risk of trauma during periods of
thrombocytopenia. Menstruating women are also advised to be on hormonal pills to avoid
menstrual cycles that are likely to be heavy due to thrombocytopenia.
In the extension phase of the study, three patients achieved a multi-lineage response. Four of
those patients subsequently tapered off treatment and maintained the response (median
followup 8.1 months, range 7.2-10.6 months). [88,
Medication Summary
The goals of pharmacotherapy in cases of aplastic anemia are to reduce morbidity and
prevent complications.
Presentasi klinis pasien dengan anemia aplastik mencakup gejala yang terkait dengan
penurunan produksi sumsum tulang sel hematopoietik. Awitannya sangat berbahaya, dan
gejala awal sering dikaitkan dengan anemia atau perdarahan, walaupun demam atau infeksi
dapat dicatat pada saat presentasi.
Diagnosa
Pengujian
Pengujian laboratorium untuk anemia aplastik yang dicurigai meliputi:
• hitung darah lengkap
• Pemeriksaan darah perifer
• Elektroforesis hemoglobin dan pengujian golongan darah
• Profil biokimia
• Serologi untuk hepatitis dan entitas virus lainnya
• Evaluasi penyakit autoimun untuk bukti penyakit kolagen-vaskular
• Penyortir selotip selektif fluoresensi
• Pengujian aerolinin toksin tanpa label yang tidak aktif
• Diepoxybutane inkubasi
• Pengujian histokompatibilitas
• Penelitian fungsi ginjal
• Penelitian fungsi hati
• Tingkat transaminase, bilirubin, dan laktat dehidrogenase
Prosedur
Biopsi sumsum tulang dilakukan selain aspirasi untuk menilai seluler secara kualitatif dan
kuantitatif. Kultur sumsum tulang mungkin bermanfaat dalam mendiagnosis infeksi
mikobakteri dan virus; Namun, imbal hasil umumnya rendah.
Pengelolaan
Anemia aplastik berat atau sangat parah adalah keadaan darurat hematologi, dan perawatan
harus segera dilakukan. Dokter harus menekankan perlunya kepatuhan pasien terhadap terapi.
Pengobatan spesifik yang diberikan tergantung pada pilihan terapi dan apakah hanya
perawatan suportif, terapi imunosupresif, atau transplantasi sel hematopoietik. [3]
Farmakoterapi
Obat berikut digunakan pada pasien dengan anemia aplastik:
• Agen imunosupresif (misalnya, siklosporin, metilprednisolon, globulin antitimokinida,
globulin antithymocyte kelinci, siklofosfamid, alemtuzumab)
• Faktor pertumbuhan hematopoietik (misalnya eltrombopag [4], sargramostim, filgrastim)
• Agen antineoplastik antimetabolit (purin) (misalnya, fludarabin)
• Agen Chelating (misalnya deferoxamine, deferasirox)
Nonfarmakoterapi
Pengelolaan nonfarmakologis anemia aplastik meliputi:
• Perawatan suportif
• Transfusi darah dengan produk darah yang telah mengalami pengurangan dan iradiasi
leukosit
• Transplantasi sel hematopoietik
Bedah pilihan
Penempatan kateter vena sentral diperlukan sebelum pemberian transplantasi sel
hematopoietik.
Latar Belakang
Paul Ehrlich memperkenalkan konsep anemia aplastik pada tahun 1888 saat dia melaporkan
kasus seorang wanita hamil yang meninggal karena gagal sumsum tulang. Namun, baru pada
1904 Anatole Chauffard menamakan gangguan ini anemia aplastik. (Lihat Etiologi.)
Masyarakat Inggris untuk Standar Hematologi telah mengeluarkan pedoman untuk diagnosis
dan pengelolaan anemia aplastik pada orang dewasa. [5] Asosiasi Italia Pediatric Haemato-
Oncology telah mengeluarkan panduan untuk diagnosis dan pengelolaan anemia aplastik
yang didapat di masa kanak-kanak. [6]
Etiologi
Dasar teoritis untuk kegagalan sumsum mencakup kerusakan primer atau kerusakan pada sel
punca atau lingkungan mikro sumsum. [7, 8, 9] Perbedaan antara penyakit yang diakuisisi
dan yang diwariskan dapat menimbulkan tantangan klinis, namun lebih dari 80% kasus
diperoleh. Observasi klinis dan laboratorium menunjukkan bahwa anemia aplastik yang
didapat adalah penyakit autoimun.
Pada evaluasi morfologis, unsur hematopoietik di sumsum tulang kurang dari 25%, dan
sebagian besar diganti dengan sel lemak. Flow cytometry menunjukkan bahwa populasi sel
CD34, yang mengandung sel punca dan nenek moyang awal yang dilakukan sebelumnya,
secara substansial berkurang. [8, 10] Data dari tes budaya koloni in vitro menunjukkan
hilangnya fungsional yang signifikan dari nenek moyang hematopoietik, sedemikian rupa
sehingga tidak responsif bahkan pada faktor pertumbuhan hematopoietik tingkat tinggi.
Sebelumnya, telah dihipotesiskan bahwa anemia aplastik mungkin disebabkan oleh cacat
pada berbagai tingkat, seperti defek intrinsik sel hematopoietik; cedera eksternal pada sel
hematopoietik; dan stroma yang rusak, yang sangat penting untuk proliferasi normal dan
fungsi sel hematopoietik. Secara teoritis, semua mekanisme ini dapat menyebabkan anemia
aplastik. Teori ini adalah dasar dari banyak percobaan kultur sel induk in vitro dengan
menggunakan desain crossover dimana sel induk dari pasien dengan anemia aplastik dikultur
dengan stroma normal dan sebaliknya. Kesimpulan dari penelitian ini mengarah pada
pemahaman bahwa defek sel induk merupakan mekanisme sentral pada sebagian besar pasien
dengan anemia aplastik. [11, 12]
Pada pasien dengan anemia aplastik berat, sel stroma memiliki fungsi normal, termasuk
faktor pertumbuhan produksi. Fungsi stroma yang memadai tersirat dalam keberhasilan
transplantasi sel hematopoietik (HCT) pada anemia aplastik, karena unsur stroma hampir
seluruhnya (sering) berasal dari host.
Peran disfungsi kekebalan disarankan pada tahun 1970, saat pemulihan autolog
didokumentasikan pada pasien dengan anemia aplastik yang gagal masuk setelah HCT.
Mathe mengusulkan agar rejimen imunosupresif yang digunakan untuk pengkondisian
mendorong kembalinya fungsi sumsum normal. Sejak itu, banyak penelitian telah
menunjukkan bahwa, pada sekitar 70% pasien dengan anemia aplastik yang didapat, terapi
imunosupresif memperbaiki fungsi sumsum. [9, 13, 14, 15, 16]
Imunitas diatur secara genetis (oleh gen respon kekebalan), dan juga dipengaruhi oleh
lingkungan (misalnya nutrisi, penuaan, paparan sebelumnya). [17, 18] Meskipun antigen
yang menghasut yang melanggar toleransi kekebalan dengan autoimmunity berikutnya tidak
diketahui, antigen leukosit manusia (HLA) -DR2 terlalu banyak diwakili oleh pasien Eropa
dan Amerika Serikat dengan anemia aplastik, dan kehadirannya merupakan prediksi respons
yang lebih baik terhadap siklosporin. .
Penekanan hematopoiesis kemungkinan dimediasi oleh populasi CD8 + HLA-DR + yang
diperluas, limfosit T sitotoksik (CTLs) yang sering terdeteksi di dalam darah dan sumsum
tulang pasien anemia aplastik. Sel-sel ini menghasilkan sitokin penghambat, seperti faktor
gamma-interferon dan tumor necrosis, yang dapat menekan pertumbuhan sel progenitor.
Polimorfisme yang terkait dengan peningkatan respons imun lebih banyak terjadi pada gen
sitokin ini pada pasien dengan anemia aplastik. Sitokin ini menekan hematopoiesis dengan
mempengaruhi siklus mitosis dan pembusukan sel dengan mendorong apoptosis yang
dimediasi Fas.
Sebagai tambahan, sitokin tersebut menginduksi oksida nitrat oksida dan produksi oksida
nitrat oleh sel sumsum, yang berkontribusi terhadap sitotoksisitas yang dimediasi oleh
kekebalan dan penghapusan sel hematopoietik. Hirano dkk melaporkan bahwa sel T
sitotoksik CD8 + yang diturunkan terhadap peptida yang diturunkan kinectin menekan unit
pembentuk koloni (CFU) dalam mode HLA class I-restricted, temuan yang menyarankan
kinectin dapat menjadi kandidat autoantigen pada patofisiologi anemia aplastik. [19]
Ekspresi konstitutif Tbet, regulator transkripsional yang sangat penting untuk polarisasi sel T
T 1 (Th1), terjadi pada mayoritas pasien anemia aplastik. [13] Perforin adalah protein sitolitik
yang diekspresikan terutama pada limfosit sitotoksik aktif dan sel pembunuh alami. Mutasi
pada gen perforin bertanggung jawab atas beberapa kasus hemofagositosis keluarga [20];
mutasi di SAP, pengkodean gen untuk protein modulasi kecil yang menghambat produksi
interferon yang tidak terdefinisi, mendasari limfoproliferasi terkait-X, penyakit fatal yang
terkait dengan respons kekebalan yang menyimpang terhadap virus herpes dan anemia
aplastik. Tingkat protein perforin dan SAP secara nyata berkurang pada beberapa kasus
anemia aplastik yang didapat.
Faktor transkripsi FOXP3 dan NFAT1 memiliki peran kunci dalam pengembangan dan
fungsi sel T (Treg), dan Treg berperan dalam autoimunitas. Treg menurun pada presentasi
hampir di semua pasien anemia aplastik; Tingkat protein dan mRNA FOXP3 juga secara
signifikan lebih rendah pada pasien dengan kondisi ini, sedangkan kadar protein NFAT1
menurun atau tidak ada. [21]
Variasi panjang telomer telah dilaporkan pada anemia aplastik parah, namun signifikansi
klinisnya tidak diketahui. Namun, walaupun panjang telomere tidak terkait dengan respons,
hal itu terkait dengan risiko kambuh, evolusi klonal, dan kelangsungan hidup secara
keseluruhan pada pasien dengan anemia aplastik berat. [22]
penyebab anemia aplastik bawaan atau bawaan bertanggung jawab atas setidaknya 25% anak
dengan kondisi ini dan mungkin sampai 10% orang dewasa. [23] Pasien mungkin memiliki
fitur dismorfik atau stigmata fisik, namun kegagalan sumsum mungkin merupakan fitur
penyajian awal. Beberapa lokus telah diidentifikasi yang terkait tidak hanya dengan
peningkatan kerentanan terhadap anemia aplastik tetapi juga dengan temuan fisik lainnya.
Anemia fanconi
Anemia fanconi ditandai dengan:
• Anomali kongenital multipel (60-75%): Perawakan pendek, pigmentasi kulit tidak normal,
malformasi jempol dengan atau tanpa radius displastik atau tidak ada, serta mikrofthalmos
dan malformasi jantung, ginjal, usus, dan telinga.
• Gagal sumsum tulang: Trombositopenia, leukopenia, atau anemia aplastik; Sebagian besar
pasien dengan anemia Fanconi mengalami kegagalan sumsum tulang pada usia dewasa
• Kanker: Keganasan hematologi umum terjadi pada anemia Fanconi dan myelodysplasia,
dengan leukemia myeloid akut (AML) yang paling umum; Tumor padat seperti kanker sel
skuamosa dan kanker leher, tumor genital wanita, dan tumor hati juga terlihat; Anemia
fanconi dikaitkan dengan peningkatan kerusakan kromosom dan pertukaran kromatid
adrenalin abnormal dengan adanya agen seperti diepoxybutane atau mitomycin C
• Pola pewarisan resesif autosomal dominan: Lima belas gen sekarang diketahui penyebab
anemia Fanconi; hanya 1 dari ini - FANCB (berlapis X resesif) - tidak diwariskan secara
autosomal resesif
• Asosiasi antara perkembangan sumsum tulang dan pola kompleks kelainan kromosom
rekuren: Beberapa kelainan kromosom umumnya ditemukan pada sindrom myelodysplastic
anemia non-Fanconi dan kelainan myeloid leukemia akut (misalnya, -7 / 7q atau RUNX1),
sedangkan yang lainnya khusus untuk anemia Fanconi (misalnya, 1q + dan 3q +)
Disperatosis kongenita
Dyskeratosis kongenita ditandai dengan triad fisik diagnostik dari kuku displastik, pigmentasi
retikuler berenda pada batang atas, dan leukoplakia oral. Namun, selama dekade terakhir,
sudah semakin diketahui bahwa penderita congenita mungkin mengalami dyskeratosis tanpa
triad. Berikut ini adalah fitur dari kondisi ini:
• Beberapa tanda penuaan dini, seperti awal beruban dari rambut
• Kegagalan sumsum tulang progresif pada usia berapapun, yang dapat menyebabkan
kombinasi sitopeni, termasuk anemia aplastik
• Keganasan: Umum; sering MDS atau AML; Tumor padat seperti kanker kepala dan leher
atau kanker genital juga bisa terlihat
• Fibrosis paru
• pola dominan autosomal dominan, autosomal resesif, dan X-linked; 6 gen diketahui
menyebabkan gangguan ini
Anemia aplastik keluarga
Ini adalah anemia aplastik yang terisolasi. Mutasi telah ditemukan pada gen TERC dan TERT
dan dianggap memberi kerentanan terhadap anemia aplastik. Gen ini mengkodekan protein
yang merupakan bagian dari aparatus telomerase yang mengembalikan daerah berulang di
telomer. [24]
Hipoplasia rambut kartilago
Hipoplasia rambut kartilago, yang disebabkan oleh mutasi pada gen RMRP, diwarisi secara
autosomal resesif. Kondisi ini ditandai dengan:
• Perawakan pendek dengan tungkai pendek dan tertekuk
• Rambut jarang berpigmen tipis
• Defisiensi imun yang sangat parah
• Anemia selama masa kanak-kanak
• Keganasan hematopoietik, serta keganasan kulit, mata, dan hati
• Malformasi gastrointestinal dan malabsorpsi
Sindrom Pearson
Sindrom Pearson menyebabkan anemia sideroblastik dan disfungsi pankreas eksokrin.
Kondisi ini diakibatkan oleh penghapusan asam deoksiribonukleat (DNA) mitokondria.
Sindrom radius trombositopenia tidak ada
Sindrom trombositopenia-absen radius (TAR) ditandai dengan delesi yang terletak pada
kromosom 1q21.1 (yang biasanya berukuran sekitar 200kb). Pasien memiliki ketiadaan radius
bilateral dengan kehadiran ibu jari, serta trombositopenia. Anomali kongenital lainnya juga
dapat terjadi (misalnya, penyakit jantung, anomali kerangka, anomali urogenital).
Sindrom Shwachman-Diamond
Sindrom Shwachman-Diamond disebabkan oleh mutasi pada gen SBDS dan diwarisi secara
autosomal resesif. Penyakit ini ditandai dengan disfungsi pankreas eksokrin dengan
malabsorpsi dan kegagalan pertumbuhan, serta sitopeni dari satu atau beberapa garis
keturunan. Pasien dengan sindrom Shwachman-Diamond juga memiliki peningkatan risiko
MDS dan AML. [25]
Sindrom Dubowitz
Sindrom Dubowitz disebabkan oleh gen yang belum diketahui. Kondisi ini ditandai dengan
retardasi pertumbuhan intrauterine, perawakannya sangat pendek, dan penampilan wajah
yang melengkung. Pasien juga mengalami microcephaly dan keterlambatan perkembangan
ringan. Sindrom Dubowitz juga terkait dengan eksim, defisiensi imun, dan anemia aplastik.
Keganasan lebih sering terjadi pada kelainan ini, terutama limfoma dan neuroblastoma.
Anemia Diamond-Blackfan
Anemia Diamond-Blackfan (DBA) ditandai dengan anemia makrositik normokromik yang
dapat diisolasi, atau dapat dikaitkan dengan retardasi pertumbuhan atau malformasi
kongenital pada sistem tungkai atas, jantung, dan genitourinari. Pada sebagian kecil pasien,
DBA dapat berkembang menjadi anemia aplastik. Sembilan gen telah ditemukan menjadi
penyebab DBA, dan mereka diwarisi secara dominan autosomal. [26] Sekitar 50% kasus
diwarisi dari orang tua, dan sekitar 50% hasil dari de novo mu
Transfusi darah
Pasien dengan anemia aplastik memerlukan dukungan transfusi sampai diagnosis ditetapkan
dan terapi spesifik dapat dilakukan. Komite Inggris untuk Standar Hematologi
merekomendasikan transfusi profilaksis pada pasien yang jumlah trombositnya di bawah 10 ×
109 / L (atau <20 × 109 / L pada pasien demam). [5] Namun, penting bahwa transfusi
dipandu oleh status klinis pasien dan bukan oleh angka saja. Menghindari transfusi dari
anggota keluarga penting karena kemungkinan sensitisasi terhadap antigen jaringan non-HLA
(human leukocant antigen) dari donor potensial.
Untuk pasien yang memerlukan transplantasi sel hematopoietik (HCT), transfusi harus
digunakan dengan bijaksana karena subjek dengan transfusi minimal telah mencapai hasil
terapeutik yang superior.
Jika menggunakan dukungan darah-bank, usahakan meminimalkan risiko infeksi
sitomegalovirus (CMV). Produk darah harus, jika mungkin, mengalami pengurangan leukosit
untuk mencegah penularan alloimunisasi dan CMV dan harus diiradiasi untuk mencegah
penyakit graft versus host (GVHD) terkait transfusi pada kandidat HCT.
Komite Inggris untuk Standar Hematologi juga merekomendasikan produk darah iradiasi
untuk semua pasien yang menerima terapi antithymocyte globulin (ATG). Pada pasien
dengan sepsis neutropenia yang mengancam jiwa, panitia menyarankan pertimbangan
transfusi granulosit yang diiradiasi. [5]
Pengembangan rencana transfusi dengan berkonsultasi dengan dokter yang berpengalaman
dalam pengelolaan anemia aplastik sangat penting.
Pengobatan Infeksi
Infeksi merupakan penyebab utama kematian pada pasien dengan anemia aplastik. [51, 52]
Faktor risiko termasuk neutropenia berkepanjangan dan kateter tinggal yang digunakan untuk
terapi spesifik. Infeksi jamur, terutama yang disebabkan oleh spesies Aspergillus,
menimbulkan risiko besar. Pasien harus menjaga kebersihan untuk mengurangi risiko infeksi.
Komite Inggris untuk Standar Hematologi merekomendasikan antibiotik profilaksis dan agen
antijamur untuk pasien yang jumlah neutrofilnya di bawah 0,2 × 109 / L. [5] Terapi antibiotik
empiris harus berbasis luas, dengan cakupan gram negatif dan staphylococcal berdasarkan
sensitivitas mikroba lokal. Terutama mempertimbangkan termasuk cakupan antipseudomonal
pada awal pengobatan untuk pasien dengan febrile neutropenia; Juga pertimbangkan
pengenalan awal agen antijamur untuk individu dengan demam terus-menerus.
Namun, strategi penggunaan antibiotik empiris juga telah menghasilkan pengembangan
organisme tahan dan oleh karena itu tidak disukai oleh beberapa klinisi. [53]
Dukungan sitokin dengan faktor stimulasi koloni granulosit (G-CSF) dan faktor stimulasi
koloni granulosit-makrofag (GM-CSF) dapat dipertimbangkan pada infeksi refrakter,
walaupun terapi ini harus dipertimbangkan terhadap biaya dan khasiatnya. [8, 54, 55, 56]
Hentikan dukungan sitokin setelah 1 minggu jika jumlah neutrofil tidak meningkat. [5]
Transplantasi Sel Hematopoietik
Penempatan kateter vena sentral diperlukan sebelum transplantasi sel hematopoietik (HCT).
Perhatikan bahwa rekomendasi berikut ini tidak berlaku untuk pasien dengan anemia Fanconi
dan jenis kegagalan sumsum lainnya yang diwariskan; [5] Pasien-pasien ini memerlukan
pertimbangan khusus.
HCT menggunakan donor sibir HLA yang cocok
HCT leukosit manusia-leukosit (HLA) -terkaitan dengan donor kandung kemih HCT adalah
pengobatan pilihan untuk pasien muda dengan anemia aplastik berat atau sangat parah (SAA
atau VSAA, masing-masing), yang umumnya diterima untuk pasien yang berusia kurang dari
40 tahun. [5] Orang yang menjalani prosedur ini tidak memerlukan regimen pengkondisian
berbasis iradiasi. [5]
Sebuah penelitian terhadap 692 pasien Jerman dengan SAA yang menerima transplantasi dari
saudara kandung HLA, mencatat bahwa cangkok sumsum tulang lebih disukai daripada
cangkok sel induk darah perifer (PBPC) pada pasien berusia di bawah 20 tahun. [57] Studi
multinasional terhadap pasien dengan SAA yang menerima HCT dari donor sibir HLA-cocok
menyimpulkan bahwa meskipun sumsum tulang pasti merupakan sumber cangkok yang lebih
disukai untuk pasien ini, PBPC dapat menjadi alternatif yang dapat diterima di negara-negara
dengan sumber daya terbatas di mana pasien hadir. Kemudian dalam perjalanan penyakit
mereka dan risiko kegagalan korupsi dan komplikasi infeksi tinggi. [58]
Meskipun bukti menunjukkan bahwa sel induk dari sumsum tulang menghasilkan hasil yang
lebih baik dibandingkan dengan PBPC, pertimbangan tambahan adalah perspektif donor,
siapa yang harus diberitahu mengenai perbedaan antara metode pemanenan. Penangkapan
sumsum tulang biasanya dilakukan dengan donor dengan anestesi umum, sementara dengan
PBPC memanen donor terjaga dan terhubung melalui kateter intravena yang besar ke mesin
apheresis, yang memisahkan sel induk (untuk deskripsi kedua metode tersebut, lihat Bone
Prosedur Donor Marak).
Seiring dengan risiko yang terkait dengan anestesi, donor sumsum tulang biasanya
mengalami nyeri sedang selama beberapa hari setelah prosedur ini berlangsung. Pendeta
PBPC biasanya mengalami nyeri tulang, yang mungkin parah, dari stimulasi sumsum tulang
yang disebabkan oleh filgrastim yang digunakan untuk memobilisasi sel induk sebelum
prosedur tersebut. Salah satu masalah utama HCT pada anemia aplastik adalah tingginya
tingkat penolakan (10%; range, 5-50% ). Ini berkorelasi positif dengan jumlah transfusi yang
diterima dan durasi penyakitnya sebelum transplantasi. Sebelumnya, dosis sel induk yang
lebih tinggi, serta penambahan penyiraman total tubuh ke pengkondisian siklofosfamid, telah
dicoba. Meskipun dikaitkan dengan berkurangnya kejadian penolakan graft, manfaatnya
ditiadakan oleh kematian terkait transplantasi (TRM) karena peningkatan penyakit graft
versus host (GVHD). Saat ini, globulin antithymocyte (ATG) dengan siklofosfamid adalah
yang umum digunakan rejimen pengkondisian untuk transplantasi pada anemia aplastik.
Penambahan ATG ke siklofosfamid untuk pengkondisian telah mengakibatkan penolakan
graft yang jarang terjadi, serta peningkatan ketahanan hidup secara keseluruhan. [16, 54, 55,
59]