Pancytopenia

Pancytopenia is not equivalent with bone marrow suppression. Pancytopenia is a lab finding that may related to either bone marrow suppression or peripheral sequestration/destruction. For details about bone marrow suppression click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ogheneochuko Ajari, MB.BS, MS [3] Shyam Patel [4]

Overview

Pancytopenia is the reduction in numbers of all three bone marrow cell types (RBCs + WBCs + platelets). It is not a disease, but rather a lab finding that may related to bone marrow suppression caused by either insufficient production (aplastic anemia), inability of cells or mature (myelodysplasia), replacement of normal bone marrow with fibrosis (myelofibrosis) or peripheral sequestration that is not related to the bone marrow (e.g. splenomegaly or hypersplenism). or destruction (such as hemolytic anemia. HIV (human immunodeficiency virus) is itself a cause of pancytopenia. Chemotherapy is associated with pancytopenia due to drug-mediated bone marrow suppression. Pancytopenia usually requires a bone marrow biopsy in order to distinguish among different causes.

Historical Perspective

The history of pancytopenia relates to the history of each of its individual entities, namely anemia, thrombocytopenia, and leukopenia. Pancytopenia was not recognized as a distinct clinical entity until after each of its other subcomponents were characterized.

The seminal discoveries for aplastic anemia were made by Bruno Speck and Georges Mathe, who noted that immunosuppression could be used to treat aplastic anemia. In the 1970s, matched sibling donor transplant was used for severe aplastic anemia.

Pathophysiology

The pathophysiology of pancytopenia relates to the underlying etiology. In most cases, pancytopenia is due to a disruption in trilineage hematopoiesis. This means that the bone marrow is not appropriately producing erythrocytes, leukocytes, and thrombocytocytes. The cause of the disruption in trilineage hematopoiesis is in turn due to the underlying cause of pancytopenia. For example, viral-mediated pancytopenia is caused by viral particles infecting hematopoietic cells and preventing normal cell division. Leukemia-mediated pancytopenia is typically due to marrow replacement of normal hematopoietic precursors, a process known as myelopthisis. Leukemic infiltration of the bone marrow creates a "crowding-out" phenomenon.

Causes

Life Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.

Common Causes

• Aplastic anemia : This is a condition characterized by immune-mediated reduction in all three hematopoietic cell lines with absence of hematopoietic precursors. It is a rare condition with a prevalence of only 1-2 cases per million annually. It is most commonly diagnosed in childhood. Epidemiologic studies have shown a greater prevalence in Southeast Asia and other countries with limited access to healthcare, as viral infection can trigger aplastic crisis. There are three categories: moderate, severe, and very severe. These categories are based upon the number and degree of cytopenias as well as bone marrow cellularity. The preferred treatment of aplastic anemia is bone marrow transplantation from an HLA-matched sibling. If there is no HLA-matched sibling available, the next best option is medical management with the immunosuppressive agents anti-thymocyte globulin (ATG) and cyclosporine A. The reason for the efficacy of immunosuppressive medications is that the pancytopenia from aplastic anemia is due to abnormal immune activation and thus destruction of hematopoietic cells. ATG from horse has been shown to be superior compared to ATG from rabbit. ATG is administered over 5 days, and cyclosporine A is administered orally for 6 months, after which response can be assessed. The combination of ATG and cyclosporine A carries a response rate of 60-70%.
• Folate deficiency
• Leishmaniasis
• Leukemia: This can be myeloid or lymphoid, and each of these can be acute or chronic.
• Megaloblastic anemia
• Myelodysplastic syndrome
• Paroxysmal nocturnal hemoglobinuria
• Viral infections e.g. (HIV most common)
• Vitamin B12 deficiency
• Copper deficiency
• Zinc deficiency

Causes by Organ System

Cardiovascular	No underlying causes
Chemical/Poisoning	Arsenic poisoning, arsenicals, benzene solvents, genotoxic therapy, glue vapors, gold, mutagen exposure, mutagen-detoxification (GSTq1-null), radium chloride, toxins, valproic acid poisoning
Dental	No underlying causes
Dermatologic	Chediak-Higashi disease, dyskeratosis congenita, eosinophilic fasciitis, melanoma, reticular dysgenesis, reticulosis, systemic lupus erythematosus, xeroderma pigmentosum
Drug Side Effect	Acetaminophen and Oxycodone, aclarubicin, albendazole, alemtuzumab, alkylating antineoplastic agent, auranofin, azathioprine, aztreonam, boceprevir, busulfan, carbamazepine, carboplatin, cefadroxil, ceftazidime, certolizumab pegol, chemotherapy, chloramphenicol, chlorpromazine, chlorpropamide, cromolyn, cidofovir, clomipramine, cyclophosphamide, cytotoxic drugs, dactinomycin, docetaxel, doxorubicin, ethosuximide, febuxostat, flucytosine, gemcitabine, gemifloxacin mesylate, genotoxic therapy, idarubicin, Imipenem-Cilastatin,indomethacin , infliximab, interferon beta-1a, lincomycin hydrochloride, minocycline hydrochloride, non steroidal anti-inflammatory drugs, ofatumumab, omacetaxine, oxaprozin, oxcarbazepine, penicillamine, phenacemide , phenylbutazone, piperacillin, pralatrexate, propylthiouracil, pyrimethamine, rabeprazole, sulfonamides , tamoxifen, temozolomide, thiothixene, tolazamide, tolbutamide, topoisomerase II interactive agents, trifluoperazine, trimethadione, trimethoprim-sulfamethoxazole, valganciclovir hydrochloride
Ear Nose Throat	Dubowitz syndrome, Jacobsen syndrome
Endocrine	Osteoporosis, panhypopituitarism, thyroid carcinoma
Environmental	No underlying causes
Gastroenterologic	Banti's syndrome, cirrhosis, Gaucher's disease, hepatosplenic T-cell lymphoma, hypersplenism, intrinsic factor deficiency, malabsorption syndrome, Plummer-Vinson syndrome, portal hypertension, sarcoidosis, Schwachman-Diamond syndrome, splenomegaly
Genetic	Albers-Schonberg disease, ataxia telangiectasia, Banti's syndrome, Bloom syndrome , cartilage-hair hypoplasia, Chediak-Higashi disease, Diamond-Blackfan anemia, DNA repair-deficiency disorder, Down syndrome, Dubowitz syndrome, dyskeratosis congenita, familial histiocytic reticulosis, familial monosomy 7, Fanconi anemia, Gaucher's disease, hemophagocytic lymphohistiocytosis, Hoyeraal-Hreidarsson syndrome, Jacobsen syndrome, intrinsic factor deficiency, neurofibromatosis 1, Niemann-Pick disease, osteopetrosis lethal, osteopetrosis, autosomal recessive 2, Pearson syndrome, Schwachman-Diamond syndrome, severe combined immunodeficiency, TAR syndrome, trisomy 8 mosaicism, Wiskott-Aldrich syndrome, xeroderma pigmentosum
Hematologic	Acute lymphoblastic leukemia, acute myeloid leukemia, aggressive NK-cell leukemia, amegakaryocytic thrombocytopenia, aplastic anemia, autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2, bleeding (Excessive), bone marrow tumor, Castleman's disease, chronic lymphocytic leukaemia, chronic myeloid leukaemia, cyclical neutropenia, Diamond-Blackfan anemia, familial histiocytic reticulosis, familial myelofibrosis, Fanconi anemia, Gaucher's disease, hairy cell leukemia, hematopoietic stem cell transplantation, hemoglobin E disease, hemoglobin H disease, hemoglobin SC disease, hemophagocytic lymphohistiocytosis , hepatosplenic T-cell lymphoma, histiocytosis X, Hodgkin's lymphoma, hypersplenism, hypoplastic myelodysplastic syndromes, ineffective erythropoiesis, intestinal lymphangiectasia, intrinsic factor deficiency, iron deficiency, langerhans cell histiocytosis, leucoerythroblastic anemia, leukemia, lymphoma, malignant histiocytosis, megaloblastic anemia, myelodysplastic syndrome, myelofibrosis, myeloma, myelopathic anemia, non-Hodgkin lymphoma, paroxysmal nocturnal hemoglobinuria, Pearson syndrome, pernicious anemia, Plummer-Vinson syndrome, precursor B acute lymphoblastic leukemia, reticulosis, Schwachman-Diamond syndrome, sickle cell disease, TAR syndrome, t-cell large granular lymphocytic leukemia, Wiskott-Aldrich syndrome
Iatrogenic	Radiation therapy, radioactive p32
Infectious Disease	Babesiosis, brucellosis, dengue, Epstein-Barr virus , hepatitis, human immunodeficiency virus , infectious mononucleosis, kala-azar, Kikuchi disease, lassa fever, legionella pneumophila, mycobacterium tuberculosis, parvovirus B19 infection, Q fever, tuberculosis, viral infections, Whipple's disease
Musculoskeletal/Orthopedic	Albers-Schonberg disease, ankylosing spondylitis, cartilage-hair hypoplasia, Ewing's sarcoma, osteoclastoma, osteopetrosis lethal, osteopetrosis, autosomal recessive 2, osteoporosis, osteosarcoma, TAR syndrome
Neurologic	Ataxia telangiectasia, Down syndrome , neuroblastoma, neurofibromatosis 1, Niemann-Pick disease
Nutritional/Metabolic	Anorexia nervosa, copper deficiency, folate deficiency, Gaucher's disease, glutathione synthase deficiency, iron deficiency, kwashiorkor, marasmus, obesity, vitamin B12 deficiency, vitamin C deficiency
Obstetric/Gynecologic	Pregnancy
Oncologic	Acute lymphoblastic leukemia, acute myeloid leukemia, aggressive NK-cell leukemia, bone marrow tumor, cancer, chondrosarcoma, chronic lymphocytic leukaemia, chronic myeloid leukaemia, epiphyseal tumors, Ewing's sarcoma, familial myelofibrosis, germ cell tumors , granuloma, hairy cell leukemia, hepatosplenic T-cell lymphoma, histiocytosis X, Hodgkin's lymphoma, hypoplastic myelodysplastic syndromes, langerhans cell histiocytosis, leukemia, lymphoma, melanoma, metastatic neoplasm, myelodysplastic syndrome, myelofibrosis, myeloma, neuroblastoma, non-Hodgkin lymphoma, osteoclastoma, osteosarcoma, precursor B acute lymphoblastic leukemia, prostate cancer, t-cell large granular lymphocytic leukemia, thymoma, thyroid carcinoma
Ophthalmologic	No underlying causes
Overdose/Toxicity	Colchicine toxicity
Psychiatric	Anorexia nervosa
Pulmonary	Sarcoidosis
Renal/Electrolyte	Renal failure, chronic, systemic lupus erythematosus
Rheumatology/Immunology/Allergy	Ankylosing spondylitis, auto-immune disorders, autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2, Castleman's disease, common variable hypogammaglobulinemia, common variable immune deficiency, eosinophilic fasciitis , Felty's syndrome, graft versus host disease, histiocytosis X, langerhans cell histiocytosis, rheumatoid disease, sarcoidosis, severe combined immunodeficiency, systemic lupus erythematosus, Wiskott-Aldrich syndrome
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	Prostate cancer
Miscellaneous	Idiopathic, radioactive p32, tobacco use

Causes in Alphabetical Order

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Causes by Pathophysiology

Bone Marrow Failure

• Insufficient production (aplastic anemia)
• Inability of cells or mature (myelodysplasia)
• Replacement of normal bone marrow with fibrosis (myelofibrosis)

Peripheral Sequestration/Destruction

• Splenomegaly
• Hypersplenism

Congenital

• Cartilage hair hypoplasia
• Diamond-Blackfan syndrome: This is a rare condition affecting 5-7 persons per million and is characterized by a macrocytic anemia and less than 5% erythroid precursors including reticulocytes. This condition is caused by mutations in ribosomal protein genes such as RPS19. Though neutropenia and thrombocytopenia do not usually occur, moderate white blood cell and platelet count reductions have been described in some cases. Fetal hemoglobin is typically increased in an effect to enhance delivery of oxygen to tissues in the setting of low hemoglobin. The only curative therapy is bone marrow transplantation.
• Dubowitz syndrome
• Dyskeratosis congenita: This is a rare condition caused by short telomeres, which normally function to maintain the length and integrity of DNA. It is characterized by skin abnormalities, nail abnormalities, and leukoplakia. The genes implicated include DKC1 (dyskerin), TERT, and TERC. Other genes implicated in this condition encode ribonucleoprotein enzymes. By age 30, approximately 80% of patients with this condition will develop bone marrow failure.
• Familial aplastic anemia
• Fanconi's anemia: This is a condition characterized by genomic instability and increased susceptibility to DNA damaging agents. Diagnosis is made by demonstration of DNA crosslinking upon exposure to diepoxybutane (DEB) and mitomycin C (MCC). Patients with Fanconi anemia have a higher risk for development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), both of which can contribute to pancytopenia.
• Pearson syndrome
• Schwachman-Diamond syndrome: This is a condition that affects approximately 1 in 50000 persons and is characterized by pancreatic exocrine insufficiency and skeletal abnormalities. It is caused by a mutation in a ribosomal protein encoded by the SBDS gene.
• TAR syndrome

Acquired

• Albers-Schonberg disease
• Banti's Syndrome
• Bone marrow tumor
• Cirrhosis
• Drugs/Toxins
• Felty's Syndrome
• Gaucher's Disease
• Graft-versus-host disease
• Infections
• Kala-Azar
• Leukemia
• Lymphoma
• Lymphoproliferative Disorders
• Myelodysplastic syndrome
• Myelofibrosis
• Niemann-Pick Disease
• Osteoporosis
• Pernicious anemia
• Reticulosis
• Sarcoidosis
• Thymoma
• Tuberculosis

Differentiating [Disease] from Other Diseases

Pancytopenia must be differentiated from a pseudo-syndromes like pseudo-thrombocytopenia, which is a laboratory artifact from platelet clumping.

Epidemiology and Demographics

Pancytopenia affects males and females equally. However, the underlying etiologies of pancytopenia can have a gender predilection.

Risk Factors

The risk factors of pancytopenia are related to the underlying cause. For example, leukemia-mediated pancytopenia can be related to risk factors such as chemical exposure, radiation, or family history.

Screening

There are no suggested screening tests for pancytopenia. The United States Preventive Services Task Force (USPSTF) does not have any recommendations for screening for pancytopenia.

Natural History, Complications, and Prognosis

Natural History

The natural history of pancytopenia is dictated by the pathophysiology of the under etiology. For example, viral-mediated pancytopenia is typically short-lived, pending clearance of the virus. Drug-induced pancytopenia typically resolves after discontinuing of the culprit drug and the drug has been metabolized by the body. Leukemia-mediated pancytopenia is usually a more long-term process, as marrow replacement by leukemia cells is difficult to overcome unless the leukemia is treated and the patient is in remission.

Complications

Complications of pancytopenia relate to deficits of the cell types that are affected. Decrease in erythrocytes causes fatigue and pallor due to decrease in oxygen delivery to tissue beds. Decrease in leukocytes and leukocyte subsets causes infections, which can be viral, bacteria, fungal, or parasitic. Decrease in thrombocytes causes bleeding, which is typically mucosal, given loss of the ability of platelets to create a hemostatic plug.

Prognosis

The prognosis of pancytopenia is related to the underlying etiology. For example, patients with unfavorable-risk leukemia will likely have a poor prognosis from a pancytopenia perspective. Patients with viral-mediated pancytopenia have a prognosis that is determined by the natural history of the virus. Epstein-Barr virus (EBV)-related pancytopenia can have a good prognosis if EBV resolves. Drug-induced pancytopenia has a favorable prognosis, as discontinuation of the offending agent can typically reverse the pancytopenia.

Diagnosis

Diagnostic Criteria

The diagnosis of pancytopenia is made when all of the following criteria are fulfilled:

• Anemia as defined by hemoglobin level < 12 grams per deciliter (g/dl)
• Leukopenia as defined by leukocyte count < 4000 per microliter
• Thrombocytopenia as defined by platelet count < 150000 per microliter

History and Symptoms

Symptoms are pancytopenia are related to decrease in erythrocytes, leukocytes, and platelets. Decrease in erythrocytes causes fatigue, shortness of breath, decreased exercise tolerance, and pallor. Decrease in leukocytes causes infection, which can affect a multitude of organ systems including the central nervous system, lungs, abdomen, urinary tract, kidneys, and skin. Decrease in platelets causes mucocutaneous bleeding, typically of the nose, mouth, gastrointestinal tract, or genitourinary tract.

Physical Examination

Key components of the physical exam include assessment of the conjunctiva, oral and nasal mucosa, lymph nodes (cervical, axillary, supraclavicular, inguinal), spleen size, liver size, and skin.

The anemia component of pancytopenia can cause conjunctival pallor, mucosal pallor, and skin pallor. The leukopenia component of pancytopenia can cause variable findings depending on whether infection is present. Exam findings can include lymphadenopathy, egophony, coarse breath sounds, malodorous urine, suprapubic tenderness, costovertebral tenderness, abdominal tenderness, skin erythema, and/or skin purulence.

Laboratory Findings

Laboratory findings in pancytopenia are, by definition: Hemoglobin level < 12 grams per deciliter (g/dl) Leukocyte count < 4000 per microliter Platelet count < 150000 per microliter

Treatment

Medical Therapy

The treatment of pancytopenia depends on the underlying cause. If pancytopenia is due to medication adverse effect, the offending agent should be discontinued.

Surgery

The is no role for surgery for pancytopenia. However, for immune thrombocytopenia purpura (ITP) and autoimmune hemolytic anemia (AIHA), splenectomy can be considered.

References

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