Pancytopenia

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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], Sadaf Sharfaei M.D.[5]

Overview

Pancytopenia is the reduction in numbers of all three bone marrow cell types, including red blood cells, white blood cells, and platelets. The prefix "pan-" means "everything," "cyto" means "cell", and the suffix "penia" means "deficiency." Pancytopenia is not a disease, but rather a laboratory finding that may related to bone marrow suppression caused by either insufficient production (aplastic anemia), inability of cells to 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). Chemotherapy is associated with pancytopenia due to drug-mediated bone marrow suppression. Pancytopenia frequently 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 sub-entities, namely anemia, thrombocytopenia, and leukopenia. Pancytopenia was not recognized as a distinct clinical entity until after each of its other subcomponents were characterized. Thus, there is no specific history for pancytopenia.

  • History of aplastic anemia:
    • 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.[1]
    • In the 1970s, matched sibling donor transplant was used for severe aplastic anemia.[2]
  • History of paroxysmal nocturnal hemoglobinuria:
    • In 1882, Dr. Paul Strubing reported the case of a patient with hematuria at night that occurred periodically.[3]
      • He noted that hemolysis was the reason for the patient's hematuria.
    • In 1925, the term paroxysmal nocturnal hemaglobinuria was coined.[3]
    • In the 1930s, Dr. T.H. Ham noted that acidified serum could induce hemolysis.
      • Thus, the Ham's acid serum test was developed.[3]
      • This became the first diagnostic test for this disease.
    • In the 1950s, the complement pathway was discovered, and it was determined that paroxysmal nocturnal hemoglobinuria was due to activation of complement proteins on the red blood cell membrane.[3]
    • In the 1980s, the genetic defect responsible for the disease was discovered, specifically, the PIG-A gene defect leading to inability to anchor complement-inhibitory proteins onto the red blood cell membrane.

Classification

There is no classification system for pancytopenia. However, some underlying disease entities that cause pancytopenia have classification. For example, aplastic anemia is classified as moderate, severe, or very severe.

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. There are no life-threatening causes of pancytopenia that require acute treatment within 24 hours. However, if pancytopenia is accompanied by fever, this should be treated as a hematologic emergency with prompt administration of IV antibiotics.

Common Causes

  • Aplastic anemia [4]
    • This is a condition characterized by immune-mediated reduction in all three hematopoietic cell lines with absence of hematopoietic precursors.[1]
    • 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.[1]
    • 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 human leukocyte antigen (HLA)-matched sibling available, the next best option is medical management with the immunosuppressive agents anti-thymocyte globulin (ATG) and cyclosporine A.[1]
    • 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.[1]
    • 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%. [2] Eltrombopag can also be added to the regimen of ATG and cyclosporine.
  • Folate deficiency
    • Folate is required for pyrimidine nucleotide synthesis, and thus folate deficiency can lead to decreased production of hematopoietic cells.[5]
    • Folate deficiency occurs in persons who consume large amounts of alcohol.
    • Folate deficiency is accompanied by macrocytosis, or large-sized cells.
    • Treatment of folate deficiency is supplementation of folate in the diet.
  • Leishmaniasis
    • This is a rare infectious cause of pancytopenia.
  • Leukemia
    • This can be myeloid or lymphoid, and each of these can be acute or chronic.
    • Acute leukemias typically cause pancytopenia via a crowding-out phenomenon, known as myelopthisis.
    • Diagnosis of acute leukemia is based by demonstration of blast count of 20% or greater in the bone marrow.
    • Treatment involves multiagent chemotherapy, such as cytarabine combined with anthracycline for acute myeloid leukemia, or vincristine-based and anthracycline-based regimen for acute lymphoblastic leukemia.
    • Treatment of the underlying leukemia can help improve pancytopenia.
  • Megaloblastic anemia [4]
    • This condition is characterized by decreased red blood cell count and increased cellular size with defective maturation.[6]
    • The cause is usually deficiency of vitamin B12 or folate.
    • The diagnosis is made with a complete blood count showing hemoglobin less than 12 g/dl, mean corpuscular volume greater than 100 femtoliter (MCV > 100 fL), and peripheral smear showing enlarged cells.
    • The treatment is supplementation with vitamin B12 or folate.[6]
  • Myelodysplastic syndrome
    • This is a disease characterized by ineffective erythropoiesis and peripheral cytopenias.
    • It is a clonal disorder of the hematopoietic stem cell.[7]
    • The subtype of myelodysplastic syndrome that causes pancytopenia is termed refractory anemia with multilineage dysplasia.
    • The pancytopenia of myelodysplastic syndrome is due to failure of maturation of hematopoietic precursors, leading to peripheral cytopenias.[7]
    • Diagnosis of myelodysplastic syndrome is made by demonstration of at least 1 cell line with 10% of greater dysplastic cells on bone marrow biopsy.
    • Bone marrow biopsy should also show myeloblasts less then 20% of total leukocytes.
    • Clinical features of myelodysplastic syndrome include manifestations of specific cytopenias, such as fatigue if there is anemia, bleeding if there is thrombocytopenia, and infections if there is leukopenia.[8]
    • The prognostication of myelodysplastic syndrome is determined by the International Prognosis Scoring System-Revised (IPSS-R), which is determined by blast count, the karyotype, and cytopenia.
    • This clinical tool is used to estimate the time to progression to acute myeloid leukemia.
    • The treatment of myelodysplastic syndrome is based on the subtype. Lenalidomide is highly effective for persons with deletion of chromosome 5q.[8]
    • DNA hypomethylating agents like azacitadine and decitabine are commonly used for those with symptomatic cytopenias and without chromosome 5q deletion.
    • In some cases, allogeneic stem cell transplantation can be done with the goal of curing myelodysplastic syndrome and preventing progression to acute myeloid leukemia.[8]
    • Adjunctive therapies include transfusion support (such as red blood cell transfusions or platelet transfusions), growth factor support (such as filgrastim), and immunosuppressive therapy, which is particularly effective in persons with PNH clones, HLA-DR15 positivity, or STAT3-mutant cytotoxic T cells.
  • Paroxysmal nocturnal hemoglobinuria
    • This is a clonal disorder of the hematopoietic stem cell characterized by hemolysis due to complement activation on the red blood cell membrane.[9]
    • It is cause of bone marrow failure.
    • The genetic defect is a deficiency in glycosylphosphatidylinositol (GPI) which is encoded by the PIG-A gene.
    • This protein normally serves to anchor complement regulatory and inhibitory proteins onto the red blood cell membrane.[9]
    • The two major regulatory proteins are CD55 (or decay accelerating factor (DAF)), which functions to degrade complement proteins C3 and C5 convertase, and CD59 (or membrane inhibitor of reactive lysis (MIRL)), which functions to prevent complement-mediated hemolysis via preventing formation of the membrane attack complex.[9]
    • The clinical manifestations include hematuria, portal venous or hepatic venous thrombosis.
    • Diagnosis is made by performing flow cytometry of peripheral blood and analyzing the expression fo CD55 and CD59 on red blood cell membranes.[9]
    • Treatment of this condition is eculizumab, a humanized monoclonal antibody that inhibits complement protein C5.[9]
  • Viral infections
    • Viruses such as HIV, EBV, or CMV can cause pancytopenia.
    • The diagnosis can be made by checking viral loads via PCR of peripheral blood or by checking antibody titers to the viruses.
    • For example, EBV can be diagnosed by assessing for EBV DNA PCR, or by assessing for IgM or IgM to EBV antigens.
  • Vitamin B12 deficiency
  • Copper deficiency
    • This is a more rare cause of pancytopenia.
  • Zinc deficiency
    • This is a more rare cause of pancytopenia. Treatment is supplementation with zinc.

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

Causes by Pathophysiology

Bone Marrow Failure

Peripheral Sequestration/Destruction

Causes by Mode of Inheritance

This is not applicable since there is no specific mode of inheritance for pancytopenia.

Congenital

  • Cartilage hair hypoplasia:
    • This is a bone marrow failure condition caused by ribosomal protein mutations.[45]
    • Clinical manifestations include cartilage and hair loss.
  • 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.[46]
    • It is the most common inherited erythrocyte failure syndrome, and it is inherited in an autosomal dominant pattern.[45]
    • 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.[46]
    • Fetal hemoglobin is typically increased in an effect to enhance delivery of oxygen to tissues in the setting of low hemoglobin.[46]
    • Clinical manifestations usually include short statute, ocular abnormalities, skeletal abnormalities.
    • It is the most common inherited erythrocyte failure syndrome.[45]
    • The only curative therapy is bone marrow transplantation.
  • Dubowitz syndrome
    • This is a rare autosomal recessive disorder characterized by increased cancer susceptibility.[47]
    • The exact genetic abnormality and etiology is yet to be identified.
    • Patients have DNA that is very sensitive to ionizing radiation and a few chemotherapy agents like anthracyclines and bleomycin.[47]
    • There is some clinical overlap with Fanconi anemia.[47]
    • Patients can develop bone marrow failure and cytopenias.
  • Dyskeratosis congenita
    • This is a rare condition caused by short telomeres, which normally function to maintain the length and integrity of DNA.[48]
    • 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.[48]
  • Fanconi's anemia
    • This is a condition characterized by erythrocyte hypoproduction due to genomic instability and increased susceptibility to DNA damaging agents.[45] [49]
    • 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.[50]
  • Pearson syndrome
  • Schwachman-Diamond syndrome
    • This is a condition that affects approximately 1 in 50000 persons and is characterized by bone marrow failure, pancreatic exocrine insufficiency, and skeletal abnormalities.[52]
    • It is caused by a biallelic (two alleles) mutation in a ribosomal protein encoded by the Schwachman-Bodian-Diamond gene SBDS, located on chromosome 7.[52]
    • Clinical manifestations in children usually include diarrhea and steatorrhea (due to pancreatic exocrine insufficiency).[53]
    • However, there have been cases of pancytopenia from schwachman-diamond syndrome in the absence of diarrhea, so this condition should still be in the differential diagnosis of children with pancytopenia and bone marrow failure.
  • TAR syndrome
    • This is a rare condition characterized by low platelet count (thrombocytopenia) and absent radius (a long bone of the lower arm).[54]
    • It is thought to be caused by an interstitial deletion in chromosome 1q21.
    • Patients can have skeletal abnormalities (like absent radius, short ulna, and absence of other long bones of the arm).[54]
    • The fingers are not affected.

Acquired

Differentiating Pancytopenia from Other Diseases

Category Condition Etiology Mechanism Congenital Acquried Clinical manifestations Para−clinical findings Gold standard Associated findings
Demography History Symptoms Signs
Lab Findings
Special Features Fever Bleeding BP Splenomegaly Jaundice Other CBC PBS Bone marrow exam PT PTT UA
Bone marrow infiltration Bone marrow failure Destruction/

sequestration/ redistribution

Plt HB WBC
Hematologic disorders Myelodysplastic syndrome[55] + + − ± + Elderly Exposure to + + Nl + + ↓ ↓ ↓ Nl Nl Nl Bone marrow examination + clinical manifestation
Malignancies such as:[56][57] + + + ± ± Any, more in adults
  • Exposure to chemicals
  • Radiation
  • Pre-existent blood disorders
 + + Nl + − ↓ ↓ ↓
  • Blast cells
 ↑ ↑ Bone marrow examination
Myelofibrosis[58] + + − + + Average 60 years old
  • Exposure to chemicals
  • Radiation
  • Pre-existent blood disorders
 + + Nl + − ↓ ↓ ↓ ↑ ↑ Bone marrow examination
Fanconi anemia[59] − + − + − Rare autosomal recessive genetic disorder, higher in Ashkenazi Jews and Afrikaners in South Africa − + Nl − − ↓ ↓ ↓ Nl Nl Nl Genetic studies
Condition Etiology Bone marrow infiltration Bone marrow failure Destruction/

sequestration/ redistribution

Congenital Acquried Demography History Appearance Fever Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam PT PTT UA Gold standard Associated findings
Aplastic anemia[60]
  • Unknown
 − + − ± ± Biphasic (the young and the elderly) − + Nl − − ↓ ↓ ↓ ↑ ↑ Nl Bone marrow examination +

laboratory findings

Paroxysmal nocturnal hemoglobinuria[61] + + − − + Any age

(usually younger adults)

  • Normal
 − − Nl − − ↓/Nl ↓ ↓/Nl Nl Nl Flow cytometry
Disseminated intravascular coagulation[62]
  • Consumption
 − − + − + Any
  • Acutely ill
 + + ↓ − + ↓/Nl ↓ ↓/Nl NA ↑ ↑ Lab findings
  • High mortality rate
Dyskeratosis congenital/telomere biology disorders[63] − + − + − Rare genetic disorder
  • Family history
 − + Nl − + ↓ ↓ ↓ Nl Nl Nl Clinical findings + genetic studies
Shwachman-Diamond syndrome[64] − + − + − Rare genetic disorder
  • Family history
 − + Nl − + ↓ ↓ ↓ Nl Nl Nl Clinical findings + genetic studies
Immunology/

Rheumatology

Condition Etiology Bone marrow infiltration Bone marrow failure Destruction/

sequestration/ redistribution

Congenital Acquried Demography History Appearance Fever Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam PT PTT UA Gold standard Associated findings
SLE[65] − + + + + More in young females
  • Family history
 + + Nl to ↓ + + ↓ ↓ ↓ ↑ ↑ Clinical findings + laboratory studies
  • Multi organ damage
  • Poor prognosis
Felty syndrome[66] − + − − + Rare autoimmune disease, more in females 50-70 years old + + Nl + + ↓ ↓ ↓ Nl Nl Nl Clinical findings + laboratory studies
Wiskott Aldrich syndrome[67] − + − + − Rare X-linked recessive disease − + Nl − − ↓ ↓ ↓ Nl Nl Nl Genetic study
GATA2 deficiency[68] − + − + − Rare − + ↓ + + − ↓ ↓ ↓ Nl Nl Nl Genetic study
Hemophagocytic lymphohistiocytosis[69] − + − + − Rare − + ↓ + + − ↓ ↓ ↓ Nl Nl Nl Genetic study
GI disorders Portal hypertension/cirrhosis[70][71] − − + − + Any − + ↓ + + − ↓ ↓ ↓ ↑ ↑ Nl Clinical manifestation
Storage diseases (eg, Gaucher)[72] + − + + − Rare in children
  • Family history
 − + ↓ + + − ↓ ↓ ↓
Infections Condition Etiology Bone marrow infiltration Bone marrow failure Destruction/

sequestration/ redistribution

Congenital Acquried Demography History Appearance Fever Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam PT PTT UA Gold standard Associated findings
Sepsis[73] + + − − + Any + ± Nl to ↓ − ± ↓/↑ ↓ ↓/↑ NA ↑ ↑ +

Depends on the etiology

Clinical manifestation + culture
  • Associated with ↑ mortality
Viral infection such as HIV, hepatitis, Epstein-Barr virus[74] − + + − + Any
  • High risk behaviors
  • Close contact
 + − Nl ± ± ↓ ↓ ↓ Nl Nl Clinical manifestation + lab tests
Nutritional Megaloblastic anemia[29] − + − + Any
  • Normal
 − − Nl − − ↓ ↓ ↓ Nl Nl Nl Laboratory findings NA
Excessive alcohol[5] − + − − + Alcoholism
  • Normal
 − − Nl + + ↓ ↓ ↓ ↑ ↑ Nl Clinical manifestation
Other nutritional deficiency such as copper deficiency, zinc toxicity[75][76] − + − − + Any
  • Normal
 − − Nl − − ↓ ↓ ↓ Nl Nl Nl Laboratory findings NA
Malnutrition[77] − + − − + Any
  • Normal
 − − Nl − − ↓ ↓ ↓ Nl Nl Nl Laboratory findings NA
Medications Medications such as:[78][79]
  • Immune destruction
 − + − − + Patients with malignancy − + Nl − − − ↓ ↓ ↓
  • Hypocellular bone marrow
  • Megakaryocytic hypoplasia or aplasia
 ↑ ↑ Hematuria Clinical manifestation + exclusion of the other causes
Category Condition Etiology Bone marrow infiltration Bone marrow failure Destruction/

sequestration/ redistribution

Congenital Acquried Demography History Appearance Fever Bleeding BP Splenomegaly Jaundice Other signs Plt HB WBC PBS Bone marrow exam PT PTT UA Gold standard Associated findings

Epidemiology and Demographics

  • Pancytopenia affects males and females equally.
  • However, the underlying etiologies of pancytopenia can have a gender predilection.
  • Please see above sections for epidemiology and demographics of the individual disease entities that cause pancytopenia.

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.
  • Please see above sections for risk factors of the individual disease entities that cause pancytopenia.

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.
  • However, if a person is suspected of having a particular condition that cause cause pancytopenia, such as viral infection, a diagnosis complete blood count (CBC) can be checked to assess 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.
  • Please see above sections for natural history of the individual disease entities that cause pancytopenia.

Complications

  • Complications of pancytopenia relate to deficits of the cell types that are affected.
  • Decrease in erythrocytes causes fatigue, pallor, lightheadedness, and shortness of breath 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.
  • The most concerning complication of decrease in leukocytes is called febrile neutropenia, which is a hematologic emergency.
  • 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.
  • Please see above sections for prognosis of the individual disease entities that cause pancytopenia.

Diagnosis

Diagnostic Criteria

The diagnosis of pancytopenia is made by assessing a complete blood count (CBC) 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 of 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, skin pallor, and tachypnea.
  • 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.
  • The thrombocytopenia component of pancytopenia can cause petechiae (pinpoint hemorrhages in the skin), mucosal bleeding, or internal bleeding.

Laboratory Findings

Laboratory findings in pancytopenia are, by definition:

Other laboratory findings, depending on the underlying cause, can include:

  • Elevated LDH
  • Elevated indirect bilirubin
  • Elevated reticulocyte count
  • Decreased haptoglobin

Imaging Findings

  • There are no imaging findings associated with pancytopenia.

Other Diagnostic Studies

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.
  • If pancytopenia is due to myelopthisis from leukemia, the underlying leukemia should be treated with cytotoxic chemotherapy.
  • If pancytopenia is due to aplastic anemia, this should be treated with either immunosuppression with anti-thymocyte globulin (ATG) and cyclosporine A, or by hematopoietic stem cell transplantation from a matched related donor.
  • Please see above sections for details of treatment of the individual disease entities that cause pancytopenia.

Surgery

Prevention

  • The prevention of pancytopenia focuses on prevention of the underlying etiologies.
  • For example, viral-induced pancytopenia can be prevented by taking precautions against acquiring viral infections.
  • This can include good hand hygiene, avoidance of exposures, anti-viral medications as prophylaxis.
  • Prevention of leukemia-induced pancytopenia can be achieved via avoidance of risk factors of leukemia such as radiation exposure, chemical exposure, or benzene exposure.
  • Drug-induced pancytopenia can be prevented by choosing an alternative medication in a similar class that does not cause pancytopenia.
  • For example, in a patient who requires prophylaxis for PCP, atovaquone can be administered in place of trimethoprim-sulfamethoxazole, as atovaquone does not cause pancytopenia.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Passweg JR, Tichelli A (2009). "Immunosuppressive treatment for aplastic anemia: are we hitting the ceiling?". Haematologica. 94 (3): 310–2. doi:10.3324/haematol.2008.002329. PMC 2649354. PMID 19252172.
  2. ↑ 2.0 2.1 Scheinberg P, Young NS (2012). "How I treat acquired aplastic anemia". Blood. 120 (6): 1185–96. doi:10.1182/blood-2011-12-274019. PMC 3418715. PMID 22517900.
  3. ↑ 3.0 3.1 3.2 3.3 Brodsky RA (2014). "Paroxysmal nocturnal hemoglobinuria". Blood. 124 (18): 2804–11. doi:10.1182/blood-2014-02-522128. PMC 4215311. PMID 25237200.
  4. ↑ 4.0 4.1 4.2 Das Makheja K, Kumar Maheshwari B, Arain S, Kumar S, Kumari S (2013). "The common causes leading to pancytopenia in patients presenting to tertiary care hospital". Pak J Med Sci. 29 (5): 1108–11. PMC 3858928. PMID 24353701.
  5. ↑ 5.0 5.1 Weston CF, Hall MJ (1987). "Pancytopenia and folate deficiency in alcoholics". Postgrad Med J. 63 (736): 117–20. PMC 2428237. PMID 3671238.
  6. ↑ 6.0 6.1 6.2 Yadav MK, Manoli NM, Madhunapantula SV (2016). "Comparative Assessment of Vitamin-B12, Folic Acid and Homocysteine Levels in Relation to p53 Expression in Megaloblastic Anemia". PLoS One. 11 (10): e0164559. doi:10.1371/journal.pone.0164559. PMC 5079580. PMID 27780269.
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