Pancytopenia

Pancytopenia is a decrease in all blood cell lineages, leading to anemia, thrombocytopenia, and leukopenia. Causes are divided into impaired blood cell production (e.g., due to nutritional deficiencies, aplastic anemia, or bone marrow infiltration) and increased cell destruction (e.g., autoimmune-mediated or splenic sequestration). Clinical manifestations arise from the cytopenias themselves, resulting in fatigue, bleeding, and infections, and from underlying conditions that may manifest with constitutional symptoms, hypersplenism, and/or lymphadenopathy. Laboratory studies to narrow the differential diagnosis include standard chemistries and a peripheral blood smear. Further testing may include bone marrow biopsy, imaging, and/or autoimmune screening. Management is tailored to the underlying cause and may involve blood product support and infection treatment.

Aplastic anemia is a type of pancytopenia caused by bone marrow insufficiency with reduced cellularity. Aplastic anemia is most often idiopathic; other causes include radiation exposure and inherited bone marrow failure syndromes. Diagnosis is confirmed with a bone marrow biopsy revealing hypocellular marrow with prominent fat spaces, and treatment typically includes immunosuppressive therapy, sometimes with allogeneic stem cell transplantation.

Impaired production ^[1][2][3]

• Nutritional deficiencies, e.g.:
  • Vitamin B₁₂ deficiency
  • Folate deficiency
  • Copper deficiency
• Aplastic anemia etiologies
  • Acquired, e.g.:
    • Idiopathic
    • Radiation injury
    • Alcohol use disorder
    • Medications,
    • Viral, bacterial, or parasitic infections
    • Sepsis
  • Inherited bone marrow failure disorders, e.g., Fanconi anemia
• Malignant bone marrow infiltration
  • Acute leukemia, e.g.:
    • Acute myeloid leukemia (AML)
    • Acute promyelocytic leukemia (APL)
    • Acute lymphoblastic leukemia (ALL)
  • Other myeloid neoplasms, e.g.:
    • Myelodysplastic syndromes (MDS)
    • Myelofibrosis
    • Chronic myeloid leukemia (CML)
  • Multiple myeloma
  • Lymphoproliferative disorders, e.g.:
    • Low-grade non-Hodgkin lymphomas with marrow involvement
    • Hodgkin lymphoma
    • Hairy cell leukemia
  • Marrow infiltration by solid organ malignancy, e.g.:
    • Lung cancer,
    • Breast cancer
    • Prostate cancer
• Nonmalignant bone marrow infiltration, e.g.:
  • Gaucher disease
  • TB
  • Leishmaniasis

Increased destruction or loss ^[1][2]

• Autoimmune, e.g.: autoimmune hemolytic pancytopenia
• Thrombotic microangiopathies, e.g.: disseminated intravascular coagulation (DIC)
• Splenic sequestration, e.g.: due to portal hypertension

Impaired production and increased destruction ^[2]

• Medications, e.g.: ^[3]
  • Antibiotics, e.g., chloramphenicol, trimethoprim
  • Antiepileptic drugs, e.g., carbamazepine, valproate
  • Chemotherapeutic agents
  • Immunosuppressants, e.g., azathioprine, methotrexate
• Infections, e.g.:
  • Malaria
  • Schistosomiasis
  • Viral infections
• Autoimmune conditions: e.g., systemic lupus erythematosus (SLE), rheumatoid arthritis
• Other, e.g.:
  • Hemophagocytic lymphohistiocytosis (HLH), e.g., due to viral infection
  • Paroxysmal nocturnal hemoglobinuria (PNH)
  • Transfusion-associated graft-versus-host disease

Focused history ^[1][2]

• Symptoms of cytopenias, e.g.:
  • Anemia: fatigue, shortness of breath, chest pain
  • Thrombocytopenia: abnormal bleeding (e.g., hematuria, abnormal bruising)
  • Leukopenia: recurrent infection
• Symptoms of underlying condition
  • Systemic symptoms (e.g., fatigue, weight loss, night sweats, fever), e.g., due to malignancy or infection
  • Hypersplenism symptoms (e.g., RUQ pain and/or fullness, referred pain to shoulder)
  • Symptoms of specific infections (e.g., clinical features of infectious mononucleosis)
  • Autoimmune or inflammatory symptoms (e.g., joint pain, fever, rash)
  • Neurological symptoms (e.g., seizures, neuropathy)
• Background
  • Detailed medication list (e.g., antiepileptic drugs, NSAIDs, steroids, chloramphenicol, chemotherapeutic agents)
  • History of radiation therapy
  • Social history: alcohol intake, travel history
  • Family history: genetic conditions

Focused physical examination ^[1][2]

• Signs of pancytopenia, e.g.:
  • Signs of anemia
  • Clinical features of thrombocytopenia
  • Signs of leukopenia, e.g., signs of infection, mouth ulcers
• Nonspecific signs
  • Lymphadenopathy, e.g., due to infection or malignancy
  • Splenomegaly
  • Hepatomegaly
  • Fever
• Signs of specific underlying cause
  • Signs of infection, e.g., clinical features of hepatitis C
  • Signs of autoimmune conditions, e.g., clinical features of RA, clinical features of SLE
  • Signs of nutritional deficiency, e.g., unexplained neurological findings
  • Clinical features of cirrhosis

Approach ^[1][2]

Take the following steps in patients with clinical features suggesting pancytopenia or an associated underlying condition:

• Perform CBC with differential to confirm the diagnosis.
• Use clinical evaluation to rule out medications or toxins as the cause.
• Perform initial studies (e.g., PBS) to identify the cause if not apparent from clinical evaluation.
• Consult hematology if cause is not identified on the initial screen.

Pancytopenia is a decrease in all blood cell lineages, manifesting as the combination of anemia, thrombocytopenia, and leukopenia. ^[2][4]

Initial studies ^[1][2]

If pancytopenia is confirmed on CBC , consider the following: ^[2][4]

• Anemia workup, including:
  • Reticuloyte index: low in impaired production and elevated in peripheral destruction
  • Diagnostic studies for iron deficiency anemia
• Testing for nutritional deficiencies: vitamin B₁₂ deficiency, folate deficiency
• Peripheral blood smear: findings may include megaloblastic anemia (e.g., in vitamin B₁₂ deficiency, folate deficiency), and/or circulating immature leukocytes (e.g., in acute leukemia, sepsis)
• LDH: elevated in acute illness, hematological malignancy, and hemolysis
• ESR and/or CRP: elevated in, e.g., infection, autoimmune conditions
• Coagulation studies: may be abnormal in DIC or liver disease
• Liver chemistries and BNP: elevated in, e.g., chronic liver disease, sepsis

Further studies ^[1][2]

If no cause is identified on the initial screen, further workup is guided by clinical picture, with specialist input from, e.g., hematology. This may include:

• Malignancy workup
  • Multiple myeloma screen: serum protein electrophoresis, immunoglobulin levels, serum free light chain assay
  • Specialist tests on peripheral blood, e.g., flow cytometry and/or genetic studies
  • Bone marrow aspirate and biopsy for morphology, flow cytometry, and genetic studies.
  • Consider imaging studies:
    • CT chest, abdomen, and pelvis: if lymphadenopathy or signs of solid organ malignancy
    • Whole body low-dose CT in suspected multiple myeloma
    • Ultrasound of spleen: a spleen size > 20 cm may indicate CML or myelofibrosis ^[1]
• Infectious workup
  • Viral screen: hepatitis serology, cytomegalovirus (CMV), EBV, HIV; HHV-6 and parvovirus B19 if indicated
  • Diagnostics for tuberculosis
  • Testing for parasites, e.g., malaria, schistosomiasis, leishmaniasis
• Autoimmunity workup: e.g., ANAs and other diagnostics for SLE
• Hemolysis workup: e.g., haptoglobin, direct antiglobulin test (DAT), fibrinogen (low in DIC)
• Additional testing: e.g., for nutritional deficiencies such as copper deficiency

Chronic pancytopenia may manifest with acute infection and/or bleeding. Consider chronic causes in acutely unwell patients.

Management is based on the underlying cause and is guided by a specialist team, e.g., hematology. Supportive care may include management of: ^[1]

• Anemia
  • Acute: Consider packed red blood cell transfusion, aiming for hemoglobin > 7.0 g/dL; see also “Indications for pRBC transfusion.” ^[1][40]
  • Chronic: Consider transfusions on a case-by-case basis, guided by symptoms.
• Thrombocytopenia
  • Consider platelet transfusion, e.g., for platelet count < 10,000/mm³ or if < 50,000/mm³ with bleeding; see also “Indications for platelet transfusion.” ^[41][42][43]
  • Consider an antifibrinolytic agent, e.g., tranexamic acid. ^[44]
• Neutropenia ^[45][46]
  • Neutropenia precautions
  • Management of neutropenic fever guided by risk stratification (e.g., MASCC score) and source of infection; may include:
    • Empiric antibiotic therapy for neutropenic fever
    • See also “Neutropenic fever: Acute management checklist.”
  • Consider the following with hematology guidance:
    • G-CSF therapy
    • Prophylactic antibiotics in chronic neutropenia

Advise patients with neutropenia to report fever immediately and admit patients with fever and absolute neutrophil count < 500/mcL urgently for IV broad-spectrum antibiotics.

In patients with severe thrombocytopenia and/or significant bleeding, initiate emergency management of thrombocytopenia and consult hematology.

Definition

• Pancytopenia caused by bone marrow insufficiency with reduced bone marrow cellularity ^[41]
• Should not be confused with aplastic crisis, a condition in which erythropoiesis is temporarily suppressed (e.g., due to parvovirus B19 infection in patients with hemolytic anemias)

Etiology of aplastic anemia ^[1][2][3]

• Idiopathic in > 50% of cases
  • Possibly immune-mediated
  • May follow acute hepatitis (hepatitis-associated aplastic anemia)
• Medications, e.g.: carbamazepine, methimazole, NSAIDs, chloramphenicol, propylthiouracil, sulfa drugs, cytotoxic drugs (esp. alkylating agents and antimetabolites)
• Exposure
  • Toxins: benzene, cleaning solvents, insecticides, toluene
  • Ionizing radiation
  • Alcohol use disorder
• Infections
  • Viral infections: e.g., HBV, EBV, CMV, HIV, parvovirus B-19, HHV-6, dengue virus
  • Bacterial infections: e.g., leptospirosis
  • Sepsis
• Fanconi anemia ^[47][48]
  • Hereditary autosomal recessive disorder due to a DNA crosslink repair defect resulting in bone marrow failure
  • Skeletal and organ abnormalities: short stature, hypo- and hyperpigmentation, cafe-au-lait spots, microcephaly, developmental delay, thumb and forearm malformations, kidney, GI, heart, eye, and ear abnormalities
  • Laboratory tests show pancytopenia and normocytic or macrocytic anemia.
  • ∼ 50% of patients with Fanconi anemia will develop AML or MDS in early adulthood. ^[49]

Agents that can cause aplastic anemia: Can't Make New Blood Cells Properly = Carbamazepine, Methimazole, NSAIDs, Benzenes, Chloramphenicol, Propylthiouracil

Clinical features ^[41]

• Malaise and fatigue
• Pallor
• Purpura, petechiae, mucosal bleeding
• Infection

Diagnosis of aplastic anemia ^[41][50]

Obtain a complete pancytopenia workup to exclude other causes. Findings consistent with aplastic anemia include:

• Laboratory studies, e.g.:
  • CBC: pancytopenia (in contrast to aplastic crisis characterized by anemia only), or normocytic or macrocytic anemia
  • Reticulocyte count: low
  • Erythropoietin level: high
• Bone marrow findings: hypocellular with prominent fat spaces (“empty marrow” appearance) ^[41]
• Further specialist studies may include:
  • Testing for inherited bone marrow failure disorders
  • HLA typing
  • Screening for a PNH clone. ^[41]

Aplastic anemia is classified as severe or very severe based on the severity of cytopenias and the degree of bone marrow cellularity ^[41]

Treatment of aplastic anemia ^[41][50]

• Consider need for supportive care, e.g.:
  • Platelet transfusions, and/or blood transfusions
  • Bone marrow stimulants (e.g., GM-CSF; , eltrombopag)
• Manage the underlying cause (e.g., cessation of the causative agent, or treatment of infections)
• If no cause is identified, treatment for idiopathic aplastic anemia may include: ^[41]
  • Immunosuppressive therapy to prevent further autoimmune marrow destruction
    • Cyclosporine
    • Antithymocyte globulin
    • Tacrolimus
    • Alemtuzumab
    • Prednisolone
  • Consider hematopoietic stem cell transplantation in patients under 50 years of age with a suitable stem cell donor. ^[51]