9.1 Anemias, Hemoglobinopathies, Leukemias & Immune Disorders
Key Takeaways
Anemias are classified by MCV: microcytic (iron deficiency, thalassemia, anemia of chronic disease), normocytic (hemolysis, chronic kidney disease) and macrocytic (vitamin B12 or folate deficiency).
Vitamin B12 deficiency causes megaloblastic anemia with hypersegmented neutrophils plus a neuropathy from dorsal column and peripheral nerve damage; elevated methylmalonic acid distinguishes it from folate deficiency.
Sickle cell disease (HBB Glu6Val) causes dactylitis in infants, avascular necrosis, Salmonella osteomyelitis and chronic leg ulcers over the malleoli.
CML carries t(9;22) BCR-ABL, APL carries t(15;17), CLL shows smudge cells, and multiple myeloma produces hypercalcemia, renal failure, anemia and punched-out lytic bone lesions.
Polycythemia vera (JAK2 V617F) can cause erythromelalgia, a burning, red, warm foot that responds to aspirin.
9.1 Anemias, Hemoglobinopathies, Leukemias & Immune Disorders
The pathology outline lists the hematopoietic system (leukemia, anemias, sickle cell) and the immune system (allergic and sensitivity reactions, immunosuppressive states) as disorder categories. Anemia reduces oxygen delivery to an ischemic foot, hemoglobinopathies cause bone infarcts and leg ulcers, and immunosuppression changes the signs of infection.
Anemia: A Morphologic Approach
Anemia is a reduced red cell mass or hemoglobin concentration. Normal ranges vary by laboratory, sex and altitude. Classifying by mean corpuscular volume (MCV, normal about 80–100 fL) narrows the cause:
| Category | Main causes | Key laboratory clues |
|---|---|---|
| Microcytic (MCV below 80) | Iron deficiency; thalassemia; anemia of chronic disease (some cases); sideroblastic anemia (lead, alcohol, pyridoxine deficiency) | Iron deficiency: low ferritin, high TIBC, high RDW. Thalassemia: normal iron studies, target cells, disproportionately low MCV |
| Normocytic (MCV 80–100) | Acute blood loss; hemolysis; anemia of chronic disease; chronic kidney disease (low erythropoietin); marrow failure | Reticulocyte count separates hemolysis and blood loss (high) from underproduction (low) |
| Macrocytic (MCV above 100) | Megaloblastic: vitamin B12 or folate deficiency, methotrexate, hydroxyurea. Non-megaloblastic: alcohol, liver disease, hypothyroidism | Megaloblastic anemia shows hypersegmented neutrophils |
Anemia of chronic disease (inflammation). Chronic osteomyelitis, rheumatoid arthritis and malignancy raise IL-6, which increases hepatic hepcidin. Hepcidin degrades ferroportin and traps iron in macrophages, producing high ferritin with low serum iron and low TIBC.
Vitamin B12 versus folate. Both cause megaloblastic anemia, but only B12 deficiency raises methylmalonic acid (both raise homocysteine), and only B12 deficiency causes neurologic damage. Subacute combined degeneration affects the dorsal columns and lateral corticospinal tracts, alongside a peripheral neuropathy that can mimic or worsen diabetic neuropathy. Causes include pernicious anemia (anti-intrinsic factor antibodies), ileal resection, strict vegan diets and long-term metformin or proton pump inhibitor use.
Hemolytic Anemias
- Hereditary spherocytosis: autosomal dominant defects of spectrin or ankyrin; spherocytes, splenomegaly and increased osmotic fragility.
- G6PD deficiency: X-linked; oxidant drugs (dapsone, primaquine, sulfonamides) or fava beans cause episodic hemolysis with Heinz bodies and bite cells (biochemistry in 17.3).
- Pyruvate kinase deficiency: chronic hemolysis from ATP depletion.
- Autoimmune hemolytic anemia: warm (IgG, extravascular; associated with SLE, CLL, drugs) or cold (IgM, complement-mediated; associated with Mycoplasma and EBV). Diagnosed with a positive direct Coombs test (6.5).
- Microangiopathic hemolysis: schistocytes from shearing in small vessels. Causes include TTP (ADAMTS13 deficiency), HUS (Shiga toxin) and DIC.
Sickle Cell Disease
A point mutation in the beta-globin gene (HBB, glutamic acid to valine at position 6) produces HbS, which polymerizes when deoxygenated. Rigid sickled cells cause vaso-occlusion and chronic hemolysis.
| Manifestation | Lower extremity relevance |
|---|---|
| Dactylitis (hand-foot syndrome) | Painful swelling of the hands and feet in infants 6 months to 2 years; often the first sign |
| Avascular necrosis | Femoral head, humeral head and talus |
| Osteomyelitis | Salmonella is characteristic, although S. aureus remains common |
| Leg ulcers | Chronic, painful ulcers over the medial or lateral malleoli |
| Autosplenectomy | Howell-Jolly bodies; risk from encapsulated organisms |
HbC disease (glutamic acid to lysine) is milder. Thalassemias reduce globin chain synthesis: alpha-thalassemia usually results from gene deletions (four alpha genes) and beta-thalassemia from point mutations, many affecting splicing.
Leukemias, Lymphomas & Plasma Cell Disorders
| Disorder | Typical patient | Diagnostic hallmark |
|---|---|---|
| Acute lymphoblastic leukemia | Children | TdT-positive lymphoblasts; can present with bone pain and limp |
| Acute myeloid leukemia | Adults | Myeloblasts with Auer rods; the acute promyelocytic subtype carries t(15;17), causes DIC and responds to all-trans retinoic acid |
| Chronic lymphocytic leukemia | Older adults | CD5+ B cells, smudge cells, warm autoimmune hemolysis |
| Chronic myeloid leukemia | Adults | t(9;22) BCR-ABL (Philadelphia chromosome); responds to tyrosine kinase inhibitors such as imatinib |
| Hodgkin lymphoma | Bimodal ages | Reed-Sternberg cells (CD15+, CD30+) |
| Multiple myeloma | Older adults | Monoclonal M-spike; CRAB: hyperCalcemia, Renal failure, Anemia, punched-out lytic Bone lesions; Bence Jones proteinuria |
Myeloproliferative neoplasms. Polycythemia vera (JAK2 V617F) raises red cell mass, causing hyperviscosity, thrombosis and pruritus after bathing. It also causes erythromelalgia: episodic burning pain, redness and warmth of the feet, relieved by cooling and characteristically responsive to aspirin. Essential thrombocythemia can cause digital ischemia.
Immune-System Pathology
Allergic and Sensitivity Reactions
- Urticaria and angioedema: IgE-mediated mast cell release, or bradykinin-mediated (ACE inhibitors, C1-inhibitor deficiency) when urticaria is absent.
- Anaphylaxis: treated first with intramuscular epinephrine in the anterolateral thigh.
- Latex allergy: Type I reactions to natural rubber latex proteins (gloves, tourniquets, catheters) and Type IV contact dermatitis from rubber accelerators. Patients with spina bifida, healthcare workers and people allergic to banana, avocado or kiwi are at higher risk.
- Severe cutaneous adverse drug reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis (epidermal necrosis; mucosal involvement; culprits include sulfonamides, anticonvulsants and allopurinol) and DRESS (eosinophilia, fever, organ involvement).
Immunosuppressive States
| State | Main defect | Infection pattern relevant to the foot |
|---|---|---|
| Diabetes mellitus | Impaired neutrophil chemotaxis and phagocytosis | Polymicrobial foot infection with blunted fever and leukocytosis |
| Corticosteroid therapy | Broad suppression of cytokines and lymphocytes | Masked inflammation, poor wound healing |
| Neutropenia (ANC below 500/µL) | Too few phagocytes | Pseudomonas (ecthyma gangrenosum), Aspergillus; little pus |
| Asplenia | Loss of splenic filtering and IgM memory B cells | Encapsulated organisms; Capnocytophaga after dog bites |
| HIV with low CD4 count | Loss of cell-mediated immunity | Proximal subungual onychomycosis, extensive warts, Kaposi sarcoma, mycobacteria |
| Transplant or biologic therapy | T-cell or cytokine blockade | Reactivated TB, fungi, herpes zoster, skin cancers |
Important
Immunosuppressed patients may show little erythema, warmth, fever or leukocytosis even with deep infection. Imaging, inflammatory markers and a low threshold for tissue culture matter more than in immunocompetent patients.
A 68-year-old with type 2 diabetes on long-term metformin has worsening numbness of both feet, a positive Romberg sign, an MCV of 112 fL and hypersegmented neutrophils. Which laboratory pattern best confirms the cause?
Elevated methylmalonic acid and homocysteine with a low vitamin B12 level
Low ferritin with high total iron-binding capacity
Normal methylmalonic acid with elevated homocysteine and low serum folate
High ferritin with low serum iron and low total iron-binding capacity
A 15-year-old with sickle cell disease has fever, tibial pain and a lytic metaphyseal lesion. Besides Staphylococcus aureus, which organism is characteristically associated with osteomyelitis in this setting?
Pseudomonas aeruginosa
Mycobacterium marinum
Pasteurella multocida
Salmonella species
A 61-year-old has episodic burning pain, redness and warmth of both feet that improves with cooling. Laboratory testing shows an elevated hemoglobin and a JAK2 V617F mutation. Which treatment characteristically relieves the foot symptoms?
Oral iron supplementation
Low-dose aspirin
Long-term loop diuretic therapy
Topical ice applied for hours at a time
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