PANCE Blueprint Hematology (5%)

Autoimmune hemolytic anemia (AIHA) is an anemia caused by the immune system making antibodies against the patient's own red cells, which are then destroyed — either removed by the spleen or lysed in the circulation — faster than the marrow can replace them. It is the mirror image of ITP: same mechanism, different target (red cells instead of platelets). The antibody type determines the disease: warm (IgG) or cold (IgM) — and that split drives everything from the associations to the treatment.

• The lab picture: ↓ hemoglobin/hematocrit · ↑ reticulocytes · ↑ LDH · ↑ indirect bilirubin · ↓ haptoglobin — plus a positive direct Coombs test, the finding that makes the diagnosis (it detects antibody or complement coating the red cells). The smear typically shows spherocytes in warm AIHA
• Warm AIHA (IgG — about 80%): antibody binds at body temperature; red cells are destroyed extravascularly in the spleen → splenomegaly, spherocytes
  • Associations: idiopathic (most) · SLE · CLL and lymphoma · drugs (methyldopa, penicillins/cephalosporins) · post-viral in children
  • Coombs pattern: IgG-positive (± C3)
• Cold AIHA / cold agglutinin disease (IgM): antibody binds in the cold periphery, fixes complement, and causes intravascular hemolysis and acrocyanosis (painful, dusky fingers, toes, ears, and nose in the cold)
  • Associations: Mycoplasma pneumoniae and EBV/mononucleosis (acute, in younger patients) · lymphoproliferative disease (chronic, in older patients)
  • Coombs pattern: C3-positive, IgG-negative
• Symptoms range widely: some patients are asymptomatic; others are tired, short of breath, and pale. Severe disease causes jaundice, dark urine, and abdominal fullness from splenomegaly
• The classic discriminator question: spherocytes appear in both hereditary spherocytosis and warm AIHA — the Coombs test separates them: positive in AIHA, negative in hereditary spherocytosis

DX:

• Step 1 — Establish hemolysis: reticulocyte count, LDH, indirect bilirubin, haptoglobin (see the box below)
• Step 2 — Direct Coombs (direct antiglobulin) test: positive = immune-mediated; the IgG vs C3 pattern then separates warm from cold. A negative Coombs points away from AIHA — think membrane, enzyme, or hemoglobin defects, or mechanical destruction
• Step 3 — Look at the smear: spherocytes (warm), red cell agglutination (cold), schistocytes (that's a microangiopathic process — TTP/HUS/DIC — not AIHA)
• Step 4 — Hunt the cause: ANA/lupus workup, medication history, Mycoplasma/EBV serologies where the story fits, and in an older adult consider CLL/lymphoma (CBC with differential, flow cytometry if indicated). Check for concurrent ITP — Evans syndrome = AIHA + ITP

TX:

• Warm AIHA: corticosteroids are first-line (prednisone ~1 mg/kg) — most patients respond within 1–3 weeks
  • Second-line: rituximab (now preferred ahead of splenectomy); splenectomy for refractory disease (vaccinate against encapsulated organisms first)
  • Treat or remove the underlying cause: stop the offending drug, treat the lupus or the lymphoma
• Cold AIHA: keep the patient warm and treat the underlying infection — corticosteroids and splenectomy are largely ineffective in cold agglutinin disease (the hemolysis is complement-mediated and intravascular, not splenic). Rituximab for chronic disease
• Everyone: folic acid (the marrow is working overtime). Transfuse for severe, symptomatic anemia — and do not withhold blood in a life-threatening anemia because the crossmatch is difficult (the autoantibody reacts with all donor cells; the blood bank will issue the "least incompatible" unit)

ITP is an autoimmune disorder in which the immune system makes antibodies against the patient's own platelets, which are then destroyed in the spleen (platelet production is also impaired). The result is an isolated low platelet count — everything else on the CBC and the smear is normal.

In children it typically follows a viral illness and resolves on its own; in adults it is more often insidious and chronic.

• Two clinical forms:
  • Acute form • seen in children (peak 2–5 years) • preceded by a viral infection in most cases • usually self-limited — 70–80% resolve spontaneously within 6 months, whether or not you treat
  • Chronic form • usually seen in adults, most commonly women between 20 and 40 • insidious onset • spontaneous remission is rare
• Bleeding is mucocutaneous: petechiae (classically the lower legs), purpura, easy bruising, epistaxis, gum bleeding, menorrhagia. Deep tissue bleeding and hemarthrosis suggest a coagulation-factor problem, not a platelet problem. Intracranial hemorrhage is the feared complication but is rare
• The lab picture: CBC normal except an isolated low platelet count — defined as <100,000/μL (often <20,000 at presentation, but the <100,000 threshold is what defines it — do not exclude ITP because the count is 45,000). Smear normal apart from large young platelets

DX: ITP is a clinical diagnosis of exclusion — there is no confirmatory test. The flow is: two tests, one question, then branch.

• Step 1 — History and exam. Hunt for what should not be there: hepatosplenomegaly, lymphadenopathy, bone pain, weight loss, or a patient who looks unwell. Take a medication history (heparin, quinine, sulfonamides, alcohol) and ask about liver disease
• Step 2 — Order two tests: a CBC with differential and a peripheral smear. These two tests are the entire required workup
• Step 3 — Ask one question: is the thrombocytopenia isolated? Normal hemoglobin, normal white count and differential, no blasts, and a smear that is normal apart from large young platelets (and no platelet clumping — pseudothrombocytopenia from EDTA is a lab artifact, not a disease)
  • Isolated thrombocytopenia + a well patient + no red flags → that is the diagnosis: ITP. No bone marrow is required — in children or in adults with a typical presentation — and no antiplatelet antibody testing
  • Any red flag, any second cytopenia, or blasts → bone marrow — and do it before any steroids (steroids can partially treat a leukemia and mask the diagnosis). In an older adult, also think of myelodysplastic syndrome
• Step 4 — Targeted add-ons, not a shotgun: HIV and hepatitis C in every adult (both cause secondary ITP); a blood group and direct antiglobulin (Coombs) test (needed before anti-D, and it screens for Evans syndrome); H. pylori testing where prevalent; and immunoglobulin levels and an ANA if the course is chronic or atypical
• Step 5 — The follow-up is part of the diagnosis. ITP should behave like ITP: if the patient fails to respond as expected, or the disease persists beyond 12 months, go back — do the marrow and work up the secondary causes (lupus, CVID, drug-induced)

TX: The two ages are managed differently — children are observed; adults are usually treated.

• Children: observation alone for no or minor (skin) bleeding — regardless of the platelet count. Most resolve spontaneously. Treat only significant mucosal bleeding: IVIG, anti-D, or a short course of corticosteroids (≤7 days)
• Adults: treat when the platelet count is below ~30,000/μL or there is bleeding. First-line is corticosteroids — prednisone, or dexamethasone 40 mg daily × 4 days — as a short course (avoid prolonged steroid exposure)
  • IVIG (or anti-D in an Rh-positive, Coombs-negative, non-splenectomized patient) when a rapid rise is needed or steroids are contraindicated. IVIG works by saturating the reticuloendothelial (splenic) Fc receptors, so the antibody-coated platelets are not taken up and destroyed
• Life-threatening bleeding: give everything at once — platelet transfusion + IVIG + high-dose IV corticosteroids. (Platelet transfusion is otherwise pointless in ITP — the transfused platelets are destroyed immediately)
• Chronic/refractory ITP: thrombopoietin receptor agonists (eltrombopag, romiplostim, avatrombopag), rituximab, or fostamatinib. Splenectomy induces durable remission in roughly two-thirds of chronic cases but is deferred at least 12 months from diagnosis when possible (spontaneous remission can still occur) — vaccinate against encapsulated organisms first
• Counsel every patient: avoid aspirin and NSAIDs, and avoid contact sports and head-injury-risk activities while the count is low

Petechiae are small, pinpoint, non-blanching red spots caused by capillary bleeding

Purpura are larger, flat, non-blanching red or purple patches resulting from blood leakage into the skin

• This deficiency in B12 leads to impaired DNA synthesis in red blood cells, resulting in megaloblastic anemia, characterized by abnormally large red blood cells with immature nuclei

Megaloblastic anemia (↑ MCV > 100), hypersegmented Neutrophils, + schilling test*, ↓ intrinsic factor, and anti-intrinsic factor antibodies (increased)

• Serum Gastrin (increased) - Second line test indicated if anti-intrinsic factor antibodies are negative
• Symptoms include fatigue and weaknesspernicious
• Untreated pernicious anemia can cause heart and nerve damage

TX: The management of pernicious anemia is twofold:

• (1.) Lifelong parenteral (IM) B12 replacement to bypass the lack of intrinsic factor
• (2.) Periodic endoscopic surveillance (e.g., every 3-5 years) to monitor for the development of gastric adenocarcinoma and neuroendocrine tumors

Hypersegmented neutrophils in a patient with vitamin B12 deficiency secondary to pernicious anemia