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Hemorrhagic Diatheses — Complete Reference (Questions 68–82)

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68. Etiological Factors Underlying Hemorrhagic Diathesis

• Hereditary: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu), Ehlers-Danlos syndrome, Marfan syndrome
• Acquired: Scurvy (vitamin C deficiency → poor collagen synthesis), corticosteroid excess, amyloidosis, vasculitis, infections (meningococcemia, rickettsiae)

• Quantitative (thrombocytopenia):
  • Decreased production: aplastic anemia, leukemia, myelosuppression
  • Increased destruction: immune thrombocytopenic purpura (ITP/Werlhof's disease), DIC, TTP, HUS, drugs, infections
• Qualitative (thrombasthenia):
  • Inherited: Glanzmann thrombasthenia (GPIIb/IIIa deficiency), Bernard-Soulier syndrome (GPIb/IX deficiency), storage pool disorders
  • Acquired: aspirin/NSAIDs, uremia, myeloproliferative disorders

• Inherited: Hemophilia A (factor VIII↓), Hemophilia B (factor IX↓), von Willebrand disease
• Acquired: Liver disease, vitamin K deficiency, DIC (consumptive coagulopathy), massive transfusion, anticoagulant therapy

"Disorders associated with abnormal bleeding inevitably stem from primary or secondary defects in vessel walls, platelets, or coagulation factors." — Robbins, Cotran & Kumar Pathologic Basis of Disease

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69. Types of Bleeding According to Z.S. Barkagan

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70. Clinical Features of Platelet Hemorrhages (Microcirculatory/Petechial Type)

• Petechiae — pinpoint (1–2 mm), non-palpable, non-blanching hemorrhages in skin and mucous membranes
• Purpura — slightly larger (≥3 mm) cutaneous hemorrhages
• Ecchymoses — superficial bruising
• Mucosal bleeding — epistaxis, gingival bleeding, gastrointestinal bleeding, menorrhagia (heavy menses), hematuria
• Prolonged bleeding time (template bleeding time ↑)
• Bleeding stops immediately with local pressure (primary plug can form if coagulation is intact)
• No deep tissue bleeding — hemarthroses and deep hematomas are rare
• More common in women (menorrhagia is a common presenting complaint)
• Feared complication: intracerebral hemorrhage with severe thrombocytopenia

"Defects of primary hemostasis often present with small bleeds in skin or mucosal membranes, which typically take the form of petechiae or purpura." — Robbins, Cotran & Kumar

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71. Clinical Features of Vascular Hemorrhages (Vasopathy)

• Palpable purpura — hallmark of vasculitis; purpura that can be felt on palpation (inflammation raises the lesion)
• Non-palpable petechiae and purpura — in non-inflammatory vascular fragility (scurvy, amyloidosis)
• Ecchymoses — easy bruising, often spontaneous
• Periarticular and perifollicular hemorrhage (classic in scurvy)
• Telangiectasias — in hereditary hemorrhagic telangiectasia
• Normal platelet count and normal coagulation tests (PT, PTT normal)
• Bleeding time may be prolonged
• Lesions predominantly on lower extremities and dependent areas
• May be associated with systemic symptoms: fever, arthralgia, rash, abdominal pain (in vasculitis)

"Generalized defects involving small vessels often present with 'palpable purpura' and ecchymoses. Purpura and ecchymoses are particularly characteristic of systemic disorders that disrupt small blood vessels (e.g., vasculitis) or that lead to blood vessel fragility (e.g., amyloidosis, scurvy)." — Robbins, Cotran & Kumar

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72. Clinical Features of Coagulation Hemorrhages (Hematoma Type)

• Deep hematomas — in muscles, retroperitoneum, soft tissues
• Hemarthroses — bleeding into joints (knees, elbows, ankles); highly characteristic of hemophilia; leads to joint deformity with repeated episodes
• Large ecchymoses after minor trauma
• Prolonged bleeding after surgery, dental extraction, or trauma (delayed onset, hours later)
• Gastrointestinal and urinary tract bleeding
• Intracranial hemorrhage (severe cases)
• No petechiae (primary hemostasis is intact — platelet plug forms normally)
• Laboratory: ↑PTT (intrinsic pathway defects), ↑PT (extrinsic), or both; bleeding time normal

"Bleeding due to coagulation factor deficiencies commonly manifest as large posttraumatic ecchymoses or hematomas, or prolonged bleeding from a laceration… Unlike bleeding seen with thrombocytopenia, bleeding due to coagulation factor deficiencies often occurs in the gastrointestinal and urinary tracts and in weight-bearing joints (hemarthrosis)." — Robbins, Cotran & Kumar

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73. Types of Hemophilia

"Severe factor IX deficiency produces a disorder clinically indistinguishable from factor VIII deficiency (hemophilia A). This should not be surprising, given that factors VIII and IX function together to activate factor X… Like hemophilia A, it is inherited as an X-linked recessive trait and shows variable clinical severity." — Robbins, Cotran & Kumar

• Severe: < 1% of normal factor activity → spontaneous bleeding
• Moderate: 1–5% → bleeding with minor trauma
• Mild: 5–30% → bleeding only with significant trauma/surgery

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74. Diagnostic Criteria for Hemophilia

• Hemophilia A: Factor VIII assay < 30% (or per severity)
• Hemophilia B: Factor IX assay confirms and distinguishes from A (PTT mixing studies can help)
• Genetic/molecular testing identifies specific mutations in F8 or F9 genes

"As with hemophilia A, the PTT is prolonged and the PT is normal. Diagnosis of Christmas disease is made by assay of factor IX levels." — Robbins, Cotran & Kumar

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75. Clinical Features of Hemophilia

• Hemarthrosis (joint bleeding) — most common site; knees > elbows > ankles > shoulders > hips
• Acute: warmth, swelling, severe pain, limited range of motion
• Chronic: synovial hypertrophy → hemophilic arthropathy → joint destruction, deformity, ankylosis

• Deep muscle hematomas (iliopsoas is particularly dangerous — can compress femoral nerve)
• Retroperitoneal bleeding

• Intracranial hemorrhage — major cause of death
• Airway hematomas (neck, pharynx)

• Prolonged bleeding after tooth extraction, surgery, circumcision

• Severe: spontaneous bleeds from infancy/childhood
• Mild: only with significant trauma

• Inhibitor development (IgG antibodies to factor VIII) — in ~15–30% of severe hemophilia A
• Historically: HIV and hepatitis C from contaminated factor concentrates (prior to recombinant era)

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76. Vasopathies: Causes and Clinical Manifestations

Hereditary Vasopathies

Acquired Vasopathies

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77. Clinical Features and Diagnosis of Werlhof's Disease (ITP — Immune Thrombocytopenic Purpura)

Pathogenesis

• May be primary (idiopathic) or secondary (SLE, HIV, HCV, lymphoma, drugs)

Forms

• Acute ITP (children): self-limited, often post-viral (1–2 weeks after infection); usually resolves spontaneously in weeks to months
• Chronic ITP (adults, especially women): insidious onset, >6 months duration; often requires treatment

Clinical Features

• Petechiae — especially on legs, oral mucosa
• Purpura — non-palpable
• Easy bruising (ecchymoses)
• Mucosal bleeding — epistaxis, gingival bleeding, menorrhagia
• No splenomegaly (unlike other thrombocytopenias)
• Feared: intracranial hemorrhage (when platelets < 10,000/μL)
• Generally well-appearing (no fever, no signs of underlying disease in primary ITP)

Diagnosis

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78 & 79. Hemorrhagic Vasculitis / Henoch-Schönlein Disease: Clinical Forms and Diagnosis

Pathogenesis

Clinical Forms / Tetrad

Diagnosis

• Clinical: classic tetrad (purpura + arthritis + abdominal pain + renal involvement)
• Lab:
  • Platelet count — normal (non-thrombocytopenic purpura — key distinguishing feature from ITP!)
  • PT, PTT — normal
  • ↑ Serum IgA (in ~50%)
  • Urinalysis: hematuria ± proteinuria
  • ↑ ESR, CRP
• Skin biopsy: leukocytoclastic vasculitis; IgA deposits on direct immunofluorescence — diagnostic
• Renal biopsy (if nephritis): mesangial IgA deposits

Clinical Evaluation Principles

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80. DIC Syndrome — Clinical Presentation

Pathogenesis

1. Release of tissue factor/procoagulants into circulation (obstetric complications, cancer, trauma)
2. Widespread endothelial injury (sepsis, burns, immune complexes)

Causes (major)

• Sepsis (most common — gram-negative or gram-positive)
• Obstetric complications — abruptio placentae, amniotic fluid embolism, eclampsia, retained dead fetus
• Malignancies — acute promyelocytic leukemia (APL), adenocarcinoma
• Major trauma / burns
• Transfusion reactions
• Snake venom

Clinical Presentation

• Petechiae, purpura, ecchymoses
• Oozing from venipuncture sites, surgical wounds, IV lines
• Mucosal bleeding, hematuria, GI bleeding
• Severe: massive hemorrhage

• Microangiopathic hemolytic anemia (schistocytes on smear)
• Acute renal failure (glomerular microthrombi → oliguria)
• Respiratory failure / ARDS (fibrin in alveolar capillaries → hyaline membranes)
• Neurologic: seizures, coma (cerebral microinfarcts)
• Shock (adrenal hemorrhage/infarction in severe sepsis → Waterhouse-Friderichsen syndrome in meningococcemia)
• Acral cyanosis, skin necrosis

Laboratory Diagnosis

"DIC can give rise either to tissue hypoxia and microinfarcts caused by myriad microthrombi or to a bleeding disorder related to pathologic activation of fibrinolysis and depletion of the elements required for hemostasis." — Robbins Basic Pathology

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81. Principles of Treatment of Hemorrhagic Vasculitis (HSP / Leukocytoclastic Vasculitis)

General Principles

1. Identify and remove the trigger — stop causative drug, treat underlying infection (antibiotics for streptococcal trigger), treat malignancy
2. Rest and elevation of affected extremities (reduces dependent edema and lesion formation)
3. Avoid cold and trauma

Medical Treatment (by severity)

Key Points

• Most cases of cutaneous LCV are self-limited (resolve in 3–4 weeks); aggressive treatment not initially needed if urinalysis is normal
• Monitoring: urinalysis at every visit (to detect HSP nephritis early — can be delayed)
• HSP in children usually resolves spontaneously; in adults tends to be more severe and chronic

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82. Methods of Hemostasis Research (Laboratory Tests)

Primary Hemostasis Tests (Platelets + Vessels)

Secondary Hemostasis Tests (Coagulation Cascade)

Fibrinolysis Tests

Other / Special Tests

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Anemia — Complete Reference (Questions 53–66)

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53. Modern Classification of Anemia

A. Morphological Classification (by MCV — Mean Corpuscular Volume)

B. Pathophysiological/Mechanistic Classification

• ↑ Reticulocytes → increased loss/destruction (hemorrhage or hemolysis)
• ↓ Reticulocytes → underproduction (bone marrow problem or nutritional deficiency)

"There are two general ways of classifying anemia. A time-honored and still practical way is by the size of the red cell, as this can help guide diagnostic workup. Another method is by mechanism of anemia." — Harrison's Principles of Internal Medicine, 22e

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54. Etiological Factors Contributing to the Development of Anemic Syndrome

I. Nutritional Deficiencies

• Iron deficiency (most common worldwide — affects 25–50% in developing countries)
• Vitamin B12 deficiency (veganism, malabsorption, pernicious anemia)
• Folate deficiency (poor diet, pregnancy, alcohol use, drugs like methotrexate)
• Vitamin C deficiency (scurvy — interferes with iron absorption and erythropoiesis)
• Copper deficiency (rare)

II. Bone Marrow Failure

• Aplastic anemia (idiopathic, drugs, toxins, radiation, viral infections)
• Myelodysplastic syndromes
• Marrow infiltration — leukemia, lymphoma, metastatic cancer, myelofibrosis, granulomatous disease (myelophthisic anemia)

III. Increased RBC Destruction (Hemolysis)

• Intrinsic (congenital): hereditary spherocytosis, G6PD deficiency, sickle cell disease, thalassemia, PNH
• Extrinsic (acquired): autoimmune hemolytic anemia, TTP/HUS, malaria, mechanical destruction (prosthetic valves), drugs, infections

IV. Blood Loss

• Acute hemorrhage
• Chronic bleeding: GI (peptic ulcer, cancer, inflammatory bowel disease), menorrhagia, hematuria

V. Decreased Erythropoietin Production

• Chronic kidney disease (↓ EPO synthesis)
• Endocrine disorders (hypothyroidism, adrenal insufficiency, hypogonadism)

VI. Anemia of Chronic Inflammation

• Chronic infections (TB, osteomyelitis), rheumatoid arthritis, malignancy
• Mechanism: ↑ hepcidin → ↓ iron release from macrophages → functional iron deficiency

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55. Classification of Hemolytic Anemias: Congenital and Acquired Forms

Congenital (Hereditary) Hemolytic Anemias

• Hereditary spherocytosis (spectrin/ankyrin defects; autosomal dominant)
• Hereditary elliptocytosis
• Hereditary stomatocytosis

• G6PD deficiency (X-linked; Heinz body formation; triggered by oxidant stress — drugs, infection, fava beans)
• Pyruvate kinase deficiency (autosomal recessive)

• Sickle cell disease (HbS; autosomal recessive)
• Thalassemias (α and β — impaired globin chain synthesis)
• HbC disease, HbE disease

Acquired Hemolytic Anemias

• Autoimmune hemolytic anemia (AIHA):
  • Warm type (IgG antibodies, react at 37°C) — most common; idiopathic, SLE, lymphoma, drugs
  • Cold agglutinin disease (IgM antibodies, react < 37°C) — post-infection (Mycoplasma, EBV), lymphoma
• Drug-induced (penicillin, methyldopa, quinidine)
• Alloimmune — hemolytic transfusion reactions, HDN

• Microangiopathic hemolytic anemia (MAHA) — TTP, HUS, DIC, malignant hypertension
• Prosthetic heart valves, march hemoglobinuria

• Malaria (Plasmodium directly destroys RBCs)
• Clostridial infections (phospholipase damages RBC membrane)

• Oxidant drugs (in G6PD-deficient patients), snake venom, burns, hypotonic solutions

• Acquired clonal defect; GPI anchor deficiency → RBCs susceptible to complement lysis

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56. Diagnostic Criteria for Iron Deficiency Anemia (IDA)

Stages of Iron Deficiency (sequential)

1. Iron depletion: ↓ storage iron (ferritin ↓), no anemia yet
2. Iron-deficient erythropoiesis: ↓ serum iron, ↑ TIBC, ↓ transferrin saturation; reticulocytes affected
3. Iron deficiency anemia: frank microcytic hypochromic anemia

Laboratory Criteria

Clinical Features

• Fatigue, pallor, dyspnea on exertion
• Pica (craving for ice, clay, starch)
• Koilonychia (spoon-shaped nails)
• Angular cheilitis, glossitis (smooth red tongue)
• Brittle hair and nails
• Plummer-Vinson syndrome (IDA + esophageal web + dysphagia)

"Iron deficiency is the most common nutritional deficiency in the world… serum ferritin level is usually a good surrogate measure of iron stores." — Robbins, Cotran & Kumar

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57. Diagnostic Criteria for B12 and Folate Deficiency Anemia

Shared (Megaloblastic) Features

• Macro-ovalocytes (large, oval red cells) — highly characteristic
• Hypersegmented neutrophils (≥5 lobes; 5 or more in ≥5% of neutrophils is diagnostic)
• Anisocytosis, poikilocytosis
• ↓ Reticulocytes

Vitamin B12 Deficiency — Specific Criteria

• Subacute combined degeneration of the spinal cord
• Posterior column (vibration/proprioception loss) + lateral corticospinal tracts (spastic paraparesis)
• Peripheral neuropathy, glossitis, psychiatric symptoms ("megaloblastic madness")

Folate Deficiency — Specific Criteria

"Findings supporting the diagnosis of vitamin B12 deficiency are (1) low serum vitamin B12 levels, (2) normal or elevated serum folate levels, (3) moderate to severe macrocytic anemia, (4) leukopenia with hypersegmented granulocytes, and (5) a dramatic increase in reticulocytes 2 to 3 days after treatment with vitamin B12. Pernicious anemia is associated with all of these findings plus the presence of serum antibodies to intrinsic factor." — Robbins Basic Pathology

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58. Diagnostic Criteria for Hypo- and Aplastic Anemia

Aplastic Anemia — Definition

Diagnostic Criteria (International Aplastic Anemia Study Group)

Laboratory Findings in Aplastic Anemia

• ↓ Hb, ↓ WBC (especially neutrophils), ↓ platelets → pancytopenia
• Normocytic (usually) or macrocytic anemia
• ↓↓ Reticulocytes (hallmark of underproduction)
• Normal RBC morphology on smear (no poikilocytes typical of hemolysis)
• Bone marrow: fatty replacement of hematopoietic tissue
• ↑ EPO (compensatory)
• Normal B12, folate, iron stores

Clinical Features

• Insidious onset of weakness, pallor, dyspnea (anemia)
• Petechiae, ecchymoses (thrombocytopenia)
• Recurrent bacterial/fungal infections (neutropenia)
• No splenomegaly (important negative finding — if present, consider alternative diagnosis)

"Aplastic anemia does not cause splenomegaly; if present, another diagnosis should be sought." — Robbins Basic Pathology

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59. Diagnostic Criteria for Hemolytic Anemia

General Evidence of Hemolysis

• Spherocytes → hereditary spherocytosis or warm AIHA
• Schistocytes/helmet cells → microangiopathic (TTP, HUS, DIC)
• Sickle cells → sickle cell disease
• Target cells → thalassemia, HbC, liver disease
• Bite cells/blister cells → G6PD deficiency
• Elliptocytes → hereditary elliptocytosis

• Direct Antiglobulin Test (DAT/Coombs test): Positive → autoimmune hemolysis; Negative → non-immune
• Osmotic fragility test: ↑ in hereditary spherocytosis
• G6PD assay: enzyme activity
• Hemoglobin electrophoresis: sickle cell, thalassemia
• Flow cytometry (CD55/CD59): PNH

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60. Differential Diagnosis of Hypo-Aplastic Anemia vs. Leukemia

"It is important to separate aplastic anemia from anemia caused by marrow infiltration (myelophthisic anemia), 'aleukemic leukemia,' and granulomatous diseases, which may have similar clinical presentations but are easily distinguished by examination of the bone marrow." — Robbins Basic Pathology

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61. Laboratory Indicators for Hypo- and Aplastic Anemia

• Severe AA: ANC < 0.5 × 10⁹/L + platelets < 20 × 10⁹/L + reticulocytes < 20 × 10⁹/L
• Very severe: ANC < 0.2 × 10⁹/L

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62. Methods of Bone Marrow Examination

1. Bone Marrow Aspiration

• Site: Posterior iliac spine (preferred); also sternum (less common), anterior iliac spine in children
• Technique: Needle inserted into marrow cavity; 1–2 mL of marrow fluid aspirated
• Stains: Wright-Giemsa stain
• What it shows:
  • Individual cell morphology
  • Differential cell count (myeloid:erythroid ratio; normal = 2:1–5:1)
  • Blast percentage
  • Iron stores (Prussian blue stain)
  • Megakaryocyte morphology
• Additional samples: flow cytometry, cytogenetics, molecular testing, microbiological culture

2. Bone Marrow Biopsy (Trephine)

• Same site (posterior iliac spine) — a core of intact marrow is removed
• Fixation, decalcification, sectioning, H&E staining
• What it shows:
  • Cellularity (normal ~50%; approximates patient's age in % fat)
  • Architecture — presence of fibrosis, infiltrates, granulomas
  • Identification of abnormal cells in context of preserved structure
• Critical for: aplastic anemia (hypocellularity), myelofibrosis, metastatic cancer, lymphoma, granulomatous disease

3. Procedure Notes

"The biopsy should precede the aspiration. If the aspiration is done first, the subsequent biopsy tends to be distorted by the bleeding induced by the aspiration." — Harrison's 22e

• Dry tap (unable to aspirate): suggests myelofibrosis, hairy cell leukemia, aplastic anemia, packed marrow — biopsy mandatory; touch imprints made
• Both aspiration AND biopsy are usually performed together

Indications for Bone Marrow Examination

• Aplastic anemia, pure red cell aplasia
• Unexplained pancytopenia or cytopenias
• Suspected leukemia, lymphoma, myeloma, myelodysplasia
• Staging of hematologic malignancies
• Suspected marrow metastases
• Unexplained fever, splenomegaly
• Confirmation of megaloblastic anemia (if diagnosis unclear)
• Evaluation of iron stores (less commonly needed)

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63. Diagnosis and Principles of Treatment of Iron Deficiency Anemia

Diagnosis (Summary)

• Microcytic, hypochromic anemia (↓ MCV, ↓ MCH, ↓ MCHC)
• ↓ Serum ferritin (< 12–30 ng/mL) — most sensitive marker
• ↓ Serum iron, ↑ TIBC, ↓ transferrin saturation (< 15%)
• Smear: microcytes, hypochromic cells, pencil cells, anisocytosis (↑ RDW)
• Absent bone marrow iron (Prussian blue stain)
• Always investigate the CAUSE — find the source of blood loss (upper/lower GI endoscopy if needed; menstrual history; dietary assessment)

Principles of Treatment

• Ferrous sulfate 325 mg (65 mg elemental iron) × 2–3 times/day on an empty stomach
• Alternatives: ferrous gluconate, ferrous fumarate
• Taken between meals (best absorption); vitamin C (ascorbic acid) enhances absorption
• Expected response: reticulocytosis within 5–7 days; Hb rises ~1–2 g/dL per week
• Continue therapy for 3–6 months after Hb normalizes to replenish stores
• Side effects: nausea, constipation, dark stools, abdominal discomfort

• Iron sucrose, ferric carboxymaltose, iron dextran, ferric gluconate
• Indications: malabsorption (Crohn's disease, post-gastrectomy), intolerance to oral iron, severe anemia requiring rapid correction, chronic kidney disease on hemodialysis

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64. Iron-Containing Drugs: Indications and Contraindications

Oral Iron Preparations

• Iron deficiency anemia (treatment and prophylaxis)
• Pregnancy (prophylaxis: 30–60 mg/day elemental iron)
• Infants and children with dietary iron insufficiency
• Chronic blood loss (menorrhagia, GI bleeding)
• Pre-operative anemia
• Chronic kidney disease (with or without EPO therapy)

• Hemochromatosis / hemosiderosis (iron overload states)
• Hemolytic anemias (thalassemia, G6PD) — iron is NOT deficient; supplementation causes iron overload
• Aplastic anemia (not iron deficient)
• Anemia of chronic disease without confirmed iron deficiency (ferritin > 100 ng/mL)
• Active peptic ulcer disease (relative contraindication; may worsen symptoms)
• Inflammatory bowel disease in remission (risk of exacerbation with oral iron)

• Known hypersensitivity / anaphylaxis to the specific preparation
• Acute phase of infection (iron can feed bacterial growth)
• Hemochromatosis

• Absorption reduced by: antacids, proton pump inhibitors, tetracyclines, fluoroquinolones, calcium, tea, phytates
• Absorption enhanced by: ascorbic acid (vitamin C)
• Iron reduces absorption of: levodopa, levothyroxine, quinolone antibiotics, bisphosphonates

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65. Diagnosis and Principles of Treatment of B12 and Folate Deficiency Anemia

Diagnosis

• Macrocytic anemia (↑ MCV), macro-ovalocytes, hypersegmented neutrophils
• ↑ LDH, ↑ indirect bilirubin (ineffective erythropoiesis)
• Pancytopenia in severe cases
• Bone marrow: megaloblastic erythroid hyperplasia, giant metamyelocytes

Principles of Treatment

• Intramuscular cyanocobalamin or hydroxocobalamin (preferred for pernicious anemia and malabsorption):
  • 1,000 mcg IM daily × 7 days → weekly × 4 weeks → monthly for life (pernicious anemia = lifelong)
• Oral B12 (high-dose): 1,000–2,000 mcg/day — effective even without IF (passive absorption), useful for dietary deficiency
• Sublingual B12 also available
• Response: reticulocytosis peaks at 5–7 days; Hb normalizes in 6–8 weeks; neurological recovery may be partial (irreversible if long-standing)
• Treat underlying cause: discontinue offending drugs, treat bacterial overgrowth, correct malabsorption

• Folic acid 1–5 mg/day orally × 4 months (until stores replenished)
• Higher doses in hemolytic anemia, pregnancy, or malabsorption
• Prophylaxis: 0.4 mg/day in pregnancy (5 mg/day if high risk) — prevents neural tube defects
• Dietary counseling: increase leafy greens, citrus, liver
• Avoid folate antagonists (methotrexate, trimethoprim — consider folinic acid rescue)

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66. Diagnosis and Principles of Treatment of Hemolytic Anemia

Diagnosis

• ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, ↑ reticulocytes, peripheral smear abnormalities

• Intravascular: hemoglobinuria (dark urine), hemoglobinemia, hemosiderinuria, very low haptoglobin → suggests mechanical (TTP, valve), PNH, ABO mismatch, G6PD crisis
• Extravascular: mild jaundice, splenomegaly, no hemoglobinuria → AIHA, hereditary spherocytosis

• DAT (Direct Antiglobulin/Coombs test): Positive = immune-mediated; Negative = non-immune
• Peripheral smear: spherocytes, schistocytes, sickle cells, target cells, bite cells
• Osmotic fragility: ↑ in spherocytosis
• Hb electrophoresis: sickle cell, thalassemia
• G6PD assay: enzyme deficiency
• Flow cytometry (CD55/CD59): PNH
• Cold agglutinin titer: cold AIHA
• Blood culture, serology: infectious causes

Principles of Treatment

• Folic acid 1–5 mg/day (all chronic hemolytic anemias — demand is increased)
• Avoid splenectomy until age 5+ (infection risk); post-splenectomy vaccines (pneumococcal, meningococcal, Haemophilus)
• Iron chelation when iron overload develops from repeated transfusions
• Monitor for gallstones (pigment gallstones from chronic hemolysis — may require cholecystectomy)

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