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Hematology & Coagulation Review (Exam Prep)

Hematopoiesis and basic hematology concepts

  • Hematopoietic stem cell (HSC) in bone marrow differentiates into two progenitor branches:

    • Myeloid progenitor

    • Lymphoid progenitor

  • Myeloid progenitor gives rise to: red cells (erythrocytes), megakaryocytes (platelets), eosinophils, basophils, monocytes/macrophages, neutrophils

  • Lymphoid progenitor gives rise to: T cells, B cells, natural killer (NK) cells, and plasma cells

  • In youth, HSCs exist in all bones; in adults, hematopoiesis is localized mainly to the heads of long bones (e.g., humerus, femur)

  • Erythropoiesis lifecycle:

    • HSC → erythroblast → reticulocyte → mature red blood cell (RBC)

    • Reticulocyte is a "baby" RBC that matures in the bloodstream over several days to a week

    • Normal RBC lifespan: ext{RBC lifespan} \,\approx\, 120\text{ days}

    • Rapid loss of RBCs (bleeding, hemolysis) increases reticulocyte release into blood (reticulocytosis)

  • Old/aged RBCs are phagocytosed in liver, spleen, and bone marrow; iron is recycled:

    • Iron binds transferrin for transport

    • Stored as ferritin in the liver

    • Reused for new RBC production

  • Splenomegaly can occur with rapid phagocytosis of abnormal RBCs

  • Iron recycling is critical; chronic iron loss (GI bleed, heavy menses) can lead to iron deficiency anemia (IDA)

  • Erythropoietin (EPO) stimulates red cell production; decreased EPO (e.g., CKD) can cause anemia

  • Leukocytes (white cells) are ~1% of total cells; normal production from HSCs; lineages:

    • Eosinophils: inflammation, allergy, parasites

    • Neutrophils: bacterial infection

    • Basophils: allergy

    • Lymphocytes (T, B, NK): viral infections

    • Monocytes → macrophages

  • Anemia is the most common hematologic condition encountered in practice; focus on understanding and classifying anemia by cause and morphology

CBC indices and approach to anemia

  • Key starting labs: CBC with differential, reticulocyte count, and iron studies

  • Indices to classify anemia by RBC size:

    • Mean corpuscular volume (MCV): size of RBCs

    • Thresholds:

    • Microcytic: MCV < 80\,\text{fL}

    • Normocytic: 80 \le MCV \le 100\,\text{fL}

    • Macrocytic: MCV > 100\,\text{fL}

  • MCH: hemoglobin content per RBC; MCHC: mean corpuscular hemoglobin concentration (less commonly used)

  • Common iron-related patterns:

    • Iron deficiency anemia (IDA): low ferritin, high TIBC, low serum iron

    • Anemia of chronic disease (inflammation): normal or high ferritin, low serum iron, low TIBC

    • Sideroblastic anemia: microcytic with high ferritin; ring sideroblasts on marrow; lead poisoning as a potential cause

  • Reticulocyte count helps differentiate production vs destruction/loss:

    • Increased reticulocytes: active RBC loss or hemolysis

    • Low reticulocytes: underproduction (bone marrow failure or nutrient deficiency)

  • Iron studies at a glance:

    • ext{Ferritin} \downarrow \quad \text{(iron stores depleted)}

    • TIBC \uparrow (capacity to bind iron increases with low iron)

    • Serum\ iron \downarrow

  • Process to approach anemia:

    • Confirm anemia with CBC and reticulocyte count

    • Determine RBC size category (MCV)

    • Check iron studies to categorize iron-related etiologies

    • If macrocytic, evaluate B12 and folate; if microcytic, evaluate iron, thalassemia, and sideroblastic etiologies

    • Use peripheral smear to look for characteristic features (e.g., hypersegmented neutrophils, schistocytes, spherocytes)

Iron deficiency anemia (IDA)

  • Epidemiology and causes

    • Most common anemia globally

    • In kids: often dietary iron deficiency (green leafy vegetables, iron-rich foods not consumed)

    • In adults: typically GI blood loss until proven otherwise

    • In older adults: colon cancer and other GI losses must be ruled out; endoscopy/colonoscopy as indicated

  • Classic differential based on patient context

    • 55-year-old man with IDA: top concern GI source (colon cancer, GI bleed, peptic ulcer disease)

    • Reproductive-age woman with IDA: menorrhagia or other menstrual blood loss as a common cause; pregnancy-related factors also considered

  • Clinical features of chronic iron deficiency

    • Cheilitis, angular cheilitis, pica (pagophagia, ice-eating), glossitis, koilonychia (spoon-shaped nails)

    • Fatigue and dyspnea on exertion

  • Diagnostic iron studies in IDA

    • Serum ferritin: storage iron; typically low in IDA

    • Transferrin/Saturation: decreased serum iron with increased TIBC

    • TIBC: total iron-binding capacity; concept: higher when iron is depleted (more “seats” available on transferrin train)

    • Example interpretation:

    • ext{Ferritin} \downarrow, \text{TIBC} \uparrow, \text{Serum iron} \downarrow

  • Workup and management

    • Rule out source of blood loss (colonoscopy/EGD as indicated)

    • Iron replacement: oral ferrous sulfate 325 mg every other day improves absorption and reduces GI side effects; take on empty stomach with vitamin C (e.g., orange juice) and avoid calcium-containing foods near dosing

    • Monitoring: reticulocyte count rises within ~2 weeks; hemoglobin typically normalizes in ~6–10 weeks for mild IDA

    • Treat underlying cause (e.g., GI bleed, menorrhagia)

  • Thalassemias as microcytic differential (see section below) when iron studies are not consistent with iron deficiency

Thalassemias (alpha and beta)

  • General concept

    • Group of inherited microcytic anemias caused by reduced or absent globin chain production

    • Alpha vs beta differences in affected globin chains and typical geographic distribution

  • Alpha-thalassemia

    • Spectrum: silent carrier → trait → HbH disease → hydrops fetalis (incompatible with life)

    • HbH disease can be clinically significant with moderate anemia and splenomegaly

    • Hydrops fetalis (Hb Barts) with all four alleles deleted; incompatible with life

    • Alpha-thalassemia major (Hb Barts) incompatible with life; not compatible with long-term survival

  • Beta-thalassemia

    • Beta-thalassemia major (homozygous): severe anemia starting around ~6 months when fetal Hb (HbF) declines; transfusion-dependent; classic facial bone changes due to marrow expansion (frontal bossing, chipmunk cheeks) and hair-on-end skull x-ray finding

    • Beta-thalassemia minor (trait): usually mild anemia seen in adulthood; more common in Mediterranean populations; often asymptomatic

    • Diagnosis: hemoglobin electrophoresis distinguishes hemoglobin types; beta-thalassemia major shows elevated HbF and absent/low HbA

    • Alpha vs beta in exam stems: age of presentation and ethnicity can guide suspicion; electrophoresis is key; Providence of bone changes suggests beta-thalassemia major in children

  • Malaria link (pathophysiology intuition)

    • Carriage of alpha/beta thalassemia traits is thought to confer some protection against malaria in endemic regions (malaria belt)

  • Key takeaways for exam stems

    • Microcytosis with low reticulocytes points toward thalassemia rather than IDA (iron studies often normal)

    • Beta-thalassemia major typically presents in childhood; globin chain abnormalities on electrophoresis confirm diagnosis

    • Beta-thalassemia minor is common in adults with mild microcytosis

Sideroblastic anemia and related microcytosis patterns

  • Sideroblastic anemia presents with microcytosis and high ferritin due to iron overload in mitochondria; basophilic stippling on smear; ring sideroblasts on bone marrow with Prussian blue stain

  • Often due to lead poisoning or other toxic/medication causes; remove offending toxin and chelate if needed

  • Not iron-deficiency anemia (iron studies show high iron stores)

Anemia of inflammation/chronic disease (ACD)

  • Mechanism: inflammation induces hepcidin-mediated sequestration of iron, decreased iron availability for erythropoiesis, and reduced erythropoietin response

  • Can be normocytic or microcytic; ferritin may be normal or elevated due to inflammation; iron studies may resemble iron-replete or iron-deficient patterns depending on the stage

  • Important to treat underlying inflammatory condition

Macrocytic anemias

  • Two major causes: Vitamin B12 deficiency and folate deficiency

  • Vitamin B12 (cobalamin) deficiency

    • Absorption requires: intrinsic factor from stomach, uptake in terminal ileum; factors affecting absorption include gastric bypass, Crohn’s disease, ileal disease, celiac disease, vegan diet

    • Pernicious anemia: autoimmune attack on gastric parietal cells → reduced intrinsic factor

    • Neurologic symptoms can predominate: paresthesias, gait disturbance/ataxia, cognitive changes, glossitis; diarrhea and other GI symptoms possible

    • Lab clues: macrocytic anemia with low reticulocytes; elevated homocysteine and methylmalonic acid (MMA)

    • Schilling test historically used; intrinsic factor antibodies may be present

    • Peripheral smear: hypersegmented neutrophils

    • Treatment: parenteral B12 replacement (intramuscular) with a typical course of daily injections for 5–7 days, then weekly for several weeks, then monthly lifelong if absorption is compromised; if dietary deficiency only, may attempt oral B12 supplementation with monitoring

  • Folate deficiency

    • Similar macrocytosis and symptoms as B12 deficiency but typically without neurologic signs

    • Common in chronic alcohol use, pregnancy, liver disease, malnutrition; certain medications (e.g., sulfonamides, phenytoin) can impair folate metabolism

    • Treatment: folic acid 1–5 mg orally daily; repletion often resolves macrocytosis and anemia if no other cause

Hemolytic anemias

  • Definition: premature destruction of circulating RBCs; consumption of cells can be intrinsic (membrane or enzyme defects) or extrinsic (autoimmune, transfusion reactions, mechanical destruction)

  • Laboratory pattern: reticulocytosis (bone marrow compensates), decreased haptoglobin, elevated LDH, indirect or unconjugated bilirubin; often scleral icterus and jaundice; splenomegaly can occur

  • G6PD deficiency (glucose-6-phosphate dehydrogenase)

    • X-linked recessive; decreased protection against oxidative stress in RBCs

    • Triggers: oxidative drugs, infections, fava beans

    • Typical presentation: normocytic, normochromic hemolytic anemia with bite cells on smear and possible hemoglobinuria

  • Hereditary spherocytosis

    • Membrane defect makes RBCs spherical; rigid and trapped by the spleen leading to hemolysis and splenomegaly

    • Possible treatment: splenectomy after immunization and vaccination precautions; often managed by hematology

  • Sickle cell disease (HbS)

    • Point mutation in beta-globin gene; HbS polymerizes under deoxygenation leading to sickling

    • Crises triggered by dehydration, hypoxia, acidosis, high altitude, cold; painful vaso-occlusive crises; chronic hemolysis leads to jaundice and pigmented gallstones; splenomegaly in childhood, autosplenectomy later

    • Treatments: hydration, pain control, oxygen, folate supplementation, hydroxyurea to reduce crises; sometimes curative approach includes hematopoietic stem cell transplant (HSC transplant)

  • Hemolytic transfusion reactions

    • ABO or other antigen incompatibility with donor RBCs; positive Coombs test; rapid onset of hemolysis with fever, flank pain, chills, or dyspnea; stop transfusion, IV fluids, ICU level monitoring as needed

Coagulation disorders and platelet disorders

  • Concept: differentiate platelet-related bleeds (mucosal, petechiae) from coagulation factor-related bleeds (deep, e.g., hemarthrosis, GI bleed, intracranial hemorrhage)

  • ITP (immune thrombocytopenia)

    • Usually post-viral in children; autoimmune antibodies target platelets; platelets extremely low (often <150,000/µL, can be <20,000/µL)

    • Presentation: healthy-appearing child with petechiae/purpura after viral illness; otherwise non-toxic

    • Treatment: many pediatric cases are self-limited; adults with platelets <30,000/µL may require prednisone; refractory cases may need thrombopoietin receptor agonists or splenectomy

  • TTP (thrombotic thrombocytopenic purpura)

    • Acute, life-threatening; pentad includes fever, neurologic changes, microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment

    • Lab finding: schistocytes on smear; INR and aPTT usually normal (coagulation factors intact)

    • Treatment: emergent plasma exchange (plasmapheresis) is essential

  • Factor V Leiden

    • Hereditary hypercoagulable state; resistance to activated protein C; presents with recurrent unprovoked VTE

  • DIC (disseminated intravascular coagulation)

    • Consumptive coagulopathy; underlying trigger (OB complication, sepsis, massive trauma, cancer)

    • Coagulation labs: prolonged PT/INR, prolonged aPTT, low fibrinogen, elevated D-dimer; platelets can be low

    • Treatment: address underlying cause; supportive care

  • Von Willebrand disease

    • Most common inherited bleeding disorder; mucosal bleeding (gums, epistaxis); menorrhagia; treatment options include DDAVP (desmopressin) and vWF-containing products

  • Hemophilias (A, B, C)

    • Factor VIII deficiency (Hemophilia A) is most common; deep tissue bleeds and hemarthrosis common; prolonged aPTT with normal PT/INR

    • Factor IX deficiency (Hemophilia B) similar presentation; treatment: factor IX replacement

    • Factor XI deficiency (Hemophilia C) less common; treatment sometimes with FFP or specific factors

  • Vitamin K deficiency and warfarin reversal

    • Vitamin K is required for II, VII, IX, X; deficiency leads to prolonged PT/INR; warfarin blocks vitamin K recycling

    • Reversal: if active bleeding, give vitamin K IV and consider fresh frozen plasma (FFP) for immediate factor replacement

  • Liver disease and coagulopathy

    • Coagulation factors are largely produced by the liver; advanced liver disease can cause prolonged PT and aPTT and thrombocytopenia; management includes FFP for active bleeding and treating underlying liver disease

Postpartum TTP scenario (exam-style emphasis)

  • Example clinical vignette from transcript:

    • 25-year-old female, 2 months postpartum, fever 102.5 F, forgetful (neuro changes), bruising, thrombocytopenia

    • Most likely diagnosis: TTP (postpartum), not DIC (coagulation abnormality required for DIC) unless labs show abnormal coagulation factors; presence of CNS symptoms and fever with thrombocytopenia strongly suggests TTP

  • Key learning: differentiate TTP from DIC using coagulation tests (INR, aPTT) which are typically normal in TTP but abnormal in DIC

Hematologic malignancies overview (solid bullets for quick recall)

  • Leukemias

    • CML (Chronic myelogenous leukemia): mean age ~53; Philadelphia chromosome positive in ~95%; three phases: chronic, accelerated, blastic; leukocytosis with blasts; treatment: imatinib (a BCR-ABL tyrosine kinase inhibitor) or other TKIs; many achieve chronic-phase control

    • CLL (Chronic lymphocytic leukemia): most common leukemia overall; older adults; small mature lymphocytes with smudge cells on smear; often asymptomatic at discovery; can be monitored (watchful waiting) until progression; may require chemo/stem cell transplant later

    • AML (Acute myeloid leukemia): most common adult acute leukemia; risk factors include radiation/chemical exposure (e.g., benzene in tires); blasts on smear; Auer rods are pathognomonic; treatment: intensive chemotherapy ± stem cell transplant

    • ALL (Acute lymphoblastic leukemia): common pediatric leukemia; peak incidence in children; symptoms include bone pain, fever, bruising; treated with chemotherapy; excellent cure rates in children

  • Lymphomas

    • Hodgkin lymphoma: bimodal age distribution; Reed-Sternberg cells (owl-eye appearance) on biopsy; often present with painless cervical lymphadenopathy and B symptoms (fever, night sweats, weight loss); often treated with chemotherapy and possibly radiation; prognosis depends on stage

    • Non-Hodgkin lymphoma: diverse subtypes; prognosis and treatment vary widely

  • Plasma cell disorders

    • Multiple myeloma: older adults; CRAB features: hypercalcemia, renal failure, anemia, bone lytic lesions; bone pain, fractures common presentation; M protein (M spike) on serum protein electrophoresis and Bence Jones proteins in urine; diagnosed with bone marrow plasma cells and other tests

  • Pediatric solid tumors and selected markers

    • Tumor markers (general reference): CA 19-9 (pancreatic, biliary, gastric cancers), CA-125 (ovarian cancer), AFP (liver, germ cell tumors), beta-hCG (testicular cancer), CEA (colon, lung, breast), PSA (prostate), Chromogranin A (neuroendocrine tumors)

Tumor markers quick reference

  • CA 19-9: pancreatic, biliary, gastric cancers

  • CA-125: ovarian cancer

  • AFP: liver cancers and germ cell tumors

  • Beta-hCG: testicular and some gestational tumors

  • CEA: colon, lung, breast cancers

  • PSA: prostate cancer

  • Chromogranin A: neuroendocrine tumors

Exam-oriented mnemonics and decision aids

  • Microcytic anemia mnemonic (Ticks):

    • T = Thalassemia

    • I = Iron deficiency anemia

    • C = Chronic disease (anemia of inflammation)

    • K = Sideroblastic anemia

  • Distinguishing macrocytic anemias: B12 vs Folate

    • B12 deficiency: neuro signs (paresthesias, gait disturbance, cognitive changes); elevated MMA and homocysteine

    • Folate deficiency: no neuro signs; elevated homocysteine (but MMA normal)

  • Visual aids and clinical cues from the transcript (memory prompts):

    • Philadelphia chromosome as a clue to CML (tricky exam cue): t(9;22)

    • Sickle cell crisis cues: dehydration, hypoxia, acidosis, high altitude, cold

    • Beta-thalassemia homozygous features include frontal bossing and chipmunk cheeks; Hb electrophoresis joint clues

    • All or nothing pathognomonic signs like Auer rods in AML; Reed-Sternberg cells in Hodgkin lymphoma

  • Practical lab interpretation cues

    • IDA: low ferritin is most specific; ferritin can be low or normal in chronic disease; in IDA, ferritin is low and TIBC high

    • Macrocytosis with B12 or folate deficiency: look for reticulocytopenia and neurologic signs for B12

    • Hemolysis markers: elevated LDH, indirect bilirubin; low haptoglobin; reticulocytosis

Quick reference numeric summaries (for rapid recall)

  • RBC and RBC-related lifespans

    • ext{RBC lifespan} \,\approx\, 120\text{ days}

  • Anemia size categories

    • Microcytic: MCV < 80\,\text{fL}

    • Normocytic: 80 \le MCV \le 100\,\text{fL}

    • Macrocytic: MCV > 100\,\text{fL}

  • Iron studies patterns in IDA

    • ext{Ferritin} \downarrow, \text{Serum iron} \downarrow, \text{TIBC} \uparrow

  • B12 deficiency labs

    • [Hcy] \uparrow, [MMA] \uparrow

  • Coagulation tests in common conditions

    • Hemophilia A (VIII deficiency): PT/INR = \text{normal}, \; aPTT \uparrow

    • Vitamin K deficiency: prolonged PT/INR; aPTT may be prolonged later

    • DIC: prolonged PT/INR, prolonged aPTT, low fibrinogen, elevated D-dimer

  • Pathognomonic chromosomal/molecular clues

    • CML: t(9;22) translocation (Philadelphia chromosome)

Connection to clinical practice and ethics

  • Always identify the underlying cause of anemia rather than stopping at a label (e.g., IDA vs thalassemia vs anemia of chronic disease)

  • Consider age, ethnicity, and geographic exposure in differential diagnoses (e.g., thalassemias in malaria belt; beta-thalassemia major in younger patients; beta-thalassemia minor in adults)

  • In suspected malignant hematologic conditions, rely on biopsy and targeted tests (e.g., electrophoresis for thalassemias, bone marrow biopsy for marrow disorders, lymph node excisional biopsy for suspected Hodgkin lymphoma)

  • Manage bleeding disorders with a patient-centered approach: weigh risks of transfusion, monitor for transfusion reactions, and tailor reversal strategies to the clinical scenario (e.g., FFP + vitamin K for active warfarin bleeding; DDAVP for certain von Willebrand disease cases)

  • In emergent settings (e.g., TTP), prioritize rapid interventions (plasmapheresis) due to high mortality if untreated

  • Tumor marker interpretation should be contextualized with imaging and histology; markers aid in monitoring rather than stand-alone diagnosis

Summary of key exam-ready takeaways

  • Hematopoiesis basics anchor understanding of many disorders: differentiate myeloid vs lymphoid and RBC vs WBC lineages

  • Use CBC indices to triage anemia: size (MCV), production (retic count), and iron studies

  • IDA: iron stores depleted; rule out GI blood loss in adults, menstrual blood loss in reproductive-age women

  • Thalassemias: microcytosis with normal iron studies; electrophoresis distinguishes alpha vs beta; beta-thalassemia major is transfusion-dependent with characteristic facial bone changes in children

  • Macrocytosis: B12 vs folate deficiency; neurological symptoms point to B12; treat with appropriate vitamin replacement

  • Hemolysis: remember G6PD deficiency triggers, hereditary spherocytosis, and sickle cell disease; manage pain in SCD and hydration; be vigilant for transfusion reactions

  • Coagulation disorders: distinguish platelet from coag cascade problems; use coagulation studies (PT/INR, aPTT) and Coombs tests as indicated

  • Postpartum TTP: consider TTP with fever, neuro changes, thrombocytopenia, and MAHA; treat with plasmapheresis promptly

  • Leukemias and lymphomas: be mindful of hallmark features (Philadelphia chromosome in CML; Reed-Sternberg cells in Hodgkin; blasts in AML/ALL; smudge cells in CLL)

  • Tumor markers are contextual tools; memorize common associations for rapid recall

If you want, I can tailor these notes to focus more on specific topics you’ll see on the exam or create a quick flashcard set from these points.