A 7-year-old girl is brought to the physician by her mother because of a 5-day history of fever, fatigue, and red spots on her body. Her temperature is 38.3°C (101.1°F), pulse is 115/min, and blood pressure is 100/60 mm Hg. Physical examination shows pallor and petechiae over the trunk and lower extremities. Laboratory studies show a hemoglobin concentration of 7 g/dL, a leukocyte count of 2,000/mm3, a platelet count of 40,000/mm3, and a reticulocyte count of 0.2%. Peripheral blood smear shows normochromic, normocytic cells. A bone marrow aspirate shows hypocellularity. Which of the following is the most likely cause of this patient's findings?

Idiopathic thrombocytopenic purpura

A 10-year-old girl with previously diagnosed sickle cell anemia presents to the emergency room with a low-grade fever, malaise, petechiae on her arms, and a rash on her face. She regularly takes hydroxyurea and receives blood transfusions to treat her condition. Her blood tests show a hemoglobin of 4.0 g/dL, MCV of 87 fl, and 2% reticulocyte count. An attempted bone marrow biopsy was a dry, empty tap. What is the most likely diagnosis?

Reaction to the blood transfusions

A 21-year-old woman comes to the physician for an annual health maintenance examination. She has no particular health concerns. Laboratory studies show: Hemoglobin 11.2 g/dL Mean corpuscular volume 74 μm3 Mean corpuscular hemoglobin concentration 30% Hb/cell Red cell distribution width 14% (N=13–15) Genetic analysis shows a point mutation in intron 1 of a gene on the short arm of chromosome 11. A process involving which of the following components is most likely affected in this patient?

Small nuclear ribonucleoprotein

A 30-year-old man presents to the emergency department with complaints of red, pinkish urine in the morning. He adds that he has been feeling some abdominal pain. The patient is not taking any medication, and his laboratory test results are as follows: Hb 11.0 g/dL RBC 3.7 x 1012/L WBC 4,000/mm3 PLT 100,000/mm3 Reticulocytes 17% of red cells Coombs test Negative Blood smear Polychromasia Which statement is true about this patient’s condition?

Eculizumab can be used to treat this condition

CD25 deficiency is expected to be seen

Patient is at great risk for bleeding

Urinary hemosiderin testing will be negative

A 36-year-old man presents to his primary care physician with increasing fatigue. He says that the fatigue started after he returned from vacation in South America 4 weeks ago and thinks that it may be related to an infection he got while abroad. He does not know the name of the infection but says that he went to a local clinic for treatment and was given an antibiotic. Since then, he has noticed that he is no longer able to perform his job as a contractor who renovates old homes because he feels short of breath after just a few minutes of work. Furthermore, he says that he has been experiencing prolonged nosebleeds that never occurred prior to this episode. He denies any neurologic symptoms. His past medical history is significant for alcoholic hepatitis secondary to alcohol abuse 3 years prior. Physical exam reveals conjunctival pallor as well as petechiae. Which of the following findings is associated with the most likely cause of this patient's symptoms?

Hypocellular bone marrow with fatty infiltration

Schistocytes on peripheral blood smear

Low circulating levels of erythropoietin

Dense lines in the metaphysis of long bones

A 38-year-old woman was brought to the emergency department after she experienced dizziness and shortness of breath while walking with her friend. She recently immigrated to the United States and is unable to report her previous medical history. Physical exam reveals pallor underneath her eyelids. Labs are obtained with the following results: Hemoglobin: 8.4 g/dL Platelet count: 62,000/mm^3 Mean corpuscular volume: 89 µm^3 Reticulocyte count: 0.1% Lactate dehydrogenase: 175 U/L Which of the following is associated with the most likely cause of this patient's symptoms?

Administration of a 50S ribosomal inhibitor

Recent infection with a toxin producing gram-negative rod

Bone marrow failure syndromes for USMLE Step 1: High-Yield Pathology Lessons

Aplastic Anemia - Empty Marrow Misery

Pathogenesis: Autoimmune T-cell destruction of multipotent hematopoietic stem cells → pancytopenia with a hypocellular, fatty marrow ("empty marrow").
Etiologies: Idiopathic (~70%), drugs (chloramphenicol, carbamazepine, NSAIDs), toxins (benzene), viral (Hepatitis, Parvovirus B19, EBV), radiation.
Clinical & Labs: Pancytopenia symptoms (fatigue, infections, bleeding). ↓ Reticulocytes, ↑ EPO. No hepatosplenomegaly.
Diagnosis: Gold standard is bone marrow biopsy → hypocellular marrow (<25%) replaced by fat.

Aplastic Anemia Bone Marrow Biopsy: Hypocellularity & Fat

Treatment: Supportive care (transfusions). Definitive: Allogeneic HSCT for young (<50 yrs), immunosuppression (ATG, cyclosporine) for older/unfit.

⭐ Up to 50% of aplastic anemia patients may have a co-existing Paroxysmal Nocturnal Hemoglobinuria (PNH) clone, detectable by flow cytometry for CD55/CD59.

PNH - Defective Anchor Drama

Acquired somatic mutation in the PIGA gene of a hematopoietic stem cell, leading to an inability to synthesize glycosylphosphatidylinositol (GPI) anchors.
Cells lack GPI-anchored proteins like CD55 (Decay Accelerating Factor) & CD59 (MAC Inhibitory Protein), making them susceptible to complement-mediated destruction.

Classic Triad: Intravascular hemolysis (dark urine, esp. in AM), pancytopenia, and venous thrombosis (often in atypical sites).
Diagnosis: Flow cytometry showing absent CD55/CD59 on RBCs and granulocytes.

⭐ A major cause of mortality in PNH is thrombosis, particularly in unusual locations like hepatic (Budd-Chiari syndrome), portal, or cerebral veins.

Treatment: C5 inhibitors (Eculizumab, Ravulizumab).

PNH flow cytometry: CD55/CD59 negative granulocytes

Myelodysplastic Syndromes - Dysfunctional Factory

Clonal hematopoietic stem cell disorders with ineffective hematopoiesis, leading to peripheral cytopenias despite a hypercellular bone marrow. It's a "factory" producing faulty cells.

Hallmark: Dysplasia in ≥1 cell line.
- Myeloid: Pseudo-Pelger-Huët cells (bilobed neutrophils).
- Erythroid: Ring sideroblasts.
- Megakaryocytic: Small, separated nuclei (pawn-ball megakaryocytes).
Diagnosis: Bone marrow biopsy shows hypercellularity, dysplasia, and < 20% blasts.
Risk: Transformation to AML (defined by ≥ 20% blasts).

Pseudo-Pelger-Huët anomaly in myelodysplastic syndrome

⭐ 5q- Syndrome: A specific MDS subtype, often in older women, with macrocytic anemia, normal/↑ platelets, and a favorable prognosis.

Inherited Syndromes - Faulty Blueprints

Fanconi Anemia (FA)
- Defect in DNA crosslink repair (e.g., BRCA genes).
- Presents with progressive pancytopenia, macrocytic anemia.
- Associated with café-au-lait spots, short stature, and thumb/radial defects.
- ↑ risk of AML, MDS, and solid tumors.
⭐ Chromosomal breakage analysis after exposure to DNA cross-linking agents (e.g., diepoxybutane) is diagnostic.
Diamond-Blackfan Anemia (DBA)
- Congenital pure red cell aplasia due to ribosomal protein gene mutations.
- Presents in infancy with macrocytic anemia, reticulocytopenia.
- Craniofacial and thumb abnormalities (triphalangeal thumb).
Dyskeratosis Congenita (DC)
- Defective telomere maintenance (TERC, TERT genes).
- Classic triad: abnormal skin pigmentation, nail dystrophy, oral leukoplakia.
- 📌 Mnemonic: CAN of worms: Cancer, Aplastic anemia, Nail/skin changes.

Fanconi Anemia: Thumb and Radial Defects

High‑Yield Points - ⚡ Biggest Takeaways

Aplastic anemia presents with pancytopenia and a hypocellular bone marrow; key causes include drugs, viruses, and autoimmune damage.

Fanconi anemia (AR) combines pancytopenia with café-au-lait spots and thumb/radial defects; diagnosed by chromosomal breakage tests.

Diamond-Blackfan anemia is a congenital pure red cell aplasia with macrocytic anemia, low reticulocytes, and physical anomalies.

PNH (PIGA mutation) causes hemolysis, thrombosis, and pancytopenia from CD55/CD59 deficiency.

Myelodysplastic syndromes (MDS) feature cytopenias despite a hypercellular marrow; carries a high risk of AML transformation.

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