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USMLE Step 2 (Fach) / Hematology/Oncology (Lektion)

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• Normal hemostasis Vascular injury leads to the release of vWF and tissue factor from subendothelial vessel walls.- vWF facilitates attachment and aggregation of platelets, forming a platelet plug- Tissue factor triggers the coagulation cascade via the extrinsic pathway with factor VII Ultimately the platelet plug and coagulation cascade create a fibrin mesh. Heparin-to-warfarin bridge is necessary because proteins C and S have shorter half-lives than the other vitamin K-dependent factors (II, VII, IX, X), leading to a transient period of paradoxic hypercoagulability before proper anticoagulation.
• Hemophilia X-linked clotting factor deficiencies of factors VIII (hemophilia A, 80% of cases), factors IX (hemophilia B), and XI (hemophilia C) that result in an ↑ tendency to bleed. Rarely, hemophilias can be acquired if antibodies against these factors are produced via autoimmune, lymphoproliferative, or postpartum states. History/PE:- Presents as a young boy with spontaneous hemorrhage into the tissues and joints that, if untreated, can lead to arthropathy and joint destruction. Spontaneous intracerebral, renal, retroperitoneal, and GI hemorrhages are also seen.- Mild cases may have major hemorrhage after surgery, trauma, or dental procedures but are otherwise asymptomatic. Diagnosis:- ↑ PTT is prolonged on basic bleeding workup. PT and bleeding time are normal.- Best initial test: Mixing studies. Mix the patient's plasma with normal plasma, which will correct the PTT in hemophilia patients as it contains all clotting factors.- Most accurate test: Obtain specific factor assays for factors VII, VIII, IX, X, XI, and XII. Treatment:- If bleeding is severe or factor level is ≤ 1% of normal, immediately transfuse missing factor or cryoprecipitate.- If bleeding is not severe and factor level is > 5% of normal (mild) or 1-3% of normal (moderate), hemophilia may be treated with desmopressin (DDAVP), which releases factor VIII from endothelial cells.
• Heparin Mechanism: Activates antithrombin Lab values: ↑ PTT Antidote is protamine sulfate.LMWH has more effect on factor Xa, can be given subcutaneously, and does not increase PTT.
• Warfarin Mechanism: Inhibits synthesis of vitamin K-dependent coagulation factors (II, VI, IX, X, proteins C and S). Lab values: ↑ PT For rapid reversal give fresh frozen plasma, otherwise give vitamin K.Teratogen.
• tPA Mechanism: Aids conversion of plasminogen to plasmin, which breaks down fibrin. Lab values: ↑ PT, ↑ PTT Treat toxicity with aminocaproic acid.
• LMWH (enoxaparin) Mechanism: Mainly inhibits factor Xa. Lab values: Anti-factor Xa, although typically unmonitored. Protamine less effective at reversal than for heparin.
• Direct thrombin inhibitors (dabigatran, argatroban) Mechanism: Directly inhibits factor II (thrombin). No reversal agent.
• von Willebrand disease An autosomal dominant defect or deficiency in vWF with decreased levels of factor VIII, which is carried by vWF. Symptoms are due to platelet dysfunction and deficient factor VIII, and are milder than in hemophila. wWD is the most common inherited bleeding disorder (1% of the population), and the most common form of wWD is type 1 vWD (mild to moderate deficiency in vWD). Type 2 includes qualitative defects in vWD, and type 3 is absence of functional vWF. History/PE:- Often presents in childhood with recurrent and prolonged mucosal bleeding (epistaxis, gums, teeth, menorrhagia) and bleeding after surgical procedures.- Often family history is present, and symptoms worsen with ASA use. Diagnosis:- Initial bleeding workup will show an ↑ bleeding time in all vWD types. ↑ PTT as in hemophilia may be seen due to low factor VIII levels. PT and platelet count will be normal.- Most accurate test: Ristocetin cofactor assay of patient plasma (measures capacity of vWF to agglutinate platelets) and vWF antigen level. Treatment:- Bleeding epidoses in mild/moderate type 1 disease can be treated with DDAAVP.- Menorrhagia can be controlled with OCPs. Avoid ASA and platelet function inhibitors.
• Hypercoagulable states - Factor V Leiden: A polymorphism in factor V, rendering it resistant to inactivation by activated protein C, is the most common cause of hereditary thromboembolic disease.- Heparin-induced thrombocytopenia (HIT): An immunologic reaction to the administration of heparin creates platelet-activating antibodies, which leads to the formation of blood clots and a rapid (50%) drop in platelet count.- Antiphospholipid syndrome (APS): Often associated with SLE and rheumatoid arthritis, APS predisposes to both arterial and venous thrombi formation and spontaneous abortions. History/PE:- Can present with recurrent thrombotic complications: DVT, pulmonary embolism, arterial thrombosis, MI, and stroke. Women may have recurrent miscarriages.- HIT: Hospitalized patient on anticoagulation with a drop in platelets.- Factor V Leiden: Young Caucasian patient with a family history of thrombosis.- APS: Middle-aged women with recurrent miscarriages or thrombosis. Diagnosis:- Acquired causes should be ruled out. Hereditary abnormality is confirmed with two abnormal values obtained while the patient is asymptomatic and untreated, with similar values obtained in two other family members.- Specific tests to confirm HIT (PF4 antibody and serotonin release assay), APS (lupus anticoagulant and anticardiolipin antibody). Treatments:- Patients with a hypercoagulable state with DVT or pulmonary embolism should be treated with heparin followed by 3-6 months of warfarin anticoagulation for the first event, 6-12 months for the second, and lifelong anticoagulation for subsequent events.- If anticoagulation is contraindicated (recent trauma, hemorrhage, severe hypertension), an inferior vena cava filter is the next best step and is also considered for patients who have recurrent DVTs on anticoagulation.- For HIT, first discontinue heparin, then start argatroban or lepirudin.- Avoid OCPs in patients with factor V Leiden.
• Disseminated intravascular coagulation An acquired coagulopathy caused by deposition of fibrin in small blood vessels, leading to thrombosis and end-organ damage. Depletion of clotting factors and platelets leads to a bleeding diathesis. It is associated with many severe illnesses and is often seen in hospitalized patients. History/PE:- Common associations with DIC: Obstetric complications, sepsis, neoplasms, acute promyelocytic leukemia, pancreatitis, hemolysis, vascular disorders (aortic aneurysm), massive trauma, drug reactions, acidosis, and ARDS.- Clinical presentation:→ Acute: Bleeding from venipuncture sites, into organs, with ecchymoses and petechiae.→ Chronic: Bruising and mucosal bleeding, thrombophlebitis, renal dysfunction, and transient neurologic syndromes. Diagnosis:- PC ↓, PT ↑, PTT ↑, bleeding time ↑- Schistocytes, ↑ fibrin degradation products (D-dimer), ↓ fibrinogen, ↓ factors V and VIII- DIC may be confused with liver diasease, but unlike liver disease, factor VIII is depressed. Treatment: Reverse the underlying cause; transfuse RBCs, platelets, FFP, and manage shock.
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• Thrombotic thrombocytopenic purpura A deficiency of the vWF-cleaving enzyme (ADAMTS-13) resulting in abnormally large vWF multimers that aggregate platelets and create platelet microthrombi. These block off small blood vessels, leading to end-organ damage. RBCs are fragmented by contact with the microthrombi, leading to hemolysis (microangiopathic hemolytic anemia). The ADAMTS-13 deficiency is either inherited or often acquired secondary to infection. History/PE:Maintain high clinical suspicion for TTP if 3/5 symptoms are present:- Low platelet count- Microangiopathic hemolytic anemia- Neurologic changes (delirium, seizure, stroke)- Impaired renal function- Fever Diagnosis: Clinical- The presence of schistocytes (broken RBCs) on peripheral smear with low platelets and rising creatinine is highly suggestive.- Hemolytic-uremic syndrome (HUS) can present similarly to TTP.--> HUS: >90% of cases in children caused by O157:H7 E coli hemorrhagic diarrhea preceding the syndrome. Characterized by renal failure, hemolytic anemia, and low platelets without neurologic symptoms. Severe ↑ in creatinine levels are more typical of HUS than of TTP. Schistocytes are seen in both. Treatment: First-line therapy for TTP is plasma exchange. Steroids can be added to ↓ microthrombus formation. Platelet transfusion is contraindicated, as additional platelets are consumed by the disease process, potentially worsening the patient's condition.
• Idiopathic thrombocytopenic purpura Diagnosis of exclusion in isolated thrombocytopenia (< 150,000/mm3) Etiology:- Primary ITP: inciting factor such as viral infection that causes an autoimmune reaction- Secondary ITP: associated with lymphoma, leukemia, SLE, HIV, HCV Epidemiology: common disorder, especially in children and women of childbearing age Pathophysiology: IgG antibodies against GpIIb/IIIa on platelets → platelet-antibody complex removed from circulation by spleen → ↓ platelet count → bone marrow megakaryocytes and platelet production increase in response Diagnosis:- CBC: normal except for decreased platelet count- Bleeding time: may be prolonged- Peripheral blood smear: Platelets are normal to large in size.- HIV and HCV screening- Consider bone marrow biopsy in atypical cases (typical bone marrow biopsy findings: ↑ megakaryocytes) Treatment:- Children:→ If no bleeding or only bruising/petechiae → observation regardless of platelet count→ If severe bleeding or increased risk of bleeding: glucocorticoids and/or IVIG- Adults→ Indication: platelet count of < 30,000/mm3→ First-line treatment: Corticosteroids or IVIG or IV Rho immunoglobulin (IV RhIG) → Second-line treatment: Splenectomy→ Third-line treatment: Thrombopoietin receptor agonists (romiplostim, eltrombopag) or rituximab
• Hemolytic anemia (a normocytic anemia) Occurs when bone marrow production is unable to compensate for ↑ destruction of circulating blood cells. Etiologies include the following:- Glucose 6-phosphate dehydrogenase (G6PD) deficiency, paroxysmal nocturnal hemoglobinuria (PNH), spherocytosis, sickle cell disease, and autoimmune anemia- Microangiopathic hemolytic anemia: TTP, HUS, DIC- Mechanical hemolysis: Associated with mechanical heart valves.- Other: Malaria, hypersplenism History/PE:- Present with pallor, fatigue, tachycardia, and tachypnea.- Patients are often jaundiced. Urine is dark with hemoglobulinemia, and there is ↑ excretion of urinary and fecal urobilinogen. Diagnosis: Clinical- ↑ LDH, ↑ indirect bilirubin, ↑ reticulocyte count, and ↓ haptoglobin are commonly seen. Treatment: Often includes corticosteroids to address immunologic causes and iron supplementation to replace losses. Splenectomy or transfusions are helpful in severe cases.
• G6PD deficiency X-linked defect in G6PD, leaving RBCs susceptible to hemolytic anemia following oxidant stress. Patients are often of Mediterranean or African descent, presenting with episodic dark urine and jaundice. Common triggers include: sulfa drugs (TMP-SMX), antimalarials (quinines), infections, fava beans. Diagnosis:- Best initial test is a CBC with smear showing hemolytic anemia with bite cells and Heinz bodies.- Most accurate test is a G6PD level a month after an episode.
• Paroxysmal nocturnal hemoglobinuria An acquired genetic defect characterized by a triad of hemolytic anemia, pancytopenia, and thrombosis Pathophysiology:- Physiologically, a membrane-bound glycosylphosphatidylinositol (GPI) anchor protects RBCs against complement-mediated hemolysis- Acquired mutation on the PIGA gene located on the X chromosome → GPI anchor loses its protective effect → RBC destruction by complement and reticuloendothelial system → intravascular and extravascular hemolysis- Can occur in aplastic anemia  Clinical symptoms:- Pallor, excessive fatigue, weakness- Intermittent jaundice and episodes of red/dark urine- Venous thrombosis in unusual locations (e.g., hepatic, cerebral, abdominal veins) - Vasoconstriction: headache, pulmonary hypertension- Abdominal pain, dysphagia, erectile dysfunction Diagnosis:- Anemia or pancytopenia → infections and bleeding - Signs of hemolysis- Flow cytometry: absence of CD55 and CD59 on the surface of RBCs- Coombs test: negative  Therapy- Eculizumab: Anti-C5 antibodies
• Hereditary spherocytosis Autosomal dominant RBC membrane protein defectFrequently affected proteins:- Spectrin- Ankyrin- Band 3- Protein 4.2 Clinical features:- Anemia and pallor- Jaundice (due to ↑ unconjugated bilirubin)- Splenomegaly with left upper quadrant pain- Black pigment gallstones (made of calcium bilirubinate), may lead to cholecystitis Diagnosis:- Normocytic anemia, ↑ MCHC, ↑ RDW- Eosin-5-maleimide binding test (EMA): test of choice- Smear: Spherocytes Treatment: Splenectomy
• Sickle cell anemia An autosomal recessive disorder caused by a mutation of adult hemoglobin (β-chain has Glu replaced by Val). Signs and symptoms are due to ↓ survival and a tendency of sickled cells to aggregate and cause vaso-occlusion. Clinical features:- Severe anemia (acute hemolytic crisis): Splenic sequestration crisis; Aplastic crisis due to an infection with parvovirus B19- Infection: Pneumonia, meningitis, osteomyelitis (most common cause: Salmonella spp., Staphylococcus aureus); sepsis (most common cause: Streptococcus pneumoniae)- Vaso-occlusive crises (painful episodes, painful crisis): deep bone pain and dactylitis; acute chest syndrome; stroke (common in children) Diagnosis:- Fastest initial test is CBC with smear showing sickle cells and Howell-Jolly bodies.- Neonatal screening (mandatory in all states) → If positive: Repeat hemoglobin electrophoresis (gold standard) Treatment: - Treat with hydroxyurea, which stimulates the production of fetal hemoglobin.- Health maintenance includes treating cholelithiasis with cholecystectomy, chronic folate supplementation, pneumococcal vaccination- Daily penicillin in patients < 5 years of age.- Vaso-occlusive crises (VOCs) must be treated with adequate pain management, O2 therapy, IV fluid rehydration, and antibiotics; exchange transfusions (erythrocytapheresis)- Sepsis is treated with IV ceftriaxone
• Aplastic anemia Failure of blood cell production due to destruction of bone marrow cells.Acquired deficiency or absence of pluripotent stem cells. Etiology:- Idiopathic (in > 50%)- Fanconi anemia is a hereditary autosomal recessive disorder due to a DNA crosslink repair defect that presents with the following features: → 50% develop acute myeloid leukemia or myelodysplastic syndromes in early adulthood→ Skeletal and organ abnormalities: short stature, hypo- and hyperpigmentation, cafe-au-lait spots, microcephaly, developmental delay, thumb and forearm malformations, kidney, GI, heart, eye, and ear abnormalities→ Labs: pancytopenia- Medication side effects/toxicity: Carbamazepine, methimazole, NSAIDs, benzene, chloramphenicol, cytostatic drugs, propylthiouracil- Ionizing radiation- Viruses: parvovirus B19, hepatitis viruses, EBV, HIV Clinical features:Patients are pancytopenic, with symptoms resulting from a lack of RBCs, WBCs, and platelets: pallor, weakness, a tendency to infection, petechiae, bruising, and bleeding. Diagnosis:- Bone marrow biopsy: Hypocellular fat-filled marrow with RBC of normal morphology Treatment: - Cessation of the offending agent or treatment for infection- Blood transfusions- Immunosuppressive therapy- Hematopoietic cell transplantation (HCT)
• Thalassemias Hereditary disorders involving ↓ or absent production of normal globin chains of hemoglobin.  Epidemiology:- Beta thalassemia: most commonly seen in people of Mediterranean descent- Alpha thalassemia: most commonly seen in people of Asian and African descent α-Thalassemia:- 1 allele deletion: No signs or symptoms- 2 allele deletion: Low MCV but asymptomatic.- 3 allele deletion: Hemoglobin H disease. Excess β-globin forms β4 (HbH).- 4 allele deletion: Hydrops fetalis. Excess γ-globin forms γ4 (Hb barts). β-Thalassemia:- 1 allele deletion: Thalassemia minor. ↑ HbA2 (α2δ2) >3.5%. Patiens are asymptomatic, but low MCV.- 2 allele deletion: Thalassemia major. ↑ HbF (α2γ2). Severe microcytic anemia in the first year of life. Diagnosis: - Microcytic hypochromic anemia- Blood smear: target cells , teardrop cells- Confirmatory test: Hemoglobin electrophoresis→ Alpha thalassemia can usually only be detected if ≥ 3 alleles are defective. Treatment: Those with β-thalassemia major and hemoglobin H disease are often transfusion dependent and require iron chelators (deferoxamine) to prevent overload.
• Polycythemia vera Chronic myeloproliferative neoplasm that is characterized by an erythropoietin-independent, irreversible increase in erythrocyte, granulocyte, and platelet counts.- Mutation in the JAK2 gene (95%) Clinical features:- Often asymptomatic (incidental finding on routine blood tests!)- Constitutional symptoms: weight loss, fatigue, sweating- Hyperviscosity syndrome: Hypertension, erythromelalgia (burning cyanosis in the hands/feet), transient visual disturbances- Thrombotic phenomena: DVT, CVA, myocardial infarction, portal vein thrombosis- Plethora: Facial flushing, cyanotic lips- Aquagenic pruritus- ↑ RBC turnover (gouty arthritis)- Splenomegaly, hepatomegaly Diagnostic criteria: All three major criteria OR the first two major criteria AND the minor criterionMajor criteria1. ↑ Hemoglobin (♂: Hb > 16.5 g/dL / ♀: Hb > 16 g/dL)2. ↑ Hematocrit (♂: Hct > 49% / ♀: Hct > 48%)3. ↑ Red cell mass4. Bone marrow biopsy showing hypercellularity with trilineage growth (increased erythropoiesis, granulopoiesis, and megakaryopoiesis)5. Evidence of a genetic mutation in the JAK2 geneMinor criterion- ↓ EPO levels Treatment:- Phlebotomy: 250-500 mL in intervals of 2-3 days until a HCT of ≤ 0.45 is established- Antiplatelet prophylaxis: aspirin- Cytoreductive therapy: recommended if risk factors are present→ Hydroxyurea→ Interferon alpha→ JAK2 inhibitor: ruxolitinib
• Blood transfusion reactions Febrile nonhemolytic reaction:- Mechanism: Cytokine formation during storage of blood.- Presentation: Fever, chills, rigors, and malaise 1-6 hours after transfusion.- Treatment: Stop the transfusion and give acetaminophen. Allergic reaction:- Mechanism: Antibody formation against donor proteins, usually after receiving plasma-containing product.- Presentation: Prominent urticaria.- Treatment: Give antihistamines. If severe reaction, stop the transfusion and give epinephrine. Hemolytic transfusion reaction:- Mechanism: Preformed (acute) or formed (delayed) recipient antibodies against donor erythrocytes. Due to ABO mismatch and Rh and Duffy antigens.- Presentation: Fevers, chills, nausea, flushing, burning at the IV site, tachycardia, hypotension during or shortly after the transfusion.- Treatment. Stop the transfusion immediately. Give vigorous IV fluids and maintain good urine output.
• Chronic lymphocytic leukemia (CLL)  B-cell lymphoma that presents with lymphocytic leukocytosis. Epidemiology:- Median age at the time of diagnosis is 70-72 years- Most common type of leukemia in adults Rai staging system:0: Isolated lymphocytosisI: + LymphadenopathyII: + Hepatomegaly and/or splenomegalyIII: + Anemia (Hb < 11 g/dL)IV: + Thrombocytopenia (< 100,000/μL) History/PE:Often asymptomatic; patients present with fatigue, malaise, and infection. Common physical findings are lymphadenopathy and splenomegaly. Diagnosis:- Blood smear: smudge cells (Gumprecht shadows)- Flow cytometry: detection of B-CLL immunophenotype (CD19, CD20, CD23), light chain restriction (kappa or lambda) - Serum antibody electrophoresis: antibody deficiency (decreased γ globulin fraction)- Bone marrow aspiration (not needed for diagnosis): High percentage (> 30%) of small, mature lymphocytes; decreased number of myeloid progenitor cells Treatment:- Asymptomatic CLL (Rai stage 0): observe and monitor disease progression- Symptomatic CLL or advanced stage (Rai stage > 0):→ Chemotherapy→ If CD20 positive: rituximab→ Targeted therapy with ibrutinib- Refractory CLL or early recurrence in fit, young patients: allogeneic stem cell transplantation
• Chronic myelogenous leukemia (CML) Clonal expansion of myeloid progenitor cells, leading to leukocytosis with excess granulocytes and basophils and sometimes ↑ erthrocytes and platelets as well. To truly be CML, the BCR-ABL translocation must be present. In > 90% of patients, this is reflected by the Philadelphia chromosome t(9,22). CML primarily affects middle-aged patients. History/PE:- Many patients are asymptomatic at diagnosis. Typical signs and symptoms are those of anemia.- Patients can have splenomegaly with LUQ pain and early satiety. Constitutional symptoms of weight loss, anorexia, fever, and chills may also be seen.- Patients with CML go through three disease phases:1. Chronic: Without treatment this phase typically lasts 3-5 yeras. Infection and bleeding complications are rare.2. Accelerated: A transition toward blast crisis, with an ↑ in peripheral and bone marrow blood counts. Should be suspected when the differential shows an abrupt ↑ in basophils and thrombocytopenia (< 100,000/mm3).3. Blast crisis: A large percentage of untreated CML patients will eventually reach this phase. Resembles acute leukemia; survival is 3-6 months. Diagnosis:- Most accurate test: Philadelphia chromosome via PCR or FISH analysis, although some cases lack the translocation.- CBC often shows a very high WBC count – often > 100,000/mm3 at diagnosis, sometimes reaching > 500,000/mm3. The differential shows granulocytes in all stages of maturation. Rarely, the WBC count will be so elevated as to cause a hyperviscosity syndrome.- CML can be confused with a leukemoid reaction (acute inflammatory response to infection with ↑ neutrophils and a left shift). In CML and other hematologic malignancies, LAP is low while in leukemoid reactions LAP is high.- LDH, uric acid, and B12 levels are also often elevated in CML.A common lab finding of CLL is lymphocytosis (elevation of NK, T, or B cells) vs CML, which shows granulocytosis (↑ of granulocytes: neutrophils, eosinophils, or basophils). Treatment: Imatinib (Gleevec)
• Hairy cell leukemia A malignant disorder of well-differentiated B lymphocytes. HCL accounts for 2% of adult leukemia cases and most commonly affects older men. History/PE:- Typically presents with pancytopenia, bone marrow infiltration, and splenomegaly.- Patients complain of weakness, fatigue, petechiae, bruising, infection (especially with atypical mycobacteria such as Mycobacterium avium-intracellulare), abdominal pain, early satiety, and weight loss. Symptoms are similar to those of CLL except that patients rarely have lymphadenopathy. Diagnosis:- Best initial test: CBC with smear showing pathognomonic "hairy cells" (mononuclear cells with many cytoplasmic projections) that stain with tartrate-resistant acid phosphatase (TRAP). Leukopenia can sometimes be seen as well.- Most accurate test: Flow cytometry identifying the "hairy cells." Treatment:- First-line therapy is cladribine. - Alternative treatment options include splenectomy and IFN-α.
• Hodgkin lymphoma Epidemiology:- Bimodal age distribution: age 30 (primarily the nodular sclerosing type) and age 60 (maily the lymphocyte-depleted type) Etiology:- Strong association with Epstein-Barr virus (EBV)- Immunodeficiency: e.g., organ or cell transplantation, immunosuppressants, HIV infection, chemotherapy- Autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis) Clinical features:- Painless lymphadenopathy→ Cervical lymph nodes (in ∼ 60-70% of patients) > axillary lymph nodes (in ∼ 25-35% of patients) > inguinal lymph nodes (in ∼ 8-15% of patients) → Mediastinal mass → chest pain, dry cough, and shortness of breath→ Splenomegaly or hepatomegaly may occur if the spleen or liver are involved. - B symptoms: Night sweats, weight loss > 10% in the past 6 months, fever > 38°C (100.4°F)- Pel-Ebstein fever (= periods of high temperature for 1-2 weeks, followed by afebrile periods for 1-2 weeks)- Alcohol-induced pain- Pruritus (focal or generalized) Diagnosis:- CBC: Elevated or decreased WBC count, anemia, eosinophilia, ↑ LDH, hypercalcemia- Lymph node excision: Reed-Sternberg cells (RSCs), CD15/30-positive, inflammatory background - Chest x-ray or CT-scan- Bone scintigraphy or PET-CT: performed before treatment to assess disease spread Treatment:- Early stage (I+II): ABVD = adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine- Late stage: BEACOPP ± Radiation = bleomycin, etoposide, adriamycin (doxorubicin), cyclophosphamide, oncovin (vincristine), procarbazine, prednisone Prognosis:- Good prognosis: 5-year survival rate ∼ 80–90% (in children > 90%) → Best prognosis: nodular lymphocyte predominant HL (NLPHL)- ∼ 10–20% of patients will develop secondary malignancies (complications related to radiation therapy and chemotherapy)- Unfavorable factors for Hodgkin lymphoma (relevant when selecting a treatment regimen) → High ESR (≥ 50 mm in the first hour)→ Involvement of three or more lymph node areas→ Large mediastinal tumor → Bulky disease (tumors measuring ≥ 10 cm across)
• Multiple myeloma Clonal proliferation of malignant plasma cells with excessive production of monoclonal immunoglobulins (typically ineffective IgA or IgG) or immunoglobulin fragments (kappa/lambda light chains). MM primarily affects the elderly, peaking in the seventh decade. Risk factors include radiation, monoclonal gammopathy of undetermined significance, and pretroleum products and pesticides. History/PE:- 70% of MM patients present with bone pain or with a pathologic fractures (MM cells infiltrate bone marrow, where they activate osteoclasts, creating lytic lesions and weak bones). Anemia, hypercalcemia, and renal abnormalities are also seen.- Patients are prone to infection (IgG and IgG produced by myeloma cells are monoclonal, thus making them ineffective) and have elevated monoclonal (M) proteins in the serum and/or urine. Diagnosis:- Best initial test: Serum protein electrophoresis showing IgG or IgA monocloncal spikes.- Most accurate test: Bone marrow biopsy showing >10% monoclonal CD138+ plasma cells.- CBC with smear may show rouleaux formation, whereas a urinanalysis may show Bence Jones protein (paraprotein). Total protein:albumin gap is often elevated.- M protein alone is insufficient for the diagnosis of MM, as MGUS, CLL, lymphoma, Waldenström macroglobulinemia, and amyloidosis can also ↑ M protein.- Patients should also be evaluated with a skeletal survey. Treatment:- Young patients: Autologous bone marrow transplant- Older patients: Melphalan (oral alkylating agent) and prednisone
• Waldenström macroglobulinemia A type of non-Hodgkin lymphoma associated with abnormal production of monoclonal IgM antibodies.  Clinical features:- Impaired platelet function → hemorrhagic diathesis with petechial bleeding- Normochromic anemia- Raynaud's phenomenon- Formation of cold agglutinins (IgM) with hyperviscosity syndrome→ Impaired acral blood flow→ Impaired vision, hearing, and renal function- Peripheral neuropathy- Cryoglobulinemia- Lymph node enlargement possible- Constitutional symptoms (e.g., fatigue, headache) Diagnosis:- ↑ ESR, ↑ uric acid, ↑ LDH, and ↑ alkaline phosphatase- Screening test: Serum protein electrophoresis- Bone marrow biopsy and aspirate: abnormal plasma cells with Dutcher bodies (intranuclear inclusions of IgM deposits)- Peripheral smear: Rouleaux formation- "Sausage-link" (dilated, segmented, tortuous) retinal veins- Anemia Treatment:- Causative: CD20 antibodies (e.g., rituximab)- Hyperviscosity syndrome: plasmapheresis
• Amyloidosis Extracellular deposition of amyloid protein fibrils due to a variety of causes. Classically a disease of the elderly. History/PE:- Clinical presentation depends on the type, amount, and tissue distribution of amyloid. In AL and AA the major sites of clinically important amyloid deposition are in the kidneys, heart, and liver.- In some disorders, amyloid deposition is limited to one organ (the brain in Alzheimer disease). AL: A plasma cell dyscrasia with deposition of monoclonal light-chain fragments. Associated with multiple myeloma and Waldenström macroglobulinemia.AA: Deposition of the acute-pahse reactant serum amyloid A. Associated with chronic inflammatory diseases (eg, rheumatoid arthritis), infections, and neoplasms.Dialysis related: Deposition of β2-microglobulin, which accumulates in patients on long-term dialysis.Senile-systemic: Deposition of otherwise normal transthyretin. Diganosis:- Most accurate test: Tissue biopsy with Congo red staining showing apple-green birefringence under polarized light. Immunohistochemistry can identify the amyloid protein type. Treatment: 1° amyloidosis is treated with experimental chemotherapy and autologous stem cell transplant. 
• Iron deficiency anemia Etiology:- Decreased absorption: Bariatric surgery (duodenum), inflammatory bowel disease- Increased demand: Pregnancy, lactation, growth spurt- Iron loss: GI bleed, menorrhagia, hemorrhagic diathesis Clinical features:- Fatigue, lethargy, pallor- Brittle nails, koilonychia, hair loss- Pica, dysphagia- Chronic/severe IDA: Angina, dyspnea on exertion, pedal edema- Angular cheilitis, atrophic glossitis- Plummer-Vinson syndrome (PVS): triad of postcricoid dysphagia, upper esophageal webs, and iron deficiency anemia Diagnostics:- ♂: < 14 g/dL- ♀: < 12 g/dL- Complete blood count: typically microcytic, hypochromic anemia- Reticulocyte count: ↓ or normal- Red cell distribution width (RDW): ↑- Smear: anisocytosis and increased zone of central pallor- ↓ Serum ferritin (< 30 ng/L) and serum iron levels- ↑ Serum transferrin and total iron binding capacity (TIBC)- ↓ Transferrin saturation (< 20%) Treatment:- Iron-rich diet (meats, fresh green leafy vegetables)- Oral iron therapy- Parenteral iron therapy→ Adverse effects: Thrombophlebitis; iron dextran can cause myalgia, arthralgia, headaches, and rarely, anaphylactic shock within 1-2 days of infusion.
• Sideroblastic anemia Etiology:- Inherited: X-linked sideroblastic anemia due to a δ-ALA-synthase gene defect- Acquired: Lead exposure, myelodysplastic syndromes, alcohol use disorder, vitamin B6, copper deficiency, isoniazid Clinical features: - Microcytic/hypochromic anemia- Microscopy usually shows two groups of RBCs: Hypochrmoic and normochromic ("dimorphic" RBC population)- ↑ Serum iron and ferritin, TIBC is ↓, which distinguishes it from iron deficiency- Bone marrow biopsy: Ringed sideroblasts Treatment: remove offending agents. Consider pyridoxine.
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• Folate deficiency Etiology:- Malnutrition: “Tea and toast” diet; alcohol use disorder- Malabsorption: e.g., celiac disease, inflammatory bowel disease- Increased requirement: e.g., pregnancy/lactation, severe hemolytic anemia- Drug-related: Methotrexate, antiepileptic drugs (e.g., phenytoin), trimethoprim Clinical features:- Signs of anemia (e.g., fatigue, pallor)- Sore tongue (glossitis) Diagnostics:- ↑ MCV (> 100 μm3)- ↑ homocysteine- Methylmalonic acid (MMA) is normal (unlike in vitamin B12 deficiency, where MMA is ↑)- Hypersegmented neutrophils and pancytopenia may be present - Folate serum levels are not reliable Treatment:- Oral folate supplementation for four months or until hematologic recovery takes place
• Myelodysplastic syndromes Group of hematological cancers in which malfunctioning pluripotent stem cells lead to hypercellularity and dysplasia of the bone marrow. Etiology:- Primary MDS (90% of cases): Tends to occur in elderly patients; unknown etiology- Secondary MDS (10% of cases): caused by exogenous bone marrow damage→ Treatment-related MDS: following cytostatic therapy (alkylating agents, topoisomerase II inhibitors, azathioprine, etc.)→ Benzene and other organic solvents→ Radiation damage: therapeutic radiation, radioiodine therapy, ionizing radiation→ Paroxysmal nocturnal hemoglobinuria Diagnostics:- Normocytic or macrocytic anemia; leukocytopenia and/or thrombocytopenia- Smear: Nucleated RBCs, ringed sideroblasts, Howell-Jolly bodies, basophilic stippling, neutrophils with hypolobulated nuclei, large, agranular platelets, and megakaryocytes (in MDS-F)- Bone marrow biopsy: hypercellular, dysplastic bone marrow with numerous cells of all three cell lines with blasts, megakaryocytes, etc.; ringed sideroblasts- Chromosome analysis: In > 50% of patients, chromosomal aberrations can be detected at the time of diagnosis. Treatment:- Mild cytopenia: "watch and wait"- Severe cytopenia: Supportive treatment- Medical therapy: → Chemotherapy: If myeloblasts are elevated and since the disease may progress to AML→ Immunosuppressive agents→ Lenalidomide- Allogenous stem cell transplant is the only curative option.
• Red blood cell transfusion thresholds < 7 g/dL: Generally indicated 7-8 g/dL:- Cardiac surgery- Oncology patients in treatment- Heart failure 8-10 g/dL:- Symptomatic anemia- Ongoing bleeding- Acute coronary syndrome >10 g/dL: Not generally indicated
• Acute intermittent porphyria Epidemiology:- Second most common porphyria- Peak incidence: ∼ 30 years- Sex: ♀ > ♂ (2:1) Etiology:- Autosomal dominant- Mutation of porphobilinogen deaminase - Attacks are triggered by:→ Anticonvulsants (especially barbiturates, benzodiazepines, phenytoin)→ Sulfonamides→ Anesthetics→ Hormone therapy→ Alcohol→ Smoking→ Sex hormones, especially progesterone→ Fasting: Increased intake of carbohydrates may alleviate symptoms.→ Stress (e.g., surgery, infection) Clinical features:- Fever- GI symptoms: severe abdominal pain, nausea, vomiting- Polyneuropathy: non-specific pain, weakness/fatigue, paresthesia, paresis- Seizures- Psychiatric abnormalities: hallucinations, disorientation, anxiety, insomnia- Autonomic dysfunction: tachycardia, hypertension- Red-purple urine- In contrast to some porphyrias, the skin is not involved Diagnosis:- Initial diagnosis of AIP is based on clinical findings. A high index of suspicion is necessary.- Urinary tests (especially during attacks): ↑ PBG and ↑ ALA- Urine may turn brown, dark red, or purple when exposed to sunlight. Therapy:- Hemin: Decreases activity of δ-aminolevulinate synthase → ↓ heme biosynthesis - Alternatives: Heme arginate, glucose loading
• Porphyria cutanea tarda Epidemiology:- Most common porphyria- Peak incidence: 40-70 years- Sex: ♂ > ♀ Etiology: Defective uroporphyrinogen III decarboxylase (UROD)- Type I: acquired insufficiency of UROD in the context of hepatic damage; Mainly occurs in older men with chronic alcoholism and hepatic cirrhosis- Type II: inherited (autosomal dominant) defective UROD Associated conditions:- Increased hepatic iron stores, hemochromatosis- Alcohol, smoking- Hepatitis C- HIV- Estrogen therapy Clinical features:- Increased fragility of sun-exposed skin → blistering and impaired healing (blistering photosensitivity)- Healing results in scarring and milia formation- Hypertrichosis- Hyperpigmentation- Scleroderma-like changes (especially forehead and scalp)- Commonly occurs on: Dorsum of the hand; Face and neck; Extensor surface of the forearm Diagnosis:- Urinary tests: ↑ uroporphyrin (tea-colored urine) - Blood tests: ↑ porphyrins, possibly abnormal LFTs Therapy:- Avoid susceptibility factors and excessive sunlight- Phlebotomy- Hydroxychloroquine or chloroquine
• Acute myeloid leukemia Epidemiology:- Most comon adult acute leukemia- Median age 65 Clinical features:- Fatigue is common (other B symptoms unusual)- Fatigue, weakness (anemia)- Bleeding, bruising (granulocytopenia)- Infection (granulocytopenia)- Hepatosplenomegaly/lymphadenopathy rare- Disseminated intravascular coagulation (if APML) Diagnostics:- Lab: Cytopenias (leukocytes may be ↑, normal, or ↓), ↑ LDH- Peripheral smear: Usually myeloblasts with Auer rods- Bone marrow biopsy: > 20% myeloblasts- Myeloperoxidase ⊕ Treatment:- Induction therapy: Cytarabine and anthracyclines (eg, daunorubicin)- AMLA: ATRA (all-trans-retinoic acid)
• Sickle cell trait Clinical features:- Often asymptomatic- Painless gross hematuria due to renal papillary necrosis: often the only symptom- Hyposthenuria: nocturia, enuresis- Recurrent UTIs- Renal medullary carcinoma Laboratory findings:- Normal hemoglobin, reticulocyte count, RBC indeces & morphology- Hemoglobin electrophoresis: Hb A > Hb S Complications:- Splenic infarction (especially at higher altitudes), venous thromboembolism, priapism- Exertional rhabdomyolysis
• Erythropoetin Stimulate red blood cell proliferation  Indications:- CKD-related anemia Adverse effects:- Hypertension (30% of patients), which occurs 2-8 weeks after treatment initiation
• Heparin-induced thrombocytopenia (HIT) HIT can be differentiated into 1 (asymptomatic), and type 2, which is antibody-related and prognostically worse. Type 1 HIT:- Frequency: 10-20%- Onset: Within the first 5 days- Thombocytopenia: > 100,000/µl- Pathophysiology: Direct interaction between platelets and heparin- Management: Continue heparin, monitor platelets Type 2 HIT:- Frequency: 1-5% for UFH, 0.1-1% for LMWH- Onset: Day 5-14- Thrombocytopenia: < 100,000/µl (or decrease > 50% compared to baseline)- Pathophysiology: Autoantibodies against a complex composed of platelet factor 4 (PF4) and heparin and arterial/venous thrombosis- Diagnostics: Serotonin release assay: Gold standard- Complications: Organ ischemia, skin necrosis, limb gangrene, anaphylactoid reaction- Management→ Discontinue all heparin-containing products→ Initiate non-heparin anticoagulation (often a direct thrombin inhibitor, eg, argatroban, or fondaparinux)→ Transition to warfarin or another long-term anticoagulant for at least 2 months
• Fanconi anemia A hereditary autosomal-recessive disorder due to a DNA crosslink repair defect.- Most common congenital cause of aplastic anemia (ie, bown marrow failure) Clinical features:- Short stature- Hypo-/hyperpigmented macules- Abnormal thumbs- Genitourinary malformations- 50% develop AML or myelodysplastic syndroms in early adulthood Laboratory findings:- Pancytopenia- Positive chromosomal breakage testing Treatment: Hematopoietic stem cell transplant
• Medications that trigger hemolysis in G6PD deficiency Avoid:- Dapsone- Isobutyl nitrite- Nitrofurantoin- Primaquine- Rasburicase Use with caution:- Acetaminophen- Aspirin- Chloramphenicol- Chloroquine- Colchine- Diphenhydramine- Glyburide- Isoniazid- L-dopa- TMP-SMX- Vitamin K
• Indications for specialized RBC treatments Irradiated:- Bone marrow transplant (BMT) recipients- Acquired or congenital cellular immunodeficiency- Blood components donated by first or second degree relatives Leukoreduced:- Chronically transfused patients- CMV seronegative at-risk patients (eg, AIDS, transplant patients)- Potential transplant recipients- Previous febrile nonhemolytic transfusion reaction Washed:- IgA deficiency- Complement-dependent autoimmune hemolytic anemia- Continued allergic reactions (eg, hives) with red cell transfusion despite antihistamine treatment
• Tumor lysis syndrome Risk: Initiation of cytotoxic chemotherapy Manifestations:- Severe electrolyte abnormalities: ↑ Phosphorus, potassium, uric acid; ↓ Calcium- Acute kidney injury- Cardiac arrhythmias Treatment:- Continuous telemetry- Aggressive electrolyte monitoring/treatment Prophylaxis: - IV fluids- Allopurinol or rasburicase
• Polycythemia - Differential diagnosis Primary (↓ EPO):- Polycythemia vera (JAK2 mutation)- EPO receptor mutations Secondary (normal/↑ EPO):- Hypoxemia→ Cardiopulmonary disease→ Obstructive sleep apnea→ High altitude- EPO-producing tumors (renal, hepatic)- Congenital (high-affinity hemoglobin)- Following renal transplantation- Androgen supplementation
• Homocysteinuria Etiology:- Methionine synthase deficiency- Cystathione synthase deficiency- Impaired affinity of cystathione synthase for pyridoxal phosphate- Methylenetetrahydrofolate reductase deficiency Inheritance: autosomal recessive Pathophysiology:- Methionine synthase (homocysteine methyltransferase) deficiency → impaired conversion of homocysteine into methionine- Cystathionine synthase deficiency → impaired conversion of homocysteine into cystathionine- All forms result in accumulation of homocysteine. Clinical features: - Nonspecific features in infancy: failure to thrive, developmental delay- Eyes: downward subluxation of the ocular lens (ectopia lentis) after age 3; myopia and glaucoma later in life- Progressive intellectual disability- Psychiatric and behavioral disorders- Fair complexion- Marfanoid habitus: tall, thin, elongated limbs, arachnodactyly - Osteoporosis, kyphosis- Vascular system: thromboembolism, premature arteriosclerosis, coronary heart disease Diagnostics:- ↑ Homocysteine in urine and serum- Urine sodium nitroprusside test: Urine changes color to an intense red.  Treatment:- Some patients respond to large doses of pyridoxine (vitamin B6).- Methionine synthase deficiency: high methionine diet - Cystathionine synthase deficiency: low methionine and high cysteine diet; vitamin B6, vitamin B12, and folate supplementation
• Antiphospholipid antibody syndrome Diagnostic criteria: 1 clinical and 1 laboratory criterion must be met. Clinical:- Arterial/venous thrombosis- ≥ 3 consecutive unexplained fetal losses before 10th week- ≥ 1 explained fetal loss after 10th week- ≥ 1 premature birth of normal neonate before 34th week due to preeclampsia, eclampsia, placental insufficiency Laboratory:- Lupus anticoagulant- Anticardiolipin antibody (IgG/IgM – medium or high titer)- Anti-beta-2 glycoprotein 1 antibody (IgG/IgM – high titer)
• Leukemoid reaction vs. CML Leukemoid reaction:- > 50'000/mm3- Cause: Severe infection, associated with certain solid tumors (e.g., lung and kidney cancer)- LAP score: High- Neutrophil precursors: More mature (metamyelocytes > myelocytes)- Absolute basophilia: Not present CML- Often > 100'000/mm3- Cause: BCR-ABL fusion- LAP score: Low- Neutrophil precursors: Less mature (metamyelocytes < myelocytes)- Absolute basophilia: Present
• Echinocytes (burr cells) Smooth, rounded, and evenly spaced cytoplasmic projections Associated conditions:- Uremia- Liver disease
• Target cells (codocytes) Bullseye appearance Associated conditions:- Thalassemias- Hemoglobin C and S- Liver disease- Asplenia
• Acanthocytes (spur cells) Thorny projections with varying length and width (vs. echinocytes/burr cells) Associated conditions:- Hemolytic anemia in hepatic disorders (eg, liver cirrhosis)- Myelodysplastic syndromes- Asplenia- In urine: glomerulonephritis

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