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USMLE Step 3 (Fach) / Hematology (Lektion)

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• Alpha thalassemia Epidemiology: most commonly seen in people of Asian and African descent Etiology:- Usually due to deletion of at least one out of the four existing alleles- Inheritance pattern: autosomal recessive- Silent carrier (minima form): one defective allele (-α/αα)- Alpha thalassemia trait (minor form)→ Two defective alleles (-α/-α or --/αα)→ Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations- Hemoglobin H disease: three defective alleles (--/-α) → results in excessive production of pathologically altered HbH (four β-chains)- Hemoglobin Bart disease (major form): four defective alleles (--/-‑) → results in excessive production of pathologically altered Hb Bart (four γ-chains) Clinical features:- Silent carrier: asymptomatic- Alpha thalassemia trait: mild hemolytic anemia with normal RBC and RDW- Hemoglobin H disease→ Jaundice and anemia at birth→ Chronic hemolytic anemia which may require transfusions → possibly secondary iron overload due to hemolysis, transfusion, or both (→ secondary hemochromatosis)→ Hepatosplenomegaly→ Skeletal deformities (less common)→ Compared to thalassemia beta, symptoms in adults are generally less severe.- Hb-Bart's hydrops fetalis syndrome (most severe variant of alpha thalassemia):→ Intrauterine ascites and hydrops fetalis, severe hepatosplenomegaly, and often cardiac and skeletal anomalies→ Incompatible with life (death in utero or shortly after birth) Diagnostics:- Microcytic hypochromic anemia: Iron deficiency anemia (IDA) usually presents with a low RBC count and a high RDW, whereas patients with thalassemia trait usually have a normal RDW and a higher RBC, and a relatively low MCV compared to IDA. IDA usually only becomes microcytic once the hemoglobin is less than 10 g/dL.- Signs of hemolysis (↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes)- Blood smear: target cells, teardrop cells  - Bone marrow biopsy: reactive hyperplasia  - Hb-electrophoresis: Alpha thalassemia can usually only be detected if ≥ 3 alleles are defective.- DNA analysis: to test for alpha thalassemia minor and minima (< 3 alleles defective) Treatment:- Minor forms: Supplementation of iron or folic acid may be indicated- HbH disease→ Curative: allogeneic stem cell transplantation  → Transfusion of erythrocyte concentrate  → Indication: Hb < 7-8 g/dL or marked clinical symptoms→ Target: Hb > 10 g/dL→ Chelating agents (e.g., deferoxamine) in patients with: Serum ferritin concentration > 1000 μg/L, Secondary iron overload→ Folic acid supplementation→ Splenectomy  
• Beta thalassemia Epidemiology: most commonly seen in people of Mediterranean descent Etiology: In a normal cell, the β-globin chains are coded by a total of two alleles. Thus, there are two forms of the disease.- Beta thalassemia minor (trait): one defective allele- Beta thalassemia major (Cooley's anemia): two defective alleles Clinical features:- Minor variant (heterozygous): unremarkable symptoms (low risk of hemolysis, rarely splenomegaly)- Major variant (homozygous): Severe hemolytic anemia that often requires transfusions → possibly secondary iron overload due to hemolysis, transfusion, or both (→ secondary hemochromatosis)→ Hepatosplenomegaly→ Growth retardation→ Skeletal deformities (high forehead, prominent zygomatic bones, and maxilla) Diagnostics:- Microcytic hypochromic anemia: Iron deficiency anemia (IDA) usually presents with a low RBC count and a high RDW, whereas patients with thalassemia minor or thalassemia trait usually have a normal RDW and a higher RBC, and a relatively low MCV compared to IDA. IDA usually only becomes microcytic once the hemoglobin is less than 10 g/dL.- Signs of hemolysis (↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes)- Blood smear: target cells, teardrop cells  - Bone marrow biopsy: reactive hyperplasia  - Confirmatory tests: Hb-electrophoresis Treatment:- Minor variants: Usually no therapy required. Supplementation of iron or folic acid may be indicated.- Major variants:→ Curative: allogeneic stem cell transplantation  → Transfusion of erythrocyte concentrate→ Indication: Hb < 7-8 g/dL or marked clinical symptoms→ Target: Hb > 10 g/dL→ Chelating agents (e.g., deferoxamine) in patients with Serum ferritin concentration > 1000 μg/L; Secondary iron overload→ Folic acid supplementation→ Splenectomy  
• Macrocytic anemia MCV = > 100 fL Megaloblastic anemia (Impaired DNA synthesis and/or repair with hypersegmented neutrophils):- Vitamin B12 deficiency  - Folate deficiency  - Medications: Phenytoin, Sulfa drugs, Trimethoprim, Hydroxyurea, MTX, 6-mercaptopurine  - Fanconi anemia  - Orotic aciduria Nonmegaloblastic anemia (Normal DNA synthesis without hypersegmented neutrophils): - Liver disease  - Alcohol use  - Diamond-Blackfan anemia- Myelodysplastic syndrome- Hypothyroidism- Multiple myeloma
• Disseminated intravascular coagulation Etiology:- Sepsis (more commonly with gram-negative organisms)- Malignancies: Acute promyelocytic leukemia; Pancreatic, ovarian, or gastric adenocarcinomas- Acute traumatic coagulopathy  - Acute hemolytic transfusion reaction (AHTR)- Obstetric complications: Amniotic fluid embolism, Pre-eclampsia, Abruptio placenta, Retained products of conception- Acute pancreatitis- Heat stroke- Extracorporeal procedures (e.g., dialysis)  - Toxins: snake bites, amphetamine overdose- Vascular malformations: aortic aneurysms Clinical features:- Bleeding manifestations→ Petechiae, purpura, ecchymoses→ Oozing of blood from surgical wounds, intravenous lines→ Hematuria→ Hematemesis, hematochezia→ Collection of blood in body cavities: features of hemoperitoneum, hemothorax- Thrombotic manifestations→ Acute renal failure: oliguria→ Hepatic dysfunction: jaundice→ ARDS: dyspnea, rales→ Pulmonary thromboembolism: dyspnea, chest pain, hemoptysis→ Deep vein thrombosis: lower limb edema→ Neurological dysfunction: altered mental status, stroke→ Purpura fulminans: DIC with extensive skin necrosis→ Waterhouse Friderichsen syndrome: adrenal infarcts → adrenal insufficiency Diagnostics:- Thrombocytopenia, elevated D-dimer, increased PT and aPTT, and low fibrinogen should immediately raise suspicion for DIC! Differential diagnoses:- Severe hepatic dysfunction: clinical features, and/or laboratory findings of liver injury, normal factor VIII assay - Thrombotic thrombocytopenic purpura/immune thrombocytopenic purpura: no consumption coagulopathy → normal PT, aPTT- Heparin-induced thrombocytopenia: history of heparin use, heparin-PF4 (HIT) antibodies in serum Treatment:- Platelet concentrate if:→ Platelet count < 10,000 in asymptomatic individuals→ Platelet count < 50,000 in patients with active bleeding or if a surgical procedure is planned- Fresh frozen plasma if PT or APTT > 1.5 times the normal value- Cryoprecipitate if fibrinogen < 150 mg/dL- Packed RBCs if:→ Massive hemorrhage without hemodynamic response to fluid therapy→ Hb < 7 g/dL- If acute traumatic coagulopathy → transfuse packed RBC, FFP, and platelet concentrate in a 1:1:1 ratio- Synthetic protease inhibitor (e.g., Gabexate mesilate®, nafamostat®)- Antifibrinolytic therapy (e.g., tranexemic acid)
• Hemolytic uremic syndrome Epidemiology: Mainly children < 5 years of age   Etiology:- Shiga-like toxin (verotoxin) from enterohemorrhagic E. coli (EHEC) strain O157:H7  → Usually transmitted via contaminated foods, e.g., undercooked beef or raw leafy vegetables- Shiga toxin produced by Shigella dysenteriae- Streptococcus pneumoniae infection Clinical features:- A diarrheal illness (usually bloody) for the past 5-10 days precedes the onset of HUS symptoms in many children. The triad of clinical findings occurring in HUS consists of:  1. Low platelets (i.e., thrombocytopenia)- Petechiae, purpura- Mucosal bleeding- Prolonged bleeding after minor cuts2. Microangiopathic hemolytic anemia- Fatigue, dyspnea, and pallor- Jaundice3. Impaired renal function- Hematuria, proteinuria- Oliguria, anuria Diagnostics:- Hematology: ↓ Platelets, ↑ WBC count, ↓ Hemoglobin, ↑ Reticulocytes, ↓ Haptoglobin, Normal/slightly elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT), ↑ Fibrin degradation products and D-dimer levels, Negative Coombs test, Large number of schistocytes on blood smear (up to 10% of RBCs) - Serum chemistry: ↑ LDH, ↑ indirect bilirubin (hemolytic anemia), ↑ BUN and ↑ creatinine (impaired renal function)- Urinalysis: hematuria, proteinuria Treatment:- Avoid antibiotics and antimotility agents  - Monitor and correct: Fluid status abnormalities, Electrolyte disturbances, Acid-base abnormalities, Blood pressure, RBC transfusions  - Dialysis as indicated for AKI: Up to 50% of HUS patients require dialysis.- Only in refractory cases: plasma exchange therapy- Eculizumab (Monoclonal antibody to complement factor C5; blocks complement activation): may be beneficial in HUS with neurological symptoms- Post-diarrheal HUS is a nationally notifiable condition.
• Thrombotic thrombocytopenic purpura Epidemiology:- Primarily adult patients (median age at diagnosis: ∼ 40 years)  - More common in women and black populations Etiology:- ADAMTS13 deficiency→ Acquired TTP (∼ 95%): autoantibodies against ADAMTS13, a vWF-cleaving metalloprotease→ Congenital TTP (∼ 5%): gene mutations resulting in deficiency of ADAMTS13  - Risk factors: → Drugs→ Pregnancy→ Systemic disease: cancer, HIV, SLE, infections Clinical features:- TTP patients are typically previously healthy adults. The pentad of clinical findings consists of:  1. Fever2. Neurological signs and symptoms- Altered mental status, delirium- Seizure, focal defects, stroke- Headache, dizziness3. Low platelet count (i.e. thrombocytopenia): Petechiae, purpura, mucosal bleeding, prolonged bleeding after minor cuts4. Microangiopathic hemolytic anemia: Fatigue, dyspnea, and pallor, jaundice5. Impaired renal function: Hematuria, proteinuria, oliguria, anuria Diagnostics:- Hematology: ↓ Platelets, ↓ Hemoglobin, ↑ Reticulocytes, ↓ Haptoglobin, Normal/slightly elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT), ↑ Fibrin degradation products and D-dimer levels, Negative Coombs test, Large number of schistocytes on blood smear (up to 10% of RBCs) - Serum chemistry: ↑ LDH, ↑ indirect bilirubin (hemolytic anemia), ↑ BUN and ↑ creatinine (impaired renal function)- Urinalysis: hematuria, proteinuria- ADAMTS13 activity and inhibitor testing: ↓ ADAMTS13 activity  - Identification of secondary causes (e.g., tests for pregnancy, SLE, HIV, malignancy) Treatment:- Monitoring and correction: Fluid status abnormalities, Electrolyte disturbances, Acid-base abnormalities, RBC transfusions  - Prompt initiation of plasma exchange therapy (PEX)  - Glucocorticoids (e.g., prednisone)- Rituximab is reserved for severe cases.- Platelet transfusion should only be reserved for patients who are bleeding or require an invasive procedure.  
• Sickle cell anemia Pathophysiology:- Point mutation in the β-globin gene (chromosome 11) → glutamic acid replaced with valine → 2 α-globin and 2 mutated β-globin subunits create pathological hemoglobin S (HbS).- Heterozygotes (HbSA): carry one sickle allele and one other (usually normal) → sickle cell trait- Homozygotes (HbSS): carry two sickle alleles → sickle cell anemia Pathomechanism: - HbS polymerizes when deoxygenated, causing deformation of erythrocytes (“sickling”): Hypoxia, Infections, Dehydration, Acidosis, Sudden changes in temperature, Stress, Pregnancy- Sickle cells lack elasticity and adhere to vascular endothelium, disrupting microcirculation and causing vascular occlusion and subsequent tissue infarction.- Extravascular hemolysis and intravascular hemolysis are common.- Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency. Sickle cell trait:- Often asymptomatic- Painless gross hematuria due to renal papillary necrosis: often the only symptom- Hyposthenuria: nocturia, enuresis- Recurrent urinary tract infections- Renal medullary carcinoma   Sickle cell disease:- Onset: ∼ 30% develop symptoms in the first year of life; > 90% by age 6 years- Acute hemolytic crisis (severe anemia)→ Splenic sequestration crisis: Splenic vaso-occlusion → entrapment and pooling of large amounts of blood in the spleen → acute left upper quadrant pain, anemia, reticulocytosis, and signs of intravascular volume depletion (e.g., hypotension)→ Aplastic crisis: aplastic anemia with an acute, severe drop in hemoglobin and associated reticulocytopenia 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): recurrent episodes of severe deep bone painand dactylitis → most common symptom in children and adolescents!- Acute chest syndrome- Stroke - Infarctions of virtually any organ with corresponding symptoms - Chronic hemolytic anemia: fatigue, weakness, pallor; usually well tolerated- Chronic pain  - Cholelithiasis (pigmented stones) Diagnosis:- Prenatal testing: may be conducted in select cases: chorionic villus sampling and DNA analysis at 8-12 weeks of gestation- Neonatal screening (mandatory in all states)  → If positive: Repeat hemoglobin electrophoresis (gold standard)→ Migration towards the anode: HbA > HbF > HbS > HbC- Older children and adults: Liquid chromatography and isoelectric focusing to quantify hemoglobin subtypes (best tests)- Sickle cell test: detects sickle cells in a blood smear under anaerobic conditions.  - Peripheral blood smear: Sickle cells (drepanocytes), Target cells, Possibly Howell-Jolly bodies, Reticulocytosis Treatment:- Hydroxyurea: first-line treatment  → If the response to hydroxyurea alone is not adequate: Combine with erythropoietin, Blood transfusions, Folic acid supplementation- Prevent infections→ Pneumococcal, Meningococcal vaccines→ Daily penicillin prophylaxis (at least until the age of 5 years)→ If sepsis is suspected, treat with IV third-generation cephalosporin (e.g., ceftriaxone). If meningitis is also suspected: add vancomycin.- Acute sickle cell crisis: Hydration, Pain management with nonsteroidal anti-inflammatory agents and opioids, Thromboembolic prophylaxis, Nasal oxygen→ Blood transfusions→ Exchange transfusions in acute vaso-occlusive crisis- Allogeneic bone marrow transplantation: Indications: homozygotes, children < 16 years with severe disease
• Polycythemia vera Clinical features:- Often asymptomatic (incidental finding on routine blood tests!)- Constitutional symptoms: weight loss, fatigue, sweating- Hyperviscosity syndrome (triad of mucosal bleeding, neurological symptoms, and visual changes)- Plethora: Facial flushing, Cyanotic lips  - Pruritus: Itching typically worsens when the skin comes into contact with warm water (aquagenic pruritus).  - Nonspecific neurological symptoms: dizziness, headache, visual disturbances, tinnitus- Hypertension (Due to hyperviscosity)- Splenomegaly: associated with early satiety and abdominal discomfort; less commonly hepatomegaly- Peptic ulcer disease (Caused by excessive histamine production by mast cells) - Symptoms of thrombotic and hemorrhagic complications Diagnostics:- Laboratory findings: ↑ Hb/Hct, ↑ RBCs, ↑ Platelets (> 450,000/μL),↑ Leukocytes (> 12,000/μL), ↑ Uric acid, ↑ LDH, ↑ Leukocyte alkaline phosphatase, ↓ Serum iron levels, ↓ ESR,↓ EPO  - Arterial O2 saturation: normal   Treatment:- Phlebotomy: periodic removal of blood via venapuncture temporarily reduces cell counts and hyperviscosity.→ 250-500 mL in intervals of 2-3 days until a HCT of ≤ 0.45 is established- Antiplatelet prophylaxis: aspirin  - Cytoreductive therapy: determined on an individual basis; recommended if risk factors are present  → Hydroxyurea→ Interferon alpha→ JAK2 inhibitor: ruxolitinibIf platelet count is > 1 million/μL, platelet function is very likely to be impaired, and the risk of bleeding is significantly increased. Aspirin should be discontinued!
• Essential thrombocythemia Genetics: JAK2 mutation in 50% of cases Clinical features: - 50% asymptomatic- Thromboembolic events- Increased risk of fetal loss- Vasomotor symptoms (headache, visual disturbances, acral paresthesias)- Acute gouty arthritis  - Petechial bleeding   Diagnostics:- Thrombocytosis (> 600,000/μL)- ↑ LDH and uric acid- Bone marrow aspiration: hyperplasia of megakaryocytes Treatment:- Prevent thromboembolisms: low dose aspirin- Reduce thrombocyte count: hydroxyurea or interferon alpha
• Primary myelofibrosis Primary myelofibrosis encompasses any myeloproliferative neoplasm leading to bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly. Epidemiology: peak incidence between age 60-70 years Genetics: JAK2 mutation in 50% of cases Clinical features:- Weakness, fatigue, weight loss- Splenomegaly: left upper quadrant abdominal pain  - Hyperproliferative phase (early phase): thrombocytosis (→ thromboembolic events) and leukocytosis- Pancytopenic phase (late phase):→ Erythrocytopenia → anemia→ Thrombocytopenia → petechial bleeding→ Leukopenia → increased susceptibility to infections Diagnosis:- Laboratory studies: ↑ leukocyte alkaline phosphatase, LDH, and uric acid- Peripheral blood smear: dacrocytes (teardrop cells)- Bone marrow aspiration: punctio sicca   Treatment:- Curative: allogeneic stem cell transplantation (option for younger patients)- Hyperproliferative phase:→ Prevent thromboembolisms: antiplatelet drug (aspirin 100 mg)→ Control cell count: hydroxyurea, interferon alpha, cladribine- Pancytopenic phase→ JAK2 inhibitor: ruxolitinib  → Periodic transfusions  → Low-dose thalidomide plus glucocorticoids  
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• Immune thrombocytopenic purpura (ITP) 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 Clinical features:- Commonly asymptomatic- Include easy bruising, petechiae, bleeding, hematuria, melena- Acute ITP (typically in children): following a viral infection- Chronic ITP (typically women of childbearing age): insidious onset or incidental finding   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: increased megakaryocytes Treatment:- Children→ If no bleeding or only bruising/petechiae → observation regardless of platelet count  → If severe bleeding (e.g., intracranial, gastrointestinal) or increased risk of bleeding (e.g., contact sports, coagulopathy): glucocorticoids and/or IVIG  - Adults→ Indication: platelet count of < 30,000/mm3  → First-line treatment: corticosteroids  → Alternative (if intolerance to corticosteroids): IVIG or IV Rho immunoglobulin (IV RhIG)  → Second-line treatment: splenectomy  → If splenectomy is contraindicated or ITP remains refractory: Thrombopoietin receptor agonists: romiplostim, eltrombopag or Rituximab  
• Heparin-induced thrombocytopenia (HIT) Type 1 HIT:- Frequency: Appr. 10-20%- Onset: Within the first 5 days after beginning treatment- Severity of thrombocytopenia: Moderate: > 100,000 platelets/μL- Pathophysiology: Direct interaction between heparin and platelets (e.g., heparin directly induces platelet aggregation), no antibodies involved- Clinically insignificant- Management: Continue heparin, Monitor platelets Type 2 HIT:- Frequency: 1-5% for UFH; 0.1-1% for LMWH- Timing : onset 5-10 days after heparin initiation or ≤ 1 day with prior, recent heparin exposure- Severity: Massive reduction: < 100,000 platelets/μL (or decrease of > 50% compared to baseline)- Pathophysiology: Autoantibodies against a complex composed of platelet factor 4 (PF4) and heparin → induce both thrombocytopenia (via antibody-coated platelet removal by macrophages/reticuloendothelial system and by platelet consumption in thrombi) and arterial/venous thrombosis (by an unclear mechanism, which appears to involve platelet activation by the autoantibodies)- Features of thrombocytopenia: Bleeding is rare because platelet nadir (lowest point) is usually > 20,000 platelets/μL.- Venous > arterial thrombi manifestations: Involving legs (e.g., DVT), cardiac vessels (e.g., myocardial infarction), and skin- Complications: Organ ischemia or infarction, Skin necrosis, Limb gangrene- Management:→ Immediate discontinuation of all heparin-containing products→ Send confirmatory test (ELISA, serotonin release assay, or functional assay against PF4 autoantibody)→ Initiate non-heparin anticoagulation (often a direct thrombin inhibitor [e.g., argatroban] is first-line or synthetic heparin; NOT warfarin) until platelet count has normalized (> 150,000 platelets/μL)→ Transition to warfarin or other long-term oral anticoagulants for at least two months (often longer if patient had thrombosis)
• Hyperfibrinolysis Pathological fibrinolysis, which leads to bleeding (caused by, e.g., congenital or metabolic causes, trauma, decreased hepatic clearance caused by liver dysfunction, sepsis, etc)   Mechanism: Excessive plasmin activity causes increased fibrin degradation → Blood clots become unstable or dissolve shortly after forming.   Can occur in:- Surgery in tPA-rich organs such as the prostate and uterus- Prostate carcinoma (paraneoplastic)- Peripartum complications  - Disseminated intravascular coagulation (secondary to liver dysfunction, sepsis etc.)- Coagulation lysis therapy following a stroke
• Von Willebrand disease Epidemiology: most common congenital hemostatic disorder   Clinical findings:- Mostly asymptomatic  - Ecchymosis (esp. mucosal hemorrhages) → from reduced half-life of factor VIII  - Petechial hemorrhages in severe cases → caused by impaired platelet aggregation- Other symptoms include epistaxis, gingival bleeding, menorrhagia, GI bleeding, and excessive bleeding during surgical procedures. Type 1 (80%) - Autosomal dominant- Quantitative deficiency of vWF and factor VIII Type 2 (15-20%) - Autosomal dominant- Qualitative defect in vWF Type 1 (1%)- Autosomal recessive- Complete absence of vWF and factor VIII Acquired: Multiple myeloma and monoclonal gammopathy, lymphoma Diagnosis:- Prolonged bleeding time and sometimes prolonged activated partial thromboplastin time (aPTT)  - ↓ Factor VIII levels  - Quantitative assessment by vWF antigen assay: ↓ factor levels- Qualitative assessment by a collagen or glycoprotein Ib binding assay, or a ristocetin cofactor activity assay→ Ristocetin normally activates vWF to bind to glycoprotein Ib→ Failure of aggregation with a ristocetin assay or a ristocetin cofactor level < 30 IU/dL is considered definitive for vWD Therapy: only if symptoms occur- Recombinant von Willebrand factor (rVWF) concentrate  - Desmopressin: Stimulates vWF release from endothelial cells.  - Other treatment options: factor VIII concentrates; oral contraceptives in cases with menorrhagia; antifibrinolytic drugs (i.e., aminocaproic acid, tranexamic acid)  - Avoid aspirin, NSAIDS, and intramuscular injections
• Warfarin Inhibit hepatic vitamin K epoxide reductase→ ↓ hepatic synthesis (recycling) of the active, reduced form of vitamin K → ↓ γ-carboxylation of glutamate residues on coagulation factors II, VII, IX, and X Advantages:- Well-known effects and side effects- Low costs- In cases of life-threatening bleeding: direct reversal by replacement → First line: prothrombin complex concentrate→ Second line: FFPor indirect/delayed reversal by increasing production of coagulation factors (e.g., vitamin K) Disadvantages:- Difficult to manage  - Regular monitoring of the PT/INR required  - Requires bridging before surgery - Broad range of interactions- Not suited for acute therapy of pulmonary embolism or deep vein thrombosis
• Management of supratherapeutic INR INR < 5: Hold warfarin for 1 or 2 days or decrease dose INR 5-9: Hold warfarin & resume when INR is therapeutic; administer low-dose (1-2.5 mg) oral vitamin K if there is increased risk of bleeding > 9: Hold warfarin & administer high-dose (2.5-5 mg) oral vitamin K Any INR with serious bleeding: Hold warfarin & administer intravenous vitamin K 10 mg, FFP, recombinant factor VIIa, or prothrombin complex concentrate
• Acute chest syndrome Diagnostic criteria: New pulmonary infiltrate on chest x-ray PLUS ≥1 of the following:- Increased work of breathing, cough, tachypnea, wheezing- Temperature > 38.5 °C - Hypoxemia- Chest pain Initial treament:- Ceftriaxone PLUS azithromycin- Intravenous fluids- Pain control
• Bleeding in CKD Secondary to platelet dysfunction (Abnormal platelet adhesion and aggregation) Diagnostics:- Coagulation testing: ↔︎ PT, PTT, platelet count, ↑ bleeding time caused by uremic coagulopathy Treatment:- Desmopressin (DDAVP): first-line therapy- Cryoprecipitate: life-threatening bleeding resistant to treatment with desmopressin- Conjugated estrogens: for chronic control of bleeding  - Correction of anemia  - Dialysis
• Lead Sources of exposure- Battery manufacturing, metallurgy, corrosion inhibition- Gun range- Tableware containing lead- Drinking water (from lead plumbing or contaminated sources)- Antique or imported toys painted with lead-containing paint Action: heme synthesis disruption via inhibition of aminolevulinate dehydratase (catalyzes the conversion of aminolevulinic acid to porphobilinogen) Clinical features:- Nervous system:→ Polyneuropathy, encephalopathy, headache, fatigue, muscle weakness, paresthesias, delirium, seizures→ Paralysis of the radial or peroneal nerve (wrist/foot drop)→ Cognitive impairment, memory loss→ Acute encephalopathy: persistent vomiting, ataxia, seizures, coma- Kidneys: Nephropathy, renal cell carcinoma- Red blood cells: Symptoms of anemia- Purple-bluish line on the gums (lead line or Burton line)  - Severe abdominal pain (lead colic)- Constipation- Hypertension- Miscarriages, infertility- Children are especially susceptible to the neurologic effects of lead poisoning→ Many children are asymptomatic and should be assessed for blood lead levels if they have risk factors Diagnosis:- Blood lead level (BLL) measurement  → Basophilic stippling of erythrocytes on peripheral blood smear  → Microcytic, hypochromic anemia  - Imaging (not routinely indicated): lead flecks on abdominal x-ray, lead lineson long-bone x-rays  - Inspection of the patient's environment for lead sources to prevent further exposure Screening in high-risk pediatric populations:- Living in older housing under renovation or with peeling paint- Sibling or playmate with lead poisoning- Recent immigrant, refugee, or foreign adoptee- History of pica Treatment:- Decrease exposure: professional lead paint abatement, dust reduction, minimization of contact with bare soil- Nutrition: Calcium, iron, zinc, and vitamins C and D-rich diet  - Chelation therapy indications:  → Oral succimer with/without intravenous or intramuscular CaNa2EDTA (Calcium disodium ethylenediamine tetraacetic acid)a) Children with BLL ≥ 45 μg/dlb) Asymptomatic adults with BLL ≥ 80 μg/dlc) Symptomatic adults with BLL ≥ 50 μg/dl→ IM dimercaprol (British antilewisite, BAL) with/without CaNa2EDTAa) Patients with lead encephalopathyb) BLL ≥ 70 μg/dl
• Ginkgo biloba An herbal supplement commonly used to treat several conditions. Many patients use as a "memory booster" because of its suggested propensity for increasing cerebral blood flow.  Some studies have suggested that ginkgo is at least somewhat effective in the treatment of intermittent claudication and Alzheimer disease. Ginkgo has been associated with a number of side effects, including seizures, headaches, irritability, restlessness, diarrhea, nausea, and vomiting.  It is most notorious for increasing the risk of bleeding and its potentiation of the effects of anticoagulant therapy through various mechanisms, including the inhibition of platelet-activating factor. 
• Cyanides Examples: CN-, HCN, KCN   Brief description: chemical compound containing a cyano group (gas, liquid, or solid)   Exposure:- Fires: Cyanide is released by various substances during combustion (e.g., plastics, upholstery, rubber). - Long-term or high-dose treatment with sodium nitroprusside, especially in individuals with chronic renal failure  - Industrial: metal industry, manufacture of nitrogen-containing materials and products (plastics and wool), electroplating Pathophysiology: - Absorbed through the skin, respiratory system, and gastrointestinal tract- Cyanide blocks the electron transport chain by binding to cytochrome complex IV → ↓ oxidative phosphorylation → anaerobic metabolism, ↑ lactic acid Clinical features:- Onset of symptoms: 15-60 minutes after oral ingestion/few seconds after inhalation- Breath smells of bitter almonds  - Neurologic symptoms: confusion, agitation, vertigo, headache, seizures, coma- Gastrointestinal: nausea, vomiting, discomfort- Cardiac symptoms: chest pain, cardiac arrhythmia- Pulmonary symptoms: dyspnea, tachypnea, pulmonary edema, respiratory failure- Bright red bleeding of mucous membranes- Flushing of the skin- Necroses in mouth and esophagus- Bright red retinal veins on fundoscopic examination- Postmortem, bright red livor mortis (cherry red skin) can be seen- Blood tests: high anion gap metabolic acidosis,↑ lactic acid Management:- Patient decontamination (e.g., remove clothes, wash skin)- Administration of 100% oxygen regardless of saturation readings- Supportive care- Antidote  → Hydroxycobalamin (precursor of vitamin B12): binds cyanide directly and forms cyanocobalamin, which is excreted in urine (first-line antidote)→ Sodium nitrite, amyl nitrite, or 4-dimethylaminophenol (4-DMAP) to induce methemoglobinemia: Methemoglobin binds to cyanide to form cyanomethemoglobin, which diverts cyanide from cytochrome complex IV and increases oxidative phosphorylation. → Sodium thiosulfate: supplies sulfur donors to the mitochondrial enzyme rhodanese. Rhodanese detoxifies cyanide into thiocyanate, which is excreted in urine (usually coadministered with hydroxocobalamin). Induction of methemoglobinemia (e.g., with amyl nitrite or sodium nitrite) is contraindicated in patients with inhalation injury unless concomitant carbon monoxide toxicity has been excluded because of the risk of worsening tissue hypoxia. Consider cyanide poisoning in a patient with chronic renal failure who has very recently undergone treatment for a hypertensive emergency and is now presenting with altered mental status and lactic acidosis.
• Saw palmetto A popular herbal preparation most often used by men to treat benign prostatic hyperplasia.  Its use has not been shown to significantly improve urinary symptoms or flow measures.   Side effects:- Mild stomach discomfort- Increased bleeding risk
• Kava kava An herbal preparation that may help with symptoms of anxiety and insomnia; however, its use is not recommended due to the potential risk of severe liver toxicity.
• Ginseng Uses: Improved mental performance Side effects: Increased bleeding risk
• Black cohosh Uses: Postmenopausal symptoms (hot flashes & vaginal dryness) Side effects: Hepatic injury
• St John's wort Uses:- Depression- Insomnia Drug interactions: - Antidepressants (serotonin syndrome), OCs, anticoagulants (↓ INR), digoxin- Hypertensive crisis
• Licorice Uses:- Stomach ulcers- Bronchitis/viral infections Side effects:- Hypertension- Hypokalemia
• Echinacea Uses: Treatment & prevention of cold & flu Side effects: Anaphylaxis (more likely in asthmatics)
• Ephedra Uses:- Treatment of cold & flu- Weight loss & improved athletic performance Side effectts:- Hypertension- Arrhythmia/MI/sudden death- Stroke- Seizure
• Salicylate toxicity Clinical features- Early symptoms: tinnitus, nausea, vomiting, tachypnea, hyperpnea- Late symptoms: hyperthermia, agitation, delirium, seizures, noncardiogenic pulmonary edema  Diagnostics:- ABG: mixed respiratory alkalosis and increased anion gap metabolic acidosis  - Serum salicylate level: > 40 mg/dL  - BMP: hypokalemia, ↑ BUN, ↑ creatinine  - Toxicology screen: evaluate for concurrent ingestionsBecause salicylate levels are not always elevated initially and do not necessarily correlate with clinical presentation, a high index of suspicion should be maintained when caring for a patient with symptoms of salicylate toxicity. Rapid treatment is essential! Treatment:- Stabilization of vitals: With an emphasis on adequate oxygenation, IV fluids, IV glucose, and correction of hypokalemia. Salicylates impair glucose utilization and cause symptoms of hypoglycemia even in the presence of normal glucose levels. Tepid sponging should be done in patients with hyperthermia.- Oral/orogastric activated charcoal (Contraindicated in patients with altered consciousness who do not have a protected airway)- IV sodium bicarbonate: To alkalinize the urine and serum- Hemodialysis
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• Iron deficiency anemia in young children Risk factors:- Prematurity- Lead exposure- Age <1→ Delayed introduction of solids (ie, exclusive breastfeeding after 6 months)→ Cow's, soy, or goat's milk- Age >1→ > 24 oz/day cow's milk→ < 3 servings/day iron-rich foods Diagnosis:- Screening hemoglobin at age 1- Hemoglobin < 11 g/dL, ↓ MCV, ↑ RDW Treatment:- Empiric trial of iron supplementation
• Treatment of asymptomatic lead toxicity Mild: 5-44 μg/dL- No medication Moderate: 45-69 μg/dL- Meso-2,3-dimercaptosuccinic acid (DMSA, succimer) Severe: ≥70 μg/dL- Dimercaprol (British Anti-Lewisite)plus- Calcium disodium edetate (EDTA)

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