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00 Hematology - Lange Outline Review USMLE Step 2

00 Hematology - Lange Outline Review Usmle Step 2

by susucapp9, Jun. 2011

Subjects: hematology

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ANEMIA Microcytic (MCV < 80) differential diagnosis	• Iron deficiency • Thalassemia • Anemia of chronic disease • Sideroblastic anemia
ANEMIA Normocytic (MCV 80–100)differential diagnosis	• Anemia of chronic desease • Uremia • Endocrinopathy (i.e., hypothyroid) • Bone marrow failure (i.e., aplastic anemia)
ANEMIA Macrocytic (MCV > 100)differential diagnosis	• Vitamin B12 deficiency • Folate deficiency • Myelodysplastic syndrome • Drug induced • Hepatic dysfunction • Reticulocytosis
Symptoms Acute presents with signs of hypoxia and hypovolemia: weakness, hypotension, tachycardia. Significant hypovolemia (blood loss > 1,000 cc) is manifest by postural signs. Chronic presents with fatigue, dyspnea, pallor, but often can be asymptomatic.	Blood Loss (Acute and Chronic) Description Chronic is usually gastrointestinal (GI) or uterine. Diagnosis If acute, no significant drop in hematocrit initially. Increased blood urea nitrogen (BUN) if GI bleeding. Hemoccult can detect 5 mL bleeding in 24 hours. Do three to six specimens. Remember false positives (e.g., broccoli, turnips, rare meat).	Treatment Steps 1. Correct hypovolemia. Packed red blood cells and intravenous fluids (normal saline, lactated Ringer’s). 2. Look for source of bleeding. 3. Remember to check coagulation tests and order tests before transfusing Testing for anemia should include: • Iron studies (iron, TIBC, % saturation, and ferritin) • Folate • B12 • Thyroid-stimulating hormone • LDH, billirubin, and haptoglobin (helps diagnose hemolysis) • Reticulocyte count • PT/INR/PTT
Symptoms Fatigue, palpitations, dizziness, dyspnea, headache. Angular stomatitis; glossitis. Thinning and flattening of nails, spoon-shaped nails (koilonychia) in advanced disease. Pica. Diagnosis Anisocytosis (increased RDW), decreased MCV, mean corpuscular hemoglobin (MCH), MCH concentration (MCHC). Central red cell pallor. Thrombocytosis. Low serum ferritin (< 12 μg/dL). Decreased serum iron (< 60); increased total iron-binding capacity (TIBC) (> 360). Marrow not usually needed, but iron stores absent or severely reduced.	Iron Deficiency Anemia (IDA) Description The most common anemia; almost always due to blood loss. Men and postmenopausal women must be evaluated for GI bleeding. Premenopausal females: Etiology can include normal menses, menorrhagia, and uterine fibroids. Other causes include pregnancy; diagnostic venipunctures; soft tissue bleeding after hip fracture/surger	Treatment Steps 1. Find the source of iron loss and correct. 2. Supplement with oral iron daily for 6–12 months. 3. Parenteral iron for special circumstances (e.g., patient unable to tolerate oral iron). 4. Check reticulocyte count in 5–10 days (to assess response).
Symptoms Of anemia; neurologic changes in cobalamin and folate deficiency. Diagnosis Macro-ovalocytic anemia, leukopenia, thrombocytopenia; increased bilirubin, iron, and iron saturation; decreased haptoglobin and uric acid. Increased RDW and MCV. Hypersegmented polys. Increased lactate dehydrogenase (LDH).	Description A macrocytic nutritional anemia (with pancytopenia) due to impaired deoxyribonucleic acid (DNA) synthesis. Etiology usually cobalamin (vitamin B12) or folate deficiency, drugs. Pathology Impaired DNA, but normal ribonucleic acid (RNA) synthesis leads to ineffective erythropoiesis and nonimmune hemolysis.	Marrow biopsy needed to rule out myelodysplastic syndrome, hematologic malignancy. Nuclear–cytoplasmic asynchrony (mature cytoplasm, immature nucleus). Marrow very cellular; increased mitotic figures; decreased M:E ratio (1:1); megaloblastic changes in erythrocytic and granulocytic series
Symptoms Of anemia. Neurologic symptoms: Neurologic symptoms can precede anemia: • Symmetric paresthesias in feet and fingers • Disturbed proprioception and vibratory sense • Irritability • Somnolence • Abnormal taste or smell • Central scotomas (vision)	Cobalamin (B12) Deficiency Description Usually pernicious anemia, rarely dietary deficiency, gastrectomy, pancreatic disease, blind loop syndrome. Takes several years to develop.	Diagnosis Decreased serum cobalamin. Responds within hours to cobalamin therapy. Folate usually increased. (Increased serum and urine methylmalonic acid and homocysteine, but not routinely measured.)
Diagnosis Presence of antiparietal cell antibodies in serum. Achlorhydria after histamine stimulation. Decreased cobalamin absorption (Schilling test = decreased urinary excretion of [657Co]cyanocobalamin in 24 hours, corrected by oral IF).	Pernicious Anemia Description A gastric atrophy condition, autoimmune, leading to decreased intrinsic factor (IF) and cobalamin deficiency. Typically in older, fairskinned, northern Europeans. Blocking and binding anti-IF antibodies.	Treatment Steps 1. Cobalamin to replete the normal stores and to provide daily need for life. 1,000 micrograms IM daily for 1 week; two times per week for 4 more weeks; then monthly for life. 2. Must also give iron if deficient. Folate given alone may worsen neurologic picture
Decreased serum folate; response to therapy; history of precipitating factors.	Folate Deficiency Description Usually a dietary deficiency of folic acid. Folic acid is found in green vegetables, liver, kidney, yeast, mushrooms. Takes 4 months to become deficient. Causes include • Inadequate diet—as in chronic alcohol use • Malabsorption (sprue) • Phenytoin • Oral contraceptives • Pregnancy • Chronic hemolytic anemias • Altered folate metabolism—alcohol, methotrexate, 5-FU	Treatment Steps Folic acid, 1 mg PO daily (4–5 weeks to replace stores). Patients with chronic hemolysis may require more.
Symptoms Of anemia, jaundice, pallor, splenomegaly	Hemolytic Anemias: General Description Premature destruction of red cells due to defective red cells, or toxic factors. Can be intravascular or extravascular (more common)— cells sequestered by liver or spleen and destroyed.	Diagnosis Reticulocytosis, polychromatophilia, marrow hyperplasia; increased indirect bilirubin, LDH, free hemoglobin, urine hemosiderin and hemoglobin
Diagnosis Variable anemia, increased MCV, occasionally decreased WBCs and platelets. Spherocytosis, rouleaux formation, anisocytosis, reticulocytosis. Positive direct Coombs’.	Autoimmune Hemolytic Anemia (AIHA) Due to IgG Warm Antibodies Description Anemia that may be secondary to underlying neoplastic or collagen vascular disease. Symptoms of anemia and underlying disorder.	Treatment Steps 1. Treat the underlying disorder. 2. If hemolysis mild, no treatment. If severe, glucocorticoids. 75% obtain control with steroids. 3. IV gamma globulin. 4. Immunosuppressive drugs. 5. Splenectomy. 6. Transfusion anytime if necessary to stabilize hemodynamics.
Symptoms Mild if from infection, worse if idiopathic or from lymphoma. Hemoglobinuria with severe chilling. Diagnosis Jaundice. Anticoagulated blood clumps. Warming to 37°C corrects. Positive cold agglutinin titer and direct Coombs’.	Cold-Agglutinin Disease Description IgM cold agglutinins are increased by infection (mycoplasma, Epstein– Barr, trypanasomiasis, malaria), but only rarely cause hemolysis. Lymphomas (especially B-cell lymphoma). Idiopathic in some elderly	Treatment Steps 1. Treat underlying disorder. 2. Avoid cold. 3. Transfuse if necessary with blood warmer. 4. Plasma exchange in critical situations. 5. Steroids/splenectomy no value.
Symptoms Pallor, jaundice. Veno-occlusive events. Abdominal/back pain. Diagnosis Chronic hemolysis, hemoglobinuria after periods of sleep, variable pancytopenia. Increased LDH and decreased to absent haptoglobin. Hemosiderinuria. Ham’s test (more specific), sucrose hemolysis test. Decreased to absent iron stores.	Paroxysmal Nocturnal Hemoglobinuria (PNH) Description Rare acquired disorder of an intrinsic membrane protein which acts as an anchor for other membrane proteins, thereby predisposing to complement-mediated membrane damage. May develop aplastic anemia or acute leukemia. Most die within 10 years, usually from thrombotic events, some with aplastic anemia or acute myelogenous leukemia.	Treatment Steps 1. Correct anemia with glucocorticoids, folate, iron, and transfusion. 2. Treat and prevent thrombosis. 3. Bone marrow transplantation
Symptoms Acute intravascular hemolysis with jaundice 1–3 days after exposure. Abdominal and back pain. Symptoms of anemia. Occasional renal failure. Diagnosis Hemoglobinemia, hemoglobinuria, jaundice, Heinz bodies, increased RBC methemoglobin. Can assay enzyme levels.	Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Description Enzyme deficiency leading to hemolysis. The G6PD deficiency decreases production of glutathione. Precipitating causes of acute hemolysis; infection of fava beans or certain medications can precipitate hemolysis Pathology Oxidation of hemoglobin produces methemoglobin, with characteristic Heinz bodies (denatured hemoglobin), which lead to red cell fragility and splenic “bites.” DRUGS THAT CAUSE HEMOLYSIS IN G6PD DEFICIENCY Antimalarials: • Primaquine • Pamaquine • Dapsone Sulfonamides: • Sulfamethoxazole Nitrofurantion Analgesics: • Acetanilid Miscellaneous: • Vitamin K • Doxorubicin • Methylene blue • Furazolidone • Niridazole • Phenazopyridine	Treatment Steps 1. Avoid offending agents. 2. Support with pRBC transfusion.
Symptoms Symptoms vary depending on particular hemoglobinopathy, ranging from mild anemia to chronic cyanosis, constant fatigue, and intrauterine death. Diagnosis • With high oxygen affinity hemoglobins—cyanosis with normal PO2. • With methemoglobin level > 30%—chocolate brown serum.	Hemoglobinopathies Pathology Usually inherited; rarely acquired (toxin, neoplasms). Classification1: a. Structural hemoglobinopathies—mutated amino acid sequences, as in (1) Abnormal polymerization—(hemoglobin S) see section H.3. (2) Reduced solubility—(unstable hemoglobin). (3) Altered oxygen affinity—two types: (a) Increased oxygen affinity (e.g., Hb Zurich). (b) Decreased oxygen affinity (e.g., Hb Kansee). (4) M hemoglobins—(methemoglobinemia). b. Thalassemias—see sections H.2–2 and 2–3. c. Hereditary persistence of hemoglobin F. d. Acquired hemoglobinopathies—methemoglobinemia. Description Oxidation of hemoglobin from ferrous (Fe++) to ferric (Fe+++) state, which doesn’t transport oxygen. May be due to: a. Globin mutation leading to methemoglobin formation (M hemoglobin). b. Methemoglobin reductase deficiency (very rare). c. “Toxic” oxidation to methemoglobinemia by foreign substances (acetanilid, phenacetin, nitrites, aniline, and many others).	Treatment Steps 1. M hemoglobin: No treatment. 2. Reductase deficiencies: Oral methylene blue (1 mg/kg IV in emergency situations or orally if milder), or ascorbic acid.
Symptoms In those patients with severe defects or multiple gene deletions they may appear normal at birth but by 6 to 9 months have severe anemia, failure to thrive, hepatosplenomegaly, and bone changes secondary to expanding marrow. Mild to moderate defects are generally asymptomatic, manifesting only as a mild to moderate microcytic anemia.	Thalassemia Hypochromic, microcytic hemolytic anemia due to defective globin synthesis, leading to unbalanced production of α or β chains. Thalassemia trait believed to be protective against malaria Description Defective β-globin synthesis can be severe—thalassemia major, moderate— thalassemia intermedia, or very mild—thalassemia trait. Defective α-globin synthesis also has variations depending on the number of genes deleted (mild—1 or 2, moderate—3, not compatible with life ex utero—4) Diagnosis In severe disease, thalassemia major, the hemoglobin is 3–6 g. There is severe microcytosis, hypochromia, and cell fragmentation (see Fig. 5–7). Thalassemia trait is usually found in both parents. In the patient, if β-thalassemia, there is low or absent Hb A, large amount of Hb F, and increased Hb A2 of 4–10%. Fetal DNA analysis from chorionic villus biopsy (early pregnancy), or amniotic fluid (later pregnancy) allows option of therapeutic abortion. Pathology Ineffective erythropoiesis leads to severe anemia, hypercellular marrow, osteoporosis, compression fractures.	Treatment Steps 1. Transfusion to keep Hb > 9 g/dL. 2. Iron chelation to prevent iron overload—start early. 3. Administer Pneumovax, penicillin prophylaxis, and folate supplementation. 4. Splenectomy—delay until 5–6 years old if necessary because of high transfusion needs. 5. In thalassemia intermedia or with mild α-thalassemia, treatment is not always needed unless other issues arise, such as iron deficiency, pregnancy, or other sources of blood loss. Some patients with thalassemia intermedia do require transfusion if their anemia is more significant, and can develop hemochromatosis, Organ damage from iron overload generally occurs later but should be monitored as this is a preventable complication
Symptoms Hb 6.5–10 g. Retics 10–25%. Mild jaundice. Increased indirect bilirubin. Vaso-occlusive crisis (pain in back, chest, extremities) precipitated by infection, dehydration, acidosis, hypoxia. Can see cerebrovascular accident (CVA), seizures, pulmonary infarction, priapism. Occasional hypoplastic or aplastic crisis, especially with infection (parvovirusB19). Megaloblastic crisis due to folate deficiency. Aseptic necrosis of hip.	Sickle Cell Anemia Description Hemolytic anemia with red cells assuming characteristic sickle cell shapes (drepanocytes) due to abnormal β globin subunit of adult hemoglobin β chain of Hb S (α2βs 2) (see Fig. 5–8). Associated with other abnormal hemoglobins. People of African descent, but also in those around the Mediterranean, Saudi Arabians, Indians. May be malaria protective. In the United States, trait in 8–10% of blacks. Pathology Aggregation or polymerization of hemoglobin S molecules, leading to gel state when in the deoxy conformation (reversible, to a point), chronic hemolysis, tissue damage, and acute painful vaso-occlusive crises. Sickle cell trait. Asymptomatic. Not anemic. If anemia present, search for other causes. Sickle cell anemia. Chronic compensated hemolytic anemia. Sickle/β-thalassemia and sickle cell anemia less severe, less sickling. Fewer vaso-occlusive events. (More eye complications, aseptic necrosis of femoral head in sickle cell anemia.) Splenic sequestration crisis. Seen in children who still have an enlarged spleen. Uncontrolled hemorrhage into the spleen.	Diagnosis Screening: sickle cell prep (sodium metabisulfate) or solubility test. Hemoglobin electrophoresis for precise diagnosis (may need special electrophoresis). May be diagnosed at birth with screening hemoglobin electrophoresis. Treatment Steps Prevention. Genetic counseling. Prenatal diagnosis with fetal DNA analysis. In childhood: 1. Prophylactic Pen VK. 2. Immunizations critical—usual ones plus Haemophilus influenza and pneumoccal. 3. Consider chronic transfusions. Vaso-occlusive crisis: 1. Analgesics—oral if possible, morphine IV if necessary. Avoid Demerol. 2. Identify and treat infections. 3. Oral and IV fluids. 4. Oxygen if hypoxic. 5. Consider hydroxyurea or hypertransfusion if frequent. Aplastic crisis: 1. Early recognition by checking reticulocyte count (should be elevated in sickle cell disease). 2. Transfuse. Splenic sequestration: 1. Treat as any significant bleed. 2. Last resort—resect.
Symptoms Anemia, jaundice, splenomegaly. Hemolysis at all ages; worsened with some infections (mono) and intense physical activity. Crises: hemolytic (mild). Aplastic (severe)—frequently caused by human parvovirus. Megaloblastic (with pregnancy)—maintenance folic acid. Gallstones (bilirubin), gout, ankle ulcers.	Hereditary Spherocytosis Description Inherited hemolytic anemia with increased osmotic fragility. Autosomal dominant in 75%. Instability of the red cell membrane.	Diagnosis Reticulocytosis. Microspherocytosis. Incubated osmotic fragility test. Treatment Steps 1. Splenectomy for anemia or significant hemolysis; defer until age 6 to 7 because of sepsis potential. 2. Pneumococcal vaccine.
Diagnosis Increasing anemia. Slight reticulocytosis, schistocytes. Chronic urinary iron loss (hemosiderin) may lead to iron deficiency. Elevated LDH, depressed haptoglobin.	Other Nonimmune Hemolytic Disorders 1. Hypersplenism—excessive trapping and destroying of even normal (nonsenescent) RBCs by an enlarged spleen of any cause. Cytopenias correlate poorly with spleen size. 2. Chemicals—inorganic cations (arsenic, copper), organic substances (e.g., chloroamine from water purification with alum and chlorine), amphotericin B. Toxins from Clostridium welchii, spiders, snake venom. 3. Metabolic abnormalities—spur cell hemolytic anemia: in severe liver disease with poor prognosis. 4. Red cell parasites a. Malaria—especially Plasmodium species. A major cause of hemolysis worldwide. Splenomegaly, fevers (see Chapter 9). b. Babesiosis. Protozoans in red cells. Thrombocytopenia, disseminated intravascular coagulation (DIC). Deer tick vector. More common in northeastern United States. Coinfection with Lyme disease is possible. c. Bartonellosis. Bartonella bacilliformis. South America. Sand fly vector. Fever, chills, headache, musculoskeletal pain. Hemolysis. Responds to antibiotics. 5. Trauma to red cells (e.g., dialysis, pheresis, cardiac bypass). 6. March hemoglobinuria—seen with marching, running, other repetitive contact (karate). See hemoglobinemia and hemoglobinuria. 7. Fragmentational hemolysis—due to cardiac or large vessel abnormality. Usually left side of heart etiology; mild hemolysis from severe aortic stenosis (AS) or aortic insufficiency (AI), ruptured sinus of Valsalva, traumatic arteriovenous fistula, aortofemoral bypass surgery. More severe hemolysis from prosthetic valves (especially with aortic,	Treatment Steps Based on specific etiology.
Diagnosis Schistocytes, helmet cells. Hemolysis revealed as: increased indirect bilirubin and LDH, decreased haptoglobin, hemosiderinuria. Also, elevated reticulocyte count (see Fig. 5–9).	Microangiopathic Hemolytic Disorders Description Red cells are injured flowing through partially blocked channels. Three main types: 1. Disseminated intravascular coagulation (DIC)—Thrombocytopenia. Prolonged prothrombin time (PT), partial thromboplastin time (PTT), and thrombin time. Increased fibrin degradation products (FDP) and D-dimers. May be caused by gram-negative endotoxin-containing bacteria, amniotic fluid embolus, metastatic cancer, and HIV. 2. Vascular lesions—cavernous hemangioma, organ transplant undergoing rejection, malignant hypertension, eclampsia. 3. Thrombotic thrombocytopenic purpura (TTP) and hemolytic– uremic syndrome are characterized by hemolysis, thrombocytopenia, renal failure, fever, and neurologic changes.	Treatment Steps 1. Treat the cause. 2. Steroids, fresh frozen plasma (FFP), and plasmapheresis for TTP. 3. Transfusion of blood products. 4. Rarely, anticoagulation with heparin may help.
Symptoms Of anemia and the underlying disease. Diagnosis Decreased iron, transferrin, and transferrin saturation (but usually > 10%). Normal or increased ferritin and marrow iron stores.	Anemia Associated with Chronic Disease (ACD) Description A very common condition in patients with chronic medical conditions. A usually normocytic, normochromic anemia, but often hypochromic and occasionally microcytic, seen with chronic infection, inflammatory disease, or cancer. Pathology Impaired iron utilization, shortened RBC life span, mild hemolysis.	Treatment Steps 1. Correct underlying problem. 2. Erythropoietin injections. 3. Additional iron supplementation should not be used.
Diagnosis Hemoglobin 5–8 g. MCV normal. Burr cells.	Anemia Associated with Chronic Renal Insufficiency Description Due to decreased erythropoietin production, but worsened by poor nutrition, blood loss, hemolysis	Treatment Steps Erythropoietin injections. Iron stores need to be adequate prior to starting erythropoietin. Intravenous iron is given in certain instances.
Symptoms Bleeding (petechial, retinal), fatigue, pallor, infections.	Aplastic Anemias, Pancytopenias Description Marrow failure, which may be due to Aplastic Process—Failure of stem cells to undergo differentiation. Myelophthisic Process—Destruction of the marrow environment by invaders or inflammatory tissue. May see isolated deficiency (e.g., pure red cell aplasia [PRCA], agranulocytosis, thrombocytopenia). Pathology Peripheral pancytopenia and marrow replaced with fat. Pathogenesis: 1. Idiopathic (50%). 2. Dose-dependent, drug-related (cytotoxic drugs, phenytoin, phenothiazines, chloramphenicol, thiouracil). 3. Idiosyncratic, drug related (chloramphenicol). 4. Environmental toxins (solvents such as benzene; insecticides). 5. Infections (hepatitis, parvovirus). 6. Myelodysplastic syndromes.	Diagnosis Pancytopenia. Bone marrow biopsy. Ham test or sucrose hemolysis test (paroxysmal nocturnal hemoglobinuria); serum immunoglobulins (hypoglobulinemia); CT chest (thymoma). Must distinguish from leukemia, myelofibrosis, or myelodysplasia. Treatment Steps 1. Bone marrow transplantation. 2. Antilymphocyte globulin. 3. High-dose steroids. 4. Immunosuppressive therapy. 5. Androgens. 6. Red cell and platelet transfusions—try to minimize if patient is transplant candidate
Symptoms Erythematous maculopapular rash, edema, severe pruritus (especially around toes). Cough, pneumonia, fever if severe pulmonary involvement.	Hookworm Description Hookworm disease is an infection by Necator americanus (“New World hookworm”), Ancylostoma duodenale (“Old World hookworm”), or A. ceylonicum (Far East). Adults live in upper part of small intestine. Each adult extracts 0.2 mL blood daily (equal to 0.1 mg iron). Diagnosis Iron deficiency anemia, hypoalbuminemia. In young children, may see severe anemia; cardiac insufficiency; anasarca; retarded physical, mental, and sexual development. Hookworm eggs in fecal smear. Eosinophilia (as high as 70–80%).	Treatment Steps 1. Antihelmintic agents (mebendazole). 2. Iron replacement. 3. Transfusion. 4. Maintain good nutrition.
Symptoms Petechiae, ecchymoses, epistaxis, menorrhagia.	a. Idiopathic Thrombocytopenic Purpura (ITP) Description Autoimmune bleeding disorder with antibodies to one’s platelets. In children there is usually an acute onset; seen after viral illness; 70% recover in 4–6 weeks. In adults it can be drug related (e.g., sulfas) but usually is more chronic; onset more gradual. Diagnosis By exclusion of other disorders. Platelet antibody tests rarely helpful. Bone marrow exam usually shows increased megakaryocytes, but can be normal or have decreased megakaryocytes.	Treatment Steps 1. Observation. If count > 50,000 and asymptomatic. 2. Prednisone. 3. Intravenous gamma globulin. 4. WinRhoD. 5. Splenectomy. 6. Danazol. 7. Alkylating agents.
Diagnosis Microangiopathic hemolytic anemia; mild to moderate thrombocytopenia; prominent renal failure, severe hypertension, no neurologic signs, fever less common.	Hemolytic Uremic Syndrome (HUS) Description Thrombocytopenic and hemolytic syndrome with renal failure, usually in infants and young children. Often follows an infection (diarrhea in about 90% of cases, upper respiratory infection in 10%). Mitomycin is the drug most commonly associated with HUS. Pathology Thrombosis and necrosis of intrarenal vessels.	Treatment Steps 1. Correct hypovolemia. 2. Establish diuresis. 3. Dialysis. 4. Plasmapheresis. 5. FFP if pheresis not available. 6. Transfuse if needed.
Symptoms Epistaxis; telangiectases on face, mucous membranes, GI tract; serious GI bleeding, cerebrovascular accident.	Hereditary Hemorrhagic Telangiectasia (Rendu–Osler–Weber Disease) Description The most common genetic cause of vascular bleeding; autosomal dominant.	Treatment Steps Can treat some lesions surgically or with laser.
Diagnosis Hemangioma with thrombocytopenia, mild DIC.	Congenital: Cavernous Hemangioma (Kasabach–Merritt Syndrome)	Treatment Steps Surgery, laser, radiation, induced thrombosis; may involute spontaneously. Choice depends on size and location of lesion.
Lower extremity, perifollicular bleeding.	Scurvy Vitamin C deficiency
Symptoms Level of factor VIII correlates with bleeding frequency. Hematomas in muscle or soft tissue (retroperitoneum). Hemarthroses (elbow, knee, ankle) may lead to crippling. Bleeding after surgery (must prep with factor VIII). Diagnosis Factor VIII level < 5% and usually < 1% of normal. History of joint and soft tissue bleeding. Must distinguish from factor IX deficiency (hemophilia B), von Willebrand’s disease. Have normal PT, abnormal aPTT. Factor VIII level.	Hemophilia A (Factor VIII Deficiency) Description X-linked recessive inheritance. Of affected male: daughters will be carriers; sons will be normal. Of carrier female: 50% chance of producing a hemophiliac male or carrier daughter. Extreme lyonization can result in symptomatic heterozygous females.	Treatment Steps 1. Factor VIII—Prophylactic infusion beginning in childhood significantly decreases bleeding and increases long-term function. 2. Physical activity counseling. 3. Acquired immune deficiency syndrome (AIDS) risk: Use of recombinant factor VIII has virtually eliminated new cases of HIV, but most older factor VIII–deficient patients have the infection.
Symptoms Variable. Usually superficial bleeding, epistaxis, easy bruising. Postop bleeding a major hazard; postdental extraction common. Menorrhagia. Diagnosis Low levels of activated factor VIII (rarely < 5%, so bleeding generally mild); low level of immunoreactive vWf; long bleeding time. Abnormal platelet aggregation in response to ristocetin. Levels can be variable within the same person.	von Willebrand’s Disease Description The most common hereditary bleeding disorder, due to deficient or abnormal von Willebrand’s factor (vWf). Autosomal dominant. Types: • I—decreased synthesis of vWf. • IIa—synthesize only small multimers. • IIb—synthesize only large, abnormal multimers. • III—virtually absent vWf. • Pseudo-vWd—abnormal affinity of platelets for plasma vWf.	Treatment Steps 1. Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is effective in type 1. Useless or harmful in IIa, IIb, and pseudo-vWD. 2. Replacement with single-donor cryoprecipitate (contains factors VIII and vWf). 3. Platelets in pseudo-vWD. 4. EACA (epsilon aminocaproic acid) useful addition to dental or minor surgery.
Symptoms Similar symptoms as in hemophilia A. Diagnosis Normal PT, prolonged aPTT. Factor IX level.	Hemophilia B (Factor IX Deficiency; Christmas Disease) Description Similar to factor VIII deficiency with inheritance, with fewer symptoms, but with potential for severe bleeding.	Treatment Steps 1. Recombinant factor IX. 2. FFP.
Diagnosis Increased PT.	Vitamin K Deficiency and Coumarin Anticoagulants Normally adequate vitamin K in diet (green leafy vegetables). May be deficient in malabsorption states, bile-salt deficient states, poor dietary intake, and with use of antibiotics. Vitamin K Deficiency of Newborn—Routinely give vitamin K (1 mg IM at delivery) to avoid hemorrhagic disease of the newborn. Malabsorption Syndromes—Vitamin K deficiency seen with impaired fat absorption (adult celiac disease, regional enteritis, cholestyramine or neomycin use, biliary tract obstruction).	Treatment Steps Daily PO vitamin K. Antibiotics in Debilitated Patients—Prevent with vitamin K. Coumarin Anticoagulants—Therapeutic level of PT INR varies from 1.8 to 3 depending on the indication. More bleeding seen at INR > 2.0. Requirement can change with diet (vitamin K intake) and drugs that affect warfarin. Avoid aspirin. (Avoid coumarin in pregnancy between 6th and 12th week and after the 38th week.) Treatment Steps 1. Vitamin K PO or SQ. 2. FFP
Diagnosis Hypofibrinogenemia; acquired dysfibrinogenemia; increased fibrinolysis; DIC.	Liver Disease—Since the liver makes fibrinogen, plasminogen, vitamin K–dependent proteins, and antithrombin, bleeding is common with liver disease	Treatment Steps Normalize the PT, fibrinogen concentration, platelet count prior to high-risk procedures (give vitamin K, platelets, FFP). No treatment of DIC unless clinically significant bleeding treat the underlying disorder.
Prolonged bleeding time. Platelet function abnormal; platelet count occasionally low.	Renal Disease	Treatment Steps 1. Correct the anemia. 2. DDAVP. 3. Platelets.
Commonly seen in factor VIII deficiency (hemophilia A) or spontaneously in elderly patients.	Factor VIII Inhibitors	Treatment Steps If patient is actively bleeding: 1. Increase doses of factor VIII if titer is < 5 Bethesda units (BU). 2. Plasmapheresis followed by factor VIII if titer is 5–30 BU. 3. If titer > 30, very hard to control; try porcine factor VIII or factor XI concentrate.
Predispose to venous and arterial clotting.	Lupus-Type Inhibitors (Antiphospholipid Antibodies)
ongoing thrombosis and fibrinolysis in traumatized or inflamed tissues in chronic serious diseases. Normal PT, platelets, increased fibrinogen. No bleeding seen.	Compensated DIC	Treatment Steps May require long-term heparin or low-molecular-weight heparin (Trousseau syndrome of “migratory” arterial and/or venous thrombosis; underlying neoplasm). Coumadin often ineffective
massive release of tissue factor causing depletion of fibrinogen, other factors, leading to thrombosis and/or bleeding, low platelets and fibrinogen, increased FDP, increased PT. Seen with shock, sepsis (Waterhouse–Friderichsen syndrome in meningococcemia), cancer, burns, obstetric complications, rhabdomyolysis.	Defibrination Syndrome	Treatment Steps 1. Support with blood products as needed. 2. Treat underlying cause (i.e., evacuate the uterus). 3. Possibly heparin if poor response and thrombosis predominates.
Symptoms Diffuse bleeding. primary release of plasminogen activator. Seen in cancer of prostate, acute promyelocytic leukemia (APML), hemangiomas, snake venoms	Primary Fibrinolysis Diagnosis Decreased fibrinogen, increased FDP, increased PT.	Treatment Steps 1. In APML, treat with all-trans retinoic acid (ATRA) followed by standard chemotherapy. 2. Other causes: FFP, cryoprecipitate, and epsilon aminocaproic acid (EACA).
Description Syndrome seen in sepsis, malignancy, immune complex disease, vasculitis, malignant hypertension, eclampsia (HELLP syndrome). Diagnosis Low platelet count, fragmented RBCs, increased FDP, but PT and fibrinogen normal.	Microangiopathic Thrombocytopenia	Treatment Steps In eclampsia: deliver. In other causes: 1. Treat underlying disorder. 2. Support with blood products.
Snake Bite—Venom contains toxic proteins and enzymes that cause tissue injuries	Treatment Steps Antivenom, platelets, plasma.
Symptoms Range from asymptomatic to signs of severe infection. Signs of infec- tion may be absent because WBCs mediate the inﬂammatory re- sponse.	Neutropenia Description Usual WBC 4–10 109/L (varies with ethnicity, sex, hormonal status). Neutropenia = neutrophils < 2.0 109 (in blacks < 1.5 109), but usually no clinical problems until < 1.0 109, and especially if < 0.5 109. Causes: 1. Marrow failure—many are drug induced. 2. Marrow invasion—by cancer, infection. 3. Maturation arrest—in folate or B12 deﬁciency Diagnosis Must distinguish primary versus secondary neutropenia. Vacuoliza- tion suggests infection. Bandemia > 20% suggests good marrow. Need bone marrow exam (aspiration and biopsy).	Treatment Steps 1. Determine the cause. 2. Antibiotics 3. Glucocorticoids. 4. GM-CSF: colony-stimulating factor, granulocyte, bone marrow transplant.
Symptoms Of the underlying condition.	Lymphocytopenia Description Causes: 1. Decreased production—protein-calorie malnutrition, radia- tion, immunosuppressive agents, congenital lymphocytopenic immunodeﬁciency states, viruses (measles, polio, varicella- zoster, HIV). 2. Increased lymphocyte destruction—from antilymphocyte anti- bodies, or in thoracic duct ﬁstula, protein-losing enteropathy, severe congestive heart failure (CHF).	Treatment Steps Treat underlying cause.
Description Neoplastic or potentially neoplastic disorders with proliferation of monoclonal plasma cells of B-cell series producing monoclonal gam- mopathies, paraproteinemias, dysproteinemias, or immunoglobu- linopathies due to secretion of monoclonal proteins. E	Diagnosis Serum protein electrophoresis (SPEP) is good for screening, but im- munoelectrophoresis is needed for conﬁrmation. Do SPEP if multi- ple myeloma, macroglobulinemia, amyloidosis is suspected, and for unexplained weakness or fatigue, anemia, back pain, renal insufﬁ- ciency, osteoporosis, osteolytic lesions, or spontaneous fracture.	Must distinguish monoclonal (usually neoplastic) from polyclonal (usually reactive or inﬂammatory) gammopathy. Do serum viscosity for high globulins or if patient has blurred vision, mucosal bleeding, or other symptoms suggesting hyperviscosity. Urine: Do urine immu- noelectrophoresis or immunoﬁxation rather than Bence Jones. Be aware that one can have negative urine protein test and elec- trophoresis, but have positive immunoelectrophoresis or im- munoﬁxation. Rarely totally nonsecreting.
Diagnosis M-protein < 3 g; < 5% plasma cells in marrow; insigniﬁcant M-pro- teinuria; no lytic lesions or anemia, no hypercalcemia or renal insuf- ﬁciency; stable M-protein and no other abnormalities. Must distin- guish from myeloma. Follow-up of evolution may be the only way to distinguish	Monoclonal Gammopathy of Undetermined Signiﬁcance (MGUS; Benign Monoclonal Gammopathy) Description M-protein in serum without evidence of systemic disease. Signiﬁ- cance: 25% go on to develop myeloma, macroglobulinemia, amyloi- dosis, or lymphoma.	Treatment Steps Follow.
Symptoms Bone pain in back, chest; vertebral collapse. Weakness, fatigue; symptoms and signs of anemia, renal failure, hypercalcemia, amyloi- dosis. If a patient has a normal albumin but an elevated total protein level, SPEP will help diagnose what type of protein is causing the elevation. Asymptomatic multiple myeloma may be found in its earliest stages if SPEP is done.	Multiple Myeloma Description A neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin Diagnosis The diagnosis of myeloma is made with these three criteria: 1. At least 10–15% of a bone marrow aspirate demonstrates plasma cells. 2. Radiographic survey demonstrating lytic lesions. 3. Monoclonal immunoglobulins in the urine or blood. The monoclonal gammopathy most commonly seen is IgG, followed by IgA, which is usually diagnosed using SPEP. Less commonly, the monoclonal band (M-protein) is not seen on SPEP and urine protein electrophoresis is indicated. Overall, 99% of patients have M-protein in serum or urine at time of diagnosis. Other labs include elevated erythrocyte sedimentation rate (ESR), hypercalcemia, elevated alka- line phosphatase, proteinuria, and renal failure. β2-Microglobulin level is associated with activity and progression of disease. Pathology Renal involvement caused by “myeloma kidney,” hypercalcemia, amy- loidosis, hyperuricemia, acquired Fanconi syndrome, or light-chain deposition. Radiculopathy in thoracic and lumbosacral areas. Myeloma variants include smoldering myeloma and plasma cell leu- kemia.	Treatment Steps 1. Can defer treating minimal disease. 2. Chemotherapy includes melphalan + prednisone, M2 protocol(melphalan, cyclophosphamide, carmustine [BCNU], vincristine,prednisone), or VAD (vincristine, adriamycin, decadron). 3. Transfusions and erythropoietin. Treat until M-protein is stable in urine and serum, and no other evidence of disease. α-Interferon is of value in maintaining remis- sion. Refractory disease: other chemotherapy combinations, bone mar- row transplant, thalidomide. Begin all stage 2 and 3 patients on prophylactic pamidronate to decrease risk of fracture; improves quality of life and survival. Special complications include: 1. Hypercalcemia—hydration, bisphosphonates, prednisone, calci- tonin, increased physical activity. . Renal failure—allopurinol, hemodialysis if symptomatic, plasma- pheresis. 3. Lytic lesions in weight-bearing bones––consider prophylactic or- thopedic procedure. 4. Pain––liberal use of analgesics. Combine narcotics with NSAIDs. Radiation to painful spots. May be helped by bisphosphonates
Symptoms Weakness, fatigue, bleeding, pallor; impaired vision, weight loss; hepatosplenomegaly; lymphadenopathy; neurologic symptoms (sen- sorimotor peripheral neuropathy); infection; CHF. Diagnosis Normocytic, normochromic anemia; γ-globulin spike (IgM type on im- munoelectrophoresis). About 75% have κ light chains. Bone marrow biopsy shows hypercellular marrow, inﬁltrated with plasmacytoid lym- phocytes.	Waldenström’s Macroglobulinemia Description Production of large monoclonal IgM protein by abnormal prolifera- tion of plasmacytoid lymphocytcs	Treatment Steps 1. Treat if anemic, if constitutional symptoms, hyperviscosity prob- lems, or signiﬁcant hepatosplenomegaly or lymphadenopathy. 2. Chemotherapy (chlorambucil [Leukeran]; M2 protocol; α2-inter- feron). 3. Transfusions and erythropoietin. 4. Plasmapheresis for hyperviscosity. 5. Bone marrow transplant
Symptoms Occur if relative viscosity is > 4 centipoises (cp). Manifest by mucosal bleeding, retinal hemorrhages, papilledema, decreased vision, dizzi- ness, headaches, coma, aggravation of CHF	Hyperviscosity Syndrome Description Syndrome of increased serum viscosity seen in Waldenström’s macroglobulinemia, and occasionally in multiple myeloma.	Treatment Steps 1. Plasmapheresis until patient asymptomatic. 2. Treat underlying disorder.
Description Due to a monoclonal protein composed of only the heavy chain. There are γ, α, and µ types.	Heavy-Chain Disease	1. γ—lymphoma-like illness. Results fair with cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. 2. α—the most common type. Common involvement of the GI tract. Poor prognosis. Some response to chemotherapy. 3. µ—seen in chronic lymphocytic leukemia or lymphoma. Bence Jones proteinuria in two thirds. Treat with steroids and alkylating agents.
Diagnosis Hypertensive, smoking, middle-aged male. Symptoms May have no symptoms; risk of increased incidence of thromboem- bolic events.	Relative Polycythemia (also called Stress Polycythemia, Gaisbock Syndrome) Description Consider relative polycythemia after ruling out dehydration, the most common cause of polycythemia. Pathology Common factors are smoking and diuretics (in hypertensives	Treatment Steps 1.Discontinue smoking. 2.May need phlebotomy. 3.Use nondiuretic antihypertensives.
Symptoms Ruddy cyanosis, headache, tinnitus, fullness in head and neck, light- headedness; increased thrombotic events; epistaxis; upper GI (UGI) bleeding	Secondary Polycythemia Two types: Physiologically appropriate response to tissue hypoxia. In- creased erythropoietin. Seen in: 1.High altitude. Diagnosis: increase anterioposterior diameter of chest, ruddy cyanosis, engorged capillaries of skin, mucous mem- branes. 2.Cardiopulmonary disease. Right-to-left shunts, chronic obstruc- tive pulmonary disease (COPD). 3.Alveolar hypoventilation (e.g., pickwickian syndrome). 4.Abnormalities of oxygen-hemoglobin dissociation curve. High oxy- gen–afﬁnity hemoglobinopathies; hereditary methemoglobine- mias; carbon monoxide exposure (smoking, industrial exposure). Physiologically inappropriate. 1.Neoplasms and non-neoplastic renal disease. Neoplastic includes renal and adrenal cancer, cerebellar hemangioblastoma, hepato- cellular carcinoma; non-neoplastic includes renal cysts and hy- dronephrosis. Increased erythropoietin production. 2.Drug-induced. Testosterone, adrenal corticosteroids	Diagnosis Serum erythropoietin. O2 level to evaluate hypoxia. Computed to- mography (CT) of abdomen and chest x-ray. Bone marrow biopsy with chromosomal analysis. Treatment Steps 1.In “inappropriate” group, phlebotomize to hematocrit < 50%. 2.In “appropriate” group, phlebotomy may do more harm, so aim for hematocrit < 60%.
Symptoms Headache, tinnitus, lightheadedness, vertigo, blurred vision. Throm- botic and hemorrhagic episodes (epistaxis, easy bruising, UGI bleed- ing). Increased incidence of peptic ulcer disease and pruritus. Se- vere pain in the feet and hands (erythromyalgia).	3–2.Polycythemia Rubra Vera Description Malignant proliferative disorder of erythroid, myeloid, and megakaryocytic elements of marrow leading to increased red cell mass and often to increased granulocytes and platelets in blood. Re- lated to myeloproliferative disorders. If treated, median survival in- creased from 1 to 10 years. Thrombosis the major cause of death closely followed by infection. Diagnosis Splenomegaly in 75%. Hepatomegaly in 40%. Increased hemoglobin, hematocrit, red cell count. Low mean corpuscular volume (MCV). Low serum iron. Hematocrit is best guide to red cell mass (> 60% is very suggestive). Increased red cell mass (> 36 in men; > 32 in women). In- creased WBCs, platelets, trending to higher levels and more immature forms later in disease. Increased numbers of basophils and eosinophils. Increased leukocyte alkaline phosphatase, B12, and lysozyme levels. Normal O2 saturation (> 92%). Low or absent erythropoietin. Pathology Hypochromic, microcytic cells. Leukocytosis to leukemoid picture. Often marked thrombocytosis (> 400,000). Marrow hyperplastic, panmyelosis, megakaryocytic hyperplasia. Absent iron stores.	Treatment Steps 1.Phlebotomy to Hct < 45%. 2.Myelosuppression with hydroxyurea if < 70 years old, p32 if > 70 or with signiﬁcant medical problems.
Eosinophilic Syndromes differential	1. Parasitic diseases—especially multicellular helminthic parasites. Diagnosis: often three or more stool specimens needed to diag- nose. 2. Other infections—allergic bronchopulmonary aspergillosis, coc- cidioidomycosis. Eosinophils depressed by bacterial and viral in- fections. 3. Allergic diseases—allergic rhinitis, asthma, hypersensitivity drug reaction, drug-induced interstitial nephritis. 4. Myeloproliferative disease—idiopathic hypereosinophilia syn- drome. Treatment: steroids; chemotherapy. 5. Neoplastic diseases—eosinophilic leukemia; chronic myelocytic leukemia; occasionally in Hodgkin’s disease; some carcinomas. HEMATOLOGY Neoplastic Disorders 1426. Cutaneous diseases—scabies, bullous pemphigoid, episodic an- gioedema with eosinophilia. 7. Pulmonary eosinophilias—see Pulmonary section. 8. Gastrointestinal disease—eosinophilic gastroenteritis; inﬂamma- tory bowel disease. 9. Immunologic disease—hypersensitivity vasculitis; allergic granu- lomatous angiitis (Churg–Strauss syndrome); some immu- nodeﬁciency syndromes (Wiskott–Aldrich syndrome, graft-ver- sus-host disease). 10. Other—Dressler syndrome; chronic peritoneal dialysis; eosinophilia–myalgia syndrome secondary to contaminated L- tryptophan; Addison’s disease; hypopituitarism.
Symptoms Fever, chest pain, wheezing, back pain, hypotension, DIC, bleeding diathesis, renal impairment.	Acute Hemolytic Transfusion Reaction Description Reaction occurs within minutes or hours of exposure. Intravascular destruction caused by complement activation. Extravascular destruc- tion caused by antibodies without complement activation. Rare.	Treatment Steps 1. Discontinue transfusion. 2. Correct hypotension. 3. Control bleeding. 4. Prevent acute renal failure (use IV ﬂuids, mannitol, diuretics to maintain output at 100 cc/hr). 5.Follow blood bank protocol for returning unit and checking urine and serum
Symptoms Transient ﬂushing, palpitations, tachycardia, cough, chest discom- fort, neutropenia. Latent period of 15–60 minutes; then increased blood pressure, headache, chills, rigors	Febrile Nonhemolytic Transfusion Reaction Description Reaction occurs within minutes or hours of exposure. In 0.5% of transfusions, relatively common. Less common since most units of pRBCs are now ﬁltered Pathology Cytotoxic or agglutinating antibodies from prior transfusion, react- ing to transfused WBCs	Treatment Steps 1. Discontinue transfusion and test for hemolysis. 2.Antipyretics. 3.WBC ﬁlter if not already done.
Symptoms Fever, chest pain, dyspnea, cyanosis, cough, blood-tinged sputum, hypoxemia. Resembles CHF, but noncardiogenic.	Acute Lung Injury Pathology Anti–human lymphocyte antigen (HLA) antibody.	Treatment Steps 1. Respiratory support, mechanical ventilation. 2. Fluid replacement.
Urticaria and pruritus in approximately 1%. Is reaction of donor protein and patient immunoglobulin E (IgE). Is usually mild. Ana- phylaxis very rare	Allergic Reactions
Reaction occurs days after exposure History of prior transfusion or pregnancy. Positive direct Coombs’.	Delayed Hemolytic Transfusion Reaction Antibodies occur as anamnestic response.
Symptoms Fever, erythema, diarrhea, liver function test (LFT) abnormalities, pancytopenia. Mortality 84%.	Graft-versus-Host Disease Description Reaction seen in immunocompromised patient or in patients get- ting treatment for lymphoma or leukemia, 4–30 days after transfusion Pathology T-lymphocyte mediated.	Prevention Pretransfusion irradiation of blood or components in high-risk pa- tients.
Thrombocytopenia 5–9 days after transfusion,	Post-transfusion Purpura Description/Pathology caused by alloanti- bodies to platelet antigens	Treatment Steps 1. Steroids. 2. IV gamma globulin. 3. Plasma/blood exchange.
Symptoms Hepatomegaly, splenomegaly, skin pigmentation, weakness, lethargy, chronic abdominal pain, arthralgia, loss of libido, impotence. Atrial tachyarrhythmias, dilated cardiomyopathy, and congestive heart fail- ure. Insulin-dependent diabetes mellitus. Cancer of liver occurs late	HEMOCHROMATOSIS (IRON-STORAGE DISEASE) Description Primary (“idiopathic”) hemochromatosis is a common autosomal re- cessive genetic disease in Europeans. Secondary hemochromatosis is seen in anemias with ineffective erythropoiesis, increased iron ab- sorption, and multiple transfusions Pathology The excess iron stored as hemosiderin is damaging to the parenchy- mal tissue, and leads to ﬁbrosis and cirrhosis (in liver) of the organ. Slate-gray skin. Testicular atrophy.	Diagnosis Requires presence of these symptoms and signs, family history, index of suspicion, and demonstration of iron overload (saturated iron- binding capacity [60–100%], and high plasma ferritin level [> 300 µg/L in male, and > 200 in female]). Liver biopsy is diagnostic. The gene has been identiﬁed. Treatment Steps 1.Early detection so phlebotomies started before organ damage oc- curs. 2.Treat with weekly phlebotomy as needed to restore iron to nor- mal in full-blown disease; then at 2- to 3-month intervals. Treat- ment increases 5-year survival from 18–92%. 3.In secondary hemochromatosis, treat with deferoxamine.