RBC Disorders - Anemia Lecture Flashcards
Aplastic Anemia
Characterized by loss of hematopoietic cells, fatty replacement of marrow, and pancytopenia
May be congenital (Fanconi’s anemia) with or without visceral/bony malformations
Secondary causes of aplastic anemia
Infection—viral hepatitis, EBV, Erythrovirus (parvovirus), HIV
Radiation—therapeutic, diagnostic
Drugs—chloramphenicol, quinacrine…risk is 1:30,000
Primary causes of aplastic anemia
Chemicals - Toluene, glue - occupational or abuse
Immunologic - autoimmune mediated, paroxysmal nocturnal hemoglobinuria (PNH)
Chronic Kidney dz in erythroid progenitor proliferation defects
Degree of anemia roughly proportional to degree of renal insufficiency
Due to several factors:
- Shortened RBC survival time
- Decreased EPO levels resulting in decreased RBC production
- Decreased RBC production independent of EPO
Clinical manifestations:
Normochromic normocytic anemia
Acanthocytes on peripheral smear
Evidence of renal failure
Causes of megaloblastic anemias
95% due to deficiency of either vitamin B12 or folic acid
Rest: drugs (sulfonamides, chemotherapeutic agents, anticonvulsants, contraceptives) or toxins (arsenic)
Megaloblastic anemia with neurologic symptoms
B12 deficiency—posterior column degeneration, combined degeneration of dorsal/lateral columns (subacute combined system disease)
Megaloblastic madness—severe B12 deficiency resulting in psychosis with macrocytic anemia
Folic acid deficiency
Body stores minimal, must have continuous supply in diet
May be due to decreased dietary intake for body demands (pregnancy, hemolytic anemias) or impaired absorption (sprue, enteritis, Whipple’s disease, diabetes)
Lab: decreased serum folate and RBC folate
Tx: supplement folate 1mg po qd
Cobalamin deficiency
impaired absorption—pernicious anemia, gastrectomy, Zollinger-Ellison syndrome, blind loop syndrome, tapeworm infestation)
- Some cases of poor intake (vegetarianism)
- Body stores significant, usually takes years to develop
Lab tests—decreased serum B12
Treatment—supplemental B12 (1000mcg IM monthly for maintenance, may need to dose more often if deficient)
Refractory megaloblastic anemia
May occur in myelodysplasia—bone marrow usually helps identify frankly dysplastic cells from more benign megaloblastic cells in classic megaloblastic anemia
Iron deficiency anemia - causes
most common anemia
Cause:
- decreased intake, increased iron loss, hemolysis, or combo
- infants - inadequate iron in milk
GI bleeding - men and postmenopausal women - PUD, angiodyplasia, inflammatory states, tumors
Pulmonary/GU losses
Hemolysis/hemoglobinuria - PNH
Post gastrectomy - insufficient acid to maintain iron in Fe2+ state
Malabsorption - intestinal resection, altered nRAMP2 gene (DCT1 aka DMT1) - facilitates Fe2+ transport across brush border
Factitious anemia
d/t auto phlebotomy
Affected patients have underlying psychiatric problems; treatment of underlying disease results in resolution of practice
Iron Deficiency anemia - clinical presentation, labs
Clinical presentation
Microcytic hypochromic anemia (may be normocytic in ~35%)
Constitutional symptoms
Lab features
Decreased serum iron and ferritin (a measure of total body iron stores)
Increased total iron binding capacity— transferrin is less saturated with iron and increased capacity for transporting iron exists
Anemia of chronic disease
Usually occurs in chronically ill, debilitated patients or patients with multiple medical problems
Etiology:
Decreased RBC survival time Decreased erythropoiesis Disturbed iron metabolism
Lab features:
Decreased serum iron and TIBC Normal or increased serum ferritin
Normocytic normochromic anemia with normal reticulocyte count
Therapy:
Iron supplementation is NOT effective in most cases Supportive care only if anemia is mild (Hb 10-12 gm)
If anemia severe, transfusions may be helpful to keep Hb > 9gm
Marrow infiltration causing anemia
May occur secondary to malignancy (leukemia, lymphoma, myeloma, breast, lung, prostate, etc.)
May occur with benign disease Myelofibrosis Gaucher's disease Histiocytosis Sarcoidosis
G6PD deficiency
Pyruvate kinase (PK) deficiency
Hereditary nonspherocytic hemolytic anemia
Clinical features:
Hemolysis with anemia
-Food/Drug induced in case of G6PD (fava beans, sulfa containing medicines)
-Some may have chronic jaundice or neuromuscular disease due to absence of enzyme
-Family history of disease (X-linked)
Lab features:
Heinz bodies—collections of denatured hemoglobin
“Bite cells”—RBCs which have had denatured hemoglobin removed in the spleen
Anemia—normochromic normocytic
Elevated reticular count
Tx:
Avoid food/drugs known to predispose to hemolysis
Splenectomy helpful for some, especially if disease aggressive
Replacement therapy?
Lab features of hemolysis
Decreased haptoglobin
Increased LDH and bilirubin
Urine hemosiderin may be elevated in some
Plasma hemoglobin may be elevated if hemolysis severe
March hemoglobinuria
Feet striking the ground repeatedly causes damage/lysis of RBCs in capillaries on plantar surface of feet
Common in marathon runners
Treat with well padded footwear and reassurance
aka sports anemia, footstrike hemolysis, others
Cardiac anemia
Patients with severe aortic stenosis (valve gradient > 50mmHg) and patients with prosthetic valves may have ongoing lysis of RBCs - shearing forces
Anemia is usually mild
Treatment usually supportive unless anemia severe, resolves when a new prosthesis is inserted
Iron replacement helpful as iron loss can be significant with time
Chemical induced hemolytic anemias
Lead:
Interferes with cation pump—results in shortened RBC survival time
Lead slows production of RBCs in marrow
Copper: - complex mechanisms
Oxygen: pure O2 atmosphere - astronauts
Insect venoms:
Bee/wasp
Spider - brown recluse spiders
Malaria
Most common cause of hemolytic anemia in the world
Hemolysis can be severe, urine can contain significant amounts of hemoglobin and color can be very dark (“blackwater fever”)
Treat with antimalarial agents and supportive care
Bartonellosis
Due to Bartonella baciliformis (Carrión’s disease)
Does not infect, but adheres to RBC membrane
Hemolysis is the initial stage of the infection (“Oroya fever”)
Transmitted by sand flea
Treatment with antibiotics and supportive care
Babesiosis
From Babesia microti
Intraerythrocytic protozoa
Normally a parasite in rodents
Mechanism of hemolysis unclear
“Maltese cross” appearance in RBCs with Giemsa-stained peripheral smears
Warm- immune mediated hemolytic anemia
warm reacting antibodies (occurs at body temperature [37°C] and is mediated by IgG)
Complement involvement unusual
Tx:
Most not in imminent danger
Transfusions may be helpful—trouble with crossmatching, watch for signs of hemolysis
Steroids—mainstay, use high doses
Remissions are usually long-lasting
Immunosuppressives—of some benefit, cyclophosphamide and azathioprine most favored; considered in refractory cases
Splenectomy—used for patients in whom chronic steroid use is required
“Georgia’s warm”
Cold- immune mediated hemolytic anemia
cold reacting antibodies (occurs below body temperature and is mediated by IgM)
Complement may directly lyse RBCs or opsonize RBCs for lysis in the spleen
Etiology:
Lymphoproliferative disorders
Cold agglutinin disease (Mycoplasma)
–Hemolysis from Mycoplasma very rare—need titers at least 1:10,000 which don’t usually occur with infection
Tertiary syphilis (Donath-Landsteiner hemolytic anemia)— cause of paroxysmal cold hemoglobinuria (PCH)
Features:
Chronic anemia or severe episodic anemia following cold exposure
Veno-occlusive phenomena d/t sludging of RBCs in affected capillaries
Tx: Supportive, avoid cold, tx infections
“Minnesota’s cold”
Clinical features of immune mediated hemolytic anemia
Positive direct antiglobulin test (DAT, Coomb’s test) indicating Ig or complement coating RBC surface
May have positive indirect Coomb’s test, indicating RBC-targeted Ig in serum, may also indicate complement activation/opsonization
Normochromic normocytic anemia
Elevated retic. count
Evidence of hemolysis on lab tests
Hypersplenism
Spleen actively removes and destroys RBCs faster than usual
May result in splenomegaly
Splenectomy may alleviate the problem
Acute Intermittent Porphyria (AIP) - incidence and pathology
Most common in peoples of Scandinavian, British, and eastern European descent
Due to deficiency of porphobilinogen (PBG) deaminase
Increased incidence in psychiatric patients
Resultant excretion of increased amounts of ALA and PBG in urine
Acute intermittent porphyria - clinical features
Symptoms rare prior to puberty
Severity: no complaints to overwhelming debility
Abdominal pain—most common symptom
Most have occasional attacks followed by clinical improvement, some only a single attack may occur over the life of the patient
Nausea/vomiting, constipation (ileus)
Tachycardia, hypertension
Neurological changes—peripheral neuropathy, anxiety, insomnia, depression, hallucinations/paranoia (usually worse during attacks), seizures
Precipitating factors of acute intermittent porphyria
Hormones—AIP has more frequent expression in women than men and attacks have occurred with pregnancy
Drugs—anticonvulsants (Dilantin, Tegretol, Valproic acid), barbiturates, sulfonamides, alcohol
Low caloric intake—carbohydrate reduction can increase ALA and PBG levels and precipitate an attack
Infection
Surgery
Tx of acute attacks of acute intermittent porphyria
Hydration with carbohydrate solutions (D5 or D10)
Hemin infusion—similar molecule to heme which decreases porphyrin production (negative feedback effect) and terminates an attack
Beta blockers—for tachycardia and hypertension
Analgesics
Acute intermittent porphyria prognosis
Minimally affected - normal life span
severely affected - chronically debilitated
Porphyria Cutanea Tarda (PCT)
Most common of the porphyrias
Due to deficiency of uroporphyrinogen decarboxylase in liver
Major clinical feature is cutaneous photosensitivity
Neurologic effects are not seen
Tends to occur in alcohol consuming cultures
Unique: has a congenital form and a “sporadic” form with no hereditary link
Clinical features of porphyria cutanea tarda
Cutaneous bulla formation on sun-exposed areas of skin
May occur after minor trauma
Skin may tighten diffusely— “pseudoscleroderma”
Exacerbations after alcohol ingestion in some
Occasional outbreaks after exposure to petrochemicals—dioxin, trichlorophenol
May occur in end stage renal disease
Increased risk for hepatoma
Lab features of porphyria cutanea tarda
Abnormal liver function tests—due to buildup of porphyrins in liver
May also have increased iron buildup in liver
Increased porphyrins in urine—ALA primarily; only slight increase
Increased porphyrins in stool
Treatment of porphyria cutanea tarda
Discontinue exacerbating factors—alcohol, suspicious drugs
Phlebotomy for iron overload—can help cutaneous manifestations as well
Chloroquin—may complex with excess porphyrins and facilitate excretion, but may be met with exacerbation of disease at outset…usually improves and allows remission of disease
Polycythemia Vera - pathogenesis
Virus
Increased sensitivity to growth factors in marrow
Very chronic malignancy of stem cells
Clinical presentation of polycythemia vera
Insidious and chronic
Facial rubor Hyperviscosity signs may be present Headache Dizziness Blurred vision Heaviness in arms or legs Pruritis with hot shower or bath
70% splenomegaly - extramedular hematopoiesis in spent phase
Labs in polycythemia vera
Increased RBC numbers (Hb/Hct)
-May see nucleated RBCs in peripheral blood
Elevated Leukocyte Alkaline Phosphatase (LAP) score
Increased WBC and/or platelet counts in 40-60% of patients
- WBC can be as high as 20-50,000/μl
- Platelets can be 650,000-1,000,000/μl
Prognosis of polycythemia vera
Without treatment, 50% mortality at 18 months
Increased risk of thrombotic and hemorrhagic complications
Has been linked to Budd-Chiari Syndrome
With treatment patients can live for years to decades
Usual cause of death in treated patients is progressive marrow fibrosis with pancytopenia a.k.a. “spent phase” polycythemia
ddx for polycythemia vera
Secondary causes of elevated RBC counts…
Hemoconcentration
Pulmonary disease-COPD (smokers polycythemia)
EPO producing tumors (renal cell carcinoma, neuroendocrine tumors)
Hemoglobinopathy with high affinity hemoglobin
–Holds on to O2 more avidly than normal hemoglobin resulting in ischemia to tissues and increased RBC mass
Living at high altitude-hypoxia from decreased FiO2
Evaluation of polycythemia vera
H/P
Routine CBC and biochem profile
Exclude hemoconcentration (dehydrated?, BUN/Cr normal?)
Exclude abel EPO (serum EPO level, US kidney)
Exclude abnl lung fxn: SaO2 with ABG if abnl - smokers have elevated carboxyhemoglobin; PFT with DLCO
Genetic mutation in polycythemia vera
JAK2 - V617F
95% of patients with myeloproliferative disorders
with normal serum EPO level correctly identified 98% of P. vera
Treatment of polycythemia vera
Lowering of RBC mass essential to avoid hyper viscosity complications:
Usually accomplished by phlebotomy of 250-500 cc whole blood every 1-2 weeks as long as Hct > 50%
Schedule phlebotomy chronically for patients as needed (usually every 6-12 weeks)
Can also be accomplished by hydroxyurea 500-1500 mg/d
Use of alkylating agents (busulfan, chlorambucil) discouraged due to risk of therapy related leukemia
