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Flashcards in RBC Disorders - Anemia Lecture Deck (43)

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

-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

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

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
Gaucher's disease


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

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

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:
Spider - brown recluse spiders



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



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



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

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

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)

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



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




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



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

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
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...
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

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