Hematopoietic dz

hypoproliferative anemias

anemias with noromocytic and normochromic cells, low reticulocytes
(normal size, normal color, simply not enough)
*most common anemias*

iron deficiency anemia

one of the most prevalent forms of malnutrition, 50% of anemia worldwide
-1 million deaths annually worldwide
-Africa and Asia 71% global mortality
-North America 1.4% global mortality

protoporphyrin

intermediate in the pathway to heme synthesis
-inadequate iron leads to impaired heme synth, this molecule accumulates

negative iron balance

stage 1 of IDA
-demand for iron exceeds the body's ability to absorp from the diet
-can be due to blood loss, pregnancy, rapid growth spurts, inadequate intake
*normal serum levels but low iron stores*

iron deficient erythropoiesis

stage 2 IDA
-as iron stores decrease, serum iron decreases
-TIBC increase, TS decrease
-hemoglobin begins to fall (7-8) and leads to IDA

IDA causes

certain clinical conditions: pregnancy, adolescence, rapid growth, blood loss (internal GI bleed)

GI bleed

What is the assumed cause of IDA in an adult male or post-menopausal female until proven otherwise?

IDA presentation

varying symptoms based on severity
-fatigue, pallor (pale mucosa or conjunctiva), reduced exercise capacity
-cheilosis, koilonychia (spooning fingernails) in advanced stages

thalassemia, anemia of inflammation, sideroblastic anemia

differentials for IDA

oral iron therapy (200 mg daily) can help as soon as 4-7 days after starting, peak at 1.5 weeks

treatment for IDA in asymptomatic pt with intact GI tract

parenteral iron therapy

treatment of IDA in pts who cannot tolerate oral iron
-acute needs, due to persistent GI bleed or menstruation

red cell transfusion

treatment of IDA of pts with symptoms, cardiovasc instability, continued excessive blood loss, need immediate intervention

renal disease and hypometabolic states

When is EPO production decreased?

chronic inflammation (will show reticulocytosis)

When is EPO production decreased, as well as bone marrow does not respond to EPO well?

marrow damage

When are elevated EPO levels found, but reticulocyte shift is found on the smear?
(hella large reticulocytes compensate)

anemia of inflammation (acute and chronic) (AI)

anemia in which inflammation, infection, injury, etc that release proinflammatory cytokines occurs
-inadequate iron delivery to marrow despite normal/increased stores
-low serum iron, increased protoporphyrin, hypoproliferative marrow, TS 15-20%, normal/increased SF

AI presentation

primary disease will determine the symptoms
-acute is mild but becomes more pronounced over time

anemia of chronic kidney disease (CKD)

moderate to severe hypoproliferative anemia
-normocytic, normochronic, decreased reticulocytes
-failure of kidneys to produce EPO

anemia of hypometabolic states

protein starvation, endocrine deficient states (castration, estrogen admin, hypothyroidism, Addison's), anemia in liver disease
*metabolic activity decrease, less demand for O2, less EPO produced*

anemia in aging

common in ppl \>65 yrs
-low hemoglobin ass. with increased falls, hospitalizations, development of frailty, mortality

treat underlying disease

treatment of hypoproliferative anemias

transfusions of packed red cells

treatment of hypoprolif anemia in pts with underlying CV or pulm disease with hemoglobin

EPO admin (50-150 U/kg 3x a week IV)

treatment of hypoprolif anemia with endogenously low EPO levels

hemoglobinopathies

disorders affecting the structure, function or production of hemoglobin
-structural, thalssemia, thalassemic variants, hereditary persistence of fetal hemoglobin, acquired
*associate with malaria*

thalassemias

What are the most common genetic disorders in the world?

sickle cell disease

What is the most common structural hemoglobinopathy?

H&P, blood smear, abnormal CBC

How are hemoglobinopathies diagnosed?

sickle cell syndrome

mutation in beta-globin gene produces sickle shaped RBCs, lose pliability to travel thru small capillaries
-microvascular occlusion, premature RBC destruction (hemolysis) in liver and spleen (hepato and splenomegaly)

sickle cell presentation

episodes of ischemic pain, infarction in the spleen, CNS, bones, joints, liver, kidneys, lungs
-episodes of pain can be brought on by infection, fever, stress, etc
-significant reticulocytosis and granulocytosis
-aseptic necrosis, chronic arthropathy, increased risk of osteomyelitis
-chronic lower leg ulcers
*chest pain, hip pain, shoulder pain*
*premature RBC destruction*
*vision changes, renal issues*

spleen

Function of what organ is often lost within the first 18-36 months of life in sickle cell?
-increase susceptibility to pneumococcal infection

stroke

symptom of sickle cell that is especially common in kids

acute chest syndrome

fatal manifestation of sickle cell with chest pain, tachypnea, fever, cough, arterial O2 desaturation
*can be FATAL*

hydration, O2 therapy, eval for pneumonia and PE, transfusion to maintain hematocrit \>30

treatment of acute chest syndrome

asymptomatic

manifestations of sickle cell trait

diagnosis of sickle cell

based on hemolytic anemia, RBC morphology, episodes of ischemic pain
-confirmed by hgb electrophoresis, mass spectroscopy, sickling tests
-usually in childhood
-perform genetic counseling

regular eye exams, antibiotic prophylaxis for procedures, oral hydration, vaccination

preventative treatment for the management of sickle cell

vigorous hydration, aggressive analgesia

management of an acute painful sickle cell crisis

hydroxyurea

treatment of sickle cell in pts with repeated episodes of acute chest syndrome or \>3 pain crises per year with hospitalization
(increases hemoglobin levels)

thalassemia

inherited disorders of globin synth leads to hypochromic and microcytic cells

thalassemia presentation

highly variable presentation
*hypochromia and microcytosis*
-minor has minimal anemia

beta thalassemia presentation

-severe hemolytic anemia
-"chipmunk face" in kids due to massive bone marrow expansion
-growth retardation
-hepatomegaly, leg ulcers, gallstones, heart failure, endocrine dysfunction
-death within 10 years of life

Asians

Who is alpha thalassemia most common in?

alpha thalassemia 2 trait

asymptomatic, silent carrier state of thalassemia
*pt education*

alpha thalassemia 1 trait

mild microcytic hypochromic anemia, very common
*pt education*

hemoglobin H disease

rare severe hemolytic anemia with ineffective erythropoiesis
survival to mid-adult life without needed transfusions

hydrops fetalis

no physiologically useful hemoglobin produced beyond the embryonic stage
*FATAL* to the fetus

diagnosis of thalassemia

for beta thalassemia major, diagnosis made in childhood based on severe anemia, lack of erythropoiesis

chronic hypertransfusion therapy to maintain hematocrit, possible splenectomy

beta thalassemia major treatment

genetic counseling, pt education on risk of iron overload

beta thalassemia intermedia and minor treatment

splenectomy, no oxidative drugs

treatment for HbH disease

transfusional hemosiderosis

risk of chronic blood transfusion that can lead to infection, alloimmunization, febrile rxn, lethal iron overload

aplastic crisis

profound cessation of erythroid activity in pts with chronic hemolytic anemia
-rapidly falling hematocrit, resolve in 1-2 weeks
-transfusion therapy if pt symptomatic

megaloblastic anemia (aka macrocytic)

anemia with many large and dysfunctional RBCs in bone marrow, hypersegmented neutrophils
-caused by B12 (cobalamin) or folate deficiney

megaloblastic anemia presentation

can be asymptomatic
-anorexia, weight loss, diarrhea, constipation
-*glossitis*, cheilosis, mild fever, jaundice, bruising
-URI infections
-older pts may have neuro symptoms: ataxic gait, hyperreflexia, impaired intellectual developmement in kids, psych disturbances

mucosa, pregnancy complications, neural tube defects, CV disease (due to increased homocysteine)

tissue effects of B12 and folate deficiency

blood smear for megaloblastic anemia

oval macrocytes with aniso and poikilocytosis, hyper seg neutrophils, leukopenia
-ineffective hematopoiesis

causes of B12 deficiency

inadequate dietary intake (vegans, infants with deficient mothers), gastric/intestinal malabsorption

pernicious anemia

lack of intrinsic factor due to gastric atrophy, stomach unable to absorb B12
-common in Europeans age 70-80
-genetic link, autoimmune disease
-may see IF antibodies in serum

GI causes of B12 deficiency

juvenile pernicious anemia, congenital IF deficiency, gastrectomy, intestinal stagnant loop syndrome (fecal material accumulation prevents absorption in an area of the intestines), ileal resection

causes of folate deficiency

lack in diet, malabsorption, excess use or loss (pregnancy, prematurity, hematologic disorders), use of antifolate drugs (phenytoin, methotrexate, pyrimethamine, trimethoprim, nitrofuratoin), alcohol use

lifelong B12 injections

treatment of B12 deficiency

oral folic acid daily for 4 months

treatment of folate deficiency

folic acid supplements

prenatal folate intake to reduce change of megaloblastic anemia and NTDs

hemolytic anemia presentation

jaundice, pallor, splenomegaly, bone changes, increased reticulocyte count
-due to hemolysis and bone marrow response to compensate

extravascular hemolysis

this type of hemolysis will cause an increase in unconjugated bilirubin and AST -\> iron overload
*iron chelation therapy needed*

intravascular hemolysis

this type of hemolysis will cause hemoglobinuria -\> considerable protein loss
*iron replacement needed*

compensated hemolysis

RBC destruction stimulates EPO production and therefore RBC production
-in many cases the bone marrow can fully balance increased destruction of cells
-can become decompensated due to stress or clinical conditions

HA of abnormalities of cytoskeleton

abnormalities of cell (spherocytosis or elliptocytosis) structure lead to hemolysis
-HS has jaundice, splenomegaly, gallstones
-treat with splenectomy

HA due to enzyme abnormalities

defective enzymes lead to failed metabolism of RBCs
-G6PD deficiency most common

G6PD deficiency

most common inherited HA
-protects red cells from oxidative damage
-common in tropical/subtropical places
*most asymptomatic, some neonatal jaundice, risk of HA*

fava beans, injections, some drugs (bactrim, nitrofurantoin, methyl blue, fluoroquinolones, ASA)

causes/triggers of G6PD deficiency

G6PD deficiency symptoms

malaise, weakness, lumbar pain
-jaundice after 2-3 days, dark urine
-moderate to severe normochromic and normocytic anemia
-hemolysis
-blood smear with anisocytosis, polychromasia, spherocytes
*bite or blister cells*
-acute renal failure

avoid exposure to triggers in screened pts, if triggered do blood transfusion, if renal failure do dialysis

treatment of G6PD deficiency

acquired HA

due to mechanical destruction bc of shearing, infection *malaria and E. coli*, autoimmune, due to toxic agents and drugs

autoimmune HA (AIHA)

rare HA with abrupt and dramatic onset
-jaundice, splenomegaly, intravascular hemolysis
-warm and cold (warm more common)
*diagnose with + Coombs test*

stages of anemia due to blood loss

1. hypovolemia: LOC, acute renal failure
2. release of ADH causes hemodilution and anemia
3. if bleeding stops, bone marrow will correct the anemia

bone marrow failure states

aplastic anemia, myelodysplastic syndrome, pure red cell aplasia, myelophthisis
-will seen pancytopenia due to deficient hematopoiesis

bone marrow cellularity

amount of hematopoietic cells relative to fat
-age dependent, more fat the older ppl get
-normal adult is 30-70%
-treatment is complex and warrants heme/onc management

aplastic anemia

pancytopenia with bone marrow hypocellularity -\> ALL cell lines decreased
-onset of low cell counts in a previously well young adult
-2 million cases per year in Europe
-biphasic age distribution

causes of aplastic anemia

majority of cases are idiopathic
-can be due to radiation, chemical such as benzene, drugs for chemo, infections such as hepatitis, autoimmune disease

aplastic anemia presentation

bleeding is the most common early symptom
-weakness, SOB, pounding sensation in the ears
-*infection*
-will see petechiae and ecchymosis on exam, pallor of skin and mucous membranes

aplastic anemia labs

-blood smear shows large erythrocytes, lack of platelets and granulocytes
-low reticulocytes and lymphocytes
-marrow cellularity

diagnosis/prognosis of aplastic anemia

made due to pancytopenia with fatty bone marrow
-disease of the young (biphasic distribution)
-poor prognosis, based on blood count

stem cell transplant, immune suppression, stop exposure to triggering toxins or drugs, broad-spectrum antibiotic prophylaxis

treatment of aplastic anemia

single lineage failure syndromes

only one cell type is affected and the marrow shows absence of precursor cells
ex. PRCA, thrombocytopenia, neutropenia
-unaffected lineages are normal

pure red cell aplasia

*anemia, reticulocytopenia, absent or rare red cell precursors in marrow*
-ass. with immune system disease, thymoma
-can be manifestation of large granular lymphocytosis or complication of chronic lymphocytic leukemia
-can see antibodies to RBC precursors in the blood or T cell inhibition
-also ass. with persistent parvovirus B19 infection

treat underlying disease, long-term supportive care (RBC transfusions and iron chelation), immunosuppression

treatment of pure red cell aplasia (PRCA)

myelodysplasia

group of disorders with *cytopenia* due to bone marrow failure and *high risk of development of AML*
-seen with anemia, thrombocytopenia, neutropenia
-often fatal, hard to diagnose
*refer to hematology immediately*
-disease of the elderly \>70 yo, M\>F

myelodysplasia presentation

anemia in early course
-gradual onset fatigue, weakness, dyspnea, pallor (1/2 are asymptomatic)

MDS (myelodysplasia) and leukemia

What are children with Down syndrome especially susceptible to?

MDS labs

blood smear shows anemia, macrocytosis, nonfunctional platelets and neutrophils
-bone marrow unremarkable - HARD to diagnose
*significant morbidity and mortality*

hematopoietic stem cell transplant, iron chelation, EPO admin, 5-azacytidine, decitabine, lenalidomide

treatment of MDS
-usually unsatisfactory

chronic myeloproliferative neoplasms (MPNs)

originate in hematopoietic cell, overproduction of one or more formed blood elements without significant dysplasia
-extramedullary hematopoiesis, myelofibrosis, transformation

polycythemia vera

normal red cells, granulocytes, platelets accumulate without physiologic stimulus

PV presentation

usually incidental discovery of high hemoglobin, hematocrit, cell count
*hyperviscosity*, vertigo, tinnitus, headache, visual disturbances, TIAs
-systolic hypertension, venous/arterial thrombosis
-erythromelelgia, (erythema, burning, pain in the extremities)
-hyperuricemia with gout, uric acid stones

complications of PV

increased blood viscosity can lead to:
-increased incidence of H pylori peptic ulcer disease
-splenomegaly and splenic infarct
-myelofibrosis (scarring of the bone marrow)
-acute myeloid leukemia
-uncontrolled can lead to thrombosis of liver, heart, brain, lungs

periodic phlebotomy to maintain hemoglobin (14), hematocrit (

treatment of PV

primary myelofibrosis (PMF)

stem cell disorder with mutations of JAK2, MPL, or CALR genes
-characterized by marrow fibrosis (scarring), extramedullary hematopoiesis, splenomegaly
-affects M\>F \>60 yo

primary myelofibrosis presentation

no specific signs or symptoms
-most pts are asymp, disease detected by discovery of splenomegaly or abnormal CBC
-night sweats, fatigue, weight loss
-mild anemia, mild hepatomegaly
*unable to perform bone marrow biopsy*

primary myelofibrosis labs

blood smear shows extramedullary hematopoiesis: teardrop shaped red cells, nucleated red cells, myelocytes, promyelocytes
-also variable leuk and platelet counts
-unable to perform bone marrow biopsy
-xrays show osteosclerosis
-markedly increased CD34+ cells
*diagnosis of exclusion*