heme part one

blood

• a connective tissue: a viscous fluid carrying cells and proteins

core jobs of blood

• oxygen and nutrient delivery to tissues

• waste removal (carbon dioxide, metabolic byproducts)

• immune defense against pathogens

• hemostasis, so injury does not become hemorrhage

• thermoregulation and acid base balance

two compartments of blood

• plasma (about 55%): water, electrolytes, proteins, clotting factors, glucose

• formed elements (about 45%): erythrocytes, leukocytes, platelets

hematopoiesis

• the continuous process of blood cell formation

• in adults, it occurs primarily in the bone marrow of the pelvis, sternum, vertebrae, and proximal long bones

• every mature blood cell traces back to the hematopoietic stem cell (HSC), a multipotent, self-renewing cell in the marrow

• from the HSC, two major progenitor lines branch:

  • myeloid line

  • lymphoid line

• cytokines and growth factors (EPO, thrombopoietin, colony-stimulating factors) direct which line a progenitor commits to

myeloid line

• erythrocytes

• platelets

• granulocytes

• monocytes

lymphoid line

• t cells

• b cells

• natural killer cells

hematopoietic stem cell

• multipotent cell that can differentiate into any blood cell line

proerythroblast

• first cell committed specifically to the red cell line

erythroblast

• begins synthesizing hemoglobin

normoblast

• hemoglobin accumulates

• nucleus is extruded near the end of this stage

reticulocyte

• young, anucleate red cell released into circulation

• still has residual RNA

• often discussed with anemias

• “window into bone marrow”

  • how well is it producing cells

  • is it notified we need RBCs effectively

  • will it makemore cells

mature erythrocyte

• biconcave disc

• no nucleus or organelles

• circulates 100 to 120 days

erythropoietin (EPO)

• released by the kidney in response to hypoxemia or blood loss

• the primary stimulus for RBC production

• falls in chronic kidney disease

iron

• required to build the heme portion of hemoglobin

• absorption is regulated by hepcidin

  • a liver hormone that limits gut uptake and release from stores

vitamin B12 and folate

• needed for DNA synthesis during rapid cell division

• deficiency stalls maturation and produces large, fragile precursors

hepcidin

• the master regulator of iron traffic

• rises with inflammation, which is why chronic disease can cause a functional iron deficiency even with normal stores

hemoglobin

• the oxygen-carrying protein built inside the developing red cell

• its structure and adequate synthesis determine RBC size and color on a smear

hypoxemia and blood loss

• the physiologic triggers that increase EPO output and push the marrow to accelerate red cell production

primary lymphoid organs

• bone marrow

• thymus

bone marrow

• site of hematopoiesis and b cell development

thymus

• site of t cell maturation and selection

secondary lymphoid organs

• spleen

• lymph nodes

• mucosa associated lymphoid tissue

spleen

• filters blood

• removes old or damaged cells

• houses immune cells

lymph nodes

• filter lymph fluid and mount immune responses to trapped antigens

mucosa associated lymph tissue

• tonsils, peyer patches

• frontline defense at mucosal surfaces

lymphoid system

• the bridge between the hematologic and immune systems

• shares a common stem cell origin with the myeloid line, so marrow disorders can affect both

• organs are also the anatomic sites where lymphomas and lymphocytic leukemias arise

mean corpuscular volume (MCV)

• average red cell size

• normal 80-100 fL

• the single most useful sorting tool for anemia

• it classifies disease before you order a single additional test

mean corpuscular hemoglobin (MCH) and MCHC

• how much hemoglobin is packed into each cell

• low suggests hypochromia, as seen in iron deficiency (pale)

• high can be seen in hereditary spherocytosis (dark cluster of RBCs)

red cell distribution width (RDW)

• variation in red cell size (anisocytosis)

• high suggests a mixed or evolving process

  • early iron deficiency or mixed anemia

• normal with a uniformly abnormal size suggests a stable inherited process

  • thalassemia trait

microcytic

• <80 fL

• iron deficiency

• thalassemia

normocytic

• 80-100 fL

• anemia of chronic disease

• acute blood loss

• aplastic anemia

• early mixed anemia

macrocytic

• >100 fL

• vitamin b12 or folate deficiency

• some myelodysplastic and liver processes

iron deficiency anemia

• microcytic

• inadequate iron supply for hemoglobin synthesis

• inadequate dietary intake or absorption (celiac disease, bariatric surgery, achlorhydria)

• chronic blood loss, gastrointestinal or menstrual, is the most common cause in adults and always deserves investigation

• typical anemia symptoms plus unique findings: pica, koilonychia (spoon nails), glossitis, pagophagia (ice craving)

  • fatigue, pallor, dizziness, syncope

• history and physical, CBC with low MCV/MCH, confirmed with iron studies

• treat with underlying cause of blood loss, then replace iron (oral first line; IV for malabsorption, intolerance, or ongoing losses)

serum iron

• circulating iron level

• fluctuates through the day and is the least reliable component on its own

• normal = 150

• depletion = 120

• deficiency = <100

total iron binding capacity (TIBC)

• reflects transferrin, the iron transport protein

• rises when the body is iron hungry

• 300-360

transferrin saturation

• serum iron divided by TIBC

• low in iron deficiency

• helps separate true deficiency from anemia of chronic disease

• 30-50%

ferritin

• the most sensitive marker for iron deficiency

• also an acute phase reactant and rises with inflammation

• does not fully rule out deficiency in an inflamed patient

• 50-200

beta-thalassemia

• microcytic

• mutation in the HBB gene reduces beta chain production

• unaffected alpha chains accumulate and precipitate inside the cell, damaging the RBC membrane and shortening lifespan

• categorized by severity: trait/minor, intermediate, and major

• more common

alpha-thalassemia

• microcytic

• mutations in the HBA1 and HBA2 genes

• four total alpha genes, so severity depends on how many are affected

• ranges from silent carrier to hemoglobin H disease to hemoglobin Bart hydrops fetalis (incompatible with life)

• less common

trait/minor

• mild or no anemia

• often found incidentally

• positive family history

• usually no management needed

• genetic counseling

intermedia

• moderate anemia

• may need intermittent transfusion

• monitor closely

• transfuse as needed

• folate supplementation

major

• severe

• transfusion dependent anemia presenting in early childhood

• regular transfusions

• iron chelation therapy

• bone marrow or stem cell transplant

• splenectomy in select cases

folate deficiency

• macrocytic

• inadequate dietary intake, increased demand (pregnancy, hemolysis), malabsorption, certain medications

• less common today due to widespread fortification and supplementation

vitamin B12 deficiency

• macrocytic

• inadequate intake, pernicious anemia (autoimmune loss of intrinsic factor), malabsorption, bariatric surgery

• also required for myelin synthesis; deficiency can cause sensory paresthesias and other neurologic deficits

• neurologic changes may not fully reverse even after the anemia corrects with supplementation

• neutrophils may show hypersegmented nuclei on smear

anemia of chronic disease/inflammation

• normocytic

• second most common anemia overall

• driven by chronic illness or inflammation: decreased marrow RBC production and shortened RBC survival

• hepcidin rises with inflammation, trapping iron in storage and starving erythropoiesis usable iron

• mild to moderate anemia, low reticulocyte count, elevated inflammatory markers, low iron and TIBC, but normal transferrin saturation

• resolve the underlying disorder

• iron repletion does not help unless true deficiency coexists

aplastic anemia

• normocytic

• bone marrow fails to produce hematopoietic stem cell precursors

• leads to pancytopenia: anemia, leukopenia, and thrombocytopenia together

• causes include autoimmune destruction, toxins, radiation, viral infections, or idiopathic

• CBC showing all three lines low, confirmed with bone marrow biopsy

• address underlying cause, immunosuppression, or stem cell transplant depending on severity

anemia of chronic kidney disease

• kidney failure reduces erythropoietin synthesis, the primary stimulus for marrow red cell production

• iron deficiency is frequently present alongside the EPO deficit and should always be checked before starting an erythropoiesis stimulating agent

• fluid and electrolyte imbalances associated with CKD further inhibit erythropoiesis

• hemodialysis mechanically shortens RBC lifespan through repeated shear stress in the dialysis circuit

• one of the most common normocytic anemias NPs manage across primary care, nephrology, and inpatient settings

hemolytic anemia

• RBCs are destroyed faster than the marrow can replace them

• can occur intravascularly or extravascularly

• causes include inherited membrane, enzyme, or hemoglobin defects, as well as acquired autoimmune or mechanical destruction

• look for elevated reticulocyte count, elevated indirect bilirubin, elevated LDH, and low haptoglobin as the classic hemolysis panel

sickle cell disease

• a point mutation in the HBB gene produces hemoglobin S (HbS) instead of normal hemoglobin A

• under stress (hypoxia, dehydration, acidosis, cold), HbS polymerizes and distorts red cells into a rigid sickle shape

• occlude the microvasculature and are removed prematurely, driving both pain crises and chronic hemolysis

• one of the most common inherited blood disorders worldwide, autosomal recessive inheritance

• early signs: swelling and pain in the hands and feet (dactylitis) in infants

• fatigue, irritability, pallor, and jaundice from ongoing hemolysis

• vaso-occlusive crises: severe pain, and over time, stroke, acute chest syndrome, splenic infarction, and progressive organ damage

• increased infection risk from functional asplenia

• hemoglobin electrophoresis is the gold standard, distinguishing disease from trait

• hydroxyurea to reduce crisis frequency, transfusion support, pain and infection management, avoidance of known triggers, and stem cell transplant as a potential cure in select patients

polycythemia

• an above normal increase in RBC mass and hemoglobin concentration

• three types

• visual disturbances, headache, hypertension, splenomegaly, and increased thrombosis risk from hyperviscosity

primary polycythemia

• polycythemia vera

• a myeloproliferative neoplasm driven by a JAK2 mutation, marrow overproduces red cells independent of EPO

secondary polycythemia

• appropriate or inappropriate EPO elevation from chronic hypoxia (COPD, sleep apnea, high altitude) or EPO-secreting tumors

relative polycythemia

• normal RBC mass with decreased plasma volume, as in dehydration

hemochromatosis

• iron overload

• results from increased intake, increased absorption, or repeated transfusion

• hereditary involves low or ineffective hepcidin, leading to unchecked iron absorption from the gut

• excess iron saturates transferrin, then binds other proteins and accumulates in tissue, generating reactive oxygen species and fibrosis

• nonspecific and slow to develop

• often not evident until organ damage has occurred, typically after decades of accumulation

• high iron, ferritin, and transferrin saturation

• low TIBC

• genetic testing

• MRI can quantify iron deposition in liver and heart

• therapeutic phlebotomy first line

• chelation therapy when phlebotomy is not tolerated, aimed at preventing organ damage