Hematology
Disorders of Red blood cells
RBC Structure & Function
Non-nucleated, biconcave disk
Provides larger surface area for O2 diffusion
Flexible membrane
Allows for easier passage through capillaries
48% of blood volume in men and 42% in women
Transport oxygen to tissues *
Hemoglobin (Hgb)
Hemoglobin facilitates the transport of oxygen to tissues
95-98% of oxygen is bound to hemoglobin
Hemoglobin is composed to 2 pairs of different alpha and beta polypeptide chains
Globin unit (protein) + heme unit (surrounds iron atom)
This allows one hemoglobin molecule to carry 4 molecules of oxygen
Adult Hemoglobin (HbA):
2 alpha chains (α)
2 beta chains (β)
Fetal Hemoglobin (HbF):
2 alpha chains (α)
2 gamma chains (γ)
Predominant fetal hemoglobin
Higher affinity for oxygen than HbA
Hgb increases by 1g/dL every 2-3 weeks
The rate at which it is synthesized depends on the amount of iron present
Hemoglobin levels decline after middle age
Mean Hgb ranges from 12.4-15.3g/dL - the lowest found among older adults
Mostly due to IDA (iron deficiency anemia) & anemia of chronic disease (malignancy, CKD)
RBC production starts to decline due to decreasing amount of progenitor cells with increasing age
Hematopoiesis
The production of blood cells
Occurs in the liver and spleen of the fetus
Occurs only in bone marrow after birth
Continues throughout life, increases as a result to replace aged RBCs or destroyed circulating RBCs or in response to infection
Chronic diseases = greater increase than acute conditions (ie: hemorrhage)
All blood cells are generated from the progenitor cell, hematopoietic or pluripotent stem cell (HSC)
Erythropoiesis
Definition: the production of red blood cells
Until 5 years of age: all bones produce RBC
In adults: *
Vertebrae
Sternum
Ribs
Pelvis
Steps in Erythropoiesis:
Pluripotent stem cells
Proerythroblasts (committed stem cell)
Phase 1: Erythroblasts: precursor cells from which RBCs are derived
Phase 2: Normoblasts : nucleus condenses and is reabsorbed
Phase 3: Reticulocytes
Erythrocytes: hemoglobin synthesis stops
Regulation of Erythropoiesis
The period from stem cell development to reticulocyte formation = 1 week
Reticulocyte to erythrocyte maturation = 24-48 hours
Remain in bone marrow for 24 hours, then released into circulation
Reticulocytes make up 1% of RBCs
The total amount of circulating erythrocytes in healthy individuals remains constant
Hypoxia (low oxygen) stimulates the kidneys to increase the production of erythropoietin (EPO)
EPO goes to bone marrow
binds to EPO receptors on proerythroblasts
increased production of RBCs
Nutritional requirements for Erythropoiesis
Development of erythrocytes and hemoglobin synthesis is dependent on essential proteins, vitamins and minerals
If lacking, erythrocyte production will slow down, leading to anemia
Erythropoiesis stops in the absence of vitamins such as: B12, B5, folate, niacin, Vitamin C, Vitamin E = Anemia
Red Cell destruction
RBC life span: 120 days (4months)
Removed from circulation in the spleen
As RBC ages, changes occur, making the RBC more fragile:
Metabolic, enzyme & ATP activity decreases
Membrane lipids decrease and membrane becomes more fragile red cell to self destruct as it passes through narrow spaces in circulation and spleen
Rate of destruction (1% per day) = rate of production
Except in diseases like hemolytic anemia – where the cell’s life span is shorter
Facilitated by phagocytes (found in spleen, liver, bone marrow, lymph nodes)
Phagocytes ingest and destroy defective red cells -> amino acids and iron are salvaged and reused
Heme: converted to bilirubin -> attached to plasma proteins for transport removed from blood by liver and excreted in the bile
Excessive red blood cell destruction -> increased bilirubin production -> unconjugated bilirubin accumulation = jaundice
The Iron Cycle and erythropoiesis
25mg of iron is needed daily for erythropoiesis
1-2mg is dietary
Remaining iron is obtained from recycling of erythrocytes
67 % of iron is bound to heme and muscle cells (myoglobin)
30% of iron is stored in mononuclear phagocytes (macrophages) and the liver
3% of iron is lost daily in urine, sweat or bile
Recycled iron can bind again to transferrin or be stored as ferritin or hemosiderin
The Composition of Blood
Plasma: 55%
91% water
7% proteins
Albumin – regulates movement of water/solutes; maintains oncotic pressure
Fibrinogen – clotting
2%: ions, nutrients, waste products, and gases
Carries nutrients/ions to maintain acid-base balance
Formed elements: 45%
Red blood cells – measured by hematocrit
Buffy Coat
White blood cells
Platelets
Normal Values & RBC INDICES
RBC Indices
Red Cell Count
MCV (Mean corpuscular volume): Reflects the volume or size of the RBCs
MCHC (Mean corpuscular hemoglobin concentration): Concentration of hemoglobin in each cell (amt of hgb each cell)
Hemoglobin is responsible for the color of the cell
MCH (Mean cell hemoglobin) : Refers to mass of the red cell
Less useful in classifying anemias
RBC Indices – putting it all together
Size (MCV)
Normocytic (normal)
Macrocytic (large) – high MCV
Microcytic (small) – low MCV
Color (MCHC)
Normochromic
Hypochromic (pale) – low MCHC
The naming convention is based on size and color. For example:
Macrocytic, normochromic
Microcytic, hypochromic
Normocytic, normochromic
Cell Shape and Size
Anisocytosis – abnormal variation in cell size
Quantifies RDW (red cell distribution width)
Poikilocytosis – abnormal variation in cell shape
Flat, elongated, teardrop-shaped, crescent-shaped, sickle-shaped, or other abnormal features
Complete Blood Count -- “CBC”
Includes the ‘formed elements’ of blood
RBC/Hgb/Hct/red cell indices/reticulocytes
WBC
Platelets
“Differential” “CBC w/ diff”
Gives a percentage of each different type of WBC:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
“ Left Shift”
Increase in number of immature WBC or ‘bands’
Typically signifies infection until proven otherwise
Bone marrow is prematurely releasing WBC into bloodstream
Anemia: Overview
Definition: Decrease in the number of red blood cells, hemoglobin or both, leading to decreased oxygenation of tissues
It can develop due to: (this is also how we classify the anemias)
Excessive loss of RBCs (bleeding/hemorrhaging)
Inadequate RBC production (bone marrow failure)
Increased RBC destruction (hemolysis)
Defective red blood cells
It is not a disease
Clinical Presentation – Symptoms they all have in common
Fatigue
Weakness
Dyspnea
Angina
Headache
Lightheadedness
Dim vision
Pallor of skin, mucous membranes, conjunctiva, nail beds
Tachycardia
Palpitations
Diffuse bone or sternal tenderness
Due to accelerated erythropoiesis
Types of Anemia
Excessive loss of RBCs
Blood loss anemia
Increased RBC destruction / defective RBCs
Hemolytic anemia
Hereditary Spherocytosis
G6PD Deficiency
Autoimmune
Sickle cell anemia
Thalassemia
Inadequate RBC production
Iron Deficiency Anemia
Megaloblastic Anemia
Vitamin B12 Deficiency/Pernicious
Folic Acid Deficiency
Aplastic Anemia
Anemia of Chronic Disease
Excessive loss of RBCs
Blood loss anemia
Results from excess loss of RBC
Acute or chronic
CBC: normocytic and normochromic
Acute bloos loss anemia
Loss of intravascular volume
Patho:
Blood loss results in hypoxia of tissues and cells
Stimulates EPO
Proliferation of erythroid stem cells
Reticulocyte production
Etiology
Trauma
GI hemorrhage
Dissection
DIC
Splenic rupture
SAH
Clinical manifestations
Signs of vascular instability occurs when 10-15% of total blood olume is lost
Can lead to circulatory shock and collapse
Hemoglobin and hematocrit do not reflect volume of blood lost in acute hemorhage
Hypotension and decreased organ perfusion are main concerns
(+) orthostatic hypotension, tachycardia
Hypovolemic shock (lose over 40% of volume)
Confusion
SOB
Diaphoresis
Hypotension
Tachycardia
Treatment:
Stop the bleeding, volume replacement, transfusion!
Iron supplements
Because iron is recycled and lost sm blood, need to build the store up again
Hemoglobin will take 6-8 weeks to return to baseline
Complications:
MI, CVA, death, organ damage/failure
Chronic blood loss anemia
Occurs when the blood loss is greater than the replacement capacity by the bone marrow
Commonly caused by GI bleeding and menstrual disorders
Does not affect intravascular volume (blood loss is slow)
Often leads to IDA
May not show clinical symptoms until more than 50% of red cell mass is lost / Hgb < 8g/dL
Increased RBC destruction / defective RBCs
Hemolytic Anemia
Definition: Premature and accelerated destruction of red blood cells from the bloodstream before they can be replaced
CBC: Mostly all normocytic, normochromic
Pathophysiology:
RBC destruction
Intravascular – due to mechanical (karate or marathon running)/toxic injuries (clostridial sepsis, snake venom, lead poisoning), complement fixation (ie: transfusion reactions) hemoglobinuria, hemosiderinuria, jaundice*
Initiated by RBC destruction in circulation by complement or antibodies
Extravascular – due to cells becoming less deformable sequestration & phagocytosis by macrophages (spleen, bone marrow and liver) jaundice*
Initiated by age-related changes in the RBC surface that makes them more rigid, less able to change shape
Retention of iron and other products of hemoglobin destruction
Increase in erythropoiesis
Congenital vs Acquired
Congenital
Result from intrinsic defects in erythrocytes, including the cell membrane
Ie: hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria
Defect in enzymatic pathways
Ie: G6PD deficiency
Abnormality in hemoglobin synthesis
Ie: thalassemia, sickle cell anemia
Acquired
Immunologic or allergic in nature – autoantibodies are produced in response to erythrocyte antigens -> RBC destruction
Increased shear stress in narrow vessels (ie: DIC, damage caused by cardiac valve prosthesis)
Clinical Manifestations:
RBC life span is shortened, making the bone marrow hyperactive -> Reticulocytosis
Bone marrow can increase red cell production up to 8x its normal rate
Severity of symptoms is related to degree of hemolysis and anemia and efficiency of compensatory erythropoiesis
Hemoglobinuria
Hemosiderinuria
Jaundice*
Splenomegaly in congenital cases
Diagnosis
CBC: Mostly all normocytic, normochromic
Hemolysis labs:
Reticulocytosis > 2%
Schistocytes on peripheral smear
↓ haptoglobin < 30
↑ indirect bilirubin 2/2 heme breakdown
↑ LDH
Hereditary Spherocytosis
A type of hemolytic anemia
Affects 1:2000 of NE European descent
Etiology:
Inherited molecular defect in one or more proteins of the red cell membrane
Pathophysiology:
Molecular defect leads to the loss of lipid bilayer of the RBC spherical/circular rather than biconcave and get stuck in splenic fenestration and lyse
Clinical manifestations:
Hemolytic anemia, jaundice, splenomegaly and bilirubin gallstones
Diagnosis: normocytic anemia, hemolysis on labs
Hyperchromic cells (high MCHC)
Spherocytes on peripheral smear
Osmotic fragility test – most sensitive test for diagnosis
Treatment: blood transfusion, splenectomy
Complications: aplastic crisis (parvovirus b19)
G6PD Deficiency
Glucose-6-phosphate dehydrogenase deficiency
X-linked recessive disorder
Most common inherited enzyme defect resulting in hemolytic anemia
Most commonly occurs in African and Mediterranean groups & males
Enzyme defect makes RBC more vulnerable to oxidants and causes direct oxidation of hemoglobin to methemoglobin (cannot transport O2) -> hemoglobin denaturing -> Heinz bodies *
Etiology:
Drugs – Primaquine, sulfonamides, ASA, nitrofurantoin
Infection – Hep A/B, typhoid fever, pneumonia
Foods – “fava beans” * peanuts, peas, artificial food dyes
Clinical manifestations:
Most people remain clinically asymptomatic throughout life
Occurs 2-3 days after trigger
Hemoglobinemia
Hemoglobinuria
Jaundice
Malaise, weakness, abdominal/lumbar pain
Not associated with chronic hemolytic anemia in African Americans because the enzyme defect is only mildly expressed
Diagnosis
CBC is normal between hemolytic episodes
During episodes:
Hemolysis lab findings
Peripheral smear: bite cells, bizarre poikilocytes
Quantitative UV spectrophotometric assay (gold standard) or rapid spot test for G6PD
Treatment
Avoid offending agents
Transfuse as needed
Folic acid supplements if anemia is not severe
Autoimmune Hemolytic anemia
The immune system recognizes RBCs as foreign
Production of autoantibody adheres to the RBC membrane surface antigen, leading to cell destruction and phagocytosis
Etiology
Idiopathic (50%)
SLE
Lymphomas
Chronic lymphocytic leukemia
Drugs (PCN, Fludarabine, Ceftriaxone, Piperacillin-Tazobactam)
Clinical Manifestations
Triad of symptoms:
Abrupt and dramatic onset (ie: Hgb 4 g/dL)
Splenomegaly
Jaundice
Diagnosis
CBC: Normocytic anemia
Direct Coombs test (DAT) – test of choice
Confirms presence of antibodies attached to RBCs
98% sensitive for autoimmune hemolytic anemia
Treatment
Hold transfusion unless blood threatening anemia
Prednisone 1mg/kg – first line
Rituximab (100mg/week x 4) – used with prednisone
Second line treatment – azathioprine, cyclophosphamide, cyclosporine
Splenectomy – removes major site of hemolysis, but not a cure
Stem cell transplant
Sickle Cell Anemia
Sickle Cell Disease vs Trait
Both conditions are inherited disorders characterized by a recessive inheritance pattern of the hemoglobin S (HbS) gene
Sickle cell disease: Homozygous with 2 HbS genes
Sickle cell trait: Heterozygous with 1 HbS gene
Etiology: A point mutation in beta chains of the Hb molecule leads to abnormal structure of HbS
Mutation changes the 6th amino acid from glutamic acid to valine*
Pathophysiology:
Sickle cell disease: HbS becomes sickled in times of physiologic stress, when deoxygenated or at low O2 tension
Sickled cells lose the pliability needed to traverse through capillaries
Their outer membranes become “sticky” and adhere to endothelial venules
Above produces vasoocclusion and hemolytic anemia as RBCs occlude capillaries and venules, leading to tissue ischemia, acute pain, and end-organ damage
Cell may return to normal shape with oxygenation in the lungs
With repeated episodes of deoxygenation, the cells will remain permanently sickled
Physiologic stressors: Hypoxia, dehydration, acidosis, extreme temperatures, stress, menses
Clinical Manifestations:
Sickle cell disease (homozygous):
Onset – first year of life as Hgb F levels fall
Severe hemolytic anemia
Hyperbilirubinemia – from hemoglobin breakdown -> jaundice
Vaso-occlusive crises - m/c presentation
Acute pain, fever, tachycardia and anxiety
Can develop anywhere in the body and last from few hours – 2 weeks
Sickle cell trait: less HbS = less tendency to sickle = asymptomatic
Vaso-occlusive Crises/Sickle Cell Crisis
Acute chest syndrome*
Secondary to vessel occlusion in lungs
Leading cause of death in people with sickle cell disease
Characterized by sudden onset of chest pain; cough and SOB may develop as a result of pulmonary infiltrates and respiratory insufficiency
Bone Crises*: due to infarcts in bone marrow - long bones, back, pelvis, chest, abdomen
Dactylitis – pain and swelling b/l hands and feet
Retinal vessel occlusion – hemorrhage, neovascularization, detachment
TIA/CVA
Renal necrosis – renal failure
Splenic injury -> asplenia -> susceptibility to life-threatening infections caused by encapsulated organisms
ie: Streptococcus pneumoniae, Haemophilus influenzae type b, and Klebsiella
Diagnosis
Normocytic anemia with hemolytic findings
Peripheral smear: 5-50% sickled cells
Hematocrit = 15-30%, significant reticulocytosis
Hemoglobin electrophoresis confirms diagnosis
> 50% of Hgb will be Hgb S
All newborns are screened in the US
Treatment
No known cure
Prevent sickling episodes, symptomatic treatment, and treating complications
Avoidance of situations that precipitate sickling episodes
Infection
Cold exposure
Severe physical exertion
Acidosis
Dehydration
Symptomatic treatment – IVF, rest, pain control, oxygen
Blood transfusions
Daily lifelong hydroxyurea 10-30mg/kg per day with or without L-glutamine
Increases fetal Hgb and has beneficial effects on RBC hydration, vascular wall adherence and retic/granulocyte suppression
Bone marrow transplant - definitive cure, but safe only in children
Prophylactic exchange transfusions
Folic acid 1mg daily
Low dose penicillin prophylaxis in children <5 years old or those with recurrent invasive pneumococcal infections
Functional asplenia occurs in 94% of patients by age 5 due to vaso-occlusion within the spleen, making pt predisposed to removal of encapsulated organisms (ie: streptococcus pneumoniae)
More susceptible to infection
Complications
Cholelithiasis
Splenomegaly
Chronic lower extremity ulcers
Infection with encapsulated organisms
AVN
Priapism
Prognosis:
Life expectancy between 40-50 years old; increasing due to newer treatments and monitoring
Thalassemias – Alpha & BEta
2 types – Alpha and Beta Thalassemia
Group of inherited disorders of hemoglobin synthesis decreased synthesis of either the alpha or beta globin chains of HbA
Decreased synthesis of affected chain AND we have continued production and accumulation of the unaffected globin chain
Individuals may have the heterozygous (mild form of ds) or homozygous trait (severe form of ds)
Microcytic, hypochromic anemia OR hemolytic anemia
Both types are common in African Americans
Alpha thalassemia = more common in Southeast Asian or Chinese populations
Beta thalassemia = more common in African or Mediterranean populations
Alpha Thalassemia
Most common in Asian population
Caused by deficient synthesis of the alpha chain due to a gene deletion
Synthesis of alpha chain is controlled by 4 genes
Silent carrier: 1deletion of alpha globin gene -- asymptomatic
Thalassemia minor/trait: 2 deletions of alpha globin gene -- mild hemolytic anemic
Hemoglobin H disease: 3 deletions of alpha globin gene -- accumulation of unstable beta chain; will see chronic moderate hemolytic anemia
Beta chains are more soluble than alpha chains accumulation is less toxic to RBCs
Hydrops fetalis: 4 gene deletion of alpha globin gene -- Most severe form; occurs in infants in whom all 4 alpha globin genes are deleted
Incompatible with life, only hemoglobin B is present on electrophoresis
Beta Thalassemia
Referred to as Cooley anemia or Mediterranean anemia
Most common in Mediterranean populations of Italy, Greece
Etiology:
Caused by deficient synthesis of the beta chain
Pathophysiology:
Alpha chains are denatured -> Heinz Bodies* -> impair DNA synthesis -> damage of RBC membrane
Types:
β Thalassemia minor/trait (Heterozygous) – 1 gene mutation
β Thalassemia major (Homozygous) – 2 gene mutations
β Thalassemia minor/trait
Do not develop severe form of disease
CBC: Hypochromic (bc less hbg), microcytic , no hemolysis (as anemia is minimal)
β Thalassemia major (AKA Cooley’s anemia):
ineffective hematopoiesis and hemolysis -> erythropoietin secretion and hyperplasia in bone marrow
Clinical Manifestations:
Severe anemia requiring frequent transfusions
Hemosiderosis
Growth delay
Thinning of cortical bone -> fracture
Formation of new bone in the maxilla and frontal bones of the face
Frontal bossing
Splenomegaly, Hepatomegaly
Treatment:
Regular blood transfusions, iron chelation therapy, stem cell transplant (only curative treatment)
Complications:
Iron overload -> cardiac hepatic, and endocrine diseases = common causes of morbidity/mortality
Diagnosis
MCV < 60-70: microcytic
Iron studies and ferritin within normal limits
Marked anemia – hemoglobin 3-6 g/dL
Target cells, chronic hemolysis
Inadequate RBC production
Iron Deficiency Anemia
Definition: decreased hemoglobin synthesis as a result of iron loss from dietary sources, through bleeding or increased demands
RBC breakdown leads to release of iron, which is reused in production of new RBCs
CBC: Microcytic, Hypochromic
Poikilocytosis (irregular shape)
Anisocytosis (irregular size)
High RDW*: variation of volume and size
Etiology:
Dietary deficiency – not common in developed countries
Average western diet = 20mg of daily iron
Daily iron requirement - Men: 7-10mg l Women: 7-20mg
Bioavailability - Only 10-15% of ingested iron is absorbed
Chronic blood loss – most common cause in Western world*
Women of childbearing age
Menstrual bleeding
Men/Post-menopausal women:
GI bleeding, peptic ulcer, hemorrhoids, esophageal varices, cirrhosis, cancer
Blood loss of 2-4mL/day is enough to cause IDA
Impaired absorption
Celiac disease, chronic diarrhea
Increased requirement
Eating disorders, surgical procedures, H.Pylori
Pathophysiology
Demand for iron exceeds the supply
Iron stores are depleted, erythropoiesis occurs normally, Hgb remains normal
Iron transportation to the bone marrow is diminished, erythropoiesis produces iron-deficient Hgb
Hemoglobin-deficient cells enter the circulation to replace the normal aged RBCs
Excessive blood loss and inadequate dietary intake deplete iron stores and lead to reduction in hemoglobin synthesis
With metabolic or functional iron deficiency, metabolic disorders insufficient iron delivery or impaired use of iron within the bone marrow inadequate heme synthesis
Iron regulates immune function
Any inflammation or acute phase response within the body can result in anemia
Clinical Manifestations
Fatigue, palpitations, dyspnea, angina, tachycardia
Pica syndrome*
Koilonychia* (spoon shaped nail)
Smooth tongue/glossitis
Angular stomatitis
Diagnosis
CBC: Microcytic, Hypochromic
Poikilocytosis (irregular shape)
Anisocytosis (irregular size)
High RDW* (variable volume and size)
Elevated TIBC
Wants to bind to iron
Low iron < 30 ng/mL
Low ferritin - <30-almost always indicates IDA
Decreased reticulocytes < 1%
Bc cant make RBC without iron
Treatment
Treat the underlying cause
Work up for occult blood loss
Ferrous sulfate 325mg PO QOD x 2-6mo
Ferrous fumarate 305mg PO QOD x 2-6mo
Monitor Hgb the first 4 weeks for response
Continue for 3 months after normalization of Hgb
Parenteral iron
Consider when oral iron is contraindicated, ineffective or not tolerated
Megaloblastic Anemia [MCV >100]
Vitamin B12 and Folic Acid Deficiency
Definition:
Results from impaired DNA synthesis -> large RBC
RNA production proceeds normally
The cells have slow maturing nuclei, but have normal maturing cytoplasm
“Nuclear-cytoplasmic asynchrony” produces megaloblastic changes in the bone marrow *
Defective erythrocytes die prematurely -> anemia
Secondary to a lack of Vitamin B12 or Folate
CBC: Macrocytic, Normochromic
Vitamin b12 Deficiency Anemia
Megaloblastic Anemia [MCV >100]
Definition: Megaloblastic anemia secondary to a lack of Vitamin B12
Pathogenesis:
B12 is released from animal protein -> stomach -> binds to intrinsic factor* (secreted by gastric parietal cells) -> ileum -> binds to epithelial cells -> separates and is transported into circulation
Intrinsic factor protects Vitamin B12 from digestion by intestinal enzymes
Etiology
Inadequate absorption = mc cause*
Lack of intrinsic factor (Pernicious anemia)*
Bacterial overgrowth
Parasites
Decreased acid secretion/ long-term use of PPIs
Celiac disease, ileitis
IBD
Gastric or bariatric surgery
Nitrous oxide = rapid depletion of B12
Inadequate intake – rare, mostly in strict vegans/vegetarians
Decreased utilization
Enzyme deficiencies
Transport protein abnormality
Vitamin b12 Deficiency – Pernicious Anemia
Specific form of megaloblastic anemia that leads to Vitamin B12 deficiency as a result of atrophic gastritis and lack of intrinsic factor
Intrinsic factor is secreted by gastric parietal cells
Impaired intrinsic factor etiology:
Autoimmune destruction of gastric mucosa
Gastrectomy
Congenital disease
Lack of gastric mucosa -> loss of parietal cells
Basically pernicious anemia is the autoimmune destruction of parietal cells so less intrinsic factor-> less B12 absorbed
Clinical Manifestations
Mild jaundice
Glossitis
Neurologic changes* irreversible!
Symmetric paresthesia of feet, fingers
Loss of vibratory and position sense
Gait abnormalities
Spastic ataxia
Confusion, dementia neuropsychiatric changes
Diagnosis
CBC- Macrocytic anemia (MCV 110-140)
Megaloblastic changes to RBC’s
Low serum vitamin B12 level < 200 pg/mL
Elevated serum methylmalonic acid (MMA) & homocysteine level
Hypersegmented neutrophils
Reticulocytes < 1%
If pernicious anemia: presence of anti-intrinsic factor autoantibodies
Treatment
Oral or SL therapy
Vitamin B12 1000 mcg daily
Parenteral therapy 1000 mcg IM or deep SC
Always indicated if patient has neurologic symptoms
Pernicious anemia: Parenteral B12 once per week x 4 weeks, then monthly indefinitely
GI related: Parenteral B12 monthly indefinitely or until issue resolved
Folic Acid Deficiency Anemia
Megaloblastic Anemia [MCV >100]
Definition:
Megaloblastic anemia secondary to a lack of folic acid
Pathogenesis:
Folates: coenzymes required in the synthesis of thymine and purines and the conversion of homocysteine to methionine
Deficiency in thymine affects cells undergoing rapid division (ie: erythropoiesis)
Readily absorbed from the small intestine -> stored in liver
Poorly stored*
Deficiency develops in weeks to months *
Found in green, leafy vegetables/ lost in cooking
Flour and grain products/cereal
Required to have folic acid supplementation
Etiology
Dietary deficiency = most common
Found in green, leafy vegetables/ lost in cooking
Flour and grain products/cereal - required to have folic acid supplementation
Daily requirement: 50-200mcg/day
Alcohol use
Celiac disease
Neoplastic disease
Methotrexate
Pregnancy-> neural tube defects
Clinical Manifestations
No neurologic changes*
Diagnosis
Megaloblastic, macrocytic anemia
Red blood cell folic acid level < 150 ng/mL (diagnostic)
Normal serum B12 level
Normal MMA
Elevated homocysteine
Treatment
Folic Acid 5-15mg PO Daily x 4 months
All women of childbearing age with male partners should take 0.4mg to maintain adequate serum levels in event of pregnancy
Will see total correction of anemia in 2-3 months
Aplastic Anemia
Definition: Hematopoietic failure or bone marrow aplasia -> pancytopenia: reduction of all 3 cell lines (RBC, WBC and platelets)
Anemia results from failure of the marrow to replace the destroyed red cells
CBC: Normocytic, normochromic (macrocytic in association with stress erythropoiesis)
Pathophysiology:
Characteristic lesion – hypocellular bone marrow replaced with fat
Pathogenesis is uncertain
Thought to be related to
Extrinsic: immune-mediated suppression of bone marrow progenitor cells
Intrinsic: abnormality of stem cells
Those with a genetic defect as an etiology may have an abnormality in human leukocyte antigens( HLA) or inhibitory cytokines
Cytotoxic T cells may be the culprit behind aplastic crisis in those with an autoimmune process as underlying etiology
Etiology:
High doses of radiation, chemotherapy -> bone marrow suppression -> pancytopenia
Chemical agents: alkylating agents, antimetabolites, arsenicals
Toxins: benzene, chloramphenicol
Infections: viral hepatitis, CMV, Epstein-Barr, HIV, Herpes Zoster
Inherited: Fanconi anemia, telomerase defects
Acquired: paroxsymal nocturnal hemoglonbinuria (PNH)
Idiopathic - 75%
Clinical Manifestations:
Fatigue, weakness, pallor
Petechiae, purpura*
Epistaxis, bleeding gums, GI bleeding
Increased susceptibility to infection
Bc WBC count is also low
Rapidly progressing: hypoxemia, pallor, fever, dyspnea, signs of bleeding
Slow onset: weakness, fatigue
50% of cases progress rapidly
Highest risk of death is from infection of bleeding
Diagnosis
Hallmark lab finding: Pancytopenia
Varying degrees of anemia, leukopenia, thrombocytopenia
Reticulocytopenia (reticulocyte count < 1)
Bone marrow biopsy:
Bone marrow aspiration and bx are needed to make the diagnosis
Hypocellular, fatty biopsy; no fibrosis or cancerous cells
Treatment
Depends on severity, age, functional status- hematology referral required
Mild-Moderate: supportive care, growth factors, transfusions
Severe:
Age < 40: Allogeneic stem cell transplant
Age > 40: Immunosuppression w/ equine antithymocyte globulin (ATG) plus cyclosporine and methylprednisolone
Kills T lymphocytes attacking bone marrow stem cells
Induces hematologic recovery in 60-70% or patients
Anemia of Chronic Disease
Anemia resulting from decreased erythropoiesis and impaired iron utilization due to chronic disease states or inflammation
Decreased numbers of erythrocytes fail to increase erythropoiesis
CBC: normocytic, normochromic -> microcytic, hypochromic (overtime)
Pathophysiology:
Decreased erythrocyte life span
Suppressed production of erythropoietin
Ineffective bone marrow erythroid progenitor response to erythropoietin
Altered iron metabolism and iron sequestration by macrophages
Occurs as a result of cytokine activation due to chronic inflammation
Diagnosis
Normal MCV
Decreased reticulocytes
Ferritin-normal or increased
Treatment
If anemia is severe or affecting QOL:
PRBC transfusion
If Hgb < 8
Parenteral recombinant erythropoietin (EPO)
If Hgb < 10 and renal insufficiency (ie: HD)
Anemias due to Iron Disorders
Sideroblastic anemia
Decreased hemoglobin synthesis due to an impaired ability to incorporate iron into protoporyphyrin IX, leading to anemia, despite the presence of adequate or increased amounts of iron. Basically iron cant attach to heme.
Etiology – Acquired of Congenital
Acquired
Typically acquired and a subtype of myelodysplastic syndrome (MDS)
Alcoholism, lead poisoning, copper deficiency, medications (isoniazid, chloramphenicol)
Congenital
Caused by one of many X-linked or autosomal mutations
Diagnosis
CBC
Microcytic in congenital causes
Macrocytic in acquired causes
Increased RDW (wide variation in size)
Serum iron, ferritin and transferrin are increased
Peripheral smear:
Dimorphic RBCs (variation of normocytic and microcytic, hence the high RDW)
Ringed sideroblasts *
Bone marrow aspiration
Shows erythroid hyperplasia
Ringed sideroblasts with Prussian Blue staining
Treatment
Stop causative agents
Blood transfusions as needed
Pyridoxine (20-200mg/day)
Chelation or phlebotomy for iron overload
Hemochromatosis
Definition: disorder of iron metabolism, causing abnormal iron build up in organs, leading to organ toxicity
Autosomal recessive disorder
1 in 200-500 people
2-3 times more common in men than women
Most common in Northern Europeans
Etiology/Pathophysiology: Classified either as primary or secondary
Primary or hereditary hemochromatosis (HH)
Mutation of 1 of 5 different gene mutation: HFE,* HJV, TFR2, SLC40A1, HAMP
HFE gene is responsible for majority of adult form of HH
HFE protein regulates production of hepcidin (“master” iron regulator)
Results in an increase in expression of an iron transport protein -> increased intestinal iron absorption -> iron overload and end organ damage
Secondary hemochromatosis
Caused by anemias of inefficient erythropoiesis, dietary overload or treatment of diseases that require repeated blood transfusions or iron injections
Blood transfusions -> RBC injury -> release of iron from heme -> accumulation of iron in body (liver, heart, skin)
Clinical Presentation:
Hereditary (75%) – asymptomatic
Fatigue
Impotence
Arthralgias
Hepatomegaly*
Liver stores iron
Skin pigmentation changes/bronzing*
Too much iron gives bronze color
Arthritis*
Bc of iron in joints
Diagnosis
Elevations in serum iron, transferrin and ferritin levels
Hemoglobin is normal or high *
Molecular genetic testing for variants in HFE gene
Treatment
Phlebotomy(ferritin <50)
Avoid dietary iron/alcohol
Genetic testing for family members
Screening for hepatocellular carcinoma
Complications:
Liver cirrhosis and hepatocellular CA
Congestive heart failure
Cardiac arrythmias
Diabetes mellitus
Hypogonadism
Thyroid dysfunction
Polycythemia Vera
Definition: abnormally high RBC, hemoglobin and hematocrit concentration
Hct: >54% in men, > 47% in women
Relative: hematocrit rises due to loss of plasma volume (red cell number stays the same)
Absolute -> primary vs secondary; hematocrit rises due to increased red cell mass
(Absolute) – Primary
Chronic neoplastic, nonmalignant disease of pluripotent bone marrow cells characterized by an absolute increase in total red cell mass and elevated WBC and platelet counts
Pathophysiology:
Erythrocytosis = principal component *
Clonal proliferation of erythroid progenitors is independent of EPO production
Cells express a normal EPO receptor
95% of individuals exhibit an acquired point mutation in the JAK2 gene, responsible for increasing the activity of the EPO receptor but is normally self-regulatory and its activity diminishes over time
In PV, the JAK2 continues to be activated independent of the EPO level
Clinical Manifestations
Variable and depend on blood volume and viscosity
Abdominal pain *
Hypertension
Angina
Headache
Dizziness
Inability to concentrate
Difficulties with vision and hearing due to decreased cerebral flow
Itching ** -- intensified by heat or exposure to water
Pain in fingers and toes
PE Findings
Splenomegaly *
Venous stasis changes
Red color of the face, hands, feet and ears
Raynaud phenomenon – fingers/toes turn white/blue in response to stress painful digits
Thromboangiitis obliterans (buerger disease) – inflammatory disease of blood vessels that leads to blockage by thrombi -> painful blue/purple fingers/toes ulcertation/gangrene
Diagnosis
Increase in the number of erythrocytes and total blood volume confirms the diagnosis
Hgb concentration is typically between 14-28 g/dL and hematocrit is > 60%
Normocytic, normochromic, but anisocytosis may be present
Presence of JAK2 mutation confirms the diagnosis
Treatment
Phlebotomy to decrease blood viscosity
Complications:
Increased viscosity -> hypercoagulable state -> vessel thrombosis and occlusion
Thrombocythemia -> increased bleeding risk -> hemorrhage
Hct >50% -> cardiac dysfunction & vascular obstruction
Hct >60% -> hypoxia
Spontaneous transformation to acute leukemia
(Absolute) – Secondary
Results from physiologic increase in erythropoietin
More common than primary
Etiology
Typically, as a compensatory response to hypoxia
Chronic conditions causing hypoxia: living at high altitudes, chronic heart and lung ds, smoking
Erythropoietin secreting neoplasms
Kidney disease/hydronephrosis/renal cysts -> blood flow obstruction -> increase in erythropoietin
Treatment
Focused on relieving hypoxia
Pharmacotherapy of Anemias
What is anemia?
Anemia is a decrease in hemoglobin (Hgb) and hematocrit (Hct) concentration below the normal range for age and gender
Hgb = iron-rich protein found in RBCs
Main purpose = carry O2 from lungs to tissues
Etiology
Blood loss
Nutritional deficiency / malabsorption
Inflammation or malignancy
Inherited genetic conditions
Medication-induced
Symptoms
Mild or early stage = asymptomatic
Severe and/or prolonged:
Fatigue
Dizziness
Weakness
Headache
Pallor
SOB
anorexia
Microcytic Anemias
Iron Deficiency Anemia (IDA)
Causes of IDA
Inadequate dietary intake
Iron-poor diets (e.g., vegetarian, vegan); malnutrition; disease-related (e.g., dementia, psychosis)
Blood loss
Acute (e.g., GI hemorrhage); chronic (e.g., heavy menses, blood donations, peptic ulcer disease, inflammatory bowel disease); or drug-induced (e.g., NSAIDs, steroids, antiplatelets, anticoagulants)
Decreased iron absorptio
Drugs (e.g., PPIs, H2 blockers, fluoroquinolones, tetracyclines, calcium supplements); GI diseases/procedures (e.g., celiac disease, inflammatory bowel disease, gastrectomy, gastric bypass); foods (dietary fiber, coffee, tea, eggs, milk)
Increased iron requirements
Pregnancy, lactation, infants, rapid growth (e.g., adolescence)
Diagnosis of IDA
Low Hgb
Microcytosis
Low reticulocyte
Low serum and ferritin
Low transferrin saturation
High TIBC (binding affinity)
IDA: Goals of Therapy
Normalize laboratory abnormalities and improve quality of life
Consists of dietary supplementation & iron preparations (PO/IV)
Hgb should increase by 0.7-1 g/week
May take 6-8 weeks for hemoglobin to improve, and up to 6 months to replete iron stores
Serum ferritin > 500 ng/L
Treatment of IDA
Oral iron supplementation
Will adequately treat the majority of patients with IDA
Recommended dose: 100-200 mg elemental iron per day
Parenteral iron supplementation
Typically reserved for select patient populations due to a higher risk of side effects, cost, and burden of administration
Newer studies suggest every other day administration is associated with improved absorption and less side effects
Treatment of IDA: Oral Iron
Dose: 100-200 mg elemental iron per day, or every other day
Ferrous fumarate has 33% Fe
Ferrous gluconate has 11.6% Fe
Oral Iron: Adverse Effects
Metallic taste
NV- Take with food!
Constipation- use stool softener
Dark stool
Oral Iron: Drug Interactions
Drugs that decrease iron absorption
Drugs that reduce acidity of stomach bc iron is absorbed best in acidic environment
Basic ions Al-, Mg- Ca- like antacids
Histamine-2 receptor antagonist
PPI
Tetracycline antibiotics: binds to iron to form insoluable complex
Vitamin C can increase absorption of iron bc increase acidity
Iron decreases the absorption of these drugs
Bisphosphanates
Levodopa
Levothyroxine
Fluoroquinolone antibiotics - bind to form insoluable complex
Tetracycline antibiotics - bind to form insoluable complex
Oral Iron: Patient Counseling
Monitor CBC and iron studies:
Monthly x 3 months; then,
Every 3 months x 1 year (depending on length of treatment)
WARNING
Accidental overdose of iron-containing product = LEADING cause of death in children < 6 years
Educate on proper storage – keep out of reach of children
Antidote = deferoxamine
Indications for IV Iron
Chronic bleeding
Intestinal malabsorption
Intolerant to PO iron
Non-adherence
Hgb under 6 and poor perfusion
IV Iron Preparations
Iron Dextran
Ferumoxytol
Iron sucrose
Sodium ferric gluconate
Ferric carboxymaltose
IV Iron: Adverse Effects
Black Box Warning (Iron Dextran)
Anaphylaxis (hypotension, syncope, unresponsiveness, cardiac arrest)
MUST administer test dose with trained personnel
Side effects:
Nausea, vomiting, pruritis, headache, flushing
Myalgia, arthralgia, back pain, chest pain – resolve within 48 hours
Monitor:
CBC, reticulocyte count, iron studies, symptom improvement
Macrocytic Anemias
Vitamin B12 Deficiency/aka Pernicious Anemia
Causes of Vitamin B12 Deficiency
Dietary deficiency
Malnutrition, strict vegan diet
Decreased production of intrinsic factor
Alcoholism, gastrectomy, surgical resection of ileum, inherited genetic condition
Disease
Chronic (pancreatic insufficiency, Crohn’s disease); acute (H. pylori infection, fish tapeworm); malignancy
Drug-induced
Long-term use (i.e., > 2 years) of metformin, histamine-2 receptor blockers, proton pump inhibitors
Symptoms of Vitamin B12 Deficiency
Gastric mucosal atrophy
Neuropsychiatric abnormalities
Paranoia
Delirium
Confusion
Irritability
Dementia
Yellow-blue color blindness
GI manifestations
Anorexia
Intermittent constipation and diarrhea
Poorly localized abdominal pain
EARLY SYMPTOMS
Glossitis
Weight loss
Neurologic:
- Weakness
- Loss of reflexes
- Peripheral loss of position/vibratory
sensation in extremities
LATE-STAGE SYMPTOMS
Spasticity
Babinski responses
Ataxia
Early diagnosis is IMPORTANT as untreated neurologic deficits are IRREVERSIBLE
Diagnosis of Vitamin B12 Deficiency
MMA elevated
Serum B12 low
Homocysteine elevated
Treatment of B12 Deficiency
Cyanocobalamin (vitamin B12)
Parenteral administration (intramuscular or subcutaneous) – indicated for lack of intrinsic factor; to bypass absorption barriers
Malabsorption, bariatric surgery, gastrectomy
Always indicated if neurologic symptoms are present
Cyanocobalamin (vitamin B12)
Oral administration – indicated for dietary deficiency
May also follow up parenteral therapy with long-term oral treatment
Goals of Therapy
Clinical improvement: increased alertness, appetite, cooperation
Avoid irreversible neurologic defects (will occur if left untreated for > 3 months)
Treatment of B12 Deficiency
Cyanocobalamin
Contraindications (PO/IV)
Hypersensitivity to cobalt or B12 (test dose if suspected)
Adverse effects (RARE)
Pain with injection
Rash, polycythemia vera
Pulmonary edema
Folate Deficiency
Folic acid is necessary to produce nucleic proteins, amino acids, purines, and thymine
Humans are unable to synthesize total daily folate requirement – depend on a dietary source
Sources of folic acid = vegetables (especially green leafy veg), fruits (citrus), yeast, mushrooms, animal organs (liver, kidney)
Minimum daily requirement = 50 to 100 mcg
Deficiency results in the development of large, functionally immature erythrocytes
Causes of Folate Deficiency
Poor eating habits
Older adults, alcoholics, chronically ill
Inadequate absorption
Malabsorption syndromes, Crohn’s disease, celiac disease
Drug-induced: methotrexate, phenytoin, phenobarbital, sulfasalazine, trimethoprim-sulfamethoxazole
Increased requirements for folic acid
Pregnancy, lactation
Increased excretion
Renal dialysis
Symptoms of Folate Deficiency
Weakness
Fatigue
Difficult concentrating
Irritability
Headache
Shortness of breath
Palpitations
No neurologic changes
Diagnosis of Folate Deficiency
Folic acid lvl low
Methymalonic acid is normal
Homocysteine is high
Treatment of Folate Deficiency
Folic acid 1 mg PO daily
Treat indefinitely:
Hemolytic anemia, malabsorption, chronic malnutrition
Adverse effects:
Erythema, skin rash, nausea, abdominal distention, altered sleep patterns, irritability, mental depression, confusion, impaired judgment
Clinical improvement noted by
Increased alertness
Appetite
cooperation
Normocytic Anemias
Anemia of Chronic Kidney Disease
Complication of renal failure, primarily due to reduced erythropoietin (EPO) production by the kidneys
EPO signals bone marrow to produce RBC
Risk factors for worsening renal function:
Hypertension
Diabetes
Family history
Older age
Presence of proteinuria
Structural abnormalities
Goals of Therapy
Treat underlying renal disease
Slow progression & prevent/treat complications of renal failure
Electrolyte management & pharmacologic adjustments
Multivitamin
Iron supplementation
Phosphorus-binding agent
Dose adjustments for renally cleared or harmful mediations
Treatment of Anemia of CKD
Erythropoiesis-Stimulating Agents (ESAs)
Target Hgb 9-11 g/dL, use lowest possible dose
Indication: anemia due to chronic kidney disease
MOA: stimulates production of RBC from progenitor cells in bone marrow
Blackbox warning:
Cardiovascular events
Cancer
CKD: greater risk for death
Contraindication
Uncontrolled hypertension
Hypersensitivity to mammalian cell products or human albumin
Adverse effects
Infection
hyper/hypotension
myalgia
Hemolytic Anemias
Sickle Cell Disease (SCD)
Autosomal recessive disorder that affects hemoglobin
Characterized by “sickle”-shaped red blood cells and painful crises
Affects > 100,000 people in the United States
1 in 3 African Americans are born with sickle cell trait
1 in 365 African Americans are born with sickle cell disease
Goals of Therapy
Primary prevention & treatment of complications
Immunizations (Refer to CDC immunization schedule for updates)
Haemophilus influenzae type B (Hib)
Hepatitis B vaccine
Pneumococcal vaccine
Meningococcal vaccine
Folic acid 1 mg PO daily
Treatment: Hydroxyurea (disease-modifying agent)
Reduced frequency of acute pain crises, reduces episodes of acute chest syndrome, reduces need for blood transfusion
Indicated for adults:
with > 3 moderate to severe pain crises in 1 year; or
with severe or recurrent acute chest syndrome, chronic symptomatic anemia, or disability
Use should be considered in all children > 9 months of age regardless of disease severity
Mechanism of Action: Antimetabolite
Stimulates production of hemoglobin F (HgbF)
Increases water content of RBC
Increases deformability of sickle cells
Alters adhesion of RBC to endothelium of vessels
Hydroxyurea: Hematologic Toxicity
Hold therapy of blood count considered toxic
May resume once recovered after reducing dose
Discontinue permanently if pt develops hematologic toxicity twice
Black box warning
Myelosuppresion and malignacy
AE
Infections
Skin ulcers
N/V/D
Low sperm count
Alopecia
Hyperpigmentation
Drug interaction
Antiretrovirals
Live vaccines: inc risk of severe infection
Use gloves while handling and wash hands before/after
Should be swallowed whole. If unable, patients may disperse tablet in small quantity of water in a teaspoon
If split tablets: must be used within 3 months once broken
Recommend sun protection and avoiding prolonged exposure
Use contraception during and after treatment (bc causes embryo-fetal toxicity)
Females: at least 6 months after completing treatment
Males: at least 12 months after completing treatment
SCD Treatment: Voxelotor
Indication: the treatment of sickle cell disease
Accelerated approval in 2019
Mechanism of Action:
Hemoglobin S (HbS) polymerization inhibitor that binds to HbS and helps to increase HbS affinity for oxygen
Has demonstrated a dose-dependent reduction in clinical measures of hemolysis (indirect bilirubin and reticulocytes)
Precautions
Hypersensitivity reaction
Includes stuff like rash, hives, SOB, mild facial swelling, eosinophilia
DRESS: drug reaction with eosinophilia and systemic symptoms
Voxelotor: Patient Counseling
Swallow tablets whole – Do not cut, crush or chew tablets
Tablets for suspension
Disperse tablet in room temperature clear liquid (water, clear soda, apple juice, clear electrolyte drinks, clear flavored drink) immediately before taking
If missed dose, skip that dose and return to normal schedule the next day
May take with or without food
SCD Treatment: Crizanlizumab
Indication: reduce freq of vaso-occlusive crisis in patients 16 and older with sickle cell disease
Precautions
Infusion related reactions
Other Anemias
Thalassemia
Hereditary disorder of hemoglobin synthesis
Decrease in production of either alpha- or beta-globins or structurally abnormal chain
Pallor and splenomegaly on examination
Complications: growth failure, bony deformities, jaundice, leg ulcers, cholelithiasis
Alpha-Thalassemia Trait
Mild anemia, Hct 28-40%, low MCV, RBC normal to high
Hemoglobin H
Hemolytic anemia, Hct 20-30%, low MCV, reticulocyte count elevated
Beta Thalassemia
Minor: modest anemia, Hct 28-40%, MCV 50-75 fL, RBC normal to high
Intermedia: hemolytic anemia, low MCV
Major: severe anemia, Hct <10%
Thalassemia: Treatment
Alpha-thalassemia & beta-thalassemia minor:
No treatment
Hemoglobin H & beta-thalassemia intermedia:
Folate supplements
Avoid iron & oxidative drugs
Beta-thalassemia major:
Regular transfusion schedule & folate supplementation
Iron chelation therapy + deferoxamine for iron overload
Hemochromatosis, heart failure, cirrhosis, endocrinopathies
Aplastic Anemia
Condition of bone marrow failure that can be hereditary or arise from injury to or abnormal expression of stem cell
Lab values: pancytopenia
Presentation & Etiology
Symptoms:
Fatigue, dyspnea, weakness, skin or mucosal hemorrhage, retinal hemorrhage (visual disturbance)
Pallor, purpura, petechiae (lack of thrombocytes so bleeding
Etiology
Exposure to toxins (pesticides and heavy metal)
Pregnancy, viral infection, autoimmune
Chemotherapy and radiation
Drug induced
Fanconi anemia
Idiopathic
Aplastic Anemia: Drugs Associated
NSAIDS
Anticonvulsants
Sulfonamides
Antihistamines
Estrogens
Allopurinol
Quinidine
Lithium
Aplastic Anemia: Goals of Therapy
Supportive Care
Blood transfusion
Antibiotics
Discontinue therapy, if drug induced
Severe acquired aplastic anemia may require stem cell transplant and/or immunosuppression therapy
Over 40: immunosuppresion
Under 40: stem cell transplant
Acute Blood Loss Anemia
Anemia from Blood Loss
Results from massive hemorrhage associated with spontaneous or traumatic rupture or incision of a large blood vessel
Acute (trauma) or chronic blood loss
Symptoms vary based on severity of volume lost
Hypotension, tachycardia, confusion, dyspnea, diaphoresis
Diagnosis
RBC count, hemoglobin and hematocrit may be high during and immediately following blood loss due to vasoconstriction
Fluid will eventually enter circulation and result in hemodilution a few hours later
Leading to a drop in RBC and hemoglobin
May require additional labs and/or procedures to determine source
Goals of therapy
Hemostasis
Restore blood volume
Treat shock