ALTERATIONS OF THE HEMATOLOGIC SYSTEM

Blood volume:

 quarts (5.5 liters)

• Plasma: 55% of blood volume

91% water

Solutes

Plasma proteins

Erythrocyte/RBC

Most abundant cell in blood

~120-day life cycle

Function: transport oxygen to tissues

Biconcave shape

Size: 6 - 8 μm diameter

Reversibly deformable

Hemoglobin (Hgb)

Oxygen-carrying protein of RBC

Up to 300 Hgb molecules per RBC

Components of a single Hgb

• Heme: four iron-protoporphyrin complexes

• Globins: two pairs of polypeptide chains

Each heme can carry one O₂ molecule

If all hemes are carrying O2, the Hgb is said to be saturated

Heme also binds CO2

Red Cell Count

Number of RBCs per μL of blood

Normals

Males: 4.6 – 6.2 million cells/mm3

Females: 4.2 – 5.4 million cells/mm3

Reticulocyte Count

Number of immature RBCs expressed as a percentage of total RBC count

• Normal: approximately 1%

Hematocrit (Hct)

Ratio of RBCs to plasma

Expressed as a percentage

Normals

• Males: 40 – 54%

• Females: 38 – 47% 

Hemoglobin (Hgb)

Expressed as grams of Hgb per volume of blood

Normals

• Males:  14 – 18 g/dL

• Females: 12 – 16 g/dL

^MEMORIZE

RBC Morphology

MCV: mean corpuscular volume

Size of RBC (80 – 100 femtoliters)

MCH: mean corpuscular Hgb

Amount of Hgb in each RBC (27 – 31 pg/cell)

MCHC: mean corpuscular Hgb concentration

Percentage of RBC occupied by Hgb (32 – 36 g/dL)

Hematopoiesis

Blood cell production from hematopoietic stem cells

Takes place in bone marrow

Constant, ongoing, responsive to cellular deficits

100 billion to 1 trillion new blood cells produced per day

Cellular signaling via cytokines and growth factors activates stem cells 🡺 proliferation and differentiation

Bone Marrow

Red (active)

Hematopoietic stem cells live here

Pelvis, vertebrae, cranium, mandible, sternum, ribs, proximal humerus/femur

Vascular

Yellow (inactive)

Fatty

Erythropoiesis

Erythrocyte (RBC) production

Erythroid progenitor cells proliferate and differentiate into proerythroblasts

Differentiation continues through several intermediate forms

Hgb is synthesized, intracellular structures are lost

Reticulocytes are last immature forms of erythrocytes

Reticulocytes enter bloodstream and soon after become mature erythrocytes

Regulation of Erythropoiesis

Decreased arterial oxygen levels 🡺 Kidneys synthesize and release erythropoietin 🡺 Erythropoietin stimulates bone marrow to increase proliferation and differentiation of proerythroblasts which become erythrocytes 🡺 Increased erythrocyte production often corrects the hypoxia 🡺 Kidneys sense normalized arterial oxygen levels 🡺 Erythropoietin synthesis/release declines (negative feedback)

Important Nutrients Required for Erythropoiesis

Vitamins

• B₁₂: DNA synthesis, maturation of RBCs

• Folate: DNA and RNA synthesis, maturation of RBCs

Minerals

• Iron: Hgb synthesis (basically make hemoglobin)

Erythrocyte Destruction

Lifespan ~ 120 days

Aged RBCs are sequestered and destroyed by macrophages, primarily in spleen

Iron in Hgb is recycled

Porphyrin is reduced to bilirubin, transported to liver, excreted in bile, feces, urine

Globin chains are broken down into amino acids

Iron

67% of total body iron is bound to heme

Remainder is stored in other cells

< 1mg lost daily in urine, sweat, minor bleeding

25mg used daily for erythropoiesis (< 2% comes from diet, the rest comes from erythrocyte recycling)

Iron travels in bloodstream to bone marrow for Hgb production

BLOOD CELL PRODUCTION AND DESTRUCTION

Hematopoiesis

Erythropoiesis

Erythrocyte Destruction

ANEMIA

Alterations of Erythrocyte Function

Anemia

Deficiency of erythrocytes and/or Hgb in blood

Result: decreased capacity to deliver oxygen to tissues 🡺 hypoxia

Laboratory values

• Males: Hgb < 14 g/dL

• Females: Hgb < 12 g/dL

General Causes of Anemia

Impaired erythrocyte production

Reduced production

Abnormal production

Blood loss

Acute loss (hemorrhage)

Chronic loss

Increased erythrocyte destruction

Hemolytic diseases

General Consequences of Anemia

Classic symptoms

Fatigue, weakness, dyspnea, pallor

Organ dysfunction

Compensation

Respiratory, cardiovascular, hematologic

** Variable symptoms based on severity of anemia and ability of body to compensate **

Classifications of Anemia

Morphology

RBC size identified by terms that end in “cytic”

Normocytic, macrocytic, microcytic

Hgb content identified by terms that end in “chromic”

Normochromic, hypochromic

MCV: mean corpuscular volume

Size of RBC

Normocytic, microcytic, macrocytic

MCH: mean corpuscular Hgb

Amount of Hgb in each RBC (by weight)

MCHC: mean corpuscular Hgb concentration

Percentage of RBC occupied by Hgb

Normochromic, hypochromic

MACROCYTIC-NORMOCHROMIC ANEMIAS

(MEGALOBLASTIC ANEMIAS)

Pernicious Anemia

Folate Deficiency Anemia

Megaloblastic Anemias

Vitamin deficiencies cause defective DNA/RNA synthesis within maturing erythrocyte

Result: extra-large stem cells (megaloblasts) become extra-large erythrocytes (macrocytes)

Hgb is normal

Defective erythrocytes die prematurely 🡺 anemia

Pernicious Anemia (PA)

Vitamin B₁₂ deficiency

Essential vitamin

Requires intrinsic factor (IF) for absorption

Stored in liver

Sources: animal products

• Meat, eggs, milk, cheese, poultry, seafood

Causes of PA

Autoimmune destruction of gastric parietal cells or IF 🡺 IF deficiency

Congenital deficiency of IF

Gastrectomy 🡺 IF deficiency

Alcoholism 🡺 chronic gastritis

Smoking 

Inadequate dietary intake 

Clinical Manifestations of PA

Slow, gradual development over 20 – 30 years

Early symptoms

• Non-specific, often ignored

• Infections, mood swings

• Vague GI, cardiac, kidney ailments

60 is median age of diagnosis

Symptoms of anemia 

• Weakness, fatigue, dyspnea, pallor

Symptoms associated with B₁₂ deficiency

• Gastrointestinal symptoms

Glossitis, decreased appetite, weight loss, abdominal pain, nausea, vomiting, diarrhea

• Neuronal demyelination 🡺 neuronal death

Proprioceptive loss, paresthesia, spasticity, ataxia, affective disorders 

Irreversible

Diagnosis of PA

Symptoms of anemia

Lab evaluation

Complete blood count (CBC)

Low Hct and Hgb

Macrocytic, normochromic RBCs

Anti-parietal cell or anti-IF antibodies

Low serum B12

Gastric biopsy

Achlorhydria

Bone marrow aspirate

Megaloblasts

Treatment of PA

Incurable but treatment is successful

Lifelong B₁₂ supplementation

• Injections

• High-dose oral B₁₂ 

Erythrocyte counts return to normal in 5 – 6 weeks

Fatal if untreated (heart failure)

Folate Deficiency Anemia

Essential vitamin

Stored in liver

Sources

• Meat, beans, lentils, spinach, lettuce, avocados, broccoli, citrus fruits, fortified grains

Causes of Folate Deficiency Anemia

Inadequate dietary intake

Malabsorption 

Alcoholism (depletes folate stores in liver)

Liver disease

Pregnancy (increased folate demand)

Clinical Manifestations of Folate Deficiency Anemia

Symptoms of anemia 

• Weakness, fatigue, dyspnea, pallor

Symptoms associated with folate deficiency

• Gastrointestinal symptoms

Stomatitis, (glossitis, cheilosis, oral ulcerations), decreased appetite, weight loss, dysphagia, diarrhea

• Neural tube defects in fetus

• Atherosclerosis/coronary artery disease

Diagnosis of Folate Deficiency Anemia

Symptoms of anemia

Lab evaluation

• Complete blood count (CBC)

Low Hct and Hgb

Macrocytic, normochromic RBCs

• Low serum folate

Treatment of Folate Deficiency Anemia

Oral/IV supplementation ~ 1 mg/day

Increased dietary intake

Symptoms of anemia may improve in 1 - 2 weeks

MICROCYTIC-HYPOCHROMIC ANEMIAS

Iron Deficiency Anemia

Microcytic-Hypochromic Anemia

Disorders of iron metabolism

Disorders of porphyrin and heme synthesis

Disorders of globin synthesis

Result: abnormally low amounts of Hgb (hypochromic) and, therefore, abnormally small erythrocytes (microcytes) 

Depleted iron stores/impaired iron delivery 🡺 decreased Hgb synthesis 🡺 anemia

Iron Deficiency Anemia

Most common type of anemia worldwide

Demand for iron exceeds supply

Higher incidence in females (during reproductive years)

Sources

Meat, eggs, leafy greens, iron-fortified foods

Causes of IDA

Excessive blood loss over time

• Gastrointestinal bleeding

Ulcers, erosive esophagitis, cancers, chronic NSAID use

• Excessive menstruation

Pregnancy (increased blood volume)

Inadequate dietary intake

Malabsorption

Stages of Iron Deficiency Anemia

Stage I

• Iron stores are used for RBC production and are not replenished

• Erythropoiesis normal

• Normal Hgb content

Stage II

• Decreased iron transportation to bone marrow

• Iron deficient erythropoiesis begins

• Microcytic hypochromic RBCs mixed with normal RBCs

Stage III

• Iron deficient erythropoiesis continues

• Microcytic hypochromic RBCs have now replaced all the normal RBCs

Clinical Manifestations of IDA

Gradual development

Symptoms of anemia 

• Weakness, fatigue, dyspnea, pallor

Epithelial structural/functional changes

• Brittle, ridged, spoon-shaped fingernails

• Stomatitis (cheilosis, glossitis, oral ulcerations)

• Esophageal web

• Hyposalivation, dysphagia, 

Gastritis

Headache, irritability, numbness/tingling

Pica

Restless leg syndrome

Diagnosis of IDA

Symptoms of anemia

Lab evaluation

• Complete blood count (CBC)

Low Hct and Hgb

Microcytic, hypochromic RBCs

Serum ferritin low (< 50 mcg/L)

NORMOCYTIC-NORMOCHROMIC ANEMIAS

Aplastic Anemia

Posthemorrhagic Anemia

Hemolytic Anemias

Normocytic-normochromic Anemias

Least common 

Several types

No common etiology or pathogenic mechanisms

Result: decreased number of normal sized erythrocytes (normocytic) with normal Hgb content (normochromic)

Aplastic Anemia (AA)

Bone marrow failure 🡺 pancytopenia

Critical condition, rare

Causes

Idiopathic

• Autoimmune disorder

• Chemical/radiation exposure

• Medications

• Viral infections (HIV, hepatitis, cytomegalovirus)

Clinical Manifestations of AA

Variable progression, potentially life-threatening 

Symptoms of anemia 

• Weakness, fatigue, dyspnea, pallor

Symptoms of leukopenia

• Infection, fever

Symptoms of thrombocytopenia

• Bruising, bleeding gums, epistaxis, hemorrhage

Diagnosis of AA

Symptoms of pancytopenia

Lab evaluation

• Pancytopenia

Bone marrow biopsy

• Reduced cellularity to < 1% of normal 

• High fat content, fibrous tissue

Treatment of AA

Remove offending agent 

Blood product administration

Treat/prevent infection

Bone marrow transplant (sibling) 🡺 cure

• Radiation/chemotherapy first

Immunotherapy

Hematopoietic growth factor

Posthemorrhagic Anemia

Acute blood loss 🡺 anemia

Symptoms after > 1 liter blood loss

Causes

• Hemorrhaging

Trauma, massive GI bleeding, uterine tube rupture in ectopic pregnancy

Internal blood loss: iron will be recycled

External blood loss: iron is lost 🡺 erythropoiesis is impeded, could become IDA

Clinical Manifestations of Posthemorrhagic Anemia

Depends on volume and rapidity of loss

Cardiovascular symptoms

• Hypotension, decreased cardiac output, renal compensation (increased ADH/aldosterone 🡺 hemodilution), tachycardia, thready pulse, cool clammy skin, shock, lactic acidosis

Respiratory symptoms

• Hyperventilation, dyspnea

Treatment of Posthemorrhagic Anemia

Identify/repair source of hemorrhage

Restore intravascular volume

• IV fluids

• Blood production transfusion if loss is severe

Possible iron supplementation 

Normal RBC count in 4 - 6 weeks

Normal Hgb in 6 - 8 weeks

Hemolytic Anemias

Premature accelerated destruction of erythrocytes 🡺 anemia

Result: elevated levels of erythropoietin and increased accumulations of byproducts of Hgb catabolism

Causes of Hemolytic Anemia

Congenital/hereditary

• Structural defects of RBC plasma membrane, enzyme deficiencies, defects of globin synthesis

  Acquired

  • Immune-mediated

  Autoantibodies formed against RBC antigens

  Allergic reaction to drug antigens that attach to RBC surface (PCN)

  Transfusion reaction

  • Traumatic: prosthetic heart valves, hemodialysis

  • Infectious: malaria, hookworm, mycoplasma pneumonia

  • Chemical: RBCs exposed to toxic agents, venoms

Hemolysis

Intravascular: takes places in vessels

• Least common

• Destruction of RBCs in circulation by antibody and complement

Extravascular: takes place in the spleen/liver

• Opsonized and/or damaged RBCs removed from circulation and phagocytized by macrophages

Clinical Manifestations of Hemolytic Anemias

Depends on degree of hemolysis and success of compensatory erythropoiesis: does RBC production exceed destruction?

Symptoms of anemia 

• Weakness, fatigue, dyspnea, pallor

Jaundice: destruction of heme exceeds liver’s ability to excrete it as bilirubin

Splenomegaly

Diagnosis of Hemolytic Anemias

Symptoms of anemia and hemolysis

Lab evaluation

• Decreased Hct and Hgb

• Increased reticulocytes

• Elevated bilirubin 

Bone marrow studies

• Increased erythrocyte stem cells

Treatment of Hemolytic Anemias

Remove cause/treat disorder

Corticosteroids/immunosuppressive meds

Splenectomy (if site of hemolysis) 🡺 long term remission

Sickle Cell Anemia: A Form of Hemolytic Anemia

Single gene mutation (autosomal recessive disorder)

Presence of abnormal Hgb (Hgb S) in addition to normal Hgb

Periodic “sickle cell crises”

Hgb S reacts to hypoxemia, dehydration, acidosis, and sometimes temperature changes

Alters RBC

Elongates shape (sickling)

Increases membrane rigidity

Initially reversible but becomes permanent with repeated exposure

Sickled cells are lysed in spleen 🡺 hemolytic anemia

Sickled cells obstruct peripheral capillaries

Vaso-occlusive/thrombotic crisis

Obstruction of blood flow in microcirculation 🡺 vasospasm 🡺 increased obstruction

Thrombosis and local infarcts

Very painful

Multi-system effects (ie: kidney)

Clinical Manifestations of Sickle Cell Anemia

Symptoms of anemia 

• Weakness, fatigue, dyspnea, pallor

Jaundice

Symptoms of crises

Treatment of Sickle Cell Anemia

Avoid precipitating causes

Provide oxygen if hypoxic

IV fluids

RBC transfusions

Pain management

Stem cell transplant (difficult to find well-matched donors)