Hematopoietic System

Equation Note

% in the equations means in actual percent, like 0.01 instead of 1

Terms for Formation of Blood

Hematopoiesis - formation of blood
Erythropoiesis - formation of red blood cells
Leukopoiesis - formation of white blood cells

Functions of the Blood

1. Transport: transportation of nutrients, O₂, hormones, wastes (nitrogenous wastes,CO₂), heat

2. Regulation: of pH, temperature, water content

3. Protection: from pathogens (phagocytosis, complement, interleukins, antibodies), bleeding (clotting system)

Blood Usual Physical Characteristics

pH: 7.35 to 7.45

Temperature: 38 Celsius

Centrifuged Blood Layers

Yellow Layer: Plasma
White Layer: Buffy Coat (Platelets and WBCs)
Red Layer: Red Blood Cells

Blood Composition

8% of total body mass

Splits into:

Plasma (55%):

• 91.5% water

• 1.5% solutes (gases, electrolytes, nutrients, wastes)

• 7% proteins (albumins, globulins, fibrinogen, others)

Formed Elements (45%):

• Red Blood Cells (Most)

• Platelets

• White Blood Cells (Least)

Medical Products of Plasma

Fresh Frozen Plasma (FFP):

• collected from whole blood donations

• centrifuged, supernatant collected

• frozen within 8 hours of collection

• uses: prevention/stopping bleeding (through plasma clotting factors), and plasma donation

Cryoprecipitate:

• FFP that is thawed, further centrifuged

• insoluble precipitate is resuspended in liquid plasma

• mostly concentrated fibrinogen and clotting factors

Hematopoiesis

note: Reticulocytes are already in circulation

Growth Factors

Erythropoietin (EPO): increases RBC formation, note that testosterone increases EPO

Thrombopoietin (TPO): increases Megakaryocyte → platelet formation

Colony Stimulating Factor (CSF):

• GM-CSF: for granulocytes and macrophages

Cytokines:

• interleukins, chemokines, interferons, and tumor necrosis factors

• also have other uses in the body

Stem Cell Therapy Indications

Hematopoietic Stem Cell Transplantation:

• for patients with certain types of leukemia

• after radiation kills bone marrow, stem cells are implanted to replace

Corneal Resurfacing:

• corneal injuries are healed by transplant of corneal stem cells (usually from a recently dead donor)

Skin Regeneration with Epidermal Stem Cells:

• for scars, burns, skin injuries

Life Cycle of a Red Blood Cells

Lifespan: around 120 days (3-4 months)

• after which, it is too damaged and is phagocytosed

• degrades into heme and globin and iron

Heme Pathway:

• heme → biliverdin → bilirubin, gets stored in the liver

• bilirubin → stercobilin (in feces through bile, makes poop brown)

• bilirubin → urobilin (in urine through circulation, makes urine yellow)

Note: acholic stools are characteristic of bile blockage due to this

Iron Pathway:

• when heme is broken down iron is released

• hepcidin prevents iron reabsorption and prevents oxidation of Fe²⁺ to Fe³⁺ if iron is too high

• Transferrin takes iron (in ferric state) to liver where it’s stored in ferritin

Globin Pathway:

• broken down into amino acids to be reused for protein synthesis

Hemoglobin and Hemoglobin Characteristics

a protein and pigment

Normal Levels:

• Male: 13-18 g/dL

• Female: 12-16 g/dL

Each hemoglobin has four hemes each with one Fe²⁺ each, which can bind one O₂ each

Each hemoglobin has two alpha + two beta/delta/gamma globin chains

Hemoglobin Types

A₁: most common (95-98%), has 2 beta chains

A₂: (2-3%), has 2 delta chains

F: fetal, (<1%), 2 gamma chains, can extract oxygen stronger to compete with mother for oxygen in the blood

Hemoglobin Disorders

Methemoglobinemia: inherited or acquired

• Fe²⁺ → Fe³⁺ in heme, changing oxygen affinity, leading to decreased oxygen release

• bluer skin

Thalassemia: genetic mutations that leads to underproduction/absence of globin chains

• Alpha Thalassemia: no alpha chains, lethal, immediate death because alpha chains are in all

• Beta Thalassemia: no beta chains, less lethal, lives but with conditions, causes microcytic, hypochromic RBCs

• can either be no/less/altered beta-globin chains

• causes anemia, hemolysis, extramedullary hematopoiesis (outside bone marrow), iron overload, etc.

Sickle Cell Disease:

• HbA₁ → HbS hemoglobin

• HbS polymerizes, forming abnormal cell structure (crescent shape instead of biconcave)

• tends to be immune to some malarias, weirdly

• prone to hemolysis, vasculopathy (abnormal blood vessels), priapism (sustained painful erection), chest pain

Erythrocyte Parameters 1

1. Hemoglobin Levels

2. Red Blood Cell Count

3. RBC characteristics (shape, color, size, parasite presence with peripheral blood smear)

   • Terms: micro/macrocytic for size, hyper/hypochromic for color

4. Hematocrit

   • % of RBC volume in centrifuged blood

   • high = polycythemia, dehydration

   • low = anemia

5. Reticulocyte Count (used as a surrogate for hematopoiesis rate)

   • normal level 0.5-1.5%

Erythrocyte Parameters 2

6. Mean Corpuscular Volume (MCV)

   • formula: (Hematocrit% x 10)/RBC Count (in millions/mm³)

   • Normal: 80-100 fL (femtoliters)

7. Mean Cell Hemoglobin (MCH)

   • formula: Hgb count/RBC count

   • normal: 27-31 picograms/cell

8. Mean Corpuscular Hemoglobin Concentration (MCHC)

   • hemoglobin per volume of RBCs

   • normochromic = 32-36 g/dL

   • vs hyper/hypochromic

9. Erythrocyte Sedimentation Rate

   • marker of inflammation

   • sedimentation rate of RBCs in vertical tube

   • increased sedimentation with increased aggregation due to clotting factors

   • too slow = not enough clotting, too fast = too much clotting

Anemias

Definition: a deficiency of either RBCs or hemoglobin

1. Hemoglobin Disorders (can cause anemia)

2. Iron Deficiency Anemia

   • microcytic, hypochromic

   • causes: reduced iron intake (vegetarian, insecure food source), bleeding, increased iron requirements (childhood, pregnancy)

   • Diagnosis: low Transferrin Saturation (TSAT) or low Ferritin

3. Pernicious Anemia

   • macrocytic/megaloblastic

   • caused by vitamin B₁₂ deficiency

   • causes: usually intrinsic factor deficiency → lower B₁₂ absorption

4. Hemolytic Anemia

   • premature RBC rupturing leads to less blood cells

   • due to many conditions (ex: sickle cell, hemolytic disease of newborn, etc.)

5. Aplastic Anemia

• bone marrow does not meet RBC production demand

Blood in Feces

Melena:

• some blood in feces

• black feces, muddy consistency

Hematochezia:

• significant blood in feces

• red blood visibly in feces, or blood coming out of anus

A Yoshiko for your troubles

Differential White Blood Cell Count

• the individual count of each different type of leukocyte

• in the past, used a handheld device but these days it is done mostly electronically

Leukocyte Types

Granular Leukocytes:

• appears to have granules under microscope

• Neutrophil

• Eosinophil

• Basophil

Agranular Leukocytes:

• still has granules but are not visible under light microscopy

• Lymphocytes

• Monocytes

Neutrophils

• the most common white blood cell

• nucleus has multiple lobes

• also called polymorphonuclear leukocytes (PMNs) or polys

• Eliminate pathogens via phagocytosis

High Count: indicator of infection, burns, stress, inflammation

Low Count: indicator of radiation exposure, immune conditions (ex: lupus), or vitamin deficiency (ex: B₁₂)

Neutrophil Migration

Steps:

1. Tethering: attaching to the wall of the blood vessel

2. Rolling: rolls across the wall to the spot it needs to go

3. Transmigration: slips between the spaces between endothelial cells

Neutrophil recognizes markers like E-selectin, Integrins, ICAM, and VCAM (adhesion molecules) as attachment points on the vessel walls

This lets neutrophil enter tissue to attack pathogens there

Also involved:

• histamine

• prostanoids

• cytokines

which produce vasodilation

Absolute Neutrophil Count

Formula: WBC Count x %(PMN + Bands)
(PMN means polys or mature Neutrophils, while Bands are immature)

• particularly important in cancer chemotherapy

Neutropenia

• defined as a low neutrophil count

• severity is based on Absolute Neutrophil Count (ANC)

Mild: ANC => 1000, but <1500 cells/μL

Moderate: ANC => 500, but <1000 cells/μL

Severe: ANC < 500 cells/μL

• Severe tends to have patient having sudden and inexplicable fevers

Benign Ethnic Neutropenia (BEN):

• congenital condition; persistently low neutrophil counts African, Middle Eastern, and West Indian descent

• ANC < 1000-1200 cells/μL

Other Granulocytes

Eosinophils:

• attacks parasites and allergies

• stains red with acidic dyes

• hence also called acidophils (?)

• High Count: indicates allergic reaction or parasitic infection

Basophils:

• important in immune and allergic response

• stains blue with basic dyes

• High Count: indicates some allergic reactions, some cancers, hypothyroidism

Lymphocytes

• attacks viruses, leukemias, cancers, malignant cells, infectious mononucleosis

High Count: viral infection, leukemia, infectious mononucleosis

Low Count: prolonged illness, HIV infection, immunosuppression, treatment with cortisol

Function by recognizing antigens and inducing apoptosis

Chimeric Antigen Receptor (CAR)-T Cells

• T Cells are collected from patients

• Collected cells are exposed to specific viruses with specific antigens

• T Cell then develops recognition for specific antigens

• These T Cells are deployed against specific cancers (some leukemias)

Monocytes

• become macrophages when they leave circulation

• kidney or horseshoe shaped nucleus

• High Count: viral & fungal infections, some leukemias, some chronic diseases

• Low Count: bone marrow suppression, treatment with cortisol

Note: tuberculosis can stay dormant within the macrophage

Characteristics and Functions of Leukocytes:

• deal with pathogens via phagocytosis or other immune response

• typically live for only a few hours or few days (except lymphocytes that live for years, ex: memory cells)

• once they leave circulation, they can not return (except lymphocytes)

High WBC Count: leukocytosis

Low WBC Count: leukopenia

Emigration (Details)

• guided by adhesion molecules

Chemotaxis: phagocytotic cells are “attracted” to the correct areas via substances secreted during inflammation and infection

(ex: cytokines)

Nico Sass for Energy

Platelets

Megakaryoblast → Megakaryocyte → Platelets

• each Megakaryocyte forms around 2000-3000 platelets

• non-nucleated cell fragments

Normal Value: 150,000 - 450,000 platelets/μL

Irregular, and disc shaped

Important for hemostasis

Hemostasis

the process of controlling blood flow out of an injured blood vessel

or

a sequence of responses that stops bleeding (prevents hemorrhage, internal or external)

Mechanisms:

1. Vascular Spasm: contraction of blood vessels limits flow to damaged area

2. Platelet Plug Formation

3. Blood Clotting/Coagulation or Coagulation Cascade

4. Fibrinolysis

Platelet Plug Fomation

• also called primary hemostasis

Steps:

Platelet Activation and Adhesion:

• governed by adhesion receptors (ex: GPIIb/IIIa on platelet surface, GP = glycoprotein)

• adhesion receptors bind to various ligands which then adhere to the receptors (ex: collagen, vWF or von Willebrand Factor)

• Rationale: these ligands (ex: collagen) are only exposed when the vessels are damaged

• other activators: Thrombin

Platelet Release Reaction:

• after binding, platelets activate and release granules

• Granules contain various molecules

• ex: 5-HT, ADP, TXA₂ contribute to further platelet activation

• 5-HT and ADP are also vasoconstrictive

• TXA₂ comes from COX pathway

Platelet Aggregation:

• Fibrinogen binds to the GPIIb/IIIa receptor

• Fibrinogen acts as a “rope” to stabilize platelets in place

• Coagulation then takes place if necessary

Specific Roles of Molecules in Platelet Release Activation

ADP:

• binds to purinergic P2Y₁₂ receptors which activate platelets

5-HT:

• binds to 5-HT_2a receptors which further promotes granule release

• synergistic with other agonists

• can coat platelets via protein serotonylation

Potential Link of Primary Hemostasis to Secondary Hemostasis

• procoagulant platelets exposing phosphatidylserine

• promotion of generation of Factor Xa and Thrombin (Factor II)

Hypothetical, won’t come up in exam

Blood Clotting

• secondary hemostasis

• also called Coagulation

• reinforces the platelet plug by creating a blood clot or thrombus

• functions via a cascade of clotting factors

• cascade is heavily reliant on calcium

Thrombosis: the abnormal formation of blood clots that can lead to stroke or heart attack

Coagulation Cascade: Extrinsic Pathway

• fast response (from seconds to minutes)

• started by tissue trauma

• relies on factors outside the blood vessels that enter due to trauma

• Tissue Factor (Factor III) or thromboplastin outside the vessels bonds with Factor VII (and activates it to Factor VIIa) (requires calcium)

• the Factor III/VIIa complex activates Factor X to Factor Xa

• Factor V is activated by calcium to Factor Va

• Factor Va combines with Factor Xa to form Prothrombinase

Coagulation Cascade: Intrinsic Pathway

• slower response (takes several minutes)

• started by endothelial cell damage (inner lining of blood vessel)

• Factor XII is activated via various stimuli (ex: collagen in vessel walls or phospholipids from damaged platelets)

• Factor XIIa activates Factor XI, which activates Factor IX

• vWF stabilized Factor VIIIa, which then binds to Factor IXa

• The Factor VIIIa/IXa complex activates Factor X into Factor Xa

• Factor Xa combines with Factor Va to form Prothrombinase

• requires Calcium

Note: thrombin can further activate Factor 8 and 11

Coagulation Cascade: Common Pathway

• Prothrombinase activates Prothrombin (Factor II) into Thrombin (Factor IIa)

• One prothrombinase can activate around a thousand thrombin (thrombin burst)

• Thrombin activates platelets

• It also activates fibrinogen (Factor I) into fibrin (Factor Ia)

• Fibrin can

• Fibrin attaches to Factor XIII which secures the platelet plug further

• The fibrin form strands and act as a “rope” securing the plug in place

Vitamin K

• can be sourced from leafy greens

• Vitamin K is required for the synthesis of Factors II, VII, IX, X (mmemonic: 1972) (9-10-7-2)

• fat-soluble, absorbed via intestine if lipid absorption is normal

• Disorders that slow lipid absorption = Vitamin K deficiency = uncontrolled bleeding

Clot Retraction

• happens once clot has formed

• fibrin clot “tightens”

• pulls the edges of the injury together, stemming blood loss and expediting healing

Hemophilia

• condition characterized by less than 5-10% of normal Clotting Factor activity

Hemophilia A: Classic - Deficiency of Factor VIII

Hemophilia B: Christmas Disease - Deficiency of Factor IX

Hemophilia C: Rosenthal Syndrome - Deficiency of Factor XI (rarer?)

Fibrinolysis

• dissolves small, inappropriate clots

• also dissolves clots from healed wounds

• Plasminogen is an inactive plasma enzyme that is incorporated into the clot when it is formed

• Body tissues and blood contain components that activate it into Plasmin (or fibrinolysin)

• ex: Thrombin (IIa) and Tissue Plasminogen Activator (t-PA)

• Plasmin dissolves fibrin threads

D-dimers

• breakdown product of fibrin

• elevated in venous thromboembolism and COVID-19 (marker for inflammation)

• can also be a marker for old age, pregnancy, contraceptive use, exercise

• used for ruling out the previous conditions (rather than diagnosis)

Other Mechanisms for Clot Regulation & Termination

Primary Hemostasis (Platelet Plug) Inhibitors: Nitric Oxide (NO) (vasodilator) and Prostaglandin I2/Prostacyclin (PGI₂)

Secondary Hemostasis (Coagulation Cascade) Regulators:

• antithrombin

• heparin

• heparan

• activated protein C

• protein S

Aplastic Anemia

rare bone marrow failure

• aplastic means no more tissue formation

• absence of blood cell formation

Causes:

• direct damage (medicine, chemicals, pathogens)

• Genetic (inherited or random mutation)

• Autoimmune disorder

S/Sx:

• Pancytopenia (meaning thrombocytopenia + leukopenia + anemia, all cell types down)

• Hypocellular Bone Marrow

• Bleeding (less platelet), Infection Prone (less WBCs), Fatigue (less RBCs)

Tx:

• transplant

• immunosuppression

• Growth Factor administration (ex: thrombopoietin receptor agonist)

Airi Toaster Appreciation

Blood Groups and Blood Types

Antigens that determine blood type are called agglutinogens and are generally glycoproteins and glycolipids

Antibodies related to blood types: agglutinins

Blood Group: based on the presence of absence of specific agglutinogens

• ex: ABO Blood Group, Rh Blood Group

Blood Type: based on the specific antigen present within a blood group

• ex: AB, O, A; Rh+, Rh-

Incidence does vary among population groups

Incompatible Blood Transfusion

Agglutination: clumping, occurs when agglutinins bind to antigens on incompatible RBCs, causing them to cross-link

• afterwards, the complex attracts complement, causing leaky RBCs and hemolysis

• liberated hemoglobin can also damage kidneys by blocking filters

ABO Blood Group

Blood can express, A antigens, B antigens, both, or neither

Type A: A only

Type B: B only

Type AB: both (universal recipient, since produces no antibodies)

Type O: neither (universal donor, since doesn’t have antigens, but can only receive O blood)

Note: the term “universal” is a misnomer since Rh Blood group is still needed to be considered, as well as other factors

Rh Blood Group

• originally discovered in Rhesus monkeys

• Rh factor is the name of the antigen displayed

Rh⁺: most common, Rh factor antigen is present

Rh^-: less common, Rh factor antigen is absent

Normally, blood does not contain anti-Rh antibodies even if Rh^-

An Rh^- person develops antibodies after receiving Rh⁺ blood, which will then cause agglutination if Rh⁺ blood is given again

Proper Blood Screening

• For ~80% of the population, ABO antibodies are present in saliva and other fluids which can be used in screening

• blood is either cross-matched to potential donor blood, or blood is screened for antibody presence

• for screening, drops are mixed with antisera (solutions containing antibodies) to observe reactions

• after screening, cross-matching occurs

• cross-matching: possible donor RBCs are mixed into patient serum to check reactions (or patient serum is checked against a test panel of RBCs)

Genetic Determination of Blood Type

• alleles code for specific antigens

• A and B are dominant, O is less dominant

• So having A/B and O will result in A/B

• having both A and B will result in AB

• To get O, one must have O and O

Hemolytic Disease of the Newborn

• blood of fetus and mother rarely come into contact, but it is possible through placenta

• if Rh⁺ baby blood leaks into Rh^- mother blood, mother will produce antibodies that attack baby

• since blood leakage is most probably during delivery, first baby is usually unaffected

• if mother has another Rh⁺ baby, the child becomes at risk

• anti-Rh gamma globulin can help mitigate effects if used correctly

note: ABO agglutinins tend to be too large to cross placenta, so mother-infant ABO incompatibility rarely causes problems