Physiology- Hematology

components of blood

• Plasma (55%)- noncellular component

• Buffy coat (<1%)

• Erythrocytes (45%)

total blood volume for humans

women = 5L

men= 5.5L

plasma

• non cellular

• PLASMA PROTEINS

  • antibodies

  • coagulation factors

  • ALBUMIN

    • drives oncotic pressure/gradient

    • carrier protein

• 90% water + dissolved substances

• vitamins and nutrients

• electrolytes (ex. Na+, K+, etc)

• hormones

functions of plasma proteins

1. EST ONCOTIC GRADIENT

2. help maintain pH (act as buffer)

3. transport poorly soluble substances (by binding to transport proteins)

4. aid in immunity (immunoglobulins)

5. promote blood clotting

what organ is primarily responsible for the production of plasma proteins?

liver

osmosis

move down concentration gradient

• high concentrate of H2O→ low concentration of H2O

albumin

• primary driver of oncotic pressure

• most abundant plasma protein

how does the presence of albumin in blood prevent edema?

the high concentration of albumin in blood pulls water/fluid into vessels instead of into tissues (osmosis)

intravascualr space/vasculature

plasma

intersistial space/fluid

fluid btwn cells

intracellular fluid

fluid inside cells

flow of blood

heart→ arteries (nutrient and oxygen rich)→ capillary beds (exchange for nutrient and oxygen poor blood)→ veins→ heart→ lungs

capillaries

• specialized vessels

  • sites of exchange btwn plasma and tissue cells

• oxygen and nutrient rich blood diffuses into tissue via FILTRATION (exits arterial end) and diffuses out of the tissue via REABSORPTION (venous end- now oxygen poor)

characteristics of capillaries

• thin walls (1 endothelial cell)

  • easier for filtration and reabsorption

• extensive branching = large surface area for exchange

• velocity of travel is slow

• walls range in “porosity” depending on the target organ

  • fenestrations= pores (larger → easier filt/reab)

capillary filtration

mvmt of fluid OUT of the capillary and into interstitial space

capillary reabsorption

mvmt of lfuid back INTO capillary

what are the forces that drive mvmt of fluid in/out of capillaries

pressure gradients

• hydrostatic pressure: mechanical force (blood pressure)

• oncotic pressure: force drawing water to area of HIGHER particle conc (albumin greater in vasculature)

arterial end of capillary bed

• hydrostatic pressure (blood pressure) > osmotic pressure

  • closer the heart, therefore greater pressure

• fluid moves out of the capillary into interstitial space (filtration)

venous end of capillary bed

osmotic/ oncotic pressure > hydrostatic pressure

• fluid moves back into capillary (reabsorption)

what happens with an increase in hydrostatic pressure

more filtration occurs → edema

what happens with a decrease in albumin?

decrease in osmotic pressure→ edema (water no longer wanting to go into vasculature/ no longer low concentration of H2O)

why is there an excess amount of fluid in the belly for Kwashiorkor

malnutrition

• there is a loss of albumin production in the liver due to lack of nutrients/proteins

• not enough solute (albumin) in vasculature→ fluid comes out due to concentration gradient

what is hematopoiesis

production of blood cells

characteristics of hematopoiesis

• ALL blood cells develop from the same HEMATOPOIETIC STEM CELL in bone marrow

• differentiation is driven by different cytokines, hormones, and growth factors

what types of cells can stem cells differentiate into

• leukocytes (WBCs)

• erythrocytes (RBCs)

• thrombocytes (platelets)

differentiation of hematopoietic stem cells into RBCs

erythropoiesis → erythropoietin

differentiation of hematopoietic stem cells into WBCs

leukopoiesis→ growth factors and cytokines

differentiation of hematopoietic stem cells into platelets

thrombopoiesis→ thrombopoietin

characteristics of erythrocytes (RBCs)

• looses most of it’s organelles

  • no nucleus

  • no mitochondria (conserve oxygen it carries)

• flexible surface membrane

  • move through small capillaries

• bioconcave

  • maximize surface area

• contains hemoglobin

  • oxygen carrying molecule

  • contains iron

structure of hemoglobin

GLOBIN

• structural protein with 4 subunits (2 alpha and 2 beta)

HEME

• iron groups found in globin subunits

• carry 1 molecule of oxygen each

how many molecules of oxygen can 1 RBC carry?

250 hemoglobin (in 1 RBC) x4 oxygens= 1 billion

why is hemoglobin needed?

oxygen is poorly soluble in the blood→ needs transport protein

what is a possibility of going wrong with binding to hemoglobin?

• other molecules can bind to heme

  • binding affinity of CO>O2—> carbon monoxide poisoning

variations of Hemoglobin

• HbA

• HbA1c

• HbF

HbA

• 2 alpha chains

• 2 beta chains

• 92% of adult Hgb

HbA1c

• avg glucose number over ~3 months

  • spontaneously binds glucose over time

• 2 alpha chains

• beta-NH glucose

• increased in diabetes

HbF

• 2 alpha chains

• 2 gamma chains

• major fetal Hgb

  • promotes oxygen transfer across placenta as it more tightly binds to O2

what drives erythropoiesis (creation of more RBCs)?

hypoxia drives erythropoietin (EPO) production in kidney→ EPO travels to bone marrow→ erythropoiesis

why is EPO produced by the kidney

the organ receives extreme high blood flow for filtration adn reabsorption, therefore is sensitive to changes in O2

clinical correlation: lance armstrong

use of synthetic EPO→ increase of erythrocyte production→ increased amount of O2 to tissues

anemia

decreased hematocrit

• normal erythrocyte count (hematocrit) is 45%

CAUSE DECREASE IN O2 and PERFUSION

causes of anemia

• destruction/loss of RBCs

  • hemorrhage

  • hemolysis

• decreased production

  • nutritional deficiencies (iron, B12, folate)

  • renal anemia (kidneys cannot produce EPO)

    • ex. pt with chronic kidney disease or renal failure

  • aplastic anemia (bone marrow dysfunction)

Vitamin B12 or folate deficiency

macrocytic anemia

• B12 and folate needed to promote DNA synthesis and cell division, therefore low levels → inhibition of DNA synthesis (cell. multiplication)

• very few, large hemoglobin rich RBCs

iron deficiency

microcytic anemia

• low levels of iron→ lack of hemoglobin→ inhibition of hemoglobin synthesis→ small hemoglobin-poor erythrocytes (pale in color)

iron absorption and metabolism

• iron is needed for hemoglobin synthesis

  • acquired through GI tract; absorbed in duodenum by enterocytes

how is iron stored

in cells within protein ferritin (in liver)

iron metabolism

• iron absorbed in GI tract needs to be transferred to the liver for storage and bone marrow for erythropoiesis

• transferred by transfer protein transferrin (in blood)

RBC life cycle

• 100-120 days

• aging→ structural proteins that allow for flexibility breakdown

  • RBCs become stiff and get stuck in small capillaries in spleen→ RBC breakdown

  • macrophages ingest and breakdown Hgb

    • IRON is RECYCLED and stored in the liver (within ferritin)

    • HEME is broken down into bilirubin (conjugated in liver → make bile)

structure of arterial wall

1) tunica intima: innermost layer

• composed of endothelial cells

• secretes chemical substances that affect blood clotting

2) tunica media: middle layer

• composed of smooth muscle

  • vasoconstriction/vasodilation

3) tunica externa; outermost layer

• composed of collagen and elastic fibers

  • give vessel great flexibility

what is hemostasis

the localized stoppage of bleeding

three major steps of hemostasis

1) vascular spasm

2) formation of platelet plug

3) blood coagulation (clotting)

cellular and molecular components of hemostasis

1) thrombocytes

2) coagulation factors

thrombocytes in hemostasis

• thrombopoiesis: thrombopoietin (TPO- produced by liver and kidney) stimulates myeloid stem cell to differentiate into thrombocyte

  • TPO producion is stimulated by inflammatory cytokines

  • ex. chronic inflammation leads to increased risk of blood clots; increased inflammatory cytokines→ increased production of TPO→ increased production of thrombocytes

coagulation factors in hemostasis

• produced by liver→ circulate throughout serum to be ACTIVATED by other protein/enzymes

  • inactive in blood

what prevents blood from spontaneously clotting?

1) endothelial cells

• release N2O- inhibits platelet adhesion to endothelial wall

• surface contains heparin -- inactivates clotting factors

2) forward mvmt of blood flow keeps platelets from sticking to endothelial surface

3) platelets and clotting factors are in their INACTIVE forms when circulating in the plasma

why are people more at risk of developing a blot clot when not consistently moving?

decrease in movement→ decrease in blood flow→ increased risk due to blood pooling

what is the underlying mechanism that results in hemostasis

1) injury triggers VASOSPASM to reduce size of vessel injury; “shrink the wound”/contract

• injured endothelial cells secrete endothelin → triggers tunica media contraction (vasoconstriction)

• direct injury to smooth muscle stimulates contraction reflex

2) platelets collect and adhere to site of injury to form platelet plug

• vWF (von willenbrand factor) binds to exposed collagen from injury ( found in connective tissue underlying endothelial lining)

• vWF serves as a bridge btwn fast moving platelets and injured vessel wall

• binding of platelets and vWF to collagen= platelet activation

• activated platelets secrete ADP and thromboxane A2 (to activate more platelets and increase ADP)

  • ADP causes nearby platelet surfaces to become sticky

  • thromboxane A2 directly promotes platelet aggregation + promotes release of more ADP from activated platelets

• injured epithelial cells are no longer abel to secrete N2O

3) coagulation cascade is activated

• loss of heparin - no longer inactivating clotting factors

what is the body’s most powerful hemostatic mechanism

clotting; reinforces the seal formed by platelet plug

two pathways to activate coagulation

intrinsic and extrinsic

intrinsic pathway

• activated by exposed collagen under vessel surface

  • damage INSIDE vasculature

  • ex. putting in a line

• longer pathway; involves factors XII, XI, IX, VIII

• goes to “common pathway” to factor X→ thrombin→ fibrinogen→ fibrin clot

• tested by aPTT

  • pt ability to clot/clotting time

extrinsic pathway

• activated by tissue damage

  • when damaged tissue releases tissue factor (III)

  • ex. cut

• shorter pathway; factor VII

• goes to “common pathway” to factor X→ thrombin→ fibrinogen→ fibrin clot

• tested by PT/INR

  • pt ability to clot/clotting time

where does the common pathway converge

factor X

what would you expect on a PT/INR from a pt with cirrhosis

elevated PT/INR

• the liver is the site of formation for most clotting factors, therefore if it is not functioning appropriately, there will be a decrease in production of clotting factors (such as factor VII), therefore increasing the time it takes to create a clot