Blood and Wound Healing

Formation of Blood

hematopoiesis

maintenance of blood

hemostasis

sickle cell disease and anemias effect hematopoiesis/ hemostasis

hematopoiesis (formation of blood)

platelet disorders and coagulation effect hematopoiesis/hemostasis

hematostasis

• iron deficiencies

• vitamin B12 deficiency

• folic acid deficiency

• chronic disease/inflammation

all of the following lead to ________ which impacts hemostasis/hematopoiesis

anemia hematopoiesis (formation of blood)

Blood is made up of ________ and ________ elements

plasma and cellular

Plasma is made up of

• Water (92%)

• ______(7%) — albumins, globulins, fibrinogen

• _____, organic molecules (lipids), _____ (1%)

• proteins

• salt GAS

Cellular Elements of Blood:

• red blood cells — also called ________

• platelets — split off from _________

• white blood cells - broader term _________

• erythrocytes

• megakaryocytes

• leukocytes

are platelets cells?

NO they don’t have nucleus they are branched from megakaryotes

ratio of red blood cells to plasma expressed as a percentage after ___________

RBC: plasma

ex (45:55)

after centrifugation

HEMATOCRIT

blood cells are produced in the

bone marrow

what is included in the white buffy coat layer between the red blood cells and plasma? what percentage of the blood do they make up?

leukocytes and platelets (less than 1% of blood)

after centrifugation which layers of the blood are on the top, middle, and bottom

top = plasma (light)

middle = sticky buffy coat (leukocytes and platelets)

bottom = red blood cells

leukopoeisis

production of white blood cells

what is the CBC that is most often the first thing we look for in patients when they come into the emergency room

complete blood count

the average volume of one blood cell (found in CBC)

mean corpusccular volume

corpuscule - small unattached cell - RBC

amount of hemoglobin per red blood cell (found in CBC)

mean corpuscular hemoglobin

the amount of hemoglobin pper blood volume of one re dblood cell

Mean corpuscle hemoglobin concentration (MCHC)

how concentrated with hemoglobin is one corpuscle

can CBC give you hematocrit?

what else can it give you?

can it tell you the number of each white blood cell type you have?

YES can give you RBC: plasma

• hemoglobin count (oxygen carrying capacity of RBC)

• red blood cell count per microliter

• total white blood cell count

• total platelet count

• NO but it can give you PROPORTION through stained smear DIFFERENTIAL

Red Blood Cells and Oxygen Transport:

RBC are crucial for their _______carrying capacity

The responsibility falls within the red blood cell ____________

Each human red blood cell contains aproximately ____ MILLION ______ molecules

Each _____ atom within hemoglobin binds to ONE oxygen molecule

So how many ___ atoms are there total in one hemoglobin molecule?

• oxygen

• hemoglobin

• 270 hemoglobin

• iron

• 4 each hemoglobin carries 4 irons and 4 oxygen molecules

each hemoglobin is composed of 4 ____ chains 2 ___ and 2 ___

each chain has a ______ in the middle

each _____ group consists of a ______ ring with an ____ atom in the center

globin

alpha and beta

heme group

heme PORPHYRIN iron

Scanning Electron Micrographs (SEMS) show _______ disk shape of red blood cells

what causes this shape?

BIOCONCAVE

cytoskeleton filament, attachment protein, actin

Development of Red Blood Cells

• all blood cells come from ________ stem cells in the ______

• what determines which cells become red blood cells vs which become white blood cells?

• as the RED blood cell matures what happens to the nucleus? does it get larger or shrink with each division?

• pluripotent bone marrow

• stem cell interactions with chemokines and cytokines

• shrink

when do red blood cells lose their nucleus?

do white blood cells have a nucleus?

nucleus shrinks with each division of the maturation process and is expelled BEFORE the red blood cell leaves the bone marrow into the blood

YES WHITE BLOOD CELL DOES HAVE NUCLEUS

erythropoiesis feedback loop:

↓ _________ signals kidney to produce and secrete ______ into plasma

under normal circumstances, RBC mass is kept almost CONSTANT by EPO matching NEW erythrocyte ________the the natural rate of ____RBCs

decreased TISSUE OXYGEN increase ERYTHROPOETIN

• production loss

Hemoglobin Red Cell Lifecycle:

1. where does the body initially get its iron from?

2. what organ absorbs the iron through ACTIVE transport ?

3. wh

4. ______ ____ USES the Fe to make hemoglobin as part of red blood cell synthesis

5. how often to Red Blood Cells live in blood after its synthesis with hemoglobin and iron?

6. after ____ days ______ destroys the red blood cells converting their hemoglobin into _______

7. some ________ as well as other metabolites are excreted as urine in the _________

8. some ______ is metabolized in the ____where it is excreted in ____ leaving as feces

9. what happens to the iron form the begining after the red blood cell dies? what will it do in the next cycle?

1. Diet

2. small intestine

3. transferrin protein

4. bone marrow

5. 120 days

6. bilirubin

7. bilirubin kidney

8. liber bile

9. stored as FERRETIN

10. Ferritin will be converted to Transferrin by Fe transferrin

how does the kidney know if it needs to secrete erythropoietin or not?

after erythropoiesis increase in

• red cell mass + destruction of old

• iron folate

• plasma volume

overall Hb concentration

what organs will signal kidney when oxygen levels are low to increase erythropoietin?

heart

lungs

vessels

• O2 consumption

• atmospheric O2 levels

Sickle Cell Anemia is the most common familial _____ anemia

• mutation of BOTH ____ globin chains causes sickle shape

• sickled red blood cells fight against which is why through SELECTIVE PRESSURE where this disease is the most prevalent many people have a gene FOR sickle cell disease

• HEMOLYTIC

• Beta

• falciparum malaria

if biliurubin is not metabolized correctly by the liver or excreted in the urine by the kidneys

what diseased state will the patient be in?

Jaundice

in the united states 8% of _____ Americans are ____zygous carriers of sickled hemoglobin (HbS) and 1 in 600 have the disease

African heterozygous

why are you only able to reoxygenate and restore sickled red blood cells initially?

what happens in each sickling episode that eventually makes it impossible to reverse sickle cell anemia?

damage to membrane skeleton prone to hemolysis

what are the two consequences of Sickle Cell Anemia:

1. chronic moderately severe _______ anemia due to red cell _______ damage (spleen will take out RBC before 120 days)

2. vascular ________ which result in ______ tissue damage and pain crises

1. hemolytic membrane

2. obstruction ischemic

Sickle Cell : Extravascular Hemolysis

1. deoxygenation

2. ____ enter and ____ and _____ leave the red blood cell CAUSING DEHYDRATION AND SICKLE CELL SHAPE

3. at this stage is the sickle cell still able to be fixed upon reoxygenation?

4. additional cycles of deoxygenation lead to nondeformable irreversible sickled shape due to damage to the _____

5. irreversible sickle cell gets digested by _______

2. Ca2+ enter H2O and K+ leave blood cell

3. YES

4. membrane

5. phagocyte

Sickle Cell Disease: Microvascular Occlusion

1. deoxygenation

2. ____ come in ___ and ___ leave causing dehydration and sickle shape

3. INFLAMATION

4. increase in ________ time

5. increased expression of ________ ________ by sickle cells

Ca2+ K+ and H2O

transit

adhesive molecules

Group of diseases characterized by

• decrease in Hb or circulating red blood cells

• reduced oxygen carrying capacity of the blood

affects about 25% of the world’s population

ANEMIA

what are three ways to get Anemia

• inadequate red blood cell PRODUCITON

• increased red blood cell DESTRUCTION

• overall blood loss

directly associated with blood loss — what can this further progress into?

hemorrhage

ANEMIA

Anemia results in deficiencies of

1. folate/ vitamin B 12 (limit RBC production)

2. iron (limit hemoglobin production)

what can mark red blood cells for premature destruction?

• autoimmune

• drug-induced immune

• drug-induced hemolytic

Hemostasis and Coagulation:

• _________

• _______factors

• __________

that occurs at the site of ______ injury and leads to ____ formation to prevent or limit the extent of __________

• platelets

• coagulation factors

• endothelium

• vascular clot bleeding

________hemostasis keeps blood INSIDE damaged blood vessel

how is this done?

• vasodilation or constriction?

• ________ _________

• ___________

PRIMARY

• vasoconstriction

• platelet plug

• coagulation

__________ hemostasis involves the coagulation cascade for the deposisiton of ________ and clot _____________

how is this done?

• maturity of _______ _____

• production of ___________

SEOCONDARY

fibrin stabilization

platelet plug

fibrin

4 Mechanisms to Facilitate Hemostasis

1. vasoconstriction or dilation through endothelin release by endothelium

2. primary ____ ____ formation (primary hemostasis)

3. _____ propagation through _____ formation (secondary hemostasis)

4. _______ breakdown through _________ (breakdown of ___)

1. vasoconstriction

2. platelet plug

3. clot fibrin

4. clot fibrinoLYSIS clots

what allows all the platelets to stick together

1. first platelet sticks

2. ____ change

3. ______ released from platelets recruiting more platelets

2. shape

3. Adenosine diphosphate and Thromboxane A2 (TXA2)

Platelet Plug Formation Simplified:

1. exposed ______ binds to and activates _______

2. release of ________ factors

3. factors attract MORE ______

4. platelets _____ into _____ ________

1. collagen platelets

2. platelet

3. platelets

4. aggregate platelet plug

Platelet Activity:

1. Platelet Adhesion: mediated largely by interactions with _____ which acts as a bridge between ____ ______ ______ _______ __ ( ) on the platelet when exposed to collagen

2. Platelets rapidly change shape following adhesion . converting from ______ discs to ______ “____ ____” with increased/decreased surface area

3. Secretion of _________ contents (release reaction , _________) occurs along with changes in shape; step 2 and 3 together called PLATELET _________

4. Platelet __________is result of platelet ________. Conformation change that occurs allows binding of _________ that forms bridges between activated platelets leading tot their aggregation

1. vWF (von Willebrand) receptor glycoprotein lb (GPlb)

2. smooth —> spiky “sea urchins INCREASE SA

3. granule degranulation ACTIVATION

4. aggregation activation FIBRIN

what is on collagen that allows platelet to bind?

what is on platelet that allows it to bind to this factor on collogen ?

• vWF (von Willebrand factor) on collagen

• platelet receptor glycoprotein lb (GPlb)

Intrinsic vs Extrinsic Coagulation Cascade:

which is due to contact activation which is due to cell injury?

intrinsic = contact

extrinsic = cell injury

which factor converts prothrombin to thrombin

which will then convert fibrinogen into fibrin

is that factor a protease?

Factor 10

YES factor 10 is protease bc/ it lyses prothrombin to thrombin

which pathway is activated through

• oxidative stress

• disease state

• inflammation

contact activation = INTRINSIC

Intrinsic Pathway (contact activation) SEQ

12

11

9 + 8

10

Prothrombin —> Thrombin

Fibrinogen —> fibrin

SEQ Coagulation due to Cell Injury

when is the positive feedback loop activated?

damage to tissue factor 3

tissue factor 3+ active factor 7

10

prothrombin —> thrombin

fibrinogen —> fibrin

positive feedback when factor 10 activated causes 3 and 7 to continue to activate more factor 10 to lead to increased fibrinogen

SEQ Fibrinolysis

what inhibits plasminogen from being activated into plasmin?

plasminogen activator activates plasminogen to plasmin which it will dissolve the clot

Vitronectin = Plasminogen Activation Inhibition

antithrombotic properties of endothelium can be divided into activities directed at

• ____________ inhibitory effects

• _________ effects

• ___________

• platelet

• anticoagulation

• fibrinolytic

what is the role of heparin- like molecule in ANTIcoagulation?

heparin like molecule binds to antithrombin and the complex binds to thrombin preventing it from turning fibrinogen to fibrin

tissue factor pathway inhibitors inactivate tissue factor _______ complexes

7a

what is the role of thrombomodulin and endothelial protein C receptor in ANTIcoagulation?

thrombomodulin activates protein C

activated protein C binds to protein C receptor (in the presence of protein S) which inactivates factors 5a (activates thrombin with X) and 8a (activates X)

which molecules are able to inhibit platelet aggregation?

• nitric oxide

• prostaglandin 2

• adenosine diphosphatase

which molecule activates fibrinolysis

t-PA

_________ may result from systemic conditions that inflame or damage endothelial cells

bleeding

deficiency of platelets that can cause bleeding

thrombocytopenia

Bleeding/ Coagulation Disorders can result from

1. increased destruction of platelets (immune or non-immune)

2. decreased production of platelets

3. platelet dysfunction

Immune reaction to the use of heparin, leading to paradoxical

• HYPER coagulation

• reduced platelet count

Heparin - Induced Thrombocytopenia (HIT syndrome)

HIT syndrome mechanism of action:

1. _______ of platelet binds to heparin

2. this complex then binds to _________

3. this new complex now binds to platelets at their ____receptors

   This binding then removes _________ by splenic __________—→ __________________

   OR

   _______ are activated leading to _______________

1. PF4

2. IgG

3. Fc

platelets macrophages thrombocytopenia

platelets thrombosis

heparin bind to PF4 from platelet

heparin + platelet PF4 binds to igG

IgG binds to Fc of Platelet

can lead to paradoxical effect

_____________ and ____________________

thrombocytopenia

thrombosis

inherited defects involving the factor 8 (VIII) and vWF

Hemophilia A and Von Willebrand Disease

vWF is present on the subendothelial matrix of normal blood vessels

vWF allows for ________ to bind to __________ using its ______

Aggregation occurs through bridging interactions between ________ and ____________

vWF allows glycoprotein lb (Gplb) of platelet to bind to collagen

fibrinogen binds to the Gplb of TWO platelets allowing for bridge for aggregation

factor _____ and _____ circulate as a complex forming a complex with activated IX (9) that activates X (10) which activates thrombin

vWF and VIII (8)

• diminished factor 8 (VIII)

• most common type of hemophilia

Hemophilia A

• diminished factor IX (9)

• Christmas disease (less common)

Hemophilia B

• diminished factor XI (11) of contact activation coagulation

• passed to both male and female children

Hemophilia C

Hemophilia (which factor is effected in each?)

• A

• B

• C

A= 8

B= 9

C= 11

abnormally high tendency of the blood to clot and is usually caused by alterations in coagulation factors

• risk factor for THROMBOSIS

hypercoagulability

which type of hypercoagulability is inheritied?

which type of hypercoagulation is due to acquired disorders?

secondary hypercoagulation

solid mass within a chamber of the heart of within a blood vessel \

can develop ANYWHERE in the cardiovascular system

thrombus

Which factors can predispose individuals to thrombus formation (VIRCHOWS TRIAD)

where do they form?

1. Stasis of Blood — VENOUS thrombi

2. Hypercoagulability — anywhere do to acquired or inherited

3. Endothelial Damage — ARTERIAL THROMBI

what 2 hereditary gene mutations can predispose one to thrombosis?

1. Factor 5 Leiden Mutation (excess factor 5)

2. Prothrombin Gene Mutation (excess level of prothrombin)

• myocardial infarction

• tissue damage

• cancer

• prosthetic cardiac valves

• disseminated intravascular coagulation (DIC)

• heparin induced thrombocytopenia

• thrombocytopenia

• anti-phospholipid antibody syndrome

the following are all diseased states that can lead to

thrombosis

The fate of thrombi depends on

• P__________

• R__________ (restoration of flow)

• O__________
  D__________

• E__________

• propagation

• recanalization

• order

• dissolution

• Embolization

Bleeding/Coagulation Disorders:

caused by the SYSTEMIC activation of coagulation and results in the formation of thrombi throughout MICROcirculation

platelets and coagulation factors are consumed and secondarily, _________ is ACTIVATED

widespread activation of both the ______ and ______ system

transient ischemic attack

fibrinolysis

fibrinolysis + coagulation

how does TRANSIENT ISCHEMIC ATTACK (TIA) start

cycle of excess coagulation then excess fibrinolysis to compensate for it

release of tissue factor and widespread change to endothelial cells

what is an embolus?

a detached thrombus (detached clot of platelet that circulates the blood and detaches elsewhere causing heart attack )

vast majority of emboli derive from ______

thus the term

dislodged thrombi

thromboembolism

most emboli are composed of dislodged thrombi others are made of

• ____ droplets

• air or _______

• _____________ debris (cholesterol emboli)

• bits of _____ ______

• amnionic fluid

• lipid

• nitrogen

• atherosclerotic

• bone marrow

why is systemic embolization a major concern?

where is it less of an issue?

ischemic necrosis (infarction — HEART ATTACK) of downstream tissues now unable to receive oxygen from the blood

cannot cause infarction of PULMONARY circulation

most ______thrombi occur in the superficial (outer) OR deep veins of the LEG

venous

NO stay as thrombi blocking circulation causing pain and swelling to leg

do superficial thrombi arising from the saphenous system tend to embolize and go to other parts of the body?

why can they predispose the overlaying skin to?

NO tend do stay in leg causing swelling, pain, and local congestion

• infection and varicose ulcers

DEEP Venous thromboses in the larger leg veins (poptilial femoral and iliac veins)

are more/less serious compared to SUPERFICIAL Venous thromboses? and WHY

MORE serious

they are more likely to EMBOLIZE

although _____ _______ ______ may cause local pain and ________

collateral channels often circumvent venous __________

they are often entirely asymptomatic and are only recognized after they have ________ TO LUNGS

deep vein thrombosis EDEMA

obstruction

EMBOLIZED

______________ ______ originate from deep venous thrombi and are responsible for the MOST COMMON form of thromboembolic disease

pulmonary emboli

Pulmonary Emboli can lead to

1. SUDDEN DEATH: if pulmonary thromboembolus obstructs more than ____% of the oulmonary vasculature

2. PULMONARY INFART: due to occlusion of blood vessel and resultant ______ injury of the lung

2. PULMONARY HYPERTENSION: obstructive legions in pulmonary _________ circulation increasing the work of the ___ ventricle leading to hypertension (higher volume)

1. 60%

2. ischemic

3. arterial right

a localized area of dead (necrotic) cells within an organ

infarct/ strokes can occur in the

• heart (myocardial)

• lung — pulmonary (embolism)

• brain (stroke)

strokes can be

1. ischemic

2. hemorrhagic

3. transient ischemic attack (cycle mini stroke)

blood clot blocks blood flow to part of the brain

ischemic stroke

artery ruptures causing bleeding around the brain

hemorrhagic stroke

STROKE RISK FACTORS:

• overweight

• drinking

• illegal drugs ______ + _______

• age: ____+

• African + hispanic

• use of _______ birth control hormone

• covid 19

• cigarette

• sleep apnea

cocaine

methamphetamine

55

estrogen