Test 1 (Part 3) Flashcards
Hemostasis
- The steps taken by the body to LIMIT BLOOD LOSS
- Hemostasis is not confined only to the production of a BLOOD CLOT!
Hemostasis Cont
Composed of Four Steps:
1) Vascular Spasm
2) Formation of a Platelet Plug
3) Formation of a Blood Clot
4) Repair of Damage
Platelets
- A cell Fragment
- Derived from Megakaryocytic
- Normal Range: 150,000 to 300,000/ um^3
- Spontaneous Bleeding doesn’t occur until we reach 25,000 to 50,000 Platelets
Production of Platelets
THROMBOPOIETIN (TPO)
- Protein Hormone
- Chromosome 3
- Amine Terminal is like ERYTHROPOIETIN (EPO)
- Carboxyl End: PROLOGS HALF-LIFE
- Produced in EQUAL Amounts by LIVER and KIDNEY
Platelets = Thrombocytes
- Have Mitochondria and part of the old Endoplasmic Reticulum
THROMBOPOIETIN: Can make ALL CELL LINEAGES!!!!!
Production of Platelets Cont
Production of Platelets Control of Thrombopoietin secretion:
- CONTINUALLY Secreted
- Platelets bind Thrombopoietin (MPL) Receptor!!!!!
MPL Receptor: is expressed on the Platelets and Thrombopoietin
*** Trigger of Erythropoietin was Hypoxia!!!
Thrombopoietin
- Binds to the MPL (CD-100) Receptor
- Found on Platelets, Megakaryocytic, and other Hematopoietic Cells
****JAK2/ STAT5
***Phosphorylation and subsequent transcription and Translation of various genes
Control of Thrombopoietin Secretion
1) High Number of Platelets:
- Lots of TPO bound to MPL Receptor on Platelets
- INTERNALIZE TPO and Destroy it!!!
- Not much free to act on MEGAKARYOCYTES
2) Low Number of Platelets:
- Little bound to Platelets
- Not being destroyed
- LOTS FREE (more free to act on Megakaryocytes)
Production of Platelets Cont
Thrombopoietin:
- INCREASE Differentiation of Stem Cells and Maturation Rate
- EFFECTS ON ALL CELL LINEAGES!!!!!!!
- A Mutation in the TPO Receptor or platelets has recently been implicated in causing POLYCYTHEMIA VERA- the platelets are UNABLE to INTERNALIZE and DETROY the TPO, so its action becomes CONTINUOUS!!!!!
- May INCREASE Platelet Function!!!
Platelets
1) Actin and Myosin
- Cell Contraction
- Empty Vesicles**
2) Mitochondria (ATP and ADP**)
3) Remnants of the ER (Ca++ Storage)
4) Cyclooxyrgenase (COX1)
- Thromboxane A2**
5) Fibrin Stabilizing Factor (Clot Stability)**
6) Platelet Derived Growth Factor (Repair)**
7) Serotonin (5-HT)
**= INSIDE VESICLE!!!
Platelets
On Cell Membrane:
1) Glycoproteins
- When activated, STICKY!!!
2) Phospholipids
- Platelet Factor 3
3) Receptors for COLLAGEN
Describe the production of Platelets
1) Platelets are cell fragments derived from Megakaryocytic
2) Production of Platelets is controlled by Thrombopoietin
- Under normal conditions, TPO is continually secreted by the Liver and Kidney, but destroyed by the Platelets
- If Platelet levels drop, there is less destruction of TPO, so TPO can act
- TPO acts on ALL CELL LINEAGES
3) Platelets contain MITOCHONDIRA, ACTIN, MYOSIN, Cyclooxygenase 1, and Vesicles containing, among other things SEROTONIN!!!
Compare and Contrast Thrombopoiesis and Erythropoiesus
ERYTHROPOIESIS:
1) Hormone:
- Erythropoietin
2) Source of Hormone:
- Kidney
3) Trigger for Hormone Release:
- Low O2 delivery to Kidney
4) Control fo [Hormone] Blood:
- HIF accumulation in Renal Cell
5) Receptor:
- EPoR
6) Cells Expressing Receptor:
- Pluripotent Stem Cell, RBC precursors
7) Effect:
- Pluripotent Stem Cell: Division with one daughter cell committed to Erythroid Lineage
- Increased erythroid lineage division and Maturation speed
THROMBOPOIESIS:
1) Hormone:
- Thrombopoietin
2) Source of Hormone:
- Liver, others?
3) Trigger for Hormone Release:
- Constitutive (Constant)
4) Control fo [Hormone] Blood:
- Internalization and Destruction of TPO by Circulating Platelets
5) Receptor:
- MPL
6) Cells Expressing Receptor:
- Platelets**, Pluripotent Stem Cell, All HEMATOPOIETIC Cell Lines
7) Effect:
- Increased division and maturation of ALL BLOOD CELL LINEAGES
Hemostasis (Step 1)
Step 1- VASCULAR SPASM
- Spasm may be strong enough where we don’t have any Blood Loss
PRIMARY CAUSES:
1) Myogenic:
- Direct response to Injury
- No neurons, reflexes Involved
2) Platelet Factors:
- Serotonin
- Thromboxane A2
***VASCULAR SPASM is INDEPENDENT of what the Brain is telling IT!!!
FACTORS CONTRIBUTINF TO THE SPASM:
- A Neural Reflex initiated by the Mechanical Injury and Pain
- Neither NECESSARY or SUFFICIENT for SPASM to OCCUR
***If we get rid of NOCICEPTORS, the Vascular Spasm will still occur!!!
Describe the Initiation and Function of Vascular Spasm
1) Myogenic response to Injury- Vascular Smooth Muscle Contracts on own
2) Serotonin (5HT) and Thromboxane A2 from Platelets contributes
3) Minor contribution from a Neural Reflex
4) Reduces blood loss by Slowing/ Stopping blood flow out
Hemostasis (Step 2)
Step 2- Formation of a Platelet Plug
A) With damage to Vessel Wall:
- COLLAGE Exposed
- Platelets will bind to COLLAGEN (2 step process)
1) Part I: VON WILLEBRAND FACTOR- Plasma Protein
- Bind between Collagen and Platelet (receptor)
- Binding of Platelet Receptor (INTEGRIN) to Collagen
B) Activation of Platelet
- Platelet Swells
- Extends Podocytes
Formation of Platelet Plug:
1) Platelets Swell
2) Contraction
- Force the vesicles out of the Platelet and release its contents into the area
3) Granules leave Platelet
4) Platelets stick to vessel wall and to each other (Thromboxane A2 and ADP)
- Platelet cell membrane becomes Increasingly Sticky
- Other platelets become attracted to the Sticky Platelet and then they themselves becomes ACTIVATED
- ***PLATELET PLUG stops bleeding from Small Breaks, Nose and Skin
- May be all that is required to stop bleeding
Describe the formation and function of the Platelet Plug
1) Formation of the platelet plug is initiated by exposed collagen on damaged blood vessels binding to receptor on the platelet
2) This triggers platelet activation and aggregation
3) Platelets swell and stick to one another
4) Plugs the “Hole” in the vessel
5) If the cut is small enough, the platelet plug may be all that is required
Hemostasis (Step 3)
Step 3- Blood Coagulation
3 Essential Steps:
1) Formation of Prothrombin Activator
2) Activation of Thrombin
3) Creation of Fibrin from Fibrinogen
***CLOT CREATION!!!!!
CLOT RETRACTION:
1) Get rid of excess fluid within Clot
2) Solidify CLOT
3) Platelets required
- Bind Firbin Polymer together
- Actin and Myosin in Platelet- Contraction
4) Also requires CALCIUM
The Blood Clot
- Platelets are bound to Fibrin and these Platelets will contract and pull the Fibrin strands together!!!
Hemostasis (Step 4)
Step 4- Repair of Damage
SECRETED BY PLATELETS:
- Platelet-derived Growth Factor
- Stimulates Fibroblast to grow into area
- Fibroblasts differentiate into Smooth Muscle, etc… to Close Hole
***Causes tissue healing by causing tissue Invasion by Fibroblasts into the damaged area
Getting Rid of the Clot
1) Plasminogen
- Made by Liver
- Floating in Plasma
- Not ACTIVE FORM
2) Activation of Plasminogen
- TISSUE PLASMINOGEN ACTIVATOR!!!!!!
- Released by DAMAGED TISSUE
- Activation is Inhibited by tPA INHIBITOR (Blood)!!!!!!
***tPA was released when the vessel was damaged by the tPA Inhibitor stopped the tPA from doing its job, and therefore the Clot will stick around longer!!!
Endothelial Cells
- When we get healing, the Endothelial cell lining will be intact and give off Thrombomodulin
- Thrombin binds to Thrombomodulin and then becomes an Antigoaculant!!!!
Describe How Clots are Removed (tPA, tPA Inhibitor, Protein C)
1) Relies on delayed activation of a Fibrinolytic Enzyme (Plasmin) that is found in the blood in an Inactive form (Plasminogen)
2) Plasminogen is prevented from becoming active by a Plasmin Inhibitor, while activation requires tissue Plasminogen Activator (tPA) released from the Damaged Tissue
3) The binding of Thrombin to Thrombomodulin activates Protein C, which inactivates the Plasmin Inhibitor
4) Once the inhibitor is inactivated, tPA can convert Plasminogen to Plasmin
5) Plasmin breaks down FIBRIN to remove the Clot
Preventing Clot
1) Blood Vessels
- Smooth Surface: Prevents Platelets from RUPTURING
- Membrane Proteins:
A) GLYCOCALYX: repels Platelets
B) THROMBOMODULIN: Changes Thrombin Activity
2) Chemicals which LIMIT CLOTTING
A) Fibrin:
- “Binds” Thrombin and prevent it from working
B) Prostacyclin (PGI2)
- Made at time of Injury by Endothelial Cells - Vasodilation - Limit Platelet Aggregation
C) Antithrombin II
- When Thrombin binds to it, works as Antigoaculant
D) Heparin
- Derived from Mast Cells - Increases Antithrombin efficacy
**Activated Protein C—–> Inactivation of VIIIa and Va —-> INHIBITION of Further FIBRIN Creation
Describe the System which limit Clotting (Fribin, Prostacyclin, Antithrombin III, Protein C)
- Because the enzymes of the Clotting Cascade are always present in the Blood, we have to work to prevent clotting that is NOT REQUIRED
- Factors that Limit Clotting Include:
A) Smooth Endothelial Lining of the VesselsB) Continuous flow of blood (preferably not Turbulent)C) Platelet repelling action of the GLycocalyxD) A variety of Endogenous Anti-Coagulants, including Fibrin, Heparin, Prostacyclin, and Anti-Thrombin IIIE) Protein C, when activated, inactivates factors V and VIII
Cardiovascular System
- Primitive vertebrate cardiovascular plan begins Mid-Week 3 and present by Week 4
- First SYSTEM TO FUNCTION!!!
- Early development necessary because of RAPID GROWTH
- Embryo can no longer meet nutritional or Oxygen needs by Diffusion
- Requires both PUMP, TUBING, and DELIVERY SYSTEM (Heart, Vessels, Blood)
- Begins with Cardiac Progenitor cells in Epiblast migration to form PRIMARY HEART FIELD (PHF)
Establishment and Patterning of PHF
- Progenitor Heart cells have migrated and formed the horsehsoe- shaped primary heart field (PHF).
- As they migrated, PHF Cells we specified to form Left and Right sides of the heart and form the ATRIA, LEFT VENTRICLE, and Part of the RIGHT VENTRICLE.
- The remainder of the RIGHT VENTRICLE and the Outflow tract consisting of CONUS CORDIS and TRUNKS ARTERIOSUS are formed by the Secondary Heart Field (SHF)
Patterning of Cardiac Progenitor Cells
- Occurs at the same time that Laterality (lift-right sidedness) is established
- Pathway is expressed in Lateral Plate mesoderm on the Left Side and involves a number of SIGNALING Molecules, including SEROTONIN (5HT), which result in expression of the Transcription Factor, PITX2, the Master Gene for LEFT Sidedness. (SSRIs and Heart Defects)
- This pathway specifies the Left side of the body and also program sHeart Cells in the primary and SHFs
- The right side is Specified as well, but genes responsible for this patterning have not been completely determined
- Disruption of the Pathway on the left results in Laterality Abnormalities, including many heart defects
Endocardial tubes
- Once cells establish the PHF, they are induced by the underlying Pharyngeal Endoderm to form Cardiac Myoblasts and Blood Islands that will FORM BLOOD CELLS and VESSELS by the process of VASCULOGENESIS
- With time, the ISLANDS UNITE and form a HORSHOE-SHAPED Endothelial-lined tube surrounded by the Myoblasts
- This region is known as the CARIOGENIC REGION
Repositioning of Heart and Pericardial Cavity and Septum Transversum
- Endocardial tubes fuse to form a single primitive Heart Tube
- Structures go from the Anterior of the Head to the Inferior of the Head
1) Pericardial Cavity
2) Endocardium
3) Myocardium
4) Epicardium
Vascular Circuits
- Embryonic Circuit
- Series of Aortic Arches that connect to Dorsal Aortae
- Dorsal Aortae subdivide into Smaller Vessels to Supply Embryo
- Blood Drained by Anterior and Posterior Cardinal veins
- Common Cardinal vein
**UMBILICAL Artery and Vein: Take oxygenated blood from mom and give it to baby while taking deoxygenated blood from baby and giving it to mom
**VITELLINE Artery and Vein: Play important role in blood circulation to and from the Yolk Sac
Extra embryonic Vascular Circuits
- “Nutritional” Circuits
1) VITELLINE- Supply and drain Yolk Sac, “Nursery fro Blood Cells”
2) Umbilical Vein carriers Oxygenated Blood from the Palcenta - Umbilical (Placental)
Major Trends in Development
- Heart is converted into a 2-Chambered and then a 4-Chambered Structure
- Extraembryonic Circuits are lost
- Ex: Vitalline (Before Birth) and Umbilical (After Birth)
- Embryonic vascular circuit separates into Systemic and Pulmonary portions
- Systemic Aterial Outfliw—-> LEFT
- Systemic Venous Return —-> RIGHT
Embryonic Structure Versus Adult
EMBYRONIC:
1) Sinus Venous
2) Primitie Atrium
3) Primitive Ventricle
4) Bulbus Cordis
5) Truncus Ateriosus
ADULT Equivalent:
1) (Sinus Venous)—–> Smooth part of Right Atrium (Sinus Venarum), Coronary Snus, Oblique Vein of left Atrium
2) (Primitie Atrium) —-> Trabeculated part of Right and Left Atria (Auricles)
3) Primitive Ventricle—–> Trabecualted part of Right and Left Ventricles
4) Bulbus Cordis —–> Smooth part of Right Ventricle (Conus Cordis), Smooth Part of Left Ventricle (Aortic Vestibule)
5) Truncus Ateriosus —-> Aorta, Pulmonary Trunk
Heart Formation
- Umbilical Vein, Vitelline Veins, and Common Cardinal All provide something to the Fetus and Heart
***Site of Apoptosis: Programed Apoptosis to kill off some of the tissue around the Heart to give it more Space!!!
How to Think of the Heart
The heart is a House with:
1) 4 Rooms (Chambers)
2) 4 Doors (Valves)
3) 4 Big hallways (Vessels)
4) 4 Small Hallways (Vessels)
- Ex: Coronary Arteries
Aortic Arches
- there are a variety of Molecular signals from the Anterior Endoderm to specify and initiate Endocardial tube Development
- Once the Endocardial tubes fuse, the Venous end is specified by RETINOID ACID (RA)
- Lower RA concentrations in more Anterior Structures (Ventricles and Outflow Tract) specify them as Anterior Structures
- Importance of RA in Cardiac signaling is Important for Incidence of CONGENITAL Abnormalities
***SEPTUM TRANSVERSUM!!!!
Day 22 and 23 of Heart
DAY 22:
- Most of the Growth in the Heart will take place in the Ventricles and the Outflow tract
- Truncus Antibiosis and Bulbus Cordis
- Ventricle
- Atrium
DAY 23:
- Cardiac Folding: The parts that are growing the fastest are folding more ANTERIORLY
- PITX2 regulates the Cardiac Folding or Looping!!!!!!
- Bulbus Cordis
- Ventricle
- Atrium
**Cardiac Looping is dependent on LATERALITY Pathway and Proper Expression of transcription Factor PITX2!!!!!
***The Fulcrum for the bending around in the LV!!!!!
Dextrocardia
- Heart bends to the LEFT instead of the RIGHT
- Heart displaced to the RIGHT with Transposition of Heart and Great Vessels
- Most common POSITIONAL ABNORMALITY
- During Gastrulation or later during Cardiac Looping
Can be Found:
- By itself
- With other laterality sequence issues
0 with SITUS INVERSUS
***Reverses the names but he Flow would be the SAME!!!
Partition of Atrioventricular Canals
- After folding, Atrium and Ventricle are separated by narrow AV Canal
- Dorsal and Ventral blocks of tissue GROW TOGETHER
- ENDOCARDIAL CUSHIONS
- Divide single AV Canal into separate RIGHT and LEFT AV Canals
- Canals (and their valves) REGULATE blood flow from Atria to Ventricles!!!!!
Atrioventricular Communis
- The formation and fusion of Endocardial Cushions is the CRITICAL FIRST STEP in the development of the 4-Chambered Heart
- Large communication between Chambers that occur when the CUSHIONS FAIL TO FUSE!!!!
Common AV Canal
- Enlarged Pulmonary Trunk
- Less resistance in the Pulmonary circulation than in the Systemic Circulation
***There is less resistance in the Pulmonary circulation compared to the Systemic Circulation so then you get an enlarged Pulmonary Trunk
**They put a and around the Pulmonary Artery which doesn’t allow the artery to expand and therefore the blood will go more towards the Systemic Circulation
Correction of Common AV Canal
- Doctors will perform a single procedure to take the Pulmonary Artery Band off, close the holes between the Upper Chambers and the Lower Chambers of the Heart, and construct Two Valves out of the Single Existing Valve to make the Heart Function NORMALLY
- This limits the amount of blood sent to the Lungs making it LESS CONGESTED
Formation of Interventricular Septum
- Two Parts
- MUSCULAR PORTION develops in the MIDLINE on the Floor of the Primitive Ventricle
- Grows UPWARD towards ENDOCARDIAL CUSHIONS and Down-Growing BULBAR RIDGES!!!!!
- The Muscular Portion does make it all the way toward the Endocardial Cushion
- This hole gets filled in by a Membranous Tissue so there are two Parts to the Septum:
1) Muscular Part
2) Membranous Part
Ventricular Septal Defects (VSDs)
- 25% of all CONGENITAL HEART DEFECTS
- Opening between Left and Right Ventricles, associated SHUNTING of BLOOD
- 4 toes based on Position and Severity
- MOST VSDs occur in MUSCULAR PORTION (these Spontaneously Close unless they’re Very Large)!!!!!!!!
- MEMBRANOUS Defects are more commonly CORRECTED SURGICALLY!!!!
Case #1
- Had VSD
- Initially with inflation of the Lungs, RV Pressure Decreases
- With Increased Blood Flow through Lungs, Increased Blood Flow to Left Heart, LV Pressure Increases
- With VSD, Left-To-Right SHUNTING (ACYANOTIC)
- Causes Increased work by RV, HYPERTROPHY and eventually, RIGHT-to-LEFT SHUNTING—-> CYANOSIS
- Rate DEPENDS on SIZE of VSD!!!!
Does a VSD cause Conduction?
- It is rather surprising to not CONDCTION Defects are not common in VSDs
- In fact it can be termed RARE. VSD, however large may be, usually spares the Conduction System. This is simply due to the fact that Developmentally the Two Systems, Ventricular Septum and the Electrical System of the Heart, come from DIFFERENT EMBRYOLOGICAL Precursors and are simply ANCHORED TOGETHER
- If the IV Septum is nor formed properly, the bundle of His and its Major Right and Left branches are SIMPLY DISPLACED and are not DESTROYED, they tend to occupy one of the rims of VSD.
- Further, a VSD located Peripherally and Distally towards the APEX has little impact on the Conduction Tissue as it has already FANNED OUT and SMALL little twigs are affected, while Central, Proximal, and Basal VSDs can have more Significance
Formation of the Atrial Septum
- There is a hole that form in the Atrial Septum, and this happens because we want the Blood to go from the RA to LA and then to the Ventricle and out!!!!
**WE NEED TO HAVE A FUNCTIONAL VALVE BETWEEN THE RA and LA!!!!
- An Atrial Septum is built so that there is an opening, but when the Child is born the Valve needs to CLOSE and STAY CLOSED!!!
- If there is a failure to close, then this could cause so many problems!!!
1) Foramen Secundum —> FORAMEN OVALE!!!!!
2) Valve of Foramen Ovale (Derived from Septum Primum)
3) Septum Secundum (Upper Limb)
4) Septum (Lower Limb Secundum)
Before Birth vs After Birth with Foramen Ovale
Before Birth:
- Right Atrium: HIGHER PRESSURE
- Left Atrium: LOWER PRESSURE
- Septum Secundum
- Foramen Ovale
- Septum Primum
- SHUNT
After Birth:
- Right Atrium: LOWER PRESSURE!!!!!!
- Left Atrium: HIGHER PRESSURE!!!!!!!
- Septum Secundum
- Fossa Ovalis
- Septum Primum
***The Higher Pressure in the Left Atrium causes the Foramen Ovalis to CLOSE!!!!
1) LIMBUS: Septum Secundum
2) Fossa Ovale (Floor): Septum Primum
3) Valve of Fossa Oale: Septum Primum
4) Fossa Ovale: Floor is Septum Secundum
Atrial Septal Defects
- ASD: Fairly common, present in 10 to 15% of patients with Congenital Cardiac Anomalies
- Osmium (Foramen) Primum Defects: Similar to Endocardial Cushion Defects
- SECUNDUM TYPE: Involve Foramen Ovale and Septum Primum
- SINUS VENOSUS: Usually Near Opening of SVC
Remember Holt-Oram Syndrome?
- Mutation in TBX5 Gene, associated with FORELIMB Development
- Although the abnormality of the Upper Extremities is more Extensive in some cases, the Characteristic findings in the Holt-Oram Syndrome (HOS) are Thumb Anomaly and Atrial Septal Defect!!!!
- Can also have VSD!!!!!!
