Flashcards in 5: Hemostasis- pathology, assessment & common disorders Deck (80):
What is hemostasis designed for?
To ensure that there is no major leakage of blood following injury & consists of a complex system of proteins & enzymes.
**any defects in these mechanisms may result in bleeding or thrombosis
How are platelets formed?
Hemocytoblast (stem cell)-->Megakaryoblast-->Promegakaryocyte-->Megakaryocyte-->Thrombocytes
Are platelets cells? Explain
-Not cells, instead fragments of cells
-They split from huge cells in the bone marrow called Megakaryocytes and enter circulation
How many platelets can a single Megakaryocyte generate?
Around 3000 platelets, which 20-30% are pooled in the spleen (as a reservoir)
Note: NORMAL = 250,000-400,000 per cubic millimeter of blood
Describe a platelet
-Like RBCs, they have no nucleus or organelles, but contain many granules. (Content of these granules are integral components of platelets biological activities )
***LIFE SPAN= 5-20 days
What is the anatomy of a typical Artery?
1) Tunica intima (Endothelial cells, CT, Interal elastic membrane)
2) Tunica media (Smooth muscle cell)
3) Tunica exteria (or adventitia)
(Collagen & elastic fibers)
What is the anatomy of a "Typical" Vein
-Thinner tunica media
-Presence of venous valves within endothelium
Anatomy of a "Typical Capillary" ?
-Tunica intima only contains endothelial cells & small amt of collagen
*******No tunica media & no tunica externa *
-All in all--> Very "thin-walled"
What is the Vasoconstrictive Phase or Vascular Spasm?
-The smooth muscle in damaged vessels contracts immediately producing local vasoconstriction
What is Vasoconstrictive Phase triggered by?
1) The direct injury itself
2) sympathetic nervous system
What is the Platelet plug formation?
-Characterized by the aggregation of platelets
-Platelets stick to exposed collagen, swell, & form spiked process
-Platelet plugs are effective in preventing blood loss due to small injuries
How do Platelets stick to the exposed collagen of damaged endothelium(or artificial surface)?
via GPIa receptors (GP= Glycoprotein)
What is the von Willebrand's Factor (vWF)?
A protein found in plasma, platelets & walls of blood vessels--via GPIb receptors.
****Specifically causes platelets to attach to & spread across the damaged endothelial surface
What is the first step of platelet formation called? What occurs?
-Platelets undergo major structural changes & deformations
-Adhesion also triggers the secretion of multiple factors from the platelets
What are the secretion factors adhesion triggers from the platelets?
ADP (adenosine diphosphate)
Thromboxane A2 (TA2; TXA2; prostaglandin)
What will ADP, TXA2 & to some extent 5-HT binding to specific receptors cause on other platelets?
Stimulation of these receptors will activate these platelets by making them more sticky & this adhere to one another to form an aggregate
Why does Aggregation occur?
As a consequence of another platelet glycoprotein receptor called GPIIb/IIIa onto which fibrinogen & other macromolecules bind tightly.
What is the Coagulation Phase (Blood Clotting) ?
-Occurs either to reinforce a platelet plug or to stop bleeding when a platelet plug fails
-Involves clotting factors
-MOST clotting factors are made in liver (Some exceptions like Ca+2)
How many clotting factors are there? Where are they present?
-20 different but 12 we will study.
-Most are present in the circulation as INACTIVE proteins (Zymogens) to prevent unwanted clotting.
-These require activation by other clotting factors to fxn in coagulation reaction.
What are the Clotting factors from I-VIII?
I = Fibrinogen
III= Tissue factor or thromboplastin
V= Proaccelerin (Labile factor)
VII= Proconvertin (Stabile factor)
VIII= Antihemophilic factor A,
What are the Clotting factors from IX-XIII?
IX= Antihemophilic factor B, plasma thromboplastin component
X= Sturant-Prower factor
XI=Plasma thromboplastin antecedent, Hemophilia C,
XIII=Fibrin stabilizing factor, LAKI- LORAND FACTOR
Which factors are vitamin K-dependent clotting factors?
2, 7, 9, and 10.
Which clotting factors are made by the liver?
1, 2, 5, 7, 8, 9, 10, 11,12
Which clotting factors are NOT made by the liver? Where are they made?
3, 4, 12* (liver & platelets), 13
3= Perivascular tissue
13= Platelets, Plasma
12*= Liver & Platelets
What is the Blood Clotting Cascade?
Comprises extrinsic and intrinsic pathways (both are initatiated simultaneously and lead to a "final common pathway")
What is the differnce between intrinsic & Extrinsic pathway?
Intrinsic= initiated within the blood (via PLATELETS)
Extrinsic= initiated outside the blood (via TISSUE THROMBOPLASTIN)
What clotting factors does the intrinsic mechanism involve?
12, 11, 9, and 8
What clotting factors does the extrinsic mechanism involve?
Damaged perivascular tissue-->3--> 7--> 5
What is the path when the intrinsic and extrinsic mechanisms combine?
Factor X-->Prothrombin-->(Prothrombin Factor II)-->Thrombin-->(Fibrinogen Factor I)-->FIBRIN--> Fibrin Polymer
What are the "Natural" Anticoagulants?
2) Antithrombin III or (Antithrombin)
3) Heparin cofactor II
-Plasma has several protease inhibitors that rapidly inactivate coagulation factors that escape the site of injury
-Anticoagulant system in place to maintain balance between coagulation & anticoagulation
What is Thrombomodulin?
A glycoprotein present on endothelial cells that combines w/ thrombin
What activates PROTEIN C, plasma protein ?
The Thrombomodulin-thrombin complex (Thrombin+ Thrombomodulin)
What is Protein C's cofactor and what does it degrade?
Cofactor, PROTEIN S, degrade factors 5 and 8 (inactivates factor V & VIII)
What is Antithrombin III (Antithrombin)
A glycoprotein produced by the liver that bind subsequently inhibits factor X & thrombin
What is Heparin Cofactor II?
A plasma protein synthesized by the liver & inhibits THROMBIN
What is the Fibrinolytic System?
After a blood clot, it allows things to be broken down to restore blood flow in a vessel.
What is the Fibrinolytic System initiated by?
Initiated by the enzyme PLASMIN which is synthesized from an inactive plasma protein synthesized by the liver called PLASMINOGEN
What is Tissue Plasminogen Activator (t-PA)?
-Converts plasminogen to the active plasmin, allowing fibrinolysis to occur.
-Released into the blood slowly by the damaged endothelium of the blood vessels, such that, after several days the clot is broken down.
(This occurs b/c plasminogen became entrapped within the clot when it formed; as it is slowly activated, it breaks down the fibrin mesh. )
What are Fibrinolysis Inhibitors?
-required in vivo to prevent prolonged or unwanted degradation of fibrinogen.
1) Plasminogen activator inhibitor 1
2) Plasminogen activator inhibitor 2
3) Alpha 2 antiplasmin
4) Alpha 2 macroglobulin
What is Thrombocytopenia?
Low platelet count--> Increased risk for bleeding
What is Petechia?
Low platelet levels that lead to bruising, particularly purpura in the forearms, (pinpoint hemorrhages on skin & mucous membranes), nosebleeds and/or bleeding of gums
How can one confirm the automated platelet count ?
Blood smear/ CBC- Platelet count
***This allows the morphology of the platelets to be assessed; some inherited platelets disorders are associated w/ large platelets.
What are Coagulation Tests (assessments for clotting system? )
Used to determine the function of the intrinsic & extrinsic components of coagulation system.
-Blood is placed into tubes containing sodium citrate.
***Citrate binds calcium--> blood will not form a clot inside tube until further calcium is added (which is required for normal functioning of the coagulation cascade)
What is Prothrombin Time (PT); PRO-TIME?
Used to assess the EXTRINSIC PATHWAY
-Calcium is added to plasma to replace that removed by citrate & brain thromboplastin is added to substitute for tissue factor.
***Clotting takes 12-15 seconds & test time is compared w/ a standart normal control in a ratio
What is the International Normalized Ration (INR)?
Due to differences between different batches & manufacturers of tissue factors (it is biologically obtained product
**Devised to standardize the results. ISI says how their tissue factor compares to the other company's. The INR is the ration of a patient prothrombin time to a normal (control) sample, raised to the power of ISI
What is the formula for INR?
INR= (PTtest/PT normal)^ISI
What is an INR?
MOST OFTEN used to monitor the effectiveness of drug such as WARFARIN(COUMADIN)
What is Coumadin?
Anti-coagulant which means it inhibits the formation of blood clots.
**Prescribed on a long-term basis to patients who have developed recurrent inappropriate blood clotting (Heart attacks, strokes, and deep vein thrombosis)
Why might Anti-coagulates given as a preventative measure?
In patients who have artificial heart valves & on a short term basis to patients who have had surgeries (knee replacements)
Why must patient on Anti-coagulants be monitored?
To maintain a balance between preventing clots & causing excessive bleeding.
What is the range of INR patients should have?
2.0-3.0 for basic "blood thinning" needs"
***High risk of clot formation value of INR needs to be HIGHER about 2.5-3.5.
What is the Activated Partial Thompoplastin Time )APTT)
Used to assess the INTRINSIC PATHWAY
-Calcium is added to plasma to reduce that removed by citrate & then kaloin and phospholipids are aded to substitute for contact factor.
**Takes 25-36 seconds
What is the APTT test clinically most often used for?
To monitor HEPARIN therapy.
***Therapeutic levels of UFH will be prolonged to 2-2.5 times that of the normal value
What is the Thrombin clotting time (TT)
-Used to asses the COMMON PATHWAY
-Calcium is added to plasma to replace that removed by citrate & then thrombin is added to substitute for the products of the intrinsic & extrinsic pathways--> this assesses the conversion of FIBRINOGEN to FIBRIN
Clinically what is TT used for?
Used when a PT and/or APTT test is prolonged, particularly if abnormal fibrinogen level or function is considered
What are Coagulation factor assays used for?
To determine actual deficiencies of specific clotting factors
What is Hemophilia A (Factor VIII Deficiency) ? Where is the mutation?
-X-linked disorder; mutations in factor 8 gene
**Prolongation of APTT; Pt is normal
In Hemophilia A who is affected more commonly?
Affects 1 in 5000 makes (due to 1 chromosome)
-Approx 30% of patients have no family history; their disease is presumably caused by NEW MUTATIONS
What does the % ACtivity of 8 for mild, moderate and severe?
What is Hemophilia B (Christmas Disease) ? Where is the mutation?
-X-lined disorder; Mutation is factor 9 gene
-Prolongation of APTT; PT is normal
In Hemophilia B who is affected more commonly?
Affects 1 in 30,000 Males
What are the clinical feature of Hemophilia?
Leads to an increased risk of prolonged bleeding form common injures , or severe causes bleeds may be spontaneous and w.out obvious causes.
In Hemophilia where can bleeding occur?
May occur anywhere in the body
***superficial bleding such as those by abrasion or shallow lacerations may be prolonged & the scab may easily be broken up due to the lack of fibrin, which may because re-bleeding.
What are the most serious sites of bleeding for a Hemophiliac?
1) Joint capsule
2) Skeletal muscles
3) SI tract
What are other clinical feature of Hemophilia?
No life threatening
-JOINT BLEEDS ARE MOST SERIOUS symptoms of hemophilia
What does repeated bleeding cause in Hemophiliacs?
Repeated bleeding into a joint capsule can causes permanent joint damage and disfigurement result in chronic arthritis and disability.
***Joint damage is NOT a result of blood in the capsule but rather the healing process.
What happens when blood in the joint is broken down by enzymes in the body?
The bone area is also degraded .
**this exert massive amounts of pain the person afflicted w/ the disease.
What is the Treatment for Hemeophila?
Patients w/ very low factor levels, who experience repeated & painful bleed into their joints & skeletal muscles, and given IV factor replacement.
****APART from "ROUTINE " Supplementation, extra factor replacement is given around surgical produces after trauma.
What is Von Willebrand's Disease (vWD) ?
Most common inherited bleeding disorder--> affects 125 per million
**Leads to mild bleeding disorder affecting males & females equally
What is the 2 major roles of Von Willebrand's Disease (vWD) ?
1) Mediating platelet adhesion
2) Stabilizing factor 8
In Von Willebrand's Disease (vWD) why is bleeding typically seen in the skin & mucous membranes?
Because of high capillary density; these tissues particularly depend on the effiecient formation of platelet plugs to stop bleeding
Like Hemophilia A, Von Willebrand's Disease (vWD) also results in a prolonged APTT & reducted factor 8 clotting activity. Why is this?
Because of its link to factor 8, and low levels of vWF.
vMF like hemophilia A also results in a prolonged APTT & reduced factor 8 clotting activity. How do they differ?
Unlike Hemophilia A, patients have prolonged PT because of a failure in platelet- vessel wall interaction.
What is Thrombocytopenia caused by?
1) Impaired production of platelets which can be a) drug induced or b) Bone marrow failure
2) Increased destruction of platelets
**Idiopathetic thrombocytopenic purpura (ITP)
Why is Idiopathetic thrombocytopenic purpura (ITP) caused?
Autoimmune response to platelets, which are removed prematurely by the reticuloendothelial system
What is Thrombophillas associated with?
Conditions associated with excessive clotting
When is a Hyper-coagulable state and Potential venous thromboembolism (VTE) seen?
When the fibrinolytic events has a defect or deficiency in one of the natural anticoagulants will swing the balance towards these conditions.
What are examples of Inherited thrombophilas ?
1) Protein C Deficiency
2) Protein S Deficiency
*These inactive Activated Factor 5 & 8
What are examples of inherited Thrombophillas?
1)Activated Protein C Resistance
2) Antithrombin III Deficiency