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Coagulation, Vitamin K and Clotting Factors

What is the most common hereditary clotting problem?
--Von Willebrand's Dz (factor is absent or abnormal, many varieties)

What do you call an inactive enzyme precursor in the clotting cascade?
--a zymogen

What do you call a coagulation deficiency from to a deficiency of Factor VIII due to an X-linked recessive gene?

--hemophilia A

Which pathway is Factor VIII a part of?
--the INTRINSIC pathway

How long does the intrinsic pathway normally take to form a clot?
--1-6 seconds

Who gets this kind of hemophilia?
--1/2 of the sons of mothers who carry the recessive gene

Which factor is deficient in hemophilia B?
--factor IX

What is the factor that allows platelets to adhere to endothelial basement membranes to begin a clot?
--Von Willebrand's factor (VWF) = large, multimeric circulating proteins which link platelet glycoproteins (Ib/IX/V) to collagen fibrils-->activating the platelets

Where does von Willebrand's factor come from?
--endothelial cells (also make plasminogen activator and possibly factor V)

What syndrome is a lack of platelet glycoproteins receptors for VWF? (also decreases clotting)
--Bernard-Soulier syndrome

Where do platelets come from?
--megakaryocytes in the bone marrow

What do platelets release from their granules once they are activated?
--ADP, serotonin, platelet-activating factor (PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2)

How do those chemicals cause increased clotting?
-->activate a Gq-linked protein receptor cascade-->increased calcium concentration in PLT cytosol-->activates protein kinase C-->activates phospholipase A2 (PLA2)-->modifies integrin membrane glycoprotein IIb/IIIa increasing its affinity for fibrinogen-->activated platelets change shape from spherical to stellate-->fibrinogen cross-links with glycoprotein IIb/IIIa aggregates more platelets

Why does clotting speed increase exponentially once started?
--autoactivation: many of the factors increase activation of themselves or other supporting factors in the cascade

What common drug irreversibly inhibits thromboxane A2 (vasoconstrictor) via the COX pathway?
--aspirin

What did Wiggins teach us activates protein C?
--excess thrombin

And what activates prothrombin-->thrombin?
--Ca2+

Calcium ions are required for promotion/acceleration of all clotting reactions EXCEPT?
--the first two steps of the intrinsic pathway

Which clotting factors are dependent on Vitamin K?
--synthesis of factors II (prothrombin), VII, IX, X
--also protein C and protein S which form the PCa/PS complex which inhibits factors V and VIII
--factor VII and protein C are MOST SENSITIVE to vit K levels
--if K deficient PT is always prolonged, PTT mb prolonged
--if factors II, VII, IX, X, PC and PS are all deficient-->diagnostic for low K

Where are clotting factors II, VII, IX, X, XI, XII, plasminogen and prothrombin made?
--in the liver
--note: plasminogen also made in kidney
--factor V may be made in liver or by endothelial cells, not sure
What causes vitamin K deficiency?
--malabsorption dt biliary tract dz

Why do you need bile to absorb vitamin K?
--it's fat soluble and won't be digested or absorbed w/o bile salts

What cofactor besides calcium and vitamin K is needed for many clotting reactions?
--platelet phospholipid

What is the most common cause of abnormal bleeding?
--thrombocytopenia, usu PLT below 70,000

What are some of the causes of thrombocytopenia?
--decreased PLT production dt BM damage
--congenital abn ie: Fanconi's aplastic anemia
--nutritional deficiency esp: B12 and folate
--splenomegaly-->sequestration
--DIC or purpura-->increased destruction of PLTs

What common hemorrhagic syndrome occurs following the uncontrolled activation of clotting factors and fibrinolytic enzymes throughout small blood vessels?
--disseminated intravascular coagulation (DIC)
--involves clotting throughout CV system
--fibrin deposited everywhere
--PLT's and clotting factors consumed
--anticoagulation systems are overwhelmed and worsen process as fibrin degradation products (incl D-dimers) inhibit fibrin polymerization and block PLT fx-->lethal tissue necrosis and bleeding

What triggers DIC?
--acute usudt massive tissue damage such as large severe burns, sepsis, or complication of pregnancy
--chronic dt certain cancers, retained dead fetuses, aneurysms or hemangiomas, insidious onset

What are the new names for the intrinsic and extrinsic coagulation pathways?
--contact activation pathway and tissue factor pathway respectively

What drug acts very quickly to antagonize thrombin in the intrinsic/&common pathway?
--heparin

What drug slows the extrinsic pathway?
--warfarin/coumarin, use PT lab to monitor

How does coumadin work?
--inhibits vit K utilization by competing with it as a cofactor
--slow acting, onset of action is 2-7 days, the half life of the factors
--usu pts use heparin therapy until coumadin takes effect

Which lab do you use to monitor conversion of X to Xa?
--PT, still

Which pathway is faster?
--the extrinsic one

Which pathway are you testing with the PT lab?
--extrinsic

At what factor do the intrinsic and extrinsic pathways merge to form the common one?
--factor Xa (activated)

How long does the intrinsic pathway take to form a clot after trauma to a vessel or blood?
--15 seconds to a minute

What lab test do you use to measure intrinsic pathway function?
--the PTT
--measure heparin therapy

What does plasmin do?
--attacks fibrin at 50 sites to break down tight clots

Where does antithrombin III come from?
--basophils and platelets

How do basophils know to release it?
--I have no idea

What does antithrombin III do?
--inhibits factors IIa, IX, Xa, XI, XII (three in the intrinsic pathway, two in the common)

What drug increases the action of antithrombin III by 1000 times?
--heparin

Note to self:
--intrinsic, heparin, PTT, slow
--extrinsic, tissue factor, warfarin, PT, fast

What's another name for tissue factor?
--factor III

What may trigger idiopathic thrombocytopenic purpura?
--a viral URI in a child

What is the most common hereditary hypercoagulability disorder amongst Eurasians?
--Factor V Leiden
--present in 3-8% of caucasians
--risk of venous thrombosis, OB complications
--increased risk for women on birth control pills (35X)!!!

What is the principle clot eliminator of the body?
--plasmin

What causes the hypercoagulability in Factor V Leiden?
--the Leiden variant of factor V cannot be inactivated by activated protein C

What is a FDP?
--fibrin degradation product (after plasmin breaks fibrin clot to fragments)

Diagnostic testing for venous thromboembolisms & pulmonary embolisms relies on finding what?
--D-dimers

What two actions does thrombin take to activate clotting?
--activates factor XIII and converts fibrinogen to fibrin monomers

What two actions does plasmin take to break down clots?
--breaks fibrinogen to FDPs and fibrin clots to D-dimers

What affects PT, prothrombin time?
--extrinsic and common coag pathways
--first effect: vactor VII, later II, IX, and X
--time INCREASED by hepatocellular liver disease, obstructive biliary disease (low vit K), and coumadin

How does coumadin increase PT?
--inhibition of vit K dependent factor depletion

What's INR?
--international normalized ratio = patient protime / normal protime
--a calculation to eliminate variation in PT measurements between labs
--used for monitoring effect of coumadin therapy

What factors can interfere with PT?
--alcohol increases time dt liver damage
--diarrhea prolongs dt vit K malabsorption
--high fat/leafy veg diet may shorten due to high vit K intake

Which factor is activated by the PTT test (partial thromboplastin time)?
--factor XII
--monitor heparin therapy

What can cause increased PTT times?
--congenital (hemophilia, A/classical is factor VIII, B and VWDz act on factor IX)
--liver cirrhosis
--vit K deficiency
--DIC
--heparin or coumadin therapy

What can decrease PTT times?
--early DIC
--extensive cancer

What screening test for platelet function abnormalities is likely to be on ND boards but barely used anymore?
--bleeding time
--PLT count under 50,000 prolongs BT

What other outdated test was mentioned in lecture and will likely be on boards?
--venous clotting time, 4-10 minutes, heparin monitoring

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