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58 Cards in this Set
- Front
- Back
What are the three main events of primary hemostasis?
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Vasoconstriction
Platelet adhesion (platelet-vessel wall) and aggregation (platelet-platelet) Formation of unstable platelet plug |
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How is vasoconstriction achieved in primary hemostasis?
What is the vasoconstriction in response to? |
Vessel injury!
Vasoconstriction caused by: -Local reflexive neurogenic response -Endoth cells releasing endothelin -Platelets relasing Thromboxane A2 |
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How is platelet adhesion achieved in primary hemostasis?
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Injured vessel exposes subendothelial matrix proteins
Exposes collagen; vWF sticks to collagen (which carries factor VIII); and platelet binds to vWF via GpIb receptor |
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What is Bernard Soulier syndrome?
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Defect/deficiency in GpIb receptor
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What is the platelet release reaction? When does it occur?
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When platelets adhere to damaged endothelium, undergo shape change and RELEASE REACTION, whereby agonists are released to recruit more platelets (AGGREGATION)
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Once a platelet is bound to vWF, how does it aggregate with other platelets?
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GpIIb/IIIa receptor binds fibrinogen, which binds to otehr GpIIb/IIIa receptors on other platelets.
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What is Glanzmann's Thrombasthenia?
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GpIIb-IIIa deficiency/defect
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What two events allow for an unstable platelet plug to be stabilized, i.e., activate coagulation cascade?
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-Once platelet shape changes, there's an alteration of platelet phospholipid surface.
-The release of tissue factor from damaged endothelial cells Both of these activate blood coagulation cascade and deposition formation of fibrin (secondary hemostasis) |
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What is the extrinsic pathway and how does it lead to the production of fibrin?
Why is this reaction localized? |
Tissue factor released from damaged endothelial cells and Factor VII released.
This activates the COMMON PATHWAY, which allow Factor X and Factor V to convert Prothrombin (Factor II) to Thrombin (Factor IIa)--10 divided by 5 is 2. Thrombin converts fibrinogen to fibrin! Extrinsic PW also activates Factor IX in the intrinsic PW which also activates common PW. THIS ONLY HAPPENS ON ACTIVATED PLATELET PHOSPHOLIPID SO IT IS NOT A SYSTEMIC RESPONSE. |
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Prothrombin Time test:
What is it? Normal value? What does it measure? How are the results standardized between labs? |
Add Tissue Factor Equivalent to plasma and measure how long blood takes to clot
Normal PT ~12 seconds Allows for assessment of EXTRINSIC PW Time is then standardized against International Normalized Ratio (INR); normal INR is 1 |
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What ion is necessary for the extrinsic, intrinsic, and common pathways to occur?
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Ca2+
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What is a Partial Thromboplastin Time?
How is it performed? Normal value? What does it measure? |
PTT assesses intrinsic pathway through blod clotting test:
Contact-activating substances added to plasma and measure how long clot takes to form Normal PTT ~30 sec |
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What three things are required for fibrinogen conversion to fibrin (and cross-linking)?
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Thrombin
Factor XIII Ca2+ |
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What is the role of plasmin?
What is its proenzyme form? What converts it to its activate form? |
Limits extent of clot formation by cleaving fibrin (fibrinolysis)
TPA activates plasminogen to plasmin. |
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List the required factors and appropriate tests for the following:
Common PW Extrinsic PW Extrinsic PW |
Common: X, V, II (10/5=2)
Extrinsic (PT--fewer factors, fewer letters): VII, TF (VII is all alone, EXtricated from the rest) Intrinsic (PTT--more factors, more letters): VIII, IX, XI, XII (INcludes all the rest) |
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Hemophilia A:
Factor involved What tests will be abnormal? Pattern of inheritance. Mutation involved |
Deficiency of Factor VIII
PTT X-linked recessive (females are carriers!) 45% of mutations = inversion of Factor VIII gene at intron 22*** |
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Factor ___ is carried by vWF.
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VIII
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Hemophilia B:
Factor Involved What tests will be abnormal? Pattern of inheritance. |
Factor IX
Abnormal PTT X-linked recessive |
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Clinical features of hemophilia.
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Mucocutaneous bleeding
Hemarthrosis: joint bleeds (knees, elbows); can lead to deformity Muscle bleeds Intracranial bleeding |
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In patients with hemophilia, is excessive bleeding seen after minor cuts or abrasions? Why or why not?
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No, primary hemostasis is normal in hemophilia. Secondary hemostasis is abnormal.
Can plug up hole. |
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How are hemophilia A and B distinguished clinically?
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Measure factor VIII, and IX levels.
Factor VIII low in hemophilia A; Factor IX low in hemophilia B. |
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Hemophilia:
Treatment |
-Recombinant factor replacement to about 30% activity
-Prophylaxis replacement |
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DDAVP (desmopressin):
Treatment role in hemophilia Treatment role in VW Disease |
Causes release of factor VIII from endothelium and can be used for low-risk bleeding in patients with mild hemophilia.
Causes release of stored vWF from endothleium in pts w/VW Dz. Note, this only works acutely bc all Factor VIII/vWF will be used up. |
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Von Willebrand Disease:
What is it? Why does it affect both primary and secondary hemostasis? |
Abnl/deficient VWF protein
VWF impt for platelet adhesion and is a carrier for FVIII |
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How is VW Disease differentiated from hemophilia A clinically?
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In addition to low factor VIII levels, patients will have low vWF levels.
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VW Disease:
Type I Type II (general) Type II A Type II B Type II N Type III |
Type I: deficiency of VWF (most common)
Type II: qualitative defect of VWF: IIA: no high molecular multimers IIB: VWF binds platelets super well and use up platelets and large multimers (THROMBOCYTOPENIA) IIN: VWF can't bind factor VIII (looks like hemophilia) Type III: rare; severe or even complete VWF deficiency |
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Utility of ristocetin in diagnosis of VW Disease.
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Upon administration, there will be defective platelet aggregation in pts w/VW Dz.
Platelet aggregation is the normal response for ristocetin (bc requires large multimers of vWF) |
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VW Disease:
Treatment |
High-purity vWF concentrates with pts w/very low vWF
Factor VIII replacement |
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Vitamin K:
Role in coagulation Site of production in body Requirements for production |
Required for final synthetic step for factors II, VII, IX, and X
Produced by bacterial gut flora Vit K is fat soluble and requires bile salts for absorption |
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Warfarin:
MOA |
Blocks reduction of vitamin K epoxide-->vitamin K so it can't participate in final step of coagulation
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Vitamin K Deficiency:
Causes Test Abnormalities Treatment |
Poor nutrtion, malabsorption, anything affecting GI flora (broad spectrum abx)
Elevations in PT, can see elevations in PTT with more severe deficiencies Tx: Vit K supplementation |
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Hemorrhagic Disease of Newborn:
Cause |
Vitamin K deficiency secondary to:
-No bacterial colonization -Low Vit K in breast milk -Liver still developing (liver responsible for production of coagulation factors) (prophylaxis dose of vit K given at birth) |
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All coagulation factors are made by ______ except ____, which is made in ____.
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All coag factors made by liver except factor VIII, which is made by endothelium and bound to vWF.
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Effect of liver disease on PT and PTT. Why?
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Will see elevations in both PT and PTT because liver makes clotting factors measured by both tests.
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Disseminated Intravascular Coagulation:
Pathophys Test Abnormalities |
Overwhelming stimulus to coaguln system (ex: bacterial sepsis)-->massive triggering of blood coagulation cascade
Paradoxically results in bleeding (consumptive coagulopathy) bc: -Dec'd clotting factors -Dec'd platelets -Dec'd fibrin production (inc'd fibrinolysis, inc'd fibrin splid prods--D-Dimer) Elevated PT and PTT |
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How can liver disease be distinguished from disseminated intravascular coagulation?
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Similarities:
Inc PT and Inc PTT Dec platelets Inc'd Fibrin Degradation Products (D-Dimer?) Dec'd factor levels DIFFERENCE: FVIII normal in liver disease (only factor NOT made in liver) FVIII depleted in DIC |
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List the three coagulation factor inhibitors.
What do they promote? |
Anti-thrombin III
Prot C Prot S Promote fibrinolysis |
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Factor V Leiden:
Pathophysiology Testing |
Point mutation in factor V leading to Activated Protein C Resistance (Prot C promotes fibrinolysis)
Resistance to APC-->unopposed clotting Testing: PCR for point mutation at 506 on Factor V OR Test for APC resistance: Perform PTT by adding APC to tube. If mutation present, PTT will not increase as expected. |
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Activated Protein C:
Function |
Inactivates Factor Va, and VIIIa
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What is the most common inherited cause of increased risk of venous thrombosis?
Effect of heterozygous and homozygous genotypes on increased risk. |
Factor V Leiden
However, 90% of persons who are heterozygous for FVL will never have clot!!! DOn't need lifelong anticoaguln. 50% of homozygotes will have clot by age 50. |
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Protein S:
Function Risk of thrombosis with deficiency |
Cofactor for Protein C; needed to activate prot C to inactivate FV and FVIII
50% will have thrombosis by age 35! |
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Protein C Deficiency:
Effects (general) Effects in infants |
50% will develop clot by age 50!
Can result in Neonatal Purpura Fulminans (Presents as DIC at birth. Tret w/Protein C concentrate and anticoaguln) |
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Warfarin Skin Necrosis:
Pathophys Treatment |
Patients with Prot C Def have further decrease in Prot C upon administration of warfarin (bc warfarin inhibits protein C)
Results in paradoxical coagulation and dermal vessel occlusion Tx: vit K (counteracts warfarin's effects) and heparin (to prevent further coagulation) |
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This deficiency may present with migraines or mesenteric vein thrombosis.
If this patient were a woman, what would exacerbate this deficiency? |
Protein S deficiency
Pregnancy and those on OCP's have lower protein S levels. |
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A child with purpura fulminans in setting of varicella infection, is likely to have ________.
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An auto-ab against Prot S
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Heparin:
MOA |
Heparin boosts antithrombin activity by 1000x
Antithrombin = anticoagulant When heparin added, AT binds and inactivates clotting enzymes (II, X, XII, XI, IX) |
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Women who are pregnant or post-partum are at greatest risk of this deficiency.
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Antithrombin Def
Often need tx w/heparin or AT to prevent clot |
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Patients with nephrotic syndrome are at risk for renal vein thrombosis because ______.
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They lose antithrombin in the urine.
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Antithrombin deficiency:
Treatment |
Heparin
Estrogens |
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Protein C Deficiency:
Treatment |
Warfarin
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Protein S Deficiency:
Treatment |
Warfarin
Estrogens |
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Prothrombin Gene Mutation (G20210A):
Effects |
Mutation leading to inc'd levels of prothrombin
Weak risk factor for cloting (like FVL), so no need for lifelong anticoaguln |
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A woman with cerebral vein thrombosis while pregnant (or on OCPs) likely has __________.
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Prothrombin Gene Mutation
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Antiphospholipid Anitbodies:
Pathophys Presents with [bleeding/clotting] |
Ab's directed against phospholipids, clotting doesn't occur bc have no phospholipids to activate cascade
CLOTTING; it's paradoxical. no one knoooows why. |
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This condition has an elevated PTT that corrects with viper venom. Why?
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Antiphospholipid Ab's
Venom uses excess phospholipid to provide clotting cascade medium (can't have clotting without phospholipids. pts w/auto-ab's against phospholipids won't have phospholipids for clotting to occur on!) |
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Venous Thrombosis:
Virchow's Triad Utility of D-Dimer assay |
1) Hemostasis
2) Hypercoag--inherited or ac'd -Vessel wall damage Can lead to DVT or PE Negative D-dimer usually r/o DVT and PE |
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Arterial thrombosis is most commonly due to _________.
Pathophys? |
Atherosclerosis-->plaque rupture and endothelial injury exposing collagen and TF
-->platelet nidus forms, adhere, aggregate |
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Criteria for weak vs strong thrombophilia.
How does screening differ between the two? |
Weak: 1st clot after age 50 and no famhx clotting
Strong: 1st clot before age 50 or hx of recurrent clots or 1st degree relative w/clot before age 50 If weak, screen for APC-R, Prothrombin Mutation, Antiphospholipid Ab's If strong: all of the above, in addition: Antithrombin Def, Prot S Def, Prot C Def |