Mkgrady8 Gpmdc 2 Bleeding Disorders

Front 1

hemostasis definition

Back 1

tightly regulated processes that maintainblood in a fluid, clot-free state in normal vessels while inducing the rapidformation of a localized hemostatic plug at the site of vascular injury.

Front 2

the pathologic form of hemostasis

Back 2

thrombosis; it involves blood clot (thrombus) formation in an uninjuried vessels or thrombotic occlusion of a vessel after relatively minor injury.

Front 3

both hemostasis and thrombosis involve what 3 components

Back 3

Vascular wall, platelets and the coagulation cascade.

Front 4

the balance between what and what determines whether thrombus formation, propagation, or dissolution occurs

Back 4

anti - and prothrombotic activities

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at baseline, endothelial cells exhibit what 3 properties

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antiplatelet, anticoagulant, and fibrinolytic properties

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on the other hand after injury they are capable of

Back 6

exhibiting numerous procoagulant activites; They also can be activated by infectious agents, hemodynamic factors and cytokines

Front 7

antithrombotic properties of endothelial cells

Back 7

Inhibiting platelet adherence; Preventing coagulation factor activation; Lysing blood clot that may form.

Front 8

prothrombotic properties of endothelial cells

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Endothelial cells can be stimulated by direct injury or various cytokines that are produced during inflammation; Such stimulation results in expression of procoagulant protiens (e.g., tissue factor and vWF (von wilibrant factor))that contribute to local thrombus formation; Also, loss of endothelial integrity exposes underlying vWF and basement membrane collagen, both substrates for platelet aggregation and thrombus formation.

Front 9

after vascular injury what happens

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Vasoconstriction; Subendothelial extracellular matrix; Tissue factor (Factor III/thromboplastin); Thrombin; Polymerized fibrin and platelet aggregates

Front 10

platelets: what is their role, what do they express

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They play a critical role in normal hemostasis.; When circulating and nonactivated they are smooth disks; They express several glycoprotein receptors and contain two types of granules

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platelets

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SIZE 2-4 um; NUMBER IN THE CIRCULATION 14,000; SPLENIC POOL 1/3 of platelets; PLATELET GRANULES

Front 12

after vascular injury platelets undergo what 3 reactions

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Adhesion and shape change; Secretion (release reaction); Aggregation

Front 13

platelet aggregation

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Endothelial injury exposes the underlying basement membrane ECM; platelets adhere to the ECM and become activated by binding to vWF through GpIb (KNOW THIS ONE) platelet receptors; Upon activation, platelets secrete granule products that include calcium (activates coagulation proteins) and ADP (mediates further platelet aggregation and degranulation); Activated platelets also synthesize TXA2 (thromboxane A2) (increases platelet activation and causes vasoconstriction); Activated platelets provide phospholipid complexes which are an important surface for coagulation-protein activation; Released ADP stimulates formation of aprimary hemostatic plug by activating platelet GPIIb-IIIa (KNOW THIS ONE) receptors that BIND FIBRINOGEN AND CAUSE FIBRINOGEN cross-linking; The formation of definitive secondary hemostatic plug requires the activation of thrombin to cleave fibrinogen and form polymerized fibrin via coagulation cascade

Front 14

coagulation cascade

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The coagulation cascade constitutes the third component of the hemostatic process and is the a major contributor to thrombosis; Coagulation occurs through the sequential enzymatic conversion of a cascade of circulating and locally synthesized proteins; Tissue factor elaborated at sites of injury is the most important initiator of coagulation cascade; At the final stage of coagulation, thrombin converts fibrinogen into insoluble fibrin, which helps to form the definitive hemostatic plug

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coagulation is normally restricted to the sites of vascular injury by:

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Limiting enzymatic activation to phospholipid complexes provided by activated platelets; Natural anticoagulants elaborated at sites of endothelial injury or during activation of the coagulation cascade.

Front 16

contact system: includes what, made where, does what, deficiencies, recommendation in some pts

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Includes factor XII (Hageman factor), prekallikrein (PK; Fletcher factor), high molecular weight kininogen(Fitzgerald factor); some authors include factor XI; Made in the liver (ECXCEPT FACTOR VIII AND vWF); Decreased activity is associated withliver disease, hepatic immaturity in newborns, antiphospholipid syndrome, Asian descent (for factorXII); Homozygous deficiencies are rare,autosomal recessive; cause prolong PTT but no bleeding disorders and no definite association with hypercoagulability; Recommended to not measure their activity in routine evaluation of patients with arterial or venous thromboembolism oracute coronary syndromes

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intrinsic pathway: involves what

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Involves factors VIII, IX, XI, XII (Hageman factor), prekallikrein, high molecular weight kininogen; Merges with extrinsic pathway into common pathway; Activated when factor XII binds to negatively charged “foreign” surface exposed to blood; Then sequentially activates factors XI,IX, X, then factor II (prothrombin to thrombin), which converts fibrinogen to fibrin (see common pathway); REMEMBER THIS BY REMEMBERING THE LAST LETTER LEADING TO THE NEXT ONE= twelevE --> EleveN --> NinE -- > EighT --> Ten

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extrinsic pathway: involves what

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Involves tissue factor (TF), originally considered “extrinsic” to blood since it is present on cell surfaces not normally in contact with (i.e. extrinsic to the circulatory system); The primary mechanism of the coagulationpathway in vivo is tissue factor binding to activatedfactor VII (factor VIIa) (KNOW THIS ONE); TF-Factor VIIa complex activates factors X; Activated factor X with activated factor V, anionicphospholipids (from activated platelets) and calcium as cofactors; convert prothrombin to thrombin

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common pathway: involves what

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Involves factor I (fibrinogen), factors II (prothrombin), V, X (KNOW THESE); Thrombinconverts soluble fibrinogen to insoluble fibrin; FactorXIII (KNOW THIS) cross links fibrin to increase stability of fibrin clot

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causes of excessive bleeding

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Increased fragility of vessels; Platelet deficiency or dysfunction; Derangement of coagulation; Combination of the above

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bleeding disorders in general: what to look at in clinical history

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(A) Single site (structural lesion) vs. multiple sites (coagulopathy); (B) For coagulopathies - hereditary (family history of bleeding or bleeding since childhood) or acquired (no previous bleeding history); (C) Time from “hemostasis challenge” to bleeding symptoms - immediate suggests platelet disorder (inability to form normal platelet plug); late suggests coagulopathy (breakthrough bleeding occurs after platelet plug due to impaired fibrin formation); (D) Physical exam: petechiae (platelet disorders) vs. hematomaor hemarthrosis (coagulation defects) vs. mucous membrane bleeding or bruising (nonspecific)

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Bleeding disorders are often classified as defects of

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primary hemostasis (platelets, vessels) or of secondary hemostasis (coagulation cascade and its regulation)

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tests used to evaluate hemostasis

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Bleeding time; Platelet function tests; Platelet counts; Prothrombintime (aka PT); Partial thromboplastin time (PTT); Factor assays; Fibrinogen; Fibrin split products; Circulating anticoagulants

Front 24

prothrombin time assay used for what

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The PT assay screens for the activity of the proteins in the extrinsic pathway (all the way through the common pathway); PT is used to monitor the efficacy of coumadin anticogulantion therapy

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PT is prolonged in:

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Factor VII deficiency; Common pathway defect (I,II, V&X); Warfarin use or overdose; Heparin overdose or contamination

Front 26

international normalized ratio (INR): used for what, range, defined as

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Used to standardize prothrombintime (PT) results for patients taking warfarin (coumadin); Therapeutic goal is usually a value of 2 to 3; Intended to make comparisons similarbetween different labs by compensating for variable thromboplastins used in PT test; Defined as patient PT divided by mean normal PT, with the result raised to the power (exponent) of the ISI (don't need to know equation)

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APTT: screens for what, is useful for what, is prolonged in what

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The PTT assay screens for the activity of proteins in the intrinsic pathway; It is useful to monitor the efficacy of heparin therapy for acute thrombosis or embolism It is prolonged in= Common pathway defect, Heparin use, Factor deficiency, DIC

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TT: prolonged in what

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tests only for fibrogen (factor I); Hypofibrinoginemia; Dysfibrinoginemia; Heparin use or contamination; DIC

Front 29

test battery: APTT abnormal, PT abnormal, TT normal, possible causes?

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Vitamin K deficiency (Factors II, VII, IX & X deficiency); Liver diseases; Inhibitor effect; answer= Factor deficiency in common pathway II, V, X

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test battery: APTT abnormal, PT normal, causes?

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Factor deficiency in intrinsic pathway; Antiphospholipid antibody; Specific factor inhibitor= FVIII inhibitor; ANSWER= both extrinsic and common are normal because of normal PT so the problem must be in the intrinsic pathway

Front 31

test battery: APTT normal, PT abnormal, causes?

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Factor deficiency in the extrinsic pathway; Specific factor inhibitor; ANSWER= APTT normal so normal intrinsic factor, PT abnormal so problem in the extrinsic pathway

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test battery: APTT abnormal, PT abnormal, TT abnormal, causes?

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Factor deficiency; Severe liver diseases; DIC; Potent inhibitor; Fibrinogen abnormality