platelet & coagulation disorders II

question

what is secondary hemostasis?
answer

exposure of the subendothelial tissue factor causing the activation of the pro-coagulant coagulation cascade -> leading to formation of the hemostatic clot which reinforces the platelet plug
question

how do bleeding disorders compare in terms of purpura, mucosal bleeding, bleeding from superficial cuts, delayed bleeding, hemarthroses, and deep thromboses?
answer

purpura, mucosal bleding, & bleeding from superficial cuts are characteristic or platelet/vessel disorders while delayed bleeding, hemarthroses, and deep hematomas are characteristic of coagulation disorders. (platelets are first responders, coagulation is responsible for prolonged bleeding situations)
question

what are important aspects of screening for bleeding disorders?
answer

detailed fam hx including: spontaneous bleeds, sx bleeding, OB hx and bruising/bleeding gums. drug hx (ASA/plavix). physical examination (bruising).
question

where does most coagulation happen from?
answer

the extrinsic pathway
question

what is the only factor unique to the extrinsic pathway? how is this tested for?
answer

factor VII which is measured by PT (elevated PT = elevated VII)
question

can problems with factor XIII be measured by PT or PTT?
answer

no
question

what do proteins C and S do? how are they activated?
answer

proteins C and S inhibit (co)factors VIII and V which halt the coagulation cascade on the final common pathway. proteins C and S are activated by thrombomodulin which endothelial cells can release. (VIII helps activate XI and XI in the instrinsic, and V helps activated prothrombin to thrombin)
question

how does prostacyclin and NO secretion by endothelial cells inhibit the coagulation cascade?
answer

they inhibit platelet aggregation, which if inhibited keeps coagulation from being possible
question

what do the heparin-like compounds do that are secreted by endothelial cells?
answer

these activate anti-thrombin which inhibits thrombin as wel as IXa, Xa, XIa, and XIIa
question

what is the end result of endothelial cells releasing thrombomodulin?
answer

thrombomodulin complexes w/thrombin and activates protein C (& S) which then deactivates factor Va and VIIIa which are cofactors needed for the intrinsic and common pathway to work (everything is inhibited)
question

what does the tissue factor pathway inhibitor do?
answer

inhibits the processes which tissue factor is involved in: the complex between VIIa and tissue factor in the extrinsic pathway which goes over to the intrinsic and activates IX, as well as tissue factor itself which activates X in the common pathway
question

can coagulation protein defects be inherited or acquired?
answer

both
question

what does prothrombin time measure? what is it used to monitor
answer

VII, V, X, prothrombin, fibrinogen – but VII is the most important b/c it is unique to the EXTRINSIC pathway. since Ca++ is important to thrombin activation, PT is used to monitor warfarin/coumadin (oral anticoagulants)
question

why is citrated blood used in blood test specimens?
answer

the citrate ion chelates calcium ions in the blood by forming calcium citrate complexes, disrupting the blood clotting mechanism
question

what is thromboplastin?
answer

tissue factor+phospholipid and Ca++
question

how is prothrombin time tested?
answer

citrated blood is mixed with thromboplastin and clotting time is averaged between 2 duplicate tests
question

what does vitamin K do?
answer

vit K is necessary to formation of factors II, VII, IX, X, and proteins C & S
question

what is warfarin?
answer

warfarin is a vitamin K antagonist which reduces the rate at which factors II, VII, IX, X, and proteins C & S are produced and decreases coagulation up to 40%
question

what will an elevated PT usually indicate?
answer

a factor VII deficiency/inhibitor
question

what is the activated partial thromboplastin time? what is it used to monitor?
answer

the aPTT tests for for abnormalities in the intrinsic (VIII, IX, XI, XII) and common pathways (V, X). it is used to monitor heparin therapy.
question

how is an aPTT test run?
answer

citrated plasma is mixed with phospholipids and surface activator (to simulate what would happen w/injury) and Ca++ to act as a cofactor. 2 duplicate tests are averaged.
question

what does aPTT measure?
answer

everything EXCEPT VII, so it measures the intrinsic pathway/monitors heparin
question

what do both the PT and aPTT measure?
answer

the common pathway: X,V, prothrombin, and fibrinogen
question

what are some hereditary coagulation protein deficiencies?
answer

factor VIII (hemophilia A), IX (hemophilia B), XI (hemophilia C), fibrinogen disorders and other rare factor deficiencies
question

what are some acquired coagulation protein deficiencies?
answer

anticoagulant therapy, DIC, liver disease, and vit K deficiency (acquired: more common)
question

what is hemophilia A? how is it inherited? how is it diagnosed?
answer

the most common severe congenital bleeding disorder resulting from reduction in quantity/activity of factor XIII. it is X-linked recessive and has variable clinical severity (spontaneous in severe states). it presents as a prolonged aPTT and dx is confirmed via factor VIII assay
question

what is hemophilia B? how is it inherited? how is it diagnosed?
answer

hemophilia B (xmas disease) results from reduction in quantity/activity of factor IX. it is X-linked recessive and has variable clinical severity. it presents as prolonged aPTT and dx is confirmed by factor IX assay
question

what is hemophilia C? how is it inherited? how is it diagnosed? what population is it common in?
answer

hemophilia C results from reduction in quantity/activity of factor XI. it is autosomally recessive and has mild to moderate clinical severity. it presents as prolonged aPTT and dx is confirmed by a factor XI assay. it is common in ashkenazi jews
question

what is disseminated intravascular coagulation (DIC)?
answer

uncontrolled generation of thrombi in blood leading to thrombi in microcirculation w/high mortality. it is associated with coagulation factor depletion
question

what is DIC initially caused by?
answer

excessive tissue factor activity (metastatic dz, burns), trauma (neurotrauma), infections, OB disorders (amniotic fluid embolus), endothelial damage, acute promyleocytic leukemia (APML), and snakebites. *it is always secondary to underlying disorder
question

how does DIC happen?
answer

tissue/endothelial injury exposes TF, factor XII, and activates platelets which cause *uncontrolled* intravascular coagulation leading to consumption of clotting factors, which leads to bleeding elsewhere. the fibrin microthrombi formed start casuing ischemia and angiopathic hemolytic anemia (RBCs sheared on fibrin) AND initiate fibrinolysis, so the clots the body might actually need are broken up = more bleeding. the fibrin split end products from fibrinolysis are also inhibitory for platelet aggregation, fibrin polymerization, and thrombin.
question

what does the D-dimerization test test for?
answer

the D-dimer test measures the breakdown of clots by detecting fibrin split end products -> test for DIC
question

what may be the presenting sign of acute promyelocytic leukemia? what is acute promyelocytic leukemia?
answer

DIC. APML causes circulation to be filled with immature neutrophils (promyleocytes) that have toxic granules that circulated and lyse = unwanted coagulation setting off the whole DIC pathway
question

how is APML treated?
answer

all-trans-retinoic acid (ATRA) is administred to mature cells so they cannot release their bad granules
question

what is amniotic fluid embolus? can it cause DIC?
answer

it is possibly due to an anaphylactic (IgE) rxn to fetal antigens and is diagnosed by fetal squamous cells in the maternal pulmonary circulation. it can cause DIC
question

how are liver disease and the coagulation linked? what is the most sensitive marker of liver disease?
answer

most coagulation factors are produced in the liver (II, V, VII, IX, X), therefore disease causes impaired production/secretion of factors so both PT and aPTT are prolonged. factor VII is the most sensitive marker of liver disease however (shortest half life), so PT is the *best test
question

how does a vit K deficiency affect the coagulation pathway? when might this be seen?
answer

vit K is a cofactor in gamma-carboxylation of glutamic acid residues to Gla residues. activities of factors II, VII, IX, and X are thus low (but NOT factor V). hospitalized pts can present with this if not getting proper nutrition. factor V is made in the liver, but does not require vit K – therefore its activity may be normal in liver disease
question

what are some inherited causes of hypercoagulability?
answer

activated protein C resistance (factor V leiden), antithrombin deficiency, protein C/S deficiency, and dysfibrinogenemia
question

what are some acquired causes of hypercoagulability?
answer

lupus inhibitor, malignancy, nephrotic syndrome, therapy (factor concentrates/heparin/oral contraceptives), hyperlipidemia, and TTP
question

what is factor V leiden? who does this usually happen to? how is it tested for?
answer

a relatively common mutation where factor V unable to be inactivated by activated protein C, making it hard to stop coagulation. this usually happens to pt <50 with their first venous thromboembolism esp at an unusual site, related to pregnancy or oral contraceptives. it is tested for with either activated protein C resistance assay or a specific DNA test which detects the mutation in the V gene
question

what is an antithrombin deficiency?
answer

this autosomal dominant disorder has incomplete penetrance and can have a quantitative/qualitative effect on antithrombin. the risk of a thrombotic event ranges from 20-80% and is usually venous. it is rare.
question

how do protein C & S deficiencies occur?
answer

a homozygous protein C deficiency and can be life-threatening when it causes purpura fulminans (neonatal thrombosis). up to .5% of the population has a heterozygous protein C deficiency and many are symptom free. clinical symptoms are similar to antithrombin III deficiencies.
question

what are genetic variations of prothrombin associated with?
answer

thrombosis, and perhaps excessive prothrombin levels
question

what are dysfibrinogenemias associated with?
answer

thrombosis
question

when PT is normal think:
answer

vWF, hemophilia A or B, thrombocytopenia (b/c platelets are the problem)
question

when PT is increased think:
answer

vit K deficiency
question

when aPTT is normal or elevated think:
answer

vWF, vit K deficiency
question

when aPTT is elevated think:
answer

hemophilia A or B
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if platelet count is normal think:
answer

vWF, hemophilia A or B, or vit K deficiency
question

if platelet count is decreased think:
answer

thrombocytopenia

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