platelet & coagulation disorders II

what is secondary hemostasis?
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
how do bleeding disorders compare in terms of purpura, mucosal bleeding, bleeding from superficial cuts, delayed bleeding, hemarthroses, and deep thromboses?
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)
what are important aspects of screening for bleeding disorders?
detailed fam hx including: spontaneous bleeds, sx bleeding, OB hx and bruising/bleeding gums. drug hx (ASA/plavix). physical examination (bruising).
where does most coagulation happen from?
the extrinsic pathway
what is the only factor unique to the extrinsic pathway? how is this tested for?
factor VII which is measured by PT (elevated PT = elevated VII)
can problems with factor XIII be measured by PT or PTT?
what do proteins C and S do? how are they activated?
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)
how does prostacyclin and NO secretion by endothelial cells inhibit the coagulation cascade?
they inhibit platelet aggregation, which if inhibited keeps coagulation from being possible
what do the heparin-like compounds do that are secreted by endothelial cells?
these activate anti-thrombin which inhibits thrombin as wel as IXa, Xa, XIa, and XIIa
what is the end result of endothelial cells releasing thrombomodulin?
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)
what does the tissue factor pathway inhibitor do?
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
can coagulation protein defects be inherited or acquired?
what does prothrombin time measure? what is it used to monitor
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)
why is citrated blood used in blood test specimens?
the citrate ion chelates calcium ions in the blood by forming calcium citrate complexes, disrupting the blood clotting mechanism
what is thromboplastin?
tissue factor+phospholipid and Ca++
how is prothrombin time tested?
citrated blood is mixed with thromboplastin and clotting time is averaged between 2 duplicate tests
what does vitamin K do?
vit K is necessary to formation of factors II, VII, IX, X, and proteins C & S
what is warfarin?
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%
what will an elevated PT usually indicate?
a factor VII deficiency/inhibitor
what is the activated partial thromboplastin time? what is it used to monitor?
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.
how is an aPTT test run?
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.
what does aPTT measure?
everything EXCEPT VII, so it measures the intrinsic pathway/monitors heparin
what do both the PT and aPTT measure?
the common pathway: X,V, prothrombin, and fibrinogen
what are some hereditary coagulation protein deficiencies?
factor VIII (hemophilia A), IX (hemophilia B), XI (hemophilia C), fibrinogen disorders and other rare factor deficiencies
what are some acquired coagulation protein deficiencies?
anticoagulant therapy, DIC, liver disease, and vit K deficiency (acquired: more common)
what is hemophilia A? how is it inherited? how is it diagnosed?
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
what is hemophilia B? how is it inherited? how is it diagnosed?
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
what is hemophilia C? how is it inherited? how is it diagnosed? what population is it common in?
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
what is disseminated intravascular coagulation (DIC)?
uncontrolled generation of thrombi in blood leading to thrombi in microcirculation w/high mortality. it is associated with coagulation factor depletion
what is DIC initially caused by?
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
how does DIC happen?
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.
what does the D-dimerization test test for?
the D-dimer test measures the breakdown of clots by detecting fibrin split end products -> test for DIC
what may be the presenting sign of acute promyelocytic leukemia? what is acute promyelocytic leukemia?
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
how is APML treated?
all-trans-retinoic acid (ATRA) is administred to mature cells so they cannot release their bad granules
what is amniotic fluid embolus? can it cause DIC?
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
how are liver disease and the coagulation linked? what is the most sensitive marker of liver disease?
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
how does a vit K deficiency affect the coagulation pathway? when might this be seen?
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
what are some inherited causes of hypercoagulability?
activated protein C resistance (factor V leiden), antithrombin deficiency, protein C/S deficiency, and dysfibrinogenemia
what are some acquired causes of hypercoagulability?
lupus inhibitor, malignancy, nephrotic syndrome, therapy (factor concentrates/heparin/oral contraceptives), hyperlipidemia, and TTP
what is factor V leiden? who does this usually happen to? how is it tested for?
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
what is an antithrombin deficiency?
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.
how do protein C & S deficiencies occur?
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.
what are genetic variations of prothrombin associated with?
thrombosis, and perhaps excessive prothrombin levels
what are dysfibrinogenemias associated with?
when PT is normal think:
vWF, hemophilia A or B, thrombocytopenia (b/c platelets are the problem)
when PT is increased think:
vit K deficiency
when aPTT is normal or elevated think:
vWF, vit K deficiency
when aPTT is elevated think:
hemophilia A or B
if platelet count is normal think:
vWF, hemophilia A or B, or vit K deficiency
if platelet count is decreased think:
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