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Flashcards in Coagulation tests Deck (21):

Primary vs secondary hemostasis

-Hemostasis: the ability to clot
-Primary: initial platelet plug (front line defense)
-Areas of body under its control: skin, mucosa, endothelium
-Things involved: platelets, vonWillebrand's (vW), fibrinogen
-Secondary: proteins to finalize the plus
-Areas under control: joints, deep tissue
-Involved: clotting factors


Manifestations of hemostasis deficiencies

-Primary: can see from the skin (petechiae, ecchymoses, purpura), prolonged bleeding time (BT)
-Secondary: can only see in joints


Tests of primary hemostasis

-History (menstrual, dental, family)
-Peripheral smear (look for abnormal platelets)
-Bleeding time (make thin slice in skin and measure time to clot, should be <9min)
-PFA100 (platelets function analyzer)


Inherited conditions that prolong BT

-Glanzmann's thrombasthenia (IIbIIIa receptor deficiency)
-Bernard Soulier (IbIX receptor deficiency)
-vW disease (vWD; defective or low vW)
-Platelet granule defects


Acquired conditions that prolong BT

-Severe anemia
-Liver disease
-Drugs (NSAIDs, aspirin)
-BT does not correlate w/ exposure to NSAIDs



-Anticoagulated whole blood passed through pore coated w/ collagen + ADP
-Measure closure time (CT), time it takes to occlude aperture via clot
-Superior test to BT as a screen for platelet dysfunction (can detect moderate to severe vWD, aspirin's effect)
-Cannot distinguish btwn type 1 vWD (not enough vW) and type 2 vWD (poor quality vWD)


Specific tests of platelet function

-Platelet aggregometry: tests platelet response to agonists that induce aggregation (rare diseases)
-vWF Ag: quantitaive measure of vWF (vW made in endothelial cells, amount in blood surrogate to amount being made)
-Ristocetin cofactor assay (RCA): tests the ability of vWF to bind to its receptor (GPIbIX)
-RCA tests the functional aspect of vW (the high weight multimer form)
-If vWF Ag and RCA do not parallel, usually means problem in activity (quality) of vW
-Comparing the vWF Ag and RCA allows you to distinguish btwn type 1 and type 2 vWD (both low-> type1, vWF Ag normal and RCA low-> type2A or M)


Secondary hemostasis (coagulation cascade) 1

-3 parts: instrinsic, extrinsic, and common pathways
-Extrinsic: starts w/ tissue factor (TF) activating factor VII to its active form VIIa (requires Ca and phospholipid, PL)
-VIIa+TF+Ca/PL is able to activate factor X to Xa


Secondary hemostasis (coagulation cascade) 2

-Common: starts w/ X being activated to Xa (requires Ca and PL), either by TF+VIIa or IXa+VIIIa complex (from extrinsic pathway)
-Once Xa is activated, it complexes w/ active Va (activated by trace thrombin) and Ca/PL (Xa/Va/Ca/PL is prothrombinase complex) to activate prothrombin (factor II) to thrombin (IIa)
-Once thrombin is active it cleaves fibrinogen (factor I) to fibrin (Ia), which is insoluble and precipitates out of solution to form the clot


Secondary hemostasis (coagulation cascade) 3

-Intrinsic: Starts w/ factor XIIa (activated by negatively charged surfaces) which complexes w/ HMWK (high molecular weight kininogen), PK (prekallekrein), and factor XI to activate XI-> XIa (XI usually activated by thrombin)
-XIa activates factor IX (w/ Ca) to IXa (IX can also be activated by VIIa+TF)
-IXa must complex w/ active VIIIa (activated by trace thrombin) and Ca to form the intrinsic tenase complex
-This IXa/VIIIa/Ca/PL tense complex activates X to Xa and thus begins the common pathway


-Tests for secondary hemostasis

-PT (prothrombin time): tests the extrinsic + common pathways
-aPTT (activate partial thromboplastin time): tests the intrinsic + common pathways



-Add citrated (anticoaged) plasma + PL + contact activator + Ca and measure time to clot
-Most sensitive to the intrinsic pathway (prolongs when 60-70% deficient)
-Only test that is sensitive to heparin (PT test the system is overloaded w/ TF and is not sensitive to heparin)
-More sensitive to VIII and XI than to IX
-Less sensitive to thrombin and fibrinogen
-Accuracy depends on reagents, mild but significant deficiencies can be missed, deficiencies in common pathway prolong both aPTT and PT
-Correlation btwn degree of prolongation and factor level better for VIII than others
-HMWK, prekallikrein, and XII affect the aPTT but deficiencies in these do not cause bleeding
-Normal aPTT in adult: 23-33


Spurious prolongation of aPTT

-Elevated HCT (increases the citrate:plasma ratio, removing some Ca)
-Heparin in tube (inactivates thrombin and Xa)
-Clotted sample (pulls factors out of solution)


Workup of a prolonged aPTT

-If an aPTT is prolonged it means there is either a deficiency in a factor or an inhibitor of a factor present, but doesn't tell you which
-Must do a 50/50 mix (50% patient blood and 50% normal blood) to increase all factor levels to at least 50% (and therefore they are all at high enough level to clot)
-If the mix clots, that means there was a deficiency in the patients blood
-If the mix doesn't clot, that means there was an inhibitor in the patients blood that is still inhibiting the factor(s) in the mix


Workup based on result of 50/50 (after prolonged aPTT)

-If the 50/50 corrected the blood, assay for individual factors (XI, IX, VIII) to see where the deficiency lies (since XII is unimportant, but the rest are)
-If the 50/50 did not correct the blood, test for lupus anticoagulant Abs, anticardiolipin Abs
-If those Ab tests are negative then test for specific inhibitor Abs


Prothrombin time (PT)

-Add citrated plasma + tissue (for TF/PL) + Ca and measure time to clot
-Measured in INR, normal being >1.3
-Measures deficiency of VII and common pathway factors
-PT begins to prolong w/ 50-60% factor deficiency
-Most common cause of isolated prolongation of PT is heterozygous deficiency of VII or gene polymorphism


Workup of prolonged PT

-Also do 50/50, results indicate the same
-If 50/50 corrects the PT then there was a deficiency
-If 50/50 does not correct the PT then there was an inhibitor
-Further workup for deficiency: test for factor deficiency (usually VII)
-Further workup for inhibitor: test for thrombin Ab, other Abs


Thrombin time (TT)

-Add thrombin + citrated plasma and measure clotting time
-Only measures amount and quality of fibrinogen (catalyzes the last step only)
-Minimal hemostatic level of fibrinogen: 75-100 mg/dl (fibrinogen <100 mg/dl prolongs TT)
-Abnormal fibrinogen quality seen in hereditary dysfibrogenemia, cirrhosis, HCC (?), newborns
-TT can also be prolonged in: heparin Rx, excess fibrinogen degradation products (FDPs), paraproteinemia (large proteins inhibit polymerization of fibrin), renal failure



-Inherited diseases, X linked recessive
-Hemophilia A (more common, less severe): deficiency in factor VIII
-Hemophilia B (less common, more severe): deficiency in factor IX
-Hemophilia C (very rare, very severe): deficiency in factor XI. NOT X linked, it is autosomal recessive, but heterozygotes can also show prolonged bleeding



-Complicated pathway to break down clots and control coagulation
-Key mediator of clot breakdown: plasmin
-Plasmin destroys fibrin polymers and breaks them up into fibrin degradation products, thus un-clotting blood


Tests for accelerated fibrinolysis

-Euglobulin lysis time (ELT): measures the time to breakdown clot in a sample of plasma
-Dilute whole blood clot lysis time (DWBCLT): measures the time to breakdown clot in a sample of whole blood
-These are shortened in: advanced cirrhosis, alpha2-antiplasmin deficiency, plasminogen activator inhibitor-1 deficiency (PAI-1), systemic fibrinolysis
-Can occasionally see prolonged in venous thrombosis and renal failure (increased PAI-1 levels)