Factors II, V, VIII, HMWK -> cofactors
Factors II, VII, 9-12, Prekallikrein -> serine proteases
Vitamin K Dependent Factors
- Serine Proteases
- Factors II, VII, IX, X
- Regulatory control proteins C, S, Z
Factor
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Other Names
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Pathway(s)
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Role
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Location of Synthesis
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I
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Fibrinogen
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Common
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II
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Prothrombin
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Common
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III
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Tissue Factor (TF)
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IV
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Ca2+
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V
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Labile factor
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Common
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VII
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Stable factor
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Extrinsic
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VIII
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Anti-hemophilic factor
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Intrinsic
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IX
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Christmas Factor
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Intrinsic
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X
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Stuart-Prower Factor
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Common
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XI
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PTA (Plasma Thromboplastin Antecedent)
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Intrinsic
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XII
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Hageman Factor
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Intrinsic
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XIII
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Fibrin Stabilizing Factor (FSF)
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Crosslinks adjacent fibrin strand D-domains to make an insoluble polymer
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VWF
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HMWK
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High Molecular Weight
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Stages of Hemostasis
- Primary hemostasis
- Secondary hemostasis
- Fibrin clot formation
- Coagulation inhibition
Protein Z
- Z-dependent protease inhibitor (ZPI)
- Protein Z enhances ZPI activity
Restoring Blood Flow
- Fibrinolytic proteins
- Plasminogen
- Converted into plasmin by TPA and UPA
- Plasmin helps restore blood flow
- TPA
- UPA
1.85*10^-3 x (100-HCT) x v
300ul citrate
Coagulation Testing
All coagulation testing uses sodium citrate (light blue top) tubes to yield plasma. Centrifuge to separate plasma from platelets, yielding platelet poor plasma (to prevent activation of coagulation).
- RT: 4 hours
- Frozen: 2 weeks (-20C) to 6 months (-80C)
What? (Test)
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Why?
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How? (Methodology)
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Associated Conditions
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RI
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PT/INR (Prothrombin Time)
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Assess deficiencies or inhibitors of extrinsic or common pathways
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- Calcium thromboplastin added to sample (calcium and tissue factor source)
- Activates coagulation cascade
- Measured optically or mechanically
- Optical: light scattered as fibrin strands form
- Mechanical: magnetic balls oscillates, movement impeded by clot
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11.5 - 13.5 s
INR: 0.9 - 1.2
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APTT
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Assess deficiencies or inhibitors of intrinsic or common pathways
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- APTT reagent added to sample (contains contact activator and phospholipids)
- Activation of factor XII and XI
- Calcium then added to activate factor IX and VIII
- Factor X activated, causing cascade to activate Factor II and I, forming fibrin clot
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23 - 35 s
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Fibrinogen (Clauss Assay)
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Assess fibrinogen activity
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- Clauss assay uses reference plasma samples with known concentrations of fibrinogen
- Run thrombin time (high thrombin concentration) and plot results of concentration vs. time
- Patient samples can then be run and compared to the curve to determine fibrinogen concentration
- Clot time inversely proportional to fibrinogen activity
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Loss or consumption of fibrinogen
- Bleeding
- Hyperfibrinolysis
- DIC
Decreased production
- Congenital hypofibrinogenemia
- Dysfibrinogenemia
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1.5 - 4 g/L
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Thrombin Time
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Assess deficiencies of fibrinogen or the presence of thrombin inhibitors
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- Low concentration of thrombin added to cleave fibrinogen → fibrin
- Measure time to form fibrin clot
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Drugs
- Heparin
- Direct thrombin inhibitors (dabigatran, apixaban, etc.)
Conditions
- Congenital fibrinogen deficiencies
- Acquired fibrinogen deficiencies
- Increased clot breakdown (e.g., DIC)
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12 - 16 s
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D-Dimer
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Assess presence of fibrinolysis activation
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- Various methods (ELISA, latex immunoassay, etc.)
- Latex immunoassays: latex beads bind to D-Dimers and decrease measured absorbance
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Negative results highly sensitive and specific for ruling out venous thromboembolism (VTE) in certain populations
Positive results non-specific
- DIC
- Various diseases and infections
- Inflammation
- Recent surgery/trauma
- Cancer
- Elderly people
- Pregnancy (especially later trimesters)
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< 600 ug/L FEU*
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Unfractionated Heparin/Anti-Xa Assay
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Assess anticoagulant activity
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- Known value of Factor Xa is added in excess to patient sample
- Complex formed between drug and coagulation factor
- Unbound FXa hydrolyzed and abosrbance measured
- Result converted to a drug concentration
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Drugs
- Unfractionated heparin
- Low molecular weight heparin
- Fondaparinux
- Direct FXa inhibitors
- Rivaroxaban
- Apixaban
- Edoxaban
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Varies by drug
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Factor Assays
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'* FEU or DEU may be used for measurement
Anticoagulant Drugs
Drug
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Mechanism of Action
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Monitoring
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Reversal
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Unfractionated Heparin (UFH)
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INDIRECT
- Various length chains of glycosaminoglycans
- Combines with antithrombin (as pentasaccharide)
- Inhibits IIa, Xa, IXa, XIa, and XIIa
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Elective
- Discontinue IV for 4 hoursEmergency
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Low Molecular Weight Heparin (LMWH)
- Dalteparin, enoxaparin, nadroparin, tinzaparin, etc.
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INDIRECT
- Smaller chains of heparin (fractionated out)
- Combine with antithrombin (pentasaccharide)
- Inhibits Xa and IIa only
- Relative inhibition of factors (Xa:IIa ratio) various by formulation
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Not usually required
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Elective
- 12-24 hours discontinuation
Emergency
- Andexanet alpha pending approval
- Protamine may reverse effects on IIa only for intravascular LMWH
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Warfarin (Coumadin)
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- Vitamin K antagonist
- Prevents activation of vitamin K-dependent factors
- II, VII, IX, X, anticoagulant proteins
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Elective
- 5 days discontinuation (bridging may be done for some patients)
- Vitamin K if non-urgent
Emergency
- Vitamin K - activates factors already present
- Prothrombin complex concentrates (PCCs - Octaplex)
- Contain Vitamin K-dependent factors and some heparin
- Contraindicated in HIT
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Fondaparinux
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INDIRECT
- Synthetic pentasaccharide
- Combines with antithrombin
- Inhibits FXa only
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Not usually required
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Elective
Emergency
- Andexanet alpha (pending approval) may be helpful
- Otherwise, none
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Direct Thrombin Inhibitors (DTIs)
- Dabigatran (VTE, stroke prevention)
- Argatroban, Bivalirudin, Lepirudin (HIT treatment)
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DIRECT
- Synthetic
- Directly inhibit thrombin, do not require antithrombin (direct-acting)
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Not usually required
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Elective varies
Emergency (dabigatran)
- Idarucizumab
- Activated charcoal (within 2 hours)
- Hydration
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Direct Xa Inhibitors
- Rivaroxaban
- Apixaban
- Edoxaban
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- Synthetic
- Directly inhibit FXa (don't require antithrombin)
- Used for prevention of VTE and stroke
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Not usually required
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Elective varies
Emergency
- Andexanet alpha (pending approval)
- Prothrombin complex concentrates (PCCs - Octaplex)
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