Blood Coagulation Overview and Acquired Hemorrhagic Disorders Flashcards
What are the natural coagulation inhibitors?
- Tissue factor pathway inhibitor (TFPI)
- Antithrombin
- Protein C
- Protein S
What does antithrombin inhibit?
Mainly thrombin and factor Xa, other plasma proteins
What converts protein C to it’s activated form?
Thrombin
Other name for thrombin?
Factor IIa
What does protein C inhibit, along with protein S?
Factor Va and Factor VIIIa
Catalysts of the coagulation cascade?
Factor V and Factor VIII
Which antithrombotic factors are made in endothelial cells?
- Protein S
- Tissue plasminogen activator (TPA)
What is the inhibitor of TPA?
Plasminogen activator inhibitor 1 (PAI-1)
What compound acts with antithrombin to inhibit thrombin and factor Xa?
Heparin SULFATE
Main enzyme in fibrinolytic pathway? What is it converted to?
Plasminogen –> Plasmin
Plasmin along with what compounds lyses clots?
tPA
uPA (in the urine)
What does plasmin dissolve clots into?
- Fibrin split products
- D-dimer
Inhibitor of Plasmin?
alpha2-antiplasmin
What is TAFI? what does it get converted to? What does it inhibit?
- Thrombin activatable fibrinolysis inhibitor–> TAFIa
- Inhibits plasmin ability to dissolve clots
Which fibrinolytic proteins can have rare congenital deficiency states? What are they associated with in theory?
- Plasmin
- tPA
-Thrombosis
What fibrinolytic inhibitors can be deficient in rare congenital disorders? What are they associated with?
- PAI-1*
- alpha-2 antiplasmin
- Associated with bleeding
- *PAI-1 deficiency found effect in Amish, mucocutaneous bleeding and bruising
What are the antifibrinolytic drugs? What are they biochemically? How do they work?
- Epsilon-aminocaproic acid
- Tranexamic acid
- amino acid analogs of lysine
- inhibit fibrinolysis by blocking plasmin’s binding site for fibrin
How does plasmin work in fibrinolysis?
Recognizes exposed lysine residues on fibrinogen
Which factor deficiency does not cause a prolonged PTT and PT?
Factor XIII
Which factors does PTT measure?
Intrinsic pathway = -Contact factors --PK --HWMK --FXI --FXII -Factor VIII -Factor IX Common pathway = -Factor X -Factor V -Prothrombin (Factor II) -Fibrinogen
Which factors does PT measure?
Extrinsic pathway= -Factor VII Common pathway = -Factor X -Factor V -Prothrombin (Factor II) -Fibrinogen
Which test assess presence and function of fibrin? Which disorders is it abnormal in? Which disorder in particular is it helpful in, and why?
- Thrombin Time
- Hypofibrinogenemia
- Afibrinogenemia
- Dysfibrinogenemia - fibrinogen level might be normal, but thrombin time abnormal
If PTT is normal and PT is prolonged, which factor deficiency?
Factor VII
What assays do you use to measure factor XIII deficiency?
- Urea clot lysis assay (qualitative only; only abnormal in seveere deficiency)
- Chromogenic assay (Quantitative but only available in selected laboratories)
What does vitamin K do to PIVKA (protein induced in vitamin K absence) factor precursors?
Adds a second carboxyl (COOH) group in the gamma position and makes them functional
Which test comes back very high in Vitamin K deficiency?
Protein induced in vitamin K absence (PIVKA)
How does warfarin work?
it inhibits Vitamin K Epoxide Reductase
What does vitamin K epoxide reductase do?
- Converts Vitamin K epoxide back to Vitamin K
- Converts Vitamin K to Vitamin K hydroxyquinone
What is the INR?
A mathematical calculation of the PT based on the sensitivity of the PT reagent the lab uses
What can lead to an early rapid rise in the INR? Why does this happen?
Decrease in factor VII due to half life of 3-6hours
How long does therapeutic warfarin effect take? Why?
- 5-7 days
- When factor X level falls
- Factor X has half life of 40 hours
Vitamin K dependent factors?
II, VII, IX, X, Protein C and Protein S
Why does warfarin-induced skin necrosis develop?
Drop in protein C early after warfarin initiation
Effects of desmopressin?
- Increases vWF
- Increased FVIII (probably due to increased vWF)
- Increases tPA release
What do the PT, PTT, TT rely on?
Sample has proper ratio of plasma to citrate (9:1)
What will happen to the PT, PTT and TT if there is too little plasma in the sample? What are causes of this?
-Elevated levels
- Tube not properly filled
- Patient has polycythemia
What will happen to the PT, PTT and TT if there is too much plasma? What can cause this?
- Falsely normal
- Anemia
Pre-analytic factors that can lead to a falsely elevated PT, PTT or TT?
- Sample not processed quickly (temperature artifact)
- Difficult lab draw (sample begins to clot consuming the factors)
- Heparin in sample (Use heparin neutralization procedure)
Important limitations for PT, PTT as pre-op tests?
- screen for factor deficiencies but NOT bleeding - e.g. no bleeding in Factor XII deficiency but very prolonged PTT, severe bleeding in factor XIII deficiency but normal screening
- Subject to false positives
- Can be truly abnormal, but no increased risk for bleeding e.g. lupus anticoagulant
Which factors are acute phase reactants?
- Factor VIII
- vWF
- Fibrinogen
Mechanism by which DIC causes bleeding?
Consumption of prohemostatic clotting factors and platelets
Mechanisms by which DIC causes thrombosis?
- Consumption of anticoagulant clotting factors
- Disruption of endothelial cell anticoagulant surface
Typical causes of DIC in children?
- Sepsis
- Kasabach-Merritt syndrome (unique to neonates)
- Trauma (brain, burns, gunshot wounds)
- Malignancy (APML)
- Severe hemolysis
- Severe protein C deficiency (unique to neonates)
What does severe protein C deficiency cause in neonates?
Purpura fulminans
- skin necrosis due to microvascular thrombosis
- acute onset
In addition to bleeding and thrombosis, what other symptom comes with DIC?
Hemolytic anemia
Diagnosis of DIC?
-No one lab test
- Common lab findings (none required):
- -Prolonged PT and PTT
- –Any clotting factor can be reduced
- -Decreased fibrinogen
- -Thrombocytopenia
- -Elevated fibrin degradation products, d-dimer, fibrinopeptide A and B
- Decreased protein C and S and antithrombin
Why are neonates slightly more at risk for DIC?
-Physiologically deficient in proteins C/S and antithrombin - impairs their protective mechanisms for DIC
Treatment of DIC?
-Treating the underlying disease is the main therapeutic option (and this will be the exam answer - e.g. antibiotics for sepsis)
Management of coagulopathy in DIC?
- No clear consensus
- Platelet transfusion not generally indicated (risk for increasing thrombosis)
- FFP
- -Provides balanced replacement of all prohemostatic clotting factors and their inhibitors (standard risks for FFP)
- -No evidence if it affects outcome
- Cryo
- -Can be given for low fibrinogen (if bleeding occurs)
- -No clear evidence of benefit (standard risks for cryo)
- Anticoagulation is NOT indicated
Factors leading to vitamin K deficiency?
- Fat soluble
- Tissue stores limited - can become deficient quickly
- Human milk has little to no vitamin K
Lab findings in early and classical vitamin K deficient bleeding?
- PT and PTT very prolonged (often unclottable,i.e. >200 seconds)
- In less severe cases, PT can be as long or longer than PTT (absence of factor VII)
- Vitamin K dependent factors (II, VII, IX, X, Pn C, PnS) severely deficient
Lab findings in late vitamin K deficient bleeding?
- PT is always prolonged (factor VII has the shortest half life)
- PTT is variably prolonged (depends on severity)
- Vitamin K dependent factors deficient
- Elevated PIVKA (sent only if diagnosis is in question)
Treatment of VKDB? How long does it take to correct the deficiency?
What to give if need to give something immediately due to bleeding?
- Oral/parenteral Vit K (Phytonadione/Vit K1)
- 12-24 hours after a parenteral dose to correct the deficiency
- Prothrombin complex concentrates
- -Plasma-derivd products containing factors II, VII, IX and X
- -Can be given if immediate correction is warranted (ICH)
- -Carries a risk for thrombosis
What can cause prolonged severe coagulopathy if accidentally ingested? Treatment?
- Pesticides (rats, mice)
- Contain warfarin-like drugs that are more potent and with much longer half-lives than human warfarin (weeks)
- Treatment is prolonged therapy with vitamin K (until poison cleared)
Mechanisms responsible for bleeding in liver disease?
- Decreased production of liver synthesize factors
- -most factors decreased
- -FVIII elevated (Acute phase reactant and not made in liver)
- Thrombocytopenia
- -Various causes
- –Hypersplenism (e.g. with portal vein hypertension)
- –Decreased TPO production (made in hepatocytes)
- Hyperfibrinolysis
- -Increased tPA release from endothelial cells
Lab features of liver disease?
- Elevated PT (early marker, short half life of Factor VII)
- Elevated PTT (decreased production of most other factors)
- Low fibrinogen (varies with severity of liver failure)
- -Can be high as acute phase reactant
- Thrombocytopenia
- Elevated D-dimer
- -Liver clears D-dimers
- -Hyperfibrinolysis
Treatment for bleeding in liver disease?
- FFP (contains all plasma clotting factors)
- Cryoprecipitate (to correct low fibrinogen; has factor VIII, vWF, factor XIII and fibrinogen)
- Platelet transfusions
- rFVIIa (useful if Factor VII particularly low)
- PCCs
- -Contain all VKD factors
- -Cases of thrombosis have been reported with PCC use in liver failure - ABP outline states contraindicated in the treatment of bleeding due to liver disease!)
