Term
| Describe the basic extrinsic and intrinsic coagulation cascades. |
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Definition
Common path- X...V..II..I...Ia (fibrin)
1) Extrinsic
- Factor VII/TF (released from endothelium of denuded vessel) activates factor X (common pathway).
2) Intrinsic (contact activation)
- XII/XI...IX...VIII...X (common pathway) |
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Term
| What are the 3 major determinants of normal hemostasis? |
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Definition
1) Blood vessel wall
- Vasoconstriction
- Release of TF by endothelium (extrinsic pathway)
- Contact activation (intrinsic)
- Platelet adhesion
2) Platelets
- Adhesion (denuded endothelium and vWF)
- Aggregation (ADP, PF-4, 5-HT)
- Agglutination (Release reaction, Ca++, vWF)
3) Coagulation
- Cascade (Zymogen, serine protease series)
- Fibrin clot stabilization (XIII)
- Clot retraction (Thrombasthenin) |
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Term
| Describe the 4 basic consequences of blood vessel wall injury. |
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Definition
1) Reflex vasoconstriction
- blood exposed to colagen and BM
- limits blood flow to damaged area
2) Release of TF by endothelium
- Activates F VII (extrinsic system)
3) Contact Activation
- XI and XII (intrinsic system)
4) Platelet Adhesion
- Exposed collagen fibrils and vWF |
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Term
| How do platelets form an initial (white) hemostatic plug (i.e. primary hemostasis)? |
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Definition
1) Adhere to damaged endothelium with vWF glycoprotein
- Reversible aggregation initially
2) Release Reaction
- Trace amounts of thrombin (IIa) begin to form, causing platelets to release ADP, PF-4 and 5-HT
3) Irreversible Agglutination
- Release reaction, along with Ca++ and vWF |
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Term
| How does primary hemostasis transition to secondary hemostasis and how to disruptions of each individual system differ? |
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Definition
1) Primary hemostasis
- occurs when white platelet plug forms following release reaction (PF-4, 5-HT and ADP) in the presence of Ca++ and vWF.
- Plug forms on surface composed of PF-3 (phospholipid membrane component) is released
**Disorders (VWD and platelet deficiency) are characterized by Mucosal Bleeding in oropharynx, GI tract and GU tract**
2) Secondary
- Coagulation waterfall leads to Fibrin formation (Ia), with Clot stabilization (FXIII) and retraction (Thrombasthenin)
**Disorders characterized by joint, muscle and body cavity bleeding (Hemophilia, Coagulation factor deficiency, Vit K deficiency, DIC, liver disease)** |
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Term
| How is the platelet plug formation regulated by arachadonic acid metabolism? |
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Definition
AA can produce either
1) TXA2 (contraction and platelet aggregation) or
2) PGI2 (vasodilation and inhibited aggregation) |
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Term
| How could you distinguish VWD from Hemophilia based upon the sites of affect, onset and severity? |
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Definition
1) VWD, like platelet disorders affect PRIMARY hemostasis
- Acute onset
- Mild severity
- Mucosal surfaces (GI, oral, GU)
2) Hemophilia, like Vit K deficiency, liver disease and DIC affect SECONDARY hemostasis
- Late onset
- Severe
- Joint, muscle and body cavity bleeding |
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Term
| How can you localize a coagulation defect in the laboratory? |
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Definition
1) PT elevation (extrinsic pathway- F VII)
- triggered by release of TF
2) APPT elevation (intrinsic pathway- XII, XI, IX, VIII)
- absorption of XII onto collagen of denuded vessel wall
3) Both APPT and PT (common pathway- X, II, I)
4) Thrombin time (TT) prolongation with normal Reptilase time (RT) indicates heparin administration
- If both are prolonged, dysfibrinogen is present.
5) Closure time for platelet function |
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Term
| How do the extrinsic and intrinsic coagulation pathways interact in the case of vessel injury? |
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Definition
1) Extrinsic pathway begins
- VII forms complex with TF, which triggers activation of F X.
2) Intrinsic maintains
- Continued activation requires F IX and F VIII |
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Term
Which of the following is not a function of Thrombin?
1. Converting fibrinogen (F1) to Fibrin (F1a)
2. Platelet aggregating agent
3. Activates anti-coagulant, Protein C
4. Activates F X
5. Activates F XIII |
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Definition
4. F X is activated by the extrinsic and intrinsic coagulation pathways, upstream of Thrombin activation by F V.
Thrombin is a multifunctional enzyme that
- stimulates platelet aggregation
- anti-coagulation clot busting (APC)
- clot stabilization (XIII)
- Fibrin activation (F1a) |
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Term
| Describe the 2 major checking mechanisms important in clot inhibition. |
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Definition
1) Clot inhibitors (prevents formation)
- Alpha-2-globulin (antithrombin III)- neutralizes IIa
- Protein C (activated by thrombin)- vitamin K-dependent inactivation of F V and VIII
2) Fibrinolytic system
- Dissolution of formed clot
- Extrinsic activators (t-PA and Urokinase)
- Intrinsic activators (factor XIIa or Streptokinase) |
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Term
| What is the pathophysiological basis of factor V leiden disorder? |
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Definition
Mutation in the protein C cleavage site of the F V protein, which prevents breakdown of activated F Va, and leads to thrombosis.
Thrombin can activate PC to APC, but it cannot cleave FV and prevent clot formation! |
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Term
18 year old woman presents complaining of frequent bleeding of her gums while brushing her teach.
She reports having "heavy" periods ever since she first had her period at 13.
On PE, there is no evidence of epistaxis or bruising.
How would you work up this patient? |
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Definition
Oral bleeding with menorrhagia suggests primary hemostasis problem and onset at time of menarche suggests VWD (vs. fibroids or tumors). This is why h/x is so important!
Lack of epistaxis and bruising, along with seemingly mild presentation suggests Type 1 VWD (quantitative deficit).
1) Get family f/x and order APTT (intrinsic coagulation) and closure time (platelet function)
- Measure VWF activity (RCoF), WVF antigen and FVIII (should be decreased)
2) Treat with Desmopressin (DDAVP), an arginine analogue that promotes release of VWF from Weibel Palade bodies in endothelial cells.
**Type 2/3 must be treated with VWF concentrate** |
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Term
| What are the characteristic diagnostic tests for VWD? |
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Definition
Type 1, 2 and 3 are distinguished by SDS electrophoresis.
1) Start with family h/x, APTT and closure time
2) Measure FVIII:C activity (Decreased because VWF is carrier protein that protects it)
- clot-based assay
3) VWF activity
- based on platelet aggregation in presence of ristocetin
4) WVF:Ag assay
- Laurell rocket electrophoresis in agar containing WVF:Ab |
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Term
| What are the major disorders of primary hemostasis? |
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Definition
Platelet plug formation issue with mild, early, mucosal bleeding.
1) VWD
- Type 1 (quantitative deficit)
- Type 2 (qualitative deficit)
- Type 3 (quantitative total absence)
2) Quantitative platelet disorder
- Bone marrow failure, leukemia, aplastic anemia, TP (immune or drug-induced or TTP), HUS
3) Qualitative
- Bernard Soulier (GP1b/IX)- adhesion
- Glanzmann thrombasthenia (GPIIb/IIIA)- aggregation |
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Term
| What are the major disorders of secondary hemostasis? |
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Definition
Fibrin clot formation with moderate, severe, late, body cavity bleeding.
1) Hemophilia A, B
- X-linked deficiency in either FVIII or FIX (intrinsic) caused by numerous gene mutations
2) Vitamin K deficiency
- Required for synthesis of II, VII, IX, X, PC and PS
- Cofactor in conversion of glutamic acid to y-carboxyglutamic acid
3) Liver Disease
- Synthesis of coagulation factors, altered degradation/activation, abnormal coagulation factors and/or platelet sequestration
4) DIC
- Excess activation of coagulation mechanism in circulation |
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Term
Male infant presents with persistent bleeding upon circumcision.
How do you work up/treat this patient? |
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Definition
Class symptom of Hemophilia (X-linked disorder with decreased FVIII or IX-intrinsic coagulation pathway).
In adults, Hemartomas (muscles) and Hemarthroses (joints) are common.
1) Measure clotting factors to determine A (VII) vs. B (IX) in order to target therapy
- Severe is < 0.01 U/ml
- Moderate is 0.01-0.04 U/ml
- Mild is > 0.5 U/ml
2) Ideal target for gene therapy, and current recombinant treatments are littered wtih complications |
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Term
Which of the following is not a contributing factor to making Hemophilia an ideal target for gene therapy?
1. Hemophilia is not lethal generally
2. Current treatment is suboptimal
3. Onset is in adolescence
4. Site of production of coagulation factors is not crucial
5. Duration of treatment is not crucial |
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Definition
| 3. Not always true and not a good reason. |
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Term
| What is the basic pathophysiology of vitamin K deficiency coagulation defects? |
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Definition
Secondary Hemostasis issue with late onset, severe, cavity bleeding. Generally caused by combination of antibiotic treatment AND reduced oral intake (context of Leukemia is good example).
1) Vitamin K is important cofactor in conversion of glutamic acid to y-carboxyglutamate
2) y-CG is required for activation of Factor II/VII/IX/X, Protein C and Protein S |
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Term
| What is the diagnosis/treatment of Vitamin K deficiency? |
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Definition
1) Diagnosis
- PT (early deficiency in FVII, t1/2 of 4-6h
- PT, APPT (late deficiency in FII)
2) Treatment
- Vitamin K: 1-2/5 mg p.p to 10-15 mg IV
- Withhold anticoagulant
- If bleeding severe- fresh frozen plasma |
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Term
| What are the 4 mechanisms of Coagulopathy in Liver Disease and their clinical manifestations? |
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Definition
Bruising, epistaxis, bleeding from venepuncture or hemorrhagic gastritis.
1) Decreased synthesis of coagulation factors
- BLEEDING
- Prolonged PT and APTT
2) Decreased degradation of activated coagulation factors
- DIC
- Increased fibrinolytic (FIBRINOLYSIS)
- Decreased fibrinogen, decreased alpha-antiplasmin, presence of FDP
3) Synthesis of abnormal coagulation factors
- Fibrinogen missing sialic acid (DYSFIBRINOGEN)
- Prolonged TT and RT
4) Platelet Sequestration
- Hypersplenism (THROMBOCYTOPENIA) |
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Term
65 year old alcoholic with jaundice and evidence of intramuscular bleeding presents to your office and when his lab work comes back, you notice prolonged Thrombin Time and Reptilase Time (RT), as well as low platelet count
What does this tell you about the underlying etiology? How do you treat? |
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Definition
Sounds like someone with liver disease and a secondary coagulation defect.
1) Prolonged TT (time for clot to form after thrombin conversion of fibrinogen to fibrin) and RT (time for clot after reptilase conversion of fibrinogen to fibrin) suggests presence of an ABNORMAL fibrin (Dysfibrinogen).
- Replace factor deficiencies with FFP and correct TP with platelet transfusion.
- If fibrinolysis is present, try Aprotonin to inhibit to reduce blood loss (may need to replace blood as well). |
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Term
| What are the common consequences of DIC? |
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Definition
Excess activation of coagulation through excess Thrombin so
1) Thrombocytopenia (Platelet agglutination, aggregation and depletion)
2) Factor Deficiency (activation and depletion)
3) AT-III Deficiency (XIII Depletion leading to AT-III activation and depletion)
4) RBC fragments and Burr Cells (Insoluble fibrin because of excess) |
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Term
| How do you diagnose DIC and what are the common causes? |
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Definition
Features of both primary and secondary coagulation defects.
1) Diagnosis (First 3 most important)
- Prolonged PT and APTT (factor deficiency)
- TP
- Hypofibrinogenemia
- Fibrin split products
- Decreased AT-III
- Red cell fragmentation
2) Causes
- Infection (endotoxin)
- Tissue injury (TF, Thromboplastic substances)
- Obstetric complications (amniotic fluid)
- Malignancy
- Liver Disease |
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Term
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Definition
Hit underlying disease (Antibiotics for infections, immediate delivery of fetus, removal of burned tissue, ect.)
Overall survival is only 40%! |
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Term
| What types of pathological coagulation factor Inhibitors exist? How can you diagnose them? |
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Definition
1) Specific Inhibitors
- Autoantibody (self) and Alloantibody (infused) responses
- Very rare with BLEEDING tendency
2) Blocking Inhibitors
- Directed against phospholipids, inhibiting surface interactions.
- Example is "Lupus anticoagulant" and tendency is THROMBOTIC
3) Diagnose with "mixing experiment"
- Take patient plasma and mix in normal plasma, TF and calcium
- In coagulation deficiency, APTT is prolonged, but APTT mix is normal (giving back 50% works)
- In specific inhibitor case, Both are prolonged, and factors are decreased
- In blocking inhibitor, Both are prolonged and factors are normal. |
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Term
| What are the 5 most important "hyper-coagulable" states? |
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Definition
AT-III, Protein C, Protein S and Factor V are VENOUS thrombosis
Factor V and Prothrombin most common
1) AT-III deficiency
- Rare/severe AD condition that can also be acquired
2) Protein C deficiency
- Vitamin K-dependent plasma protein that inactivates V and VIII (homozygous produces neonatal purpura fulminans and early death due to thrombosis)
3) Protein S deficiency
- Vitamin K-dependent plasma protein that is cofactor for protein C activation
4) Factor V mutations
- prevents anti-coagulant action of activated protein C therapy
- Diagnosed with activated PC test (APCr)
- Homozygous is HIGH risk, and heterozygote is similar to miscarriage risk.
5) Prothrombin variant
- mutation of untranslated portion of factor II that leads to elevated F II
- DNA test available, but no screening like Factor V |
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Term
Which of the following is NOT an acquired caused of AT-III deficiency?
1) Nephrotic syndrome
2) Coumadin therapy
3) Heparin therapy
4) DIC
5) Post-operative from surgery |
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Definition
Thrombosis Risk
2) Coumadin therapy blocks vitamin K, which is required for Protein C to inactivate factors V and VIII. This is unrelated to AT-III deficiency
1) Nephrotic syndrome (loss in urine)
3) Heparin binds AT-III and uses it as co-factor (consumption)
4) DIC consumes AT-III
5) Consumes AT-III for healing |
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Term
True or False:
Coumadin treatment can induce skin necrosis in patients with protein S and C deficiencies. |
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Definition
True!
Inhibits Vitamin K, which is required for protein C/S activity. |
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Term
| What are common secondary causes of hyper-coagulable states? |
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Definition
1) Sickle Cell
2) Myeloproliferative
3) Heparin-induced TP
4) Nephrotic syndrome
5) PNH
6) Clot concentrate therapy (VIII, VIIII, IX)
7) Lupus anticoagulants (Anti-phospholipid antibodies) |
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Term
Which of the following is FALSE in relation to Lupus Anticoagulants?
1. Anti-phospholipid antibodies that are almost exclusively seen in patients with SLE
2. Associated with a variety of drugs
3. Cause a variety of laboratory abnormalities that vary by patient
4. Commonly cause DVT/PE and arterial thrombosis/infarction
5. Treated primarily by addressing underlying cause |
|
Definition
1.
LAC are anti-phospholipid antibodies that are rarely found in patients with lupus (it is a misnomer!).
They are associated with variable laboratory results, drug reactions, hyper-coagulable states and treated by addressing the underlying disease etiology. |
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Term
| What are the 5 major tenants of management for patients with hypercoagulable states? |
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Definition
1) DVT prophylaxis for surgery
2) Avoid oral contraceptives (females)
3) Avoid post-menopausal estrogens
4) Indefinite anticoagulation for 1 unprovoked thrombotic event or 6 mos. of anticoagulation when reversible risk factor identified
5) Screening family members for identified genes. |
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Term
| What are the benefits/disadvantages of using Heparin as an anti-coagulant drug? |
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Definition
Give full dose (bolus and adjusted ) for DVT/PE/Unstable angina and MI.
UFH binds AT-III and potentiates its ability to inactivate thrombin (IIa) (minor inhibition of Factor Xa and platelet function as well)
1) Can be taken during Pregnancy and has little drug interactions
2) Cannot be taken orally and can cause Heparin-Induced TP (immune-related thrombosis with TP)
**Sometimes used as alternative anti-coagulant during surgery or as DVT prophylaxis** |
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Term
| Why might someone prescribe UFH vs. low MW heparin? |
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Definition
Both used safely during pregnancy
1) LMW heparin has mores specific heparin fragments that inhibit factor Xa instead of factor IIa, producing reliable, dose-response with lower post-op DVT risk and HIT.
2) LMW MUST be dose-adjusted in renal failure. |
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Term
| Which anti-coagulants are contraindicated in the case of pregnancy? |
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Definition
1) Lepirudin (Refludan)- recombinant leech venom (no cross-reactivity with UFH)
2) Dabigatran (Prandexa)- oral direct thrombin inhibitor used in patients with A fib but NOT for DVT
3) Warfarin (Coumadin)- Inhibits Vitamin K, which prevents production of II, VII, IX and X as well as APC and PS, with many drug interactions, slow onset |
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Term
How do each of the following drugs work as anti-coagulants?
1) Lepirudin
2) Argatroban
3) Fondparinux
4) Dabigatran |
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Definition
1) Recombinant leech venom with no cross-reactivity with UFH- NOT for pregnancy.
2) Synthetic arginine derivative that competitive inhibits thrombin (reduce dose in liver failure)
3) New class of LMW heparin called pentasaccharide that has long half life and is monitored by anti-Xa sssay
4) Oral DTI for patients with A fib and NOT DVT (no pregnancy) |
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Term
| What are the primary contraindications for Coumadin use? |
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Definition
Vitamin K inhibition prevents clotting factor synthesis and APC/PS synthesis.
Start at 5mg and monitor (adjust in Chinese)
**Can cause skin necrosis because of Protein S/C deficiency, as well as bleeding, unmasking of underling conditions and fetal abnormalities**
1) Pre-existing hemostatic efects
2) GI bleed
3) CNS hemorrhage
4) Pregnancy
5) Surreptitious use |
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Term
| What are the primary anti-platelet agents that are available for clinical use? |
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Definition
1) Aspirin
- irreversibly inhibits COX (TXA2)
- Advised for prevention of MI, especially in setting of unstable angina and following a primary MI.
- Also useful for stroke and to prevent CABG closure
2) Clopidogrel (Plavix)
- Oral platelet antagonists for unstable angina and prevention of MI/Stroke that inhibits ADP release from activated platelets (release reaction in plug formation)
3) Abciximab (ReoPro)
- Antibody given IV that binds GP IIb/IIA receptor on platelets and prevent aggregation
- Used as adjunct with heparin/aspirin to prevent CABG closure |
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Term
| How do Thrombolytic agents work and when are they used? |
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Definition
Streptokinase (limited by allergies), Urokinase (viral contamination) and tPA (MOST COMMON)
1) Rapidly activate plasminogen and monitored with TT or APTT
**can be reversed with frozen plasma or cryoprecipitate**
2) Used for intra-coronary thrombi following MI, occluded catheters and for new-onset stroke. |
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Term
Normal hemostasis depends upon an interaction between the blood vessel wall, blood platelets, and coagulation factors which establishes the integrity of integrity of the circulatory system after a blood vessel has been injured. Once the blood vessel wall has been violated a series of complex steps occurs in sequence: reflex vasoconstriction (this limits blood loss), release of tissue factor (this activates the coagulation system), contact activation (in this process coagulation factor XII is changed to its activate form), and platelet adhesion (platelets stick to the injured site and form a primary hemostatic plug)
True or False. Tissue factor is a complex lipid material that has the capacity to activate factor VII and initiate a sequence of complex enzymatic events ultimately resulting in the production of thrombi and fibrin. |
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Definition
True
Factor VII is synthesized in the liver. Small amounts circulate in the plasma in both activated and non-activated forms. Tissue factor is a transmembrane receptor and activator of factor VII which is constitutively expressed by the cells surrounding blood vessels (this is the so-call “hemostatic envelope”). The endothelium physically separates this potent "activator" from its circulating ligand FVII/FVIIa and prevents inappropriate activation of the clotting cascade. Breakage of the endothelial barrier leads to exposure of extravascular TF and rapid activation of the clotting cascade. It is believed that this “hemostatic envelope” provides immediate access to tissue factor and the activation small amounts of factor VII at the site injury resulting in the formation of a small amount of fibrin. The potency of activated FVII appears to be enhanced greatly in the presence of TF. This FVIIa:TF complex can enzymatically convert factor X to activated factor X (FXa) and factor IX to activated factor IX (FIXa). FXa attaches itself to factor V on the platelet surface and converts a small amount of prothrombin to thrombin; whereas, FIXa associates with the platelet surface where it interacts with factor VIII. There is some evidence that FVIIa:TF complex serves to promote an “idling” mechanism which continuously provides low level activation of Factor X and may allow to an immediate prothrombotic response to injury. The evidence for this is the detection of activation peptides of both FX and FIX in plasma of healthy subjects and their absence in subjects with FVII deficiency. Recombinant forms of activated factor VII have been introduced for clinical use and have been useful in patients with significant bleeding disorders |
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Term
You are asked to see a 60 year old female patient in the MICU because of profound, refractory thrombocytopenia (platelet count 4,000/uL). The rest of her CBC is normal. The peripheral blood smear shows a decreased number of platelets and schistocytes. Her PT and APTT is normal. She has worsening renal function (serum creatinine 3.5; normal <1.5). On physical examination, she has no ecchymoses or petechiae. Her only important medical history is that she had a small breast cancer removed 2 years before. During this admission, a bone scan, alkaline phoshatase, CT scan of the chest, abdomen and pelvis are normal. The serum LDH is markedly increased and the serum haptoglobin is undetectable. Blood and urine cultures show no growth. The MICU team placed the patient in intravenous broad spectrum antibiotics to cover her for a suspected, but undetected bacterial infection.
The absence of bleeding and petechiae, low platelet count, and worsening renal function seems consistent with TTP (thrombotic thrombocytopenic purpura). You suggest obtaining an ADAMTS13 level and ADAMTS13 autoantibody and while these results are pending suggest initiating plasmapheresis and plasma exchange and high dose steroids.
5 days after initiation of plasmapheresis her platelet count remains low and her PT and APTT are prolonged and D-dimers are elevated and fibrinogen decreased. Administration of vitamin K in appropriate amounts does not correct the prolonged prothrombin time and APTT.
True or False: This patient has intractable TTP. Plasmapheresis should be intensified and continued. |
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Definition
False:
This patient has DIC. A characteristic of TTP is that it is not associated with a coagulopathy. The prolongation in the PT and APTT which is not corrected by administration of vitamin K should alert the clinician that something else is happening. It is not uncommon for patients in the ICU setting to develop a prolongations in the PT and APTT from vitamin k deficiency. This is usually due to the administration of antibiotics. For this reason, it is never unreasonable to administer vitamin K replacement when the cause of the prolonged PT and APTT is in doubt. DIC is always secondary to something else. In this case, the patient has no evidence of infection, no history of trauma or surgery, and had no obstetrical catastrophes. However, she did have history of a resected breast cancer. A subsequent bone marrow biopsy demonstrated the presence of metastatic breast cancer involving her bone marrow. Her ADAMTS13 activity was later returned as normal as was her ADAMTS13 autoantibody. Although a normal ADAMTS13 does not completely exclude TTP is makes it highly unlikely. ADAMTS13 is susceptible to degradation by plasmin. Plasmin activity is increased in DIC. For this reason, a low ADAMTS13 activity and low ADAMTS13 autoantibody titers would have been difficult assess due to the presence of DIC. Elevated D-dimers and/or fibrin(ogen) degradation products (FDPs) are non-specific findings. These can be elevated in patients with liver and renal impairment, post trauma or surgery, and in anything that causes inflammation, besides thrombosis or DIC. Sometimes when the diagnosis is DIC is in doubt it is worthwhile to check the serum fibrinogen or antithrombin levels over several days. In healthy individuals, fibrinogen circulates for about 10 days and antithrombin for 2.5 days. Since fibrinogen is consumed during fibrin clot formation and antithrombin forms complexes with thrombin and the complexes are then removed by the liver, both of these will be rapidly removed from the plasma in the presence of DIC. This patient is said to have refractory thrombocytopenia. This definition is problematic since apparent refractoriness may be secondary to poorly matched or non-matched platelet transfusion. In general, platelet refractoriness is considered to be present when the patient has demonstrated a lack of the expected increment in the platelet count (5000 platelelets/uL for each unit of platelets transfused) after 2 to 3 infusions. It is important to note that platelet refractoriness may be caused by alloimmunization, severe immune thrombocytopenia, fever, infections, and DIC or other processes characterized by platelet consumption. The treatment of DIC is both supportive (replacement of missing plasma components and platelets; inhibiting the thrombin generation) and specific in that the underlying cause of the DIC needs be definitively addressed. |
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Term
True or False:
Antithrombin is normally made in the liver. With significant liver impairment, antithrombin production is decreased in the liver and synthesis of antithrombin is increased in non-hepatic tissue. For this reason, patients with end-stage liver disease are protected from thrombotic events. |
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Definition
| False: Antithrombin is synthesized by the hepatocytes. Patients with liver impairment may have decreased synthesis of multiple proteins including albumin, fibrinogen, antithrombin, protein C, protein S, and most of the coagulation proteins. Characteristically patients with liver disease have increased levels of factor VIII, since this molecule is manufactured as sites extraneous to the liver and its synthesis is increased in the presence of inflammation. Patients with severe liver impairment have complex coagulation abnormalities secondary to decreased liver function. They have decreased production or the production of abnormal coagulation protein and decreased plasma clearance of fibrinolytic proteins that may predispose patients to bleeding. In addition, some patients with liver disease of have abnormalities in platelet numbers (decreased platelet numbers from an associated splenomegaly or defect in production from deficient thrombopoietin production) or platelet function defects (cause unclear), which increase bleeding risk The same patients may also have decreases in the key natural inhibitors of the forward reactions of coagulation (antithrombin, PC, PS), which increases the risk of venous thrombosis |
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Term
True or False:
You are asked to evaluate a 20-year-old college female college student who has had multiple VTEs over the previous year. She states that prior to these events she was placed on oral contraceptives for irregular menses. Prior to beginning college she has an unexpected pregnancy complicated by a miscarriage. The patient has no other known predisposing factors except a vague family history of a grandparent with a blood clot in the lung. The activate partial thromboplastin time is normal. Among other tests for hypercoagulability (which are normal), the test for activated protein C resistance is reported to be shorter than expected. It is likely that this patient has a factor V Leiden mutation. |
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Definition
True:
The activated protein C resistance (APCR) assay is performed by determining the ratio of the activated partial thromboplastin times of plasma with or without the addition of exogenous activated protein C. In patients with activated protein C resistance, the ratio should be shortened. In most cases an abnormal activated protein C resistance assay is a clear indication of the presence of a factor V Leiden mutation. Other causes of an abnormal activated protein C resistance assay include: pregnancy (possibly due to decreases in free protein S), antiphospholipid antibodies (thought do directly inhibit the activity of either protein C or protein S), estrogen containing oral contraceptives or hormonal replacement (through to decrease free protein S). It is important to note that whether acquired causes of activated protein C resistance predispose patients to thrombosis is unclear. However, there exists an increasing body of evidence that at least one of the mechanisms of venous thrombosis or stroke associated with estrogen use is related to acquired APCR. In addition, present data shows that the use of estrogen containing oral contraceptives by individuals with factor V Leiden mutations increase the relative risk of thrombosis from 7:1 to approximately 40:1. For this reason, any female using estrogen containing oral contraceptives experiencing an otherwise unprovoked thrombotic event should be evaluated for an underlying hypercoagulable state (especially for factor V Leiden mutation). Because of her history of miscarriage and her “vague family history” and otherwise normal hypercoagulable evaluation, it is likely that this patient’s APCR is due to factor Leiden mutation. This patient has apparently increased her risk of thrombotic complications by smoking. The use of oral contraceptives and smoking tobacco in the presence of APCR increases the risk of an incident thrombotic event to 80 fold greater than that seen in the general population. Performing a factor V Leiden genetic test that confirms the presence of the abnormal factor V protein in the patient’s plasma can do confirmation of the presence of factor V Leiden mutation. Other factor V mutations such as factor V Cambridge or HR2 are much less frequent than factor V Leiden and for this reason the exact risk of thrombosis from heterozygous states are uncertain. It does appear, however, that heterozygous factor V HR2 alone does not increase thrombotic risk. Both the Cambridge and HR2 mutations may worsen the thrombotic risk when they occur in the presence of heterozygous factor V Leiden mutation. |
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Term
Unfractionated heparin has been around since 1916. It has been widely used in for anticoagulation. Two of the statements below are Incorrect - which ones are incorrect.
1) Heparin does not cross the placenta and can safely be used in pregnancy.
2) Unfractionated heparin (UFH) acts by binding to antithrombin potentiating its ability to inactivate thrombin, the active form of factor II in the clotting cascade.
3) Due to the wide variety of APTT reagents in use, the therapeutic range of aPTT is only accurate if the therapeutic range corresponds to a heparin level of 2-4 U/ml of heparin by the protamine titration method in the hospital laboratory.
4) The therapeutic range of Heparin is usually 1.5 to 2.5 times the control APTT value
5) Infusional heparin is commonly used in immobilized patients for prophylaxis in the hospital. |
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Definition
3) Must be 0.2-0.4 U/ml
5) Not suggested for this |
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Term
Heparin induced thrombocytopenia (HIT) is a side effect of heparin use that occurs in about 5% of patients. HIT causes platelet counts to fall usually after about 5 days of heparin use. Which of the following is TRUE?
1) heparin should be continued
2) heparin should be continued and argatroban added
3) stop heparin and change to argatroban
4) continue heparin and check for lower extremity dopplers as there is a risk of thrombosis |
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Definition
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Term
Low Molecular weight Heparin contains small molecules of heparin. Which of the following is CORRECT?
1) act by inhibiting factor IXa rather than thrombin and require a factor Xa assay for monitoring
2) Can be used safely in pregnancy
3) The risk of HIT is around 11-12% compared to unfractionated heparin
4) can be safely used in patients with previous history of HIT |
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Definition
2:
The target for low molecular weight fragments of low molecular weight heparin in predominately factor Xa with less activity toward factor IIa (thrombin).The risk of developing HIT with low molecular weight heparin is very low compared to is the risk associated with unfractured heparin. Both low molecular weight Heparin and unfractured heparin can induce the formation of HPF4 antibodies which are cross reactive. Low molecular weight heparin should not be administered in a patient with HIT from unfractured heparin. The reverse is also true. |
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Term
The following are all agents that can be used in place of heparin in patients with HIT EXCEPT:
1) Lepirudin
2) Bivalurudin
3) Dabigatran
4) Argatroban
5) Fondaparinaux |
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Definition
3:
Dabigatran is a new oral direct thrombin inhibitor recently released for use in patients with atrial fibrillation at a dose of 150 mg po qd because of a significant reduction in stroke and a favorable risk profile for bleeding compared to warfarin. |
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Term
Coumadin acts by inhibiting which of the following factors in the coagulation cascade.
1) Factor V
2) Factor XI
3) Factor X
4) Factor VIII
5) Protein B |
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Definition
3
Vitamin K dependent are II, VII, IX, X, Protein C/S |
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Term
There are several side effects to the administration of warfarin. Skin necrosis has been reported in some patients within the first few days of receiving large (loading) doses of warfarin. a proposed mechanism of skin necrosis in this setting is:
1) Gamma carboxylation of vitamin K factor V
2) rapid reduction of protein C levels, which induces a transient hypercoagulable state
3) rapid increase of protein S levels on the first day of therapy, inducing a hypercoagulable state
4) Treatment with heparin is a contraindication in this setting. |
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Definition
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Term
Which of the following medications potentiates the effect of warfarin?
1) Vitamin B12
2) Moxifloxacin
3) Barituates
4) Oral contraceptive Pill |
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Definition
| 2) Moxifloxacin doens't mix with Coumadin! |
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Term
Aspirin is an antiplatelet drug that has its effect by effect by acetylating the endoperoxide cyclo-oxygenase irreversibly. The following are all benefits of aspirin EXCEPT:
1) prevention of primary myocardial infarction (MI), particularly in males but also in females
2) prevention of coronary artery bypass graft closure
3) Prevention of primary vasculitis
4) prevention of new or recurrent stroke and death after transient ischemic attacks (TIAs) or minor stroke |
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Definition
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Term
Abciximab is a human-mouse monoclonal antibody for intravenous infusion. The major indication for abciximab is as adjunctive therapy with heparin and aspirin for prevention of abrupt coronary vessel closure after angioplasty. Mechanism of action of Abciximab on platelet inhibition is via:
1) glycoprotein IIb/IIIa receptor on human platelets
2) Glycoprotein 1B/IIIa receptor on human platelets
3) inhibition of ADP |
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Definition
1
Inhibition of ADP is by Clopidogrel |
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Term
Thrombocytic agents act by inhibiting plasminogen and is monitored by thrombin time and aptt. This effect can be reversed by Fresh Frozen Plasma and / or Cryoprecipitate.
True or False |
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Definition
False!
Thrombocytic agents enhance the conversion of plasminogen to plasmin. Plasmin dissolves the fibrin clot and the thrombosis. |
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