Coag 2.4 Inhibitors, Thrombotic Disorders, and Anticoagulant Drugs

Question 1

1. Which characteristic describes antithrombin (AT)?

A. It is synthesized in megakaryocytes
B. It is activated by protein C
C. It is a cofactor of heparin
D. It is a pathological inhibitor of coagulation

Answer 1

C. It is a cofactor of heparin

AT is a heparin cofactor and is the most important naturally occurring physiological inhibitor of blood coagulation. It represents about 75% of antithrombotic activity and is an α2-globulin made by the liver.

Question 2

2. Which laboratory test is affected by heparin therapy?

A. Thrombin time
B. Fibrinogen assay
C. Protein C assay
D. Protein S assay

Answer 2

A. Thrombin time

Heparin is an AT drug and therefore increases TT along with APTT and PT. Heparin therapy has no effect on fibrinogen, protein C, or protein S assays.

Question 3

3. Abnormal APTT caused by a pathological circulating anticoagulant is:

A. Corrected with factor VIII–deficient plasma
B. Corrected with factor IX–deficient plasma
C. Corrected with normal plasma
D. Not corrected with normal plasma

Answer 3

D. Not corrected with normal plasma

In the presence of a pathological circulating anticoagulant, a mixing test using normal plasma does not correct abnormal APTT. These anticoagulants are pathological substances and are endogenously produced. They are either directed against a specific clotting factor or against a group of factors. Prolonged APTT caused by a factor deficiency is corrected when mixed with normal plasma. Factors VIII– and factor IX–deficient plasmas are used for assaying the activities of factors VIII and IX, respectively.

Question 4

4. The lupus anticoagulant affects which of the following tests?

A. Factor VIII assay
B. Factor IX assay
C. VWF assay
D. Phospholipid-dependent assays

Answer 4

D. Phospholipid-dependent assays

The lupus anticoagulant interferes with phospholipid-dependent coagulation assays, such as the PT and APTT tests. The lupus anticoagulant does not inhibit clotting factor assays and does not inhibit in vivo coagulation.

Question 5

5. Which statement about warfarin (Coumadin) is accurate?

A. It is a vitamin B antagonist
B. It is not recommended for pregnant and lactating women
C. It needs AT as a cofactor
D. APTT test is used to monitor its dosage

Answer 5

B. It is not recommended for pregnant and lactating women

Warfarin (Coumadin) crosses the placenta and is present in human milk; it is not recommended for pregnant and lactating women. Warfarin is a vitamin K antagonist
drug that retards synthesis of the active form of vitamin K–dependent factors (II, VII, IX, and X). AT is a heparin (not warfarin) cofactor. The INR is used to monitor warfarin dosage.

Question 6

6. Which statement regarding protein C is correct?

A. It is a vitamin K–independent zymogen
B. It is activated by fibrinogen
C. It activates cofactors V and VIII
D. Its activity is enhanced by protein S

Answer 6

D. Its activity is enhanced by protein S

Protein S functions as a cofactor of protein C and, as such, enhances its activity. Activated protein C (APC) inactivates factors Va and VIIIa.

Question 7

7. Which of the following is an appropriate screening test for the diagnosis of lupus anticoagulant?

A. Thrombin time
B. Diluted Russell viper venom test (DRVVT)
C. D-dimer test
D. Fibrinogen assay

Answer 7

B. Diluted Russell viper venom test (DRVVT)

Russell viper venom (RVV) reagent contains factors X and V, activating enzymes that are strongly phospholipid dependent. The reagent also contains RVV, Ca2+, and phospholipid. In the presence of phospholipid autoantibodies, such as lupus anticoagulant, the reagent phospholipid is partially neutralized, causing prolongation of
clotting time. TT evaluates fibrinogen. D-dimer tests evaluate fibrin degradation products. Fibrinogen assay and TT are not indicated for the diagnosis of lupus anticoagulant.

Question 8

8. Which of the following is most commonly associated with activated protein C resistance (APCR)?

A. Bleeding
B. Thrombosis
C. Epistaxis
D. Menorrhagia

Answer 8

B. Thrombosis

APCR is the single most common cause of inherited thrombosis. In 90% of individuals, the cause is gene mutation of factor V (factor V Leiden). Affected individuals are predisposed to thrombosis, mainly after age 40 years. Heterozygous individuals may not manifest thrombosis unless other clinical conditions coexist.

Question 9

9. A 50-year-old man has been on heparin for the past 7 days. Which combination of tests is expected to be abnormal?

A. PT and APTT only
B. APTT, TT only
C. APTT, TT, fibrinogen assay
D. PT, APTT, TT

Answer 9

D. PT, APTT, TT

Heparin is a therapeutic anticoagulant with an AT activity. Heparin also inhibits factors XIIa, XIa, Xa, and IXa. In patients receiving heparin therapy, PT, APTT, and TT are all prolonged. Quantitative fibrinogen assay, however, is not affected by heparin therapy.

Question 10

10. Which of the following drugs inhibits ADP-mediated PLT aggregation?

A. Heparin
B. Warfarin
C. Aspirin
D. Prasugrel

Answer 10

D. Prasugrel

Prasugrel (Effient) is an antiplatelet drug that reduces PLT aggregation by irreversibly blocking P2Y12 receptors on the PLT surface membrane, thereby inhibiting PLT aggregation to ADP. Aspirin is another antiplatelet drug that inhibits PLT aggregation by blocking the action of the enzyme cyclo-oxygenase. Warfarin and heparin are anticoagulant drugs that act against clotting factors.

Question 11

11. Thrombin–TM complex is necessary for activation of:

A. Protein C
B. AT
C. Protein S
D. Factors V and VIII

Answer 11

A. Protein C

Protein C is activated by thrombin–TM complex. TM is a transmembrane protein that accelerates protein C activation 1,000-fold by forming a complex with thrombin. When thrombin binds to TM, it loses its clotting function, including activation of factors V and VIII. APC deactivates factors Va and VIIIa. Protein S is a cofactor necessary for the activation of protein C.

Question 12

12. Which test is used to monitor heparin therapy?

A. INR
B. Chromogenic anti–factor Xa assay
C. TT
D. PT

Answer 12

B. Chromogenic anti–factor Xa assay

Heparin dosage can be best monitored by the chromogenic anti–factor Xa assay. In anti–factor Xa assay, the concentration of heparin is determined by inhibition of factor Xa by AT. Anti–factor Xa assay uses a reagent with a fixed concentration of factor Xa and AT. Heparin forms a complex with AT and factor Xa reagents. Excess factor Xa combines with the chromogenic substrate to form a colored product; the color intensity is inversely proportional to the concentration of heparin. PT would be prolonged in heparin therapy, but the PT test is not sensitive enough to be used to monitor heparin therapy. Heparin inhibits thrombin and, therefore, causes prolonged TT. The TT test, however, is not used to monitor heparin therapy either.

Question 13

13. Which test is commonly used to monitor warfarin therapy?

A. INR
B. APTT
C. TT
D. Ecarin time

Answer 13

A. INR

Warfarin is a vitamin K–antagonist drug. It inhibits vitamin K–dependent factors (II, VII, IX, and X) and other vitamin K–dependent proteins, such as proteins C and S. Warfarin therapy is monitored with the INR. An INR of 2.0 to 3.0 is used as the target when monitoring warfarin therapy for prophylaxis and treatment of deep vein thrombosis (DVT). A higher dose of warfarin (giving an INR of 2.5–3.5) is required for patients with mechanical heart valves.

Question 14

14. Which clotting factors (cofactors) are inhibited by protein S?

A. Factors V and X
B. Factors Va and VIIIa
C. Factors VIII and IX
D. Factors VIII and X

Answer 14

B. Factors Va and VIIIa

Factors Va and VIIIa are deactivated by protein S and activated by protein C.

Question 15

15. Which drug promotes fibrinolysis?

A. Warfarin
B. Heparin
C. Urokinase
D. Aspirin

Answer 15

C. Urokinase

Urokinase is a thrombolytic drug that can be used to treat acute arterial thrombosis. Urokinase can also be used for the treatment of venous thromboembolism, myocardial infarction, and clotted catheters. Warfarin and heparin are anticoagulant drugs, whereas aspirin prevents PLT aggregation by inhibiting cyclo-oxygenase.

Question 16

16. Diagnosis of lupus anticoagulant is confirmed by which of the following criteria?

A. Decreased APTT
B. Correction of APPT by mixing studies
C. Neutralization of the antibody by high concentration of phospholipids
D. Confirmation that abnormal coagulation tests are related to factor deficiencies

Answer 16

C. Neutralization of the antibody by high concentration of phospholipids

The International Society of Hemostasis and Thrombosis has recommended four criteria for the diagnosis of lupus anticoagulant:
(1) prolongation of one or more of the phospholipid-dependent clotting tests, such as APTT or DRVVT;
(2) presence of an inhibitor confirmed by mixing studies (not corrected);
(3) evidence that the inhibitor is directed against phospholipids by neutralizing the antibodies with a high concentration of phospholipids (PLT neutralization test or DRVVT with platelet rich plasma or confirming phospholipid reagent);
and (4) lack of any other causes for thrombosis.

Question 17

17. Which of the following abnormalities is consistent with the presence of lupus anticoagulant?

A. Decreased APTT/bleeding complications
B. Prolonged APTT/thrombosis
C. Prolonged APTT/thrombocytosis
D. Thrombocytosis/thrombosis

Answer 17

B. Prolonged APTT/thrombosis

Lupus anticoagulant interferes with phospholipids in the APTT reagent, resulting in prolongation of APTT. However, in vivo, lupus anticoagulant decreases fibrinolytic activity, causing an increased risk of thrombosis. Lupus anticoagulant does not result in a bleeding tendency unless there is a coexisting thrombocytopenia or other coagulation abnormality.

Question 18

18. Which of the following is a characteristic of LMWH?

A. Generally requires monitoring
B. Specifically acts on factor Va
C. Has a longer half-life compared with unfractionated heparin (UFH)
D. Can be used as a fibrinolytic agent

Answer 18

C. Has a longer half-life compared with unfractionated heparin (UFH)

LMWH is a small glycosaminoglycan that is derived from UFH. LMWH has a low affinity for plasma proteins and endothelial cells and therefore has a longer half-life. The half-life of the drug does not depend on the dosage. LMWH has an inhibitory effect on factors Xa and IIa. It does not require routine monitoring except in patients with renal failure, obese patients, pediatric patients, and pregnant patients.

Question 19

19. Which of the following tests is most likely to be abnormal in patients taking aspirin?

A. PLT morphology
B. PLT count
C. PLT aggregation
D. PT

Answer 19

C. PLT aggregation

Aspirin is an antiplatelet drug. It prevents PLT aggregation by inhibition of cyclo-oxygenase. Aspirin has no effect on the PLT count, PLT morphology, or PT.

Question 20

20. Which of the following is associated with AT deficiency?

A. Thrombocytosis
B. Thrombosis
C. Thrombocytopenia
D. Bleeding

Answer 20

B. Thrombosis

AT is a physiological anticoagulant. It inhibits factors IIa, Xa, IXa, XIa, and XIIa. Deficiency of AT is associated with thrombosis. Thrombotic events commonly occur when AT deficiency is associated with another risk factor, such as pregnancy, surgery, or an inherited thrombotic disorder (e.g., factor V Leiden).

Question 21

21. Which of the following may be associated with thrombotic events?

A. Decreased protein C
B. Increased fibrinolysis
C. Afibrinogenemia
D. Idiopathic thrombocytopenic purpura

Answer 21

A. Decreased protein C

Protein C is a physiological inhibitor of coagulation. It is activated by thrombin–TM complex. APC inhibits cofactors Va and VIIIa. Protein C deficiency is associated with thrombosis. Increased fibrinolysis, afibrinogenemia, and ITP are associated with bleeding.

Question 22

22. Aspirin resistance may be associated with:

A. Bleeding
B. Factor VIII deficiency
C. Thrombosis
D. Thrombocytosis

Answer 22

C. Thrombosis

Up to 22% of patients taking aspirin become resistant to aspirin’s antiplatelet effect. Patients who are aspirin resistant have a higher risk of thrombosis (heart attacks and strokes).

Question 23

23. Prolonged TT is indicative of which of the following antithrombotic agents?

A. Prasugrel
B. Clopidogrel
C. Aspirin
D. Heparin

Answer 23

D. Heparin

Heparin is an AT drug causing prolonged TT in patients who are on heparin therapy. Prasugrel, clopidogrel, and aspirin are antiplatelet drugs causing inhibition of PLT aggregation.

Question 24

24. Screening tests for thrombophilia should be performed on:

A. All pregnant women because of the risk of thrombosis
B. Patients with a negative family history
C. Patients with thrombotic events occurring at a young age
D. Patients who are receiving anticoagulant therapy

Answer 24

C. Patients with thrombotic events occurring at a young age

Laboratory tests for evaluation of thrombophilia are justified in young patients with thrombotic events, in patients with a positive family history after a single thrombotic event, in those with recurrent spontaneous thrombosis, and in pregnancies associated with thrombosis.

Question 25

25. Prothrombin G20210A is characterized by which of the following causes and conditions?

A. Single mutation of prothrombin molecule/bleeding
B. Single mutation of prothrombin molecule/thrombosis
C. Decreased levels of prothrombin in plasma/thrombosis
D. Increased levels of prothrombin in plasma/bleeding

Answer 25

B. Single mutation of prothrombin molecule/thrombosis

Prothrombin G20210A is defined as a single-point mutation of the prothrombin gene, resulting in increased concentration of plasma prothrombin and, thus, is a risk factor for thrombosis. Prothrombin G20210A is the second most common cause of inherited hypercoagulability (after factor V Leiden). It has the highest incidence in white people from southern Europe. The thrombotic episodes generally occur before age 40 years.

Question 26

26. Factor V Leiden promotes thrombosis by preventing:

A. Inactivation of factor Va
B. Activation of factor V
C. Activation of protein C
D. Activation of protein S

Answer 26

A. Inactivation of factor Va

Factor V Leiden is a single-point mutation in the factor V gene that inhibits factor Va inactivation by protein C. APC enhances deactivation of factors Va and VIIIa.

Question 27

27. What is the approximate incidence of antiphospholipid antibodies in the general population?

A. Less than 1%
B. 1%–2%
C. 3%–8%
D. 10%–15%

Answer 27

B. 1%–2%

Question 28

28. Which of the following laboratory tests is helpful in the diagnosis of aspirin resistance?

A. APTT
B. PT
C. PLT count and morphology
D. PLT aggregation

Answer 28

D. PLT aggregation

Currently, the PLT aggregation test is considered the gold standard for evaluation of aspirin resistance. In aspirin resistance, PLT aggregation is not inhibited by aspirin ingestion. Aspirin resistance has no effect on PLT count and morphology.

Question 29

29. Which of the following complications may occur as a result of decreased tissue factor pathway inhibitor (TFPI)?

A. Increased episodes of hemorrhage
B. Increased risk of thrombosis
C. Impaired PLT plug formation
D. Immune thrombocytopenia

Answer 29

B. Increased risk of thrombosis

TFPI is released from the vasculature and is the most important inhibitor of the extrinsic pathway. TFPI inhibits factors Xa and VIIa–TF complex. Therefore, the deficiency of TFPI is associated with thrombosis.

Question 30

30. Factor VIII inhibitors occur in __________ of patients with factor VIII deficiency.

A. 40%–50%
B. 30%–40%
C. 25%–30%
D. 20%–25%

Answer 30

D. 20%–25%

Question 31

31. Which therapy and resulting mode of action are appropriate for the treatment of a patient with a high titer of factor VIII inhibitors?

A. Factor VIII concentrate to neutralize the antibodies
B. Recombinant factor VIIa (rVIIa) to activate factor X
C. Factor X concentrate to activate the common pathway
D. FFP to replace factor VIII

Answer 31

B. Recombinant factor VIIa (rVIIa) to activate factor X

rVIIa is effective for the treatment of a high-titer factor VIII inhibitor. Factor VIIa can directly activate factor X to factor Xa in the absence of factors VIII and IX. rVIIa does not stimulate anamnestic responses in patients with factor VIII inhibitor. Factor VIII concentrate is used for a low-titer factor VIII inhibitor. Factor X concentrate and FFP are not the treatments of choice for factor VIII inhibitor.

Question 32

32. The Bethesda assay is used for which determination?

A. Lupus anticoagulant titer
B. Factor VIII inhibitor titer
C. Factor V Leiden titer
D. Protein S deficiency

Answer 32

B. Factor VIII inhibitor titer

The Bethesda assay is a quantitative assay for factor VIII inhibitor. In this assay, normal plasma is incubated with different dilutions of the patient’s plasma or with a normal control. The inhibitor inactivates factor VIII present in normal plasma following incubation for 2 hours at 37°C. The residual activities in the sample are determined, and the inhibitor titer is calculated.

Question 33

33. Hyperhomocysteinemia may be a risk factor for:

A. Bleeding
B. Thrombocythemia
C. Thrombosis
D. Thrombocytopenia

Answer 33

C. Thrombosis

Elevated plasma homocysteine is a risk factor for the development of DVT, coronary heart disease and stroke. Homocystinemia may be inherited or acquired. Acquired homocystinemia is caused by dietary deficiencies of vitamins B6, B12, and folic acid.

Question 34

34. Which drug may be associated with DVT?

A. Aspirin
B. tPA
C. Oral contraceptives
D. Clopidogrel (Plavix)

Answer 34

C. Oral contraceptives

Oral contraceptive drugs are acquired risk factors for thrombosis. Aspirin and clopidogrel are antiplatelet drugs, and tPA is a fibrinolytic drug used for the treatment of thrombosis

Question 35

35. Argatroban may be used as an anticoagulant drug in patients with:

A. DVT
B. Hemorrhage
C. TTP
D. Thrombocytosis

Answer 35

A. DVT

Argatroban is a direct thrombin-inhibiting drug and may be used as an anticoagulant in patients with HIT to prevent thrombosis. Argatroban is a small synthetic molecule that binds to free and clot-bound thrombin. Argatroban affects TT, PT, APTT, and activated clotting time (ACT) tests. The APTT test is recommended for monitoring the dosage with the target therapeutic range of 1.5 to 3.0 times the mean of the laboratory reference range. In patients with lupus anticoagulant or factor deficiencies, baseline APTT is prolonged; in these conditions, Ecarin time can be used as an alternative assay.

Question 36

36. Heparin-induced thrombocytopenia (HIT) results from:

A. Antibodies to heparin
B. Antibodies to PLTs
C. Antibodies to PF4
D. Antibodies to heparin–PF4 complex

Answer 36

D. Antibodies to heparin–PF4 complex

HIT is an immune process caused by the production of antibodies to heparin–PF4 complex. This immune complex binds to PLT Fc receptors, causing PLT activation and formation of PLT microparticles, which, in turn, induce hypercoagulability and thrombocytopenia.

Question 37

37. Which laboratory test is used to screen for APCR?

A. Mixing studies with normal plasma
B. Mixing studies with factor-deficient plasma
C. Modified APTT with and without APC
D. Modified PT with and without APC

Answer 37

C. Modified APTT with and without APC

APCR can be evaluated by performing a two-part APTT test. The APTT is measured on the patient’s plasma with and without the addition of APC. The result is expressed as the ratio of the APTT with APC to the APTT without APC. The normal ratio is 2:5. Patients with APCR have a lower ratio than the reference range. A positive screening test should be followed by a confirmatory test, such as polymerase chain reaction (PCR) for factor V Leiden.

Question 38

38. Ecarin clotting time may be used to monitor:

A. Heparin therapy
B. Warfarin therapy
C. Fibrinolytic therapy
D. Bivalirudin

Answer 38

D. Bivalirudin

Ecarin clotting time, a snake venom–based clotting assay, may be used to monitor bivalirudin therapy in instances when the baseline APTT is prolonged as a result of lupus anticoagulant or factor deficiencies. Heparin therapy is monitored by using the anti–factor Xa assay; warfarin therapy is monitored with the INR. Fibrinolytic therapy may be monitored by using the D-dimer test.

Question 39

39. Which of the following may interfere with the APCR screening test?

A. Lupus anticoagulant
B. Protein C deficiency
C. AT deficiency
D. Protein S deficiency

Answer 39

A. Lupus anticoagulant

The lupus anticoagulant interferes with the APCR screening assay based on the APTT ratio with and without the addition of APC. Persons with the lupus anticoagulant have a prolonged APTT that renders the test invalid for APCR screening.

Question 40

40. Thrombophilia may be associated with which of the following disorders?

A. Afibrinogenemia
B. Hypofibrinogenemia
C. Factor VIII inhibitor
D. Hyperfibrinogenemia

Answer 40

D. Hyperfibrinogenemia

Hyperfibrinogenemia is a risk factor for thrombophilia. Fibrinogen is an acute-phase reactant and may be increased in inflammation, stress, obesity, smoking, and medications, such as oral contraceptives. Hypofibrinogenemia, afibrinogenemia, and factor VIII inhibitors are associated with bleeding.

Question 41

41. Which of the following anticoagulant drugs can be used in patients with HIT?

A. Warfarin
B. Heparin
C. Aspirin
D. Argatroban

Answer 41

D. Argatroban

Argatroban is a direct thrombin inhibitor drug and used in patients with HIT who cannot tolerate heparin or LMWH therapy. Warfarin should not be used for anticoagulation in persons with HIT because it causes a fall in protein C concentration and vitamin K–dependent coagulation factors. Aspirin is an antiplatelet drug.

Question 42

42. Which of the following is the preferred method to monitor heparin therapy at the point of care during cardiac surgery?

A. APTT
B. ACT
C. PT
D. TT

Answer 42

B. ACT

ACT is a point-of-care coagulation test used to monitor high-dose heparin therapy during cardiac surgery, cardiac angioplasty, hemodialysis, and other major surgeries. It is the preferred method to determine if sufficient heparin was administered to prevent clotting during surgery because it is more rapid than the APTT test. The test uses a clot activator, such as kaolin or Celite, to stimulate coagulation, and the time in seconds is linearly related to the dose of heparin administered. The ACT test is available in different formats, and the reference range varies, depending on the method used. At low to moderate heparin doses, the ACT test does not correlate well with the APTT test or the anti–factor Xa assay.

Question 43

43. Mrs. Smith has the following laboratory results and no history of bleeding:
    APTT = prolonged
    APTT results on a 1:1 mixture of the patient’s plasma with normal plasma:
    Preincubation: prolonged APTT
    2-hour incubation: prolonged APTT
    These results are consistent with:

A. Factor VIII deficiency
B. Factor VIII inhibitor
C. Lupus anticoagulant
D. Protein C deficiency

Answer 43

C. Lupus anticoagulant

Mixing studies differentiate factor deficiencies from factor inhibitors. Lupus anticoagulant is associated with thrombosis, and it is directed against phospholipiddependent coagulation tests, such as the APTT test. In patients with lupus anticoagulant, after the patient’s plasma is mixed with normal plasma, APTT remains prolonged immediately after mixing and following 2 hours of incubation. Factor VIII deficiency and factor VIII inhibitor are associated with bleeding.

Question 44

44. Which test may be used to monitor LMWH therapy?

A. APTT
B. INR
C. Anti–factor Xa heparin assay
D. ACT

Answer 44

C. Anti–factor Xa heparin assay

The anti–factor Xa heparin assay is used to monitor LMWH therapy, when required, because the APTT test is insensitive to LMWH. The assay can be performed by chromogenic endpoint detection used on automated analyzers. The principle of the test is to measure the inhibition of factor Xa by heparin. The reagent is a mixture of a fixed concentration of factor Xa, a substrate which is specific for factor Xa, and a fixed concentration of AT. Some kits rely on the AT in the patient’s plasma. Heparin forms a complex with AT and factor Xa (AT–heparin–factor Xa). Excess free factor Xa cleaves the chromogenic substrate and releases a yellow product. The color intensity of the
product is inversely proportional to plasma heparin concentration and is measured by a photodetector at 405 nm. LMWH therapy usually does not require monitoring; however, exceptions include pediatric, obese, and pregnant patients and those with renal failure.