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Questions 1-13 list characteristics of unfractionated heparin, low molecular weight (LMW) heparin, both or neither.  For each characteristic below, select the single best choice.  Answer the entire set of questions before reviewing the answers/explanation:

a. Unfractionated heparin
b. Low molecular weight (LMW) heparins
c. Both
d. Neither

1. Homogenous glycosaminoglycan; molecular weight 4000-6000
2. Heterogenous mixture of polysaccharide; molecular weight 3000-30,000
3. Less activation of anti-thrombin III
4. Inhibits thrombin and factor Xa to same extent
5. Releases tissue factor pathway inhibitor (TFPI) from endothelium
6. Able to inactivate clot-bound thrombin and fibrin-degradation products
7. Minimal binding to plasma proteins, endothelial cells, macrophages
8. Predictable anticoagulation
9. Shorter half-life
10. Monitoring unnecessary except in renal failure or body weight > 50 kg or < 80 kg
11. ACT used to monitor variable anticoagulant effect
12. Protamine neutralizes anti-thrombin activity
13. Can be used in patients with a history of heparin-induced thrombocytopenia, type II

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Answers:  1(a); 2(b); 3(b); 4(a); 5(c); 6(d); 7(b); 8(b); 9(a); 10(b); 11(a); 12(c); 13(d)

14. Heparin resistance and residual thrombin activity exists in up to 30% of patients despite "therapeutic" ACTs:

a. True
b. False

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Answer:  The ACT must be viewed as an indirect measure of antithrombotic efficacy. Elevated levels of fibrinopeptide A (reflecting heparin resistance and residual thrombin activity) persist in 30% of patients undergoing intervention despite "therapeutic ACTs and high heparin levels, and are associated with adverse clinical events. Unfortunately, there are no readily available bedside assays to identify these high-risk patients. (Answer: a)

15. Following prolonged heparin infusion, heparin should be:

a. Discontinued abruptly
b. Tapered slowly
c. Method of discontinuation does not matter

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Answer:  Since rebound thrombin generation and abrupt closure may be temporally associated with discontinuation of heparin infusions, heparin should be tapered slowly over 6-24 hours.   (Answer: a)

16.  A patient with unstable angina is stabilized on heparin for 3 days before successful stenting of an LAD lesion. Three days later, the platelet count falls from a baseline of 200,000/mm³ to 30,000/mm³. Platelet transfusions are recommended to increase the platelet count above 50,000/mm³:

a. True
b. False

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Answer:  Platelet transfusions should not be used in the setting of heparin-induced thrombocytopenia because of the risk of thrombotic complications. An infusion of the prostacyclin analog Iloprost, titrated to eliminate in-vitro heparin-induced platelet activation (infusion rates of 10-48 ng/kg/min), was successful in preventing recurrent HIT-2 in 11 patients requiring heparin during cardiovascular surgery. Anticoagulation has also been achieved with defibrinating viper venoms like Ancrod or Reptilase, or with the heparinoid Org 10172, in HIT-2 patients requiring anticoagulation. Low-molecular-weight-heparin reduces, but does not eliminate, the risk of HIT-1, but is absolutely contraindicated in patients with prior HIT-2. Recently, the direct-acting thrombin antagonist hirudin (Refludan) has become commercially available as an alternative to heparin for procedural anticoagulation.  (Answer: b)

17.  Interventional studies suggest a clinical benefit of LMW heparin over unfractionated heparin in patients undergoing percutaneous coronary intervention:

a. True
b. False

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Answer:  LMW heparins have been used to prevent deep venous thrombosis and pulmonary embolism, but studies during coronary intervention suggest no benefit over unfractionated heparin (UFH). Enoxaparin failed to improve PTCA success, complications, or angiographic or clinical restenosis, and reviparin failed to reduce major clinical events or angiographic restenosis (REDUCE trial), compared to UFH. Enoxaparin has been shown to be superior to UFH for primary medical therapy of unstable angina or non-ST-elevation acute coronary syndromes (ESSENCE, TIMI 11b trials), and can be used as an alternative to UFH for PCI with or without GP IIb/IIIa inhibitors (NICE trials). (Answer: b)

Questions 18-22 list characteristics of unfractionated heparin, hirudin, both or neither. For each characteristic below, select the single best answer:

a. Heparin
b. Hirudin
c. Both
d. Neither

18. Requires anti-thrombin III for its anticoagulant effect
19. Forms highly stable noncovalent complexes with circulating and clot-bound thrombin
20. Not inhibited by platelet factor 4
21. Inhibits ADP-induced platelet aggregation
22. Not associated with thrombocytopenia

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Answer: Unlike heparin, hirudin and hirulog do not require antithrombin III for anticoagulant effect, form highly stable noncovalent complexes with circulating and clot-bound thrombin, and are not inhibited by platelet factor 4. Hirudin inhibits platelet aggregation induced by thrombin but not other platelet agonists, and does not cause thrombocytopenia. Although one study reported that hirulog was similar to heparin in decreasing ischemic complications after PTCA, another study reported fewer ischemic complications with hirulog in high-risk patients with post-infarction angina. The risk of bleeding also appears to be less with hirulog than with heparin.⁶⁶ In the Hirudin European Trial versus Heparin in the Prevention of Restenosis after PTCA (HELVETICA), PTCA patients with unstable angina had fewer early ischemic events after hirudin, but no difference in restenosis. A higher incidence of intracranial hemorrhage has been reported in 3 trials combining hirudin and thrombolytic therapy (GUSTO IIa, TIMI 9A, HIT-III). Current studies are attempting to further define the optimal dose, timing, and route of administration of these agents. The ongoing CACHET trial is evaluating the efficacy of hirulog (with "rescue" IIb/IIIa antagonist if necessary) compared to unfractionated heparin (with routine IIb/IIIa antagonist). (Answers: 18(a); 19(b); 20(b); 21(d); 22(b))

23. The dose of lepirudin for heparin-induced thrombocytopenia in patients who require intravenous anticoagulation is:

a. No bolus; continuous IV infusion of 0.15 mg/kg/hr
b. Bolus 0.4 mg/kg; IV infusion of 0.75 mg/kg/hr
c. Bolus 0.4 mg/kg; IV infusion 0.15 mg/kg/hr
d. Bolus 0.8 mg/kg; no IV infusion

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Answer:  Refludan (lepirudin, a recombinant hirudin) is a direct thrombin inhibitor approved for patients with heparin-induced thrombocytopenia who require intravenous anticoagulation. In such patients, the initial bolus is 0.4 mg/kg (maximum dose = 44 mg) over 15-20 seconds, followed by a continuous intravenous infusion of 0.15 mg/kg/hour (maximum infusion rate = 16.5 mg/hr). (Answer: c)