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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬

Day 1 topic: Anticoagulant & Antiplatelet drugs

BACKGROUND ABOUT ANTI-COAGULANTS:

 Anticoagulants are used to prevent blood clots

from forming & to keep existing clots from
becoming larger
 Unlike thrombolytics they do not break down clots
 Uses:


 Pathophysiology : A number of factors can lead

to activation of the coagulation process & causing clots such as:
o Blood vessel injury
o blood stasis (stopping or slowing of blood flow) See Virchow triad pic below
o Prothrombotic conditions for more information if needed

 Coagulation involves activation of platelets and the clotting cascade (Explained in the next page)
 All of the clotting factors have an inactive & an active form. Once activated, a clotting factor will activate the
next clotting factor in the sequence until fibrin is formed
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬

*Anticoagulants
Heparins clinical uses:
1. limit the expansion of thrombi by preventing fibrin formation
2. treatment of acute venous thromboembolism (DVT or PE)
3. prophylaxis of postoperative venous thrombosis in patients undergoing surgery (for example, hip replacement)
4. prophylaxis for those with acute MI.
5. They are DOC in pregnant woman bc they do not cross the placenta
 Antithrombin III is An endogenous anticlotting protein that irreversibly inactivates thrombin and factor Xa. Its enzymatic action is markedly
accelerated by the heparins.
 Why heparins are only available as SC or IV? to avoid the risk of hematoma associated with intramuscular injection.
 LMW heparins are: (enoxaparin, dalteparin, and tinzaparin)
 Unfractionated Heparin antidote is protamine sulfate( 1mg protamine will reverse -100 units of heparin )
 Heparin-induced thrombocytopenia (HIT) is an immune-mediated IgG drug reaction.
 HIT syndrome is related to immune system forming antibodies against heparin bound to platelet factor 4 (PF 4).

Comparison Unfractionated heparin (UH) Low-molecular-weight-heparin

 HOW TO MANAGE HIT SYNDROME?
(LMWH)
Molecular weight Big (15,000–20,000 Da) Smaller(2000–6000 Da) o If HIT is suspected or confirmed,
ROA Available sub-Q or IV Available IV only stop all forms of heparin and LMWH
Onset/duration rapid onset & rapid clearance Longer t1/2 when administered o If pt. is taking warfarin, stop it too
Sub-Q compared to UH and administer Vit.K
Monitoring? Requires frequent monitoring (aPPT test) Usually no lab monitoring o Administer non-heparin
therapeutic aPTT for pts. On UH should needed, but if needed (I.e. in anticoagulants instead of heparins,
be 1.5 to 2.5 times the mean normal case of pregnancy/obese recommended in particular,
value pts./renally impaired pts.) we argatroban.
monitor anti-factor Xa level 4 hrs o Do not start warfarin therapy until
after SC inj. the platelets have recovered to >
SE? Higher incidence of thrombocytopenia & Lower incidence of induced 150,000/mm3
HIT syndrome & higher risk of bleeding thrombocytopenia & lower risk o Overlap warfarin with a non-heparin
as SE of bleeding as SE anticoagulant for a minimum of five
Difference in Unfractionated heparin accelerates LMWH selectively accelerates days and until the INR is within
MOA? interaction of antithrombin III with both interaction of antithrombin III
target range for 24 hours.
thrombin and factor Xa with factor Xa.

*Anticoagulants
Xa factor inhibitors: all oral agents can be used in Nonvalvular AFib
(stroke prophylaxis) + treatment of DVT/PE or Prophylaxis for DVT (after
knee/hip replacement).
 direct Xa inhibitor: Apixaban, betrixaban, edoxaban, rivaroxaban (ORAL
route)
 indirect Xa inhibitor: Fondaparinux (injectable SC route)
 Betrixaban is only prophylaxis in VTE
 Fondaparinux is Main treatment of VTE + also prophylaxis
 Antidote for apixaban and rivaroxaban is andexanet alfa (Andexxa)
 Fondaparinux is CI in Severe renal impairment (CrCI < 30 mL/min)
 rivaroxaban Is Not recommended with prosthetic heart valves
 Apixaban & Fondaparinux boxed warning is that if they’re given in
pts. Going for
neuraxial anesthesia (epidural, spinal) or Undergoin g spinal puncture,
they’ll have↑↑risk of hematoma & subsequent paralysis !!!
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬

*Anticoagulants
Direct thrombin inhibitors: Parenteral direct thrombin inhibitors (Argatroban, Bivalirudin ) are used as alternatives to heparin
primarily in patients with heparin-induced thrombocytopenia, they are also Safe for patients with history of HIT; + they’re also
monitored by aPTT laboratory test.

 (Bivalirudin + aspirin combo) used in percutaneous coronary angioplasty (PCI)

 Dabigatran is CI in mechanical prosthetic heart valve
 Dabigatran has gastritis-like symptoms + dyspepsia as SE
 Always counsel the patient to keep the Dabigatran tabs in their original package
& don’t put it in pill box/pill organizer bc they’re very sensitive to moist
 Dabigatran bleeding toxicity is reversed by Idarucizumab (antidote)
5 grams IV (given as 2 separate 2.5 gram

*Anticoagulants
Warfarin
 Goal INR is 2-3 (target 2.5) for most indications (DVT.AFib, bioprosthetic mitral valve,
mechanical aortic valve, antiphospholipid syndrome)
 goal INR should be 2.5-3.5 for some high-risk indications such as a mechanical
mitral valve or 2 mechanical heart valves.
 warfarin antidote is Vit.K 1-10mg PO/IV
 Ci in Pregnancy (except with mechanical heart valves)
 has risk of Tissue necrosis/gangrene in pts. with HIT, thus contraindicated as
monotherapy in the initial treatment of active HIT
 famous SE include: Bleeding, skin necrosis, purple toe syndrome
 In healthy outpatients, the initial starting dose of warfarin should be 10 mg daily for the first two days, then adjust per INR
values.
 In patients with acute DVT/PE, start warfarin on the same day as the parenteral anticoagulant (e.g., enoxaparin orUFH) and
continue both anticoagulants for a minimum of 5 days and until the INR is > 2
for at least 24 hours
 Supplement/food interaction:
o ↑ bleeding risk with warfarin (↓INR level) : "the 5 Gs"
 (garlic,ginger, ginkgo, ginseng, glucosamine)
 vitamin E, evening primrose oil, high doses of fish oils , grapefruit, willow
bark
o ↓ effectiveness of warfarin (↑INR level):
 alfalfa, green tea,coenzyme Q10 & ofc any food that’s rich in vit.k
 St. John’s wort. American ginseng
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬

CHA2DS2-VASC Scoring Systems (CHEST Guideline)

 It’s a scoring system where we Count the number of risk factors the patient has that might make him develop
stroke/thrombus, then we can tell if he/she needs an anticoagulant therapy or no.
 The higher the score, the greater the stroke risk and the more intensive the anticoagulant recommendations.
 HOW? See next 
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬

QUESTIONS

Questions 1–3. A 55-year-old lawyer is brought to the emergency department 2 h after the onset of severe chest
pain during a stressful meeting. He has a history of poorly controlled mild hypertension and elevated blood
cholesterol but does not smoke. ECG changes (ST elevation) and cardiac enzymes confirm the diagnosis of
myocardial infarction. The decision is made to attempt to open his occluded artery.
1. Which of the following drugs accelerates the conversion of plasminogen to plasmin?
(A) Aminocaproic acid
(B) Heparin
(C) Argatroban
(D) Reteplase
(E) Warfarin

2. If a fibrinolytic drug is used for treatment of this man’s acute myocardial infarction, which of the following
adverse drug effects is most likely to occur?
(A) Acute renal failure
(B) Development of antiplatelet antibodies
(C) Encephalitis secondary to liver dysfunction
(D) Hemorrhagic stroke
(E) Neutropenia

3. If this patient undergoes a percutaneous coronary angiography procedure and placement of a stent in a
coronary blood vessel, he will need to be on dual antiplatelet therapy, eg, aspirin and clopidogrel for at least a
year. Which of the following most accurately describes the mechanism of action of clopidogrel?
(A) Clopidogrel directly binds to the platelet ADP receptors
(B) Clopidogrel irreversibly inhibits cyclooxygenase
(C) Clopidogrel facilitates the action of antithrombin III
(D) The active metabolite of clopidogrel binds to and inhibits the platelet ADP receptors
(E) The active metabolite of clopidogrel binds to and inhibits the platelet glycoprotein IIb/IIIa receptors

4. The graph at the bottom of this page shows the plasma concentration of free warfarin as a function of time
for a patient who was treated with 2 other agents, drugs B and C, on a daily basis at constant dosage starting at
the times shown. Which of the following is the most likely explanation for the observed changes in warfarin
concentration?

(A) Drug B displaces warfarin from plasma proteins; drug C displaces warfarin from tissue-binding sites
(B) Drug B inhibits hepatic metabolism of warfarin; drug C displaces drug B from tissue-binding sites
(C) Drug B stimulates hepatic metabolism of warfarin; drug C displaces warfarin from plasma protein
(D) Drug B increases renal clearance of warfarin; drug C inhibits hepatic metabolism of drug B
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Ph. Noora Mh. Noureldin - MOH preparations –‫رب ارشح يل صدري و ريّس يل أمري‬

Questions 5–7. A 58-year-old woman with chronic hypertension and diabetes mellitus was recently admitted to the hospital for
congestive heart failure and new onset atrial fibrillation. She is now seeing you after discharge and, though feeling better, is still in
atrial fibrillation. An echocardiogram shows an ejection fraction of 40%; there are no valvular abnormalities. An ECG reveals only
atrial fibrillation. You calculate her risk using the CHADS (2) system and the score indicates that she requires anticoagulation rather
than antiplatelet therapy.
5. You are discussing the risks and benefits of anticoagulation therapy with her, including the option of using direct thrombin
inhibitors. Which of the following anticoagulants is a direct inhibitor of thrombin?
(A) Abciximab
(B) Dabigatran
(C) Rivaroxaban
(D) Warfarin

6. She tells you that her main reason for not wanting oral anticoagulation is that she does not want to come to clinic for frequent
blood draws. You agree on an oral alternative and start her on apixaban. You counsel her extensively on the importance of taking
the medication each day, as suddenly stopping can lead to
(A) Anaphylaxis
(B) Excess bleeding
(C) Increase in INR
(D) Stroke
(E) Thrombocytopenia

7. She is excited about not having to come in for blood tests but wonders if there is a test, just in case the doctors need to know.
Which of the following tests would provide accurate information about the coagulation status of a patient taking apixaban?
(A) aPTT
(B) Factor X test
(C) INR
(D) PT test

Questions 8 and 9. A 67-year-old woman presents with pain in her left thigh muscle. Duplex ultrasonography indicates the presence
of deep vein thrombosis (DVT) in the affected limb.
8. The decision was made to treat this woman with enoxaparin. Relative to unfractionated heparin, enoxaparin
(A) Can be used without monitoring the patient’s aPTT
(B) Has a shorter duration of action
(C) Is less likely to have a teratogenic effect
(D) Is more likely to be given intravenously
(E) Is more likely to cause thrombosis and thrombocytopenia

9. During the next week, the patient was started on warfarin and her enoxaparin was discontinued. Two months later, she returned
after a severe nosebleed. Laboratory analysis revealed an INR (international normalized ratio) of 7.0 (INR value in such a warfarin-
treated patient should be 2.0–3.0). To prevent severe hemorrhage, the warfarin should be discontinued and this patient should be
treated immediately with which of the following?
(A) Aminocaproic acid
(B) Desmopressin
(C) Factor VIII
(D) Protamine
(E) Vitamin K1
10. A patient develops severe thrombocytopenia in response to treatment with unfractionated heparin and still requires parenteral
anticoagulation. The patient is most likely to be treated with which of the following?
(A) Abciximab
(B) Bivalirudin
(C) Tirofiban
(D) Plasminogen
(E) Vitamin K1