1. Anticoagulant, Antiplatelet, and Thrombolytic Drugs

2. A few terms to know…
Coagulation- the physiologic process by which the blood clots to form solid masses, or clots. (Over 30 types of cells and substances in blood affect clotting.)
A blood clot is a thick mass of coagulated blood, platelets and other materials stuck together
A thrombus (pl, thrombi) is an intravascular clot. (A thrombus can break into smaller pieces, dislodge from the location where it was initially formed.)
An embolus is a blood clot, piece/globule of fatty deposit, or other object that is carried through the bloodstream.
An embolism refers to the obstruction of a blood vessel by a foreign substance or a blood clot that travels through the bloodstream, lodges in a smaller blood vessel, and plugs it.
Substances that can cause embolisms include: blood clots; piece/ globule of fatty deposit; clumps of bacteria, ‘vegetation’ or ‘debris’ on a heart valve; amniotic fluid; air bubble, chemicals and drugs (mainly illegal ones).
Blood clots are the most common cause of embolisms.

3. Formation of intravascular clots
Protective when injury to blood vessel would lead to hemorrhage and blood loss
Insults to blood vessels occur in normal physiology
Problematic, dangerous and even life-threatening, for example:
Certain hypercoaguable states
Genetic; iatrogenic; diseases such as leukemia
Prosthetics
artificial heart valves
Impaired mobility
Post-operative bed-rest; long airplane flights
Emergency situations
Ischemic stroke; myocardial infarction; massive pulmonary embolus
Other
Therefore, drugs are commonly used to reduce risk of clot, or to treat a clot that has formed

4. Physiology and Pathophysiology of Coagulation
Thrombosis‒ may result in severe consequences, due to reduction or cessation of blood flow to a tissue by the thrombus itself, or by rupture and release of thrombi
Arterial thrombosis-
Platelet adhesion (often ruptured atherosclerotic plaque)
Release of ADP & TXA2
Causes decreased/ absent perfusion distally -medical emergency
Depending on source of embolus, the clot may embolise to lower extremities, brain, heart, kidney, spleen, bowel
Venous thrombosis
Stagnation of blood in lower extremities
Fibrin formation
Typically embolise to right side of heart then lungs (safety net)
Paradoxical emboli (cross from venous circulation through a septal defect between the right and left sides of the heart, thereby entering the arterial circulation)

5. Complications of intravascular clots: short and long-term Arterial vs venous clots
paradoxic emboli can occur in patients with cardiac defects (usually atrial septal defect), who are at risk for the passage of emboli to the arterial circulation and resultant stroke or embolization of a peripheral artery.

6. are two of the most feared events
Ischemic cerebrovascular accident (CVA, stroke, “brain attack”) and Myocardial Infarct (MI, “heart attack”)
are two of the most feared events

7. Ex: Arterial blockage in lower extremities

11. Ex: Venous blockage in lower extremities

12. Ex: Venous blockage in lower extremities

13. Lower extremity DVT can embolise to the lungs

14. Animations of hemostasis (blood coagulation cascade)
Hemostasis, Coagulation and Fibrinolysis
The Coagulation Cascade
Hemostasis Revealed
Hemostasis - Physiology Animation
Platelet Activation and Factors for Clot Formation
Blood Clot Formation - Coagulation Factors & Platelets
Coagulation Cascade Animation - Physiology of Hemostasis

15. Clot formation begins with tissue injury, which then activates platelets.
When activated, platelets induce fibrin strand formation from platelet to platelet, thereby forming a fibrin mesh (clot)
Figure 52-1B Mechanism of platelet aggregation and actions of antiplatelet drugs.

16. Physiology of clot formation:
Stage One of Hemostasis: Formation of a “platelet plug”
Injury: Endothelial cells that line the blood vessel wall, and the sub-endothelial tissues, get injured
Components in the blood (eg platelets, clotting factors) are exposed to molecules from the injured endothelial cells and sub-endothelial tissues (eg tissue factor, collagen)
Note: Clotting factors, platelets and other molecules are inactive under normal conditions, but become activated sequentially
Platelets adhere to damaged tissue, become activated, amplify the clotting cascade, and aggregate at the site of injury
Vasoconstriction triggered by Injury to the blood vessel wall: smooth muscles in blood vessel wall immediately vasoconstrict the vessel, which reduces blood loss from the ruptured vessel

17. Physiology of clot formation, cont’d:
Stage Two of Hemostasis: Coagulation leads to fibrin formation via
Intrinsic pathway (aka contact activation pathway, turned on by contact with sub-endothelial collagen)
Extrinsic pathway (aka tissue factor pathway, turned on by release of tissue factor from damaged cells)
The intrinsic and extrinsic pathways have the common step of activating Factor X: this begins the “common pathway”.
Activation of factor X
Conversion of prothrombin to thrombin
Production of fibrin
Then, later, clot contraction
Hemostasis is kept under control by ANTITHROMBIN
Physiologic dissolution of clots (fibrinolysis) after tissue repair.
Release of Tissue Plasminogen Activator (t-PA) converts plasminogen to PLASMIN

18. INJURY Exposed collagen Damaged tissue Thrombolytics
Lehne, Figure 52-2, page 596

20. Drugs used to treat Thromboembolic Disorders
Three major classifications of drugs:
Anticoagulants:
Suppress the coagulation cascade
Heparin, warfarin
Antiplatelets:
Inhibit platelet aggregation
Aspirin, clopidogrel
Thrombolytics:
Promote lysis of fibrin strands, causing dissolution of thrombi
tissue plasminogen activator ie t-PA (alteplase) 20

21. ANTICOAGULANTS: Reduce the formation of fibrin
Two mechanisms of action
Inhibit the synthesis of clotting factors
Inhibit the activity of clotting factors

22. HEPARIN AND HEPARIN DERIVATIVES

23. Heparin (unfractionated, UFH)
Heparin (unfractionated) is not a single molecule, but a mixture of long polysaccharide chains, with molecular weights that vary from 3000 to 30,000 (units? kD?)
Active region is a unique penta-saccharide (five carbon sugar)
used for decades for prevention & treatment of thrombosis
Highly polar, cannot readily cross membranes
Mechanism: suppresses coagulation by helping antithrombin to inactivate clotting factors, primarily thrombin (factor II) & factor Xa, and thereby suppresses formation of fibrin
Particularly effective for prophylaxis of venous thromboses
BUT: variable anticoagulant effects, pharmacological properties, limited bioavailability, and highly variable anticoagulant response
Very rapid-acting anticoagulant (onset within minutes of IV administration)
Half-life only 1.5 hours, unless hepatic or renal disease
Hepatic metabolism, renal excretion 23

24. Heparin (Unfractionated, UFH)
Therapeutic uses
Preferred anticoagulant during pregnancy and when rapid anticoagulation is required
Does not enter breast milk
Pulmonary embolism (PE)
Ischemic stroke, evolving
(t-PA may be preferred if given within 2 hours of symptoms)
Massive deep vein thrombosis (DVT)
For anticoagulation during extracorporeal procedures when blood flows through machine
Open heart surgery
Renal dialysis
Low-dose therapy postoperatively (DVT prophy)
Disseminated intravascular coagulation (DIC)
Adjunct to thrombolytic therapy (eg MI) 24

25. Heparin (Unfractionated, UFH): Units, Route, & Preparations
Heparin is dosed in units
Administered only by IV or subcut
IV administration- commonly used for pts needing immediate anticoagulation
IV: Typically a “loading” dose based on weight (aka “bolus”) is administered followed by continuous infusion.
INTENSIVE LAB MONITORING is required
PT/INR is checked to evaluate degree of anticoagulation induced by therapy with heparin
Blood draw is checked 4 – 6 hours after the bolus dose is administered.
Rate of continuous infusion is adjusted up or down depending on the lab results.
Labs are drawn on continual periodic basis per hospital protocol until heparin is DC’d. Dose is adjusted based on lab results
Heparin sometimes administered by intermittent infusion (uncommon)
SQ administration; typically used for short-term, low-dose prophylactic tx. Monitoring labs aren’t usually required. (BID or TID)
Several formulations and concentrations available
Dilute vs concentrated; single dose vs multi-dose vials
Read labels carefully.
Check IV bag and infusion pump carefully.
Antidote for overdose: Protamine sulfate

26. aPTT lab is used to monitor anticoagulation with heparin
Activated partial thromboplastin time (aPTT) (Lehne, p 601) is used to determine the degree of anticoagulation induced by heparin therapy
Normal healthy people not on anticoagulation therapy have an aPTT of about 40 seconds
People on heparin for anticoagulation typically have a goal of aPTT in the range of 40 – 60 seconds
Labs must be checked per hospital protocol (or per individual prescriber)
Dose must be adjusted based on the lab results!
Typically drawn every 4 – 6 hours in initial therapy
If aPTT is too low, then heparin infusion needs to be increased per hospital protocol
If aPTT is too high, then heparin infusion needs to be reduced per hospital protocol
Usually blood draw is taken from a different extremity than the arm into which the IV heparin is infusing

27. Heparin (Unfractionated, UFH)
Adverse effects- reduce risk of bleeding by screening pts for risk factors, monitor closely and avoid antiplatelet drugs
– Hemorrhage
– Heparin-induced thrombocytopenia (HIT)
antibodies form against heparin-platelet protein complexes
Increases thrombotic events
Uses up all the platelets (↓platelet level)
Is an absolute contraindication to giving heparin again
– Hypersensitivity reactions
commercial preparations derived from animal sources
Contraindicated
Thrombocytopenia
Uncontrollable bleeding
During and immediately after surgery of the eye, brain, or spinal cord

28. Nursing Implications r/t Monitoring for, and Teaching, S/S of Bleeding
↓BP, ↑Heart Rate
Headache, faintness
Petechiae, bruises, hematoma
Red or black stools
Cloudy or discolored urine
Pelvic pain (possible ovarian hemorrhage)
Lumbar pain (possible adrenal hemorrhage)

29. Screen for risk factors
Nursing Implications r/t Minimizing the Risk of Bleeding- teach to patient/family prn
Screen for risk factors
Follow requirements for therapeutic drug monitoring
Beware drug or food interactions. Monitor blood levels carefully any time a new drug is added, or a current drug is discontinued from the drug regimen.
Minimize physical manipulation of the patient
Minimize invasive procedures (eg foley catheter)
Avoid subcut and IM injections
Minimize concurrent use of anticoagulants
for example, heparin, warfarin, dabigatran)
Minimize concurrent use of antiplatelet drugs
for example, aspirin, clopidogrel
Use in caution in those with CPR or surgery within previous 3 weeks
Avoid noncompressable vascular puncture sites
Wear identification for emergency personnel

30. Question- which lab is used to monitor effects of heparin?
A patient is receiving an intravenous infusion of heparin to treat a pulmonary embolism. What laboratory value will the nurse monitor to evaluate treatment with this medication?
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
Platelet count
Hemoglobin and hematocrit
Answer: A
Rationale: The most commonly used laboratory value that monitors the effect of heparin is the activated partial thromboplastin time (aPTT).

31. Question: antidote for heparin overdose?
What is the antidote for heparin?
Ferrous sulfate
Atropine sulfate
Protamine sulfate
Magnesium sulfate
Answer: C
Rationale: Protamine sulfate is an antidote to severe heparin overdose.

32. Low-Molecular-Weight Heparins
Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin
LMWH as effective as UFH
Mechanism: inactivates Factor Xa
not effective to inactivate thrombin
Administered subcut
Dosage based on body weight
Advantages: fixed dose, no lab, highly predictable plasma levels
Cost: considerably more expensive
Does not require labs/ monitoring; can be given at home
Pharmacokinetics
Higher bioavailability
Longer half-life- once or twice a day dosing
Antidote for toxicity: Protamine sulfate

33. Low-Molecular-Weight Heparins
Adverse effects
Bleeding (but less than with unfractionated heparin)
Heparin-induced thrombocytopenia (HIT)
Severe neurologic injury for patients undergoing spinal puncture or spinal epidural anesthesia
Therapeutic uses
First-line therapy for prevention and tx of DVT
Prevention of DVT following surgery
abdomen; hip or knee replacement
Off label use for DVT prophylaxis
in multi-trauma, or spinal surgery
Prevention of ischemic complications in pts with unstable angina, non Q-wave MI, and ST-elevation MI (STEMI)
Three on market:
Enoxaparin (Lovenox)- used in >80% of hospitals
Dalteparin (Fragmin)
Tinzaparin (Innohep)

34. All anticoagulants
Pose a risk of spinal or epidural hematoma in patients undergoing spinal puncture or spinal/ epidural anesthesia
Pressure of hematoma on spinal cord can result in prolonged or permanent paralysis
See Lehne text, p 599

35. RECOMMENDATION: Health care professionals and institutions involved in performing spinal/epidural anesthesia or spinal punctures should determine, as part of a pre-procedure checklist, whether a patient is receiving anticoagulants and identify the appropriate timing of enoxaparin dosing in relation to catheter placement or removal. To reduce the potential risk of bleeding, consider both the dose and the elimination half-life of the anticoagulant:
For enoxaparin, placement or removal of a spinal catheter should be delayed for at least 12 hours after administration of prophylactic doses such as those used for prevention of deep vein thrombosis. Longer delays (24 hours) are appropriate to consider for patients receiving higher therapeutic doses of enoxaparin (1 mg/kg twice daily or 1.5 mg/kg once daily).
A postprocedure dose of enoxaparin should usually be given no sooner than 4 hours after catheter removal.
In all cases, a benefit-risk assessment should consider both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.
Medwatch 11/2013

36. WARFARIN

37. Warfarin, the first oral anticoagulant
Originally discovered when a farmer observed that his cattle began bleeding after ingesting spoiled clover silage
Deemed too risky for humans  used as rat poison
A failed suicide attempt with large dose brought renewed clinical interest
Used to prevent thrombosis
Mechanism: suppresses coagulation by decreasing production of four clotting factors (VII, IX, X and prothrombin, all of which are dependent on vitamin K)
PK: only administered orally, well absorbed; 99% bound to albumin; unbound warfarin readily crosses into placenta and breast milk; hepatic metabolism by CYP2C9; metabolites excreted in urine & feces
Clinical considerations
Initial onset 6 – 12 hours after first dose; peak effect takes several days to develop. (Not useful in emergencies)
Effect persists 2 – 5 days after discontinuing
Drug therapy typically initiated with heparin (which has immediate onset) until warfarin is at therapeutic levels
Warfarin may need to be temporarily DC’d for elective surgery (Heparin is re-instituted during interim until safe to go back on warfarin) 37

38. Warfarin, the first oral anticoagulant
Lab monitoring ESSENTIAL!
Never does a person “not need” monitoring, although frequency of labs are somewhat individualized
Prothrombin time (PT)/ International normalized ratio (INR)
Normal PT/INR (in an uncoagulated healthy person) is 1.0
When patients are on warfarin, the therapeutic “Goal PT/INR” is somewhat individualized and depends on condition being treated
Most pts on warfarin have an anticoagulation PT/INR goal between 2.0 and 3.0.
Some pts need more anticoagulation and may have a goal PT/INR between 3.0 and 4.5.
See Lehne p. 605
Longest reasonable amount of time between PT/INR labs is 2 – 4 weeks
Patients daily dose of warfarin is titrated up or down based on PT/INR values
Antidote Vitamin K1 (phytonadione)
oral preferred (IV has risk of allergy or anaphylaxis)
Useful in emergencies (eg sudden trauma)
Therapeutic use: long-term prophylaxis of thrombosis
Prevention of venous thrombosis & associated risk of pulmonary embolism
Prevention of thromboembolism
Eg in patients with prosthetic heart valves
Prevention of thrombosis in patients with atrial fibrillation
Reduce recurrent Transient Ischemic Attacks and MI

39. Warfarin, the first oral anticoagulant
Adverse effects
Bleeding
Hemorrhage
Fetal hemorrhage and teratogenesis
Pregnancy Category X
Contraindicated during lactation
Other adverse effects
Patient Teaching
S/S of bleeding; monitoring plan- schedule of labs; drug and food interactions; must tell all providers of all drugs; wear “MedicAlert”-type identification; stop warfarin (use another method) until after an elective surgery
Take at same time every day
Warfarin has perhaps the most drug or food interactions of any medication!

40. Warfarin, the first oral anticoagulant
Drug interactions (p )
Warfarin has perhaps the most drug and food interactions of any medication!
Worrisome due to increased bleeding or loss of protection
Drugs that increase anticoagulant effects
Heparin, aspirin, acetaminophen
Drugs that promote bleeding
Drugs that compete for binding with plasma proteins
Drugs that induce or inhibit the drug-metabolizing enzymes (CYP2C9)
Drugs that decrease anticoagulant effects
Contraindicated: very large list (p 607)
severe thrombocytopenia and others at high risk of bleeding
Patients undergoing a variety of procedures or surgeries
Liver disease, alcoholism- conditions that can disrupt production of clotting factors
Pregnancy and lactation 40

41. Warfarin, the first oral anticoagulant
Teach pt to ingest the same amount of dietary Vitamin K each day
Dietary vitamin K: Mayonnaise, canola oil, soybean oil, and green leafy vegetables 41

42. Question: warfarin and drug interactions
Which patient does the nurse identify as most likely needing an increased dose of warfarin [Coumadin] to have the same anticoagulant effect?
Patient taking acetaminophen [Tylenol] for back pain
Patient taking cimetidine [Tagamet] to prevent gastric ulcers
Patient taking oral contraceptives to prevent pregnancy
Patient taking prednisone [Deltasone] for rheumatoid arthritis
Answer: C
Rationale: Oral contraceptives decrease the effects of warfarin; therefore, warfarin doses may need to be increased. Acetaminophen and cimetidine increase the effects of warfarin. Prednisone increases the risk of bleeding.

43. HEPARIN VS. WARFARIN

44. Comparison between Heparin & Warfarin
MOA
Inactivates thrombin & factor Xa
Inhibits synthesis of clotting factors
Route
injection
SQ, IV
oral
Onset
Effects begin rapidly
Begin slowly

45. Comparison between Heparin & Warfarin
Duration
Effects fade quickly
Effects persist for days
Monitoring
aPTT PT
Antidote
Protamine Sulfate
Vitamin K
Heparin and warfarin also have different therapeutic applications:
Heparin has immediate onset and is therefore used when anticoagulation needs to begin immediately (eg new diagnosis, or medical emergency). When used long-term, heparin has adverse effects (eg osteoporosis). Therefore is limited to short-term use.
Warfarin takes 2-5 days to reach therapeutic levels; therefore cannot be used for emergencies. However, warfarin is used when long-term (or permanent) anticoagulation is needed.

46. Direct Thrombin Inhibitors
Dabigatran etexilate (Pradaxa)
Oral prodrug that undergoes conversion to dabigatran
Advantages:
Doesn’t require monitoring of anticoagulation
little risk of adverse interactions
same dose can be used for all patients regardless of age or weight
Therapeutic uses
Atrial fibrillation
Knee or hip replacement
Adverse effects
Bleeding
No specific antidote to reverse dabigatran-related bleeding
Gastrointestinal (GI) disturbances
Clinical considerations
Plasma levels peak about 1 – 3 hours after oral dosing. Not metabolized by liver, excreted by kidneys. Half-life 13 hours. Take dose at same time every day. No antidote
Direct inhibition of thrombin (unlike heparin, which enhances the activity of antithrombin)

47. Direct Factor Xa Inhibitors
Rivaroxaban [Xarelto]
Binds directly with factor Xa to cause inactivation
Prevention of DVT and PE after total hip or knee replacement surgery
Prevention of stroke in patients with atrial fibrillation
Treatment of DVT and PE unrelated to orthopedic surgery
Oral
No lab test
No antidote
Dosing at same time every day is required 47

48. ANTIPLATELET DRUGS:

49. Antiplatelet Drugs Aspirin (ASA) Ticlopidine [Ticlid]
Inhibition of cyclooxygenase
Adverse effect
Increases risk for GI bleeding
Ticlopidine [Ticlid]
Inhibits ADP-mediated aggregation
Adverse effects
Hematologic effects
Clopidogrel [Plavix]
ADP receptor antagonist 49

50. Mechanism of platelet activation (causes stickiness and platelet aggregation.) Mechanisms of antiplatelet drugs are also depicted. Figure 52-1A

51. ASPIRIN

52. Antiplatelet Drugs: ASPIRIN
Aspirin (ASA)
Irreversible Inhibition of cyclooxygenase
Effects last ___ days?
Indications for use
Transient ischemic attack (TIA)
Primary prevention of Ischemic Stroke
Secondary prevention of Ischemic stroke
Primary prevention of MI
Secondary prevention of MI
Acute MI
Chronic stable angina
Unstable angina
Coronary stenting
Adverse effect
Bleeding; GI bleeding; Hemorrhagic stroke
Enteric-coated tablets may not reduce the risk of GI bleeding

53. CLOPIDOGREL

54. Antiplatelet Drugs: Clopidogrel
Clopidogrel [Plavix]
ADP receptor antagonist; Blocks P2Y12 ADP receptors on the platelet surface, preventing ADP-stimulated aggregation
Adverse effects: similar to aspirin
Bleeding
TTP (thrombotic thrombocytopenia purpura)
Drug Interactions: PPI’s, CYP2C19 inhibitors
Therapeutic uses
Prevents blockage of coronary artery stents
Reduces thrombotic events in patients with acute coronary syndromes
Prevents stenosis of coronary stents
Also for secondary prevention of MI, ischemic stroke, and other vascular events
Use with caution in combination with other drugs that promote bleeding

55. Antiplatelet Drugs: glycoprotein IIb/IIIa receptor antagonists
Glycoprotein (GP) IIb/IIIa receptor antagonists
Most effective antiplatelet drugs
“Super aspirins”
Reversible blockade of platelet GP IIb/IIIa receptors
Therapeutic use
Acute coronary syndromes
Percutaneous coronary interventions

56. THROMBOLYTICS

57. Thrombolytic Drugs Breaks down fibrin strands in the blood clot
Alteplase [tPA]
Binds plasminogen
Uses
Ischemic stroke- emergency management; must be administered within 2 hours of the onset of symptoms, preferably ASAP
Risk of bleeding increases as time passes after clot occurred
Massive pulmonary emboli
Acute coronary thrombosis (acute MI)
Deep venous thrombosis (DVT)
Clearing clogged central catheters
Adverse effects
Bleeding: Risk for intracranial bleeding higher than with streptokinase
If bleeding begins, treat with whole blood or blood products (packed red blood cells, fresh-frozen plasma)
Aminocaproic acid [Amicar] is last resort
–Fever
Advantages
Does not cause allergic reactions
Does not induce hypotension
Breaks down fibrin strands in the blood clot

58. Question
During administration of alteplase [Activase], the patient’s IV site starts to ooze blood around the catheter. Which action by the nurse is most appropriate?
Discontinue the infusion of alteplase.
Assess the patient’s vital signs.
Apply direct pressure over the puncture site.
Administer aminocaproic acid [Amicar].
Answer: C
Rationale: Alteplase may cause bleeding, and the management of bleeding depends on its severity. Oozing at sites of cutaneous puncture can be controlled with direct pressure or a pressure dressing. If severe bleeding occurs, alteplase should be discontinued. Excessive fibrinolysis can be reversed with IV aminocaproic acid [Amicar], a compound that prevents activation of plasminogen and directly inhibits plasmin.