Coagulation Modifier Drugs and Hemostasis

• Coagulation modifier drugs impact hemostasis, the process of stopping bleeding.
• Coagulation is hemostasis as a result of physiological blood clotting.
• Clot formation involves a complex interaction of substances that promote or inhibit coagulation, or dissolve existing clots.
• A thrombus is the technical term for a blood clot.
• An embolus is a thrombus that moves through blood vessels.

Coagulation System

• The coagulation system operates like a cascade, where each activated factor acts as a catalyst.
• These reactions amplify the next one.
• The final product is fibrin, which is a clot-forming substance.
• The two pathways for coagulation are the intrinsic and extrinsic pathways.

Fibrinolytic System

• The fibrinolytic system starts the breakdown of clots to balance the clotting process.
• Fibrinolysis is the mechanism by which thrombi are lysed to prevent excessive clotting and vessel blockage.
• Fibrin binds to plasminogen, a circulating protein which converts plasminogen to plasmin.
• Plasmin is an enzymatic protein that breaks down the fibrin thrombus and localizes them to prevent emboli.

Coagulation Modifier Drugs

• Anticoagulants inhibit clotting factor action or formation and prevent clot formation.
• Antiplatelet drugs block platelet aggregation and formation of platelet plugs.
• Hemorheological drugs alter platelet function without stopping platelets from working.
• Thrombolytic drugs break down existing clots.
• Antifibrinolytic or hemostatic drugs promote blood coagulation.

Anticoagulants

• Anticoagulants, or antithrombotic drugs, have no direct impact on existing clots.
• They prevent intravascular thrombosis by reducing blood's ability to coagulate.
• They are for prophylactic use.
• Prophylactic uses of anticoagulants:
  • Clot formation (thrombus).
  • Embolus (dislodged clot).

Heparins

• Heparins inhibit clotting factors IIa (thrombin), Xa, and IX.
• Factors XI and XII are also inactivated, but their role is less important than the other three factors.
• Unfractionated heparin is often just called “heparin”.

Low molecular weight heparins

• Examples of low molecular weight heparins:
  • Enoxaparin (Lovenox)
  • Dalteparin (Fragmin)
  • Nadroparin calcium (Fraxiparine)
  • Tinzaparin sodium (Innohep).
• Unfractionated heparin is derived from animal sources and is relatively large molecule.
• Frequent lab monitoring for bleeding times is required.
• Heparin can be used for catheter flush in concentrations between 10–100 units/mL.
• Monitoring is not needed for catheter flush.
• LMWHs have a smaller synthetic molecular structure.
• LMWH usage results in more predictable anticoagulant response, requiring less frequent lab monitoring.

Warfarin

• Warfarin (Coumadin) inhibits vitamin K synthesis by bacteria in the gastrointestinal tract.
• Warfarin inhibits vitamin K-dependent clotting factors II, VII, IX, and X, which are synthesized in the liver.
• The final effect of warfarin is the prevention of clot formation.

Antithrombin Medications

• Antithrombin medications, action: inhibit thrombin (factor IIa).
• Natural antithrombin medication: human antithrombin III (Thrombate)
• Synthetic antithrombin medications:
  • Lepirudin (Refludan)
  • Argatroban (Argatroban)
  • Bivalirudin (Angiomax)
  • Dabigatran (Pradaxa)

Direct Acting Xa Inhibitors

• Fondaparinux (Arixtra), rivaroxaban (Xarelto), and apixaban (Eliquis) inhibit factor Xa.
• Dabigatran directly inhibits thrombin.

Dabigatran Etexilate Mesylate

• Dabigatran etexilate mesylate (Pradaxa) is the first oral direct thrombin inhibitor.
• It is approved for preventing strokes and thrombosis in patients with nonvalvular atrial fibrillation.
• Dabigatran is a prodrug, it is activated in the liver, and reversibly binds to both free and clot-bound thrombin.
• It undergoes extensive kidney excretion, therefore the dose depends on kidney function:
  • The normal dose is 150 mg twice daily.
  • The dose should be reduced to 75 mg twice daily when creatinine clearance is less than 30 mL per minute.
• A key and serious side effect of dabigatran id bleeding,.
• No coagulation monitoring is required.

Anticoagulants: Mechanism of Action

• Anticoagulant mechanisms vary depending on the drug.
• They work at different points during the clotting cascade.
• They prevent intravascular thrombosis by decreasing blood coagulability.
• Anticoagulants do not lyse existing clots.

Anticoagulants: Indications

• Anticoagulants address conditions that make clot formation likely.
• These conditions may include:
  • Myocardial infarction.
  • Unstable angina.
  • Atrial fibrillation.
  • Indwelling devices, such as mechanical heart valves.
  • Conditions in which blood flow may be slowed and blood may pool (major orthopedic surgery, prolonged immobility).

Anticoagulants: Contraindications

• Contraindications include drug allergy and any acute bleeding process or high risk of such an occurrence.
• Warfarin is not to be used during pregnancy.
• Low-molecular-weight heparins are contraindicated in patients with a risk of epidural hematoma and indwelling epidural catheters.

Anticoagulants: Adverse Effects

• Bleeding risk increases with increased dosages and may be localized or systemic.
• Heparin may cause Heparin-Induced Thrombocytopenia, nausea, vomiting, abdominal cramps, and thrombocytopenia.
• Warfarin can cause bleeding, lethargy, muscle pain, skin necrosis, and "purple toes" syndrome.

Heparin-Induced Thrombocytopenia (HIT)

• Type I HIT: gradual reduction in platelets, heparin therapy can generally be continued.
• Type II HIT: acute fall in platelet number (more than 50% reduction from baseline); discontinue heparin therapy.

Heparin-Induced Thrombocytopenia (HIT): Clinical Manifestations

• Thrombosis can be fatal in HIT.
• Thrombin inhibitors bivalirudin and argatroban, are possible treatments.
• The incidence of HIT varies; higher with bovine heparins.

Treatment: Toxic Effects of Heparin

• Treatment for toxic effects of heparin involve reversing the underlying cause.
• Symptoms include hematuria, melena (blood in the stool), petechiae, ecchymoses, and gum or mucous membrane bleeding.
• Stop drug administration immediately.
• Administer intravenous protamine sulphate; 1 mg can reverse the effects of 100 units of heparin (1 mg of protamine for each milligram of low-molecular-weight heparin given).

Treatment: Toxic Effects of Warfarin

• Discontinue warfarin use.
• Resynthesis may take 36 to 42 hours before the liver resynthesizes enough clotting factors to reverse effects.
• Administer Vitamin K₁ (phytonadione) to hasten the return to normal coagulation.
• High doses (10 mg) of vitamin K can be given intravenously to reverse anticoagulation within 6 hours.
• Caution: Warfarin resistance can occur for up to 7 days when vitamin K is given.
• A severe bleeding instance can be treated with human plasma or clotting factor concentrates.
• Intravenous vitamin K has a risk of anaphylaxis, so dilute it and give it over 30 minutes.
• The use of injectable form of Vitmain K is common.

Drug Interactions: Anticoagulants

• Interactions are profound and complicated;
• Enzyme inhibition of metabolism, displacement of the drug from inactive protein-binding sites
• Reduced vitamin K absorption or bacterial synthesis and alteration in platelet count or activity.

Heparin Sodium

• Heparin sodium is a natural anticoagulant from lungs or intestinal mucosa of pigs.
• Administer 10 to 10000 units/mL.
• DVT prophylaxis: 5000 units subcutaneously two or three times a day, does not need monitoring when for prophylaxis.
• When used therapeutically (for treatment), continuous IV infusion
• It is weight-based according to protocol.
• Measure activated Partial Thromboplastin Time (aPTT) every 6 hours until therapeutic effects are seen.

Heparin Flushes

• Heparin Leo is a small vial of aqueous heparin IV flush solution.
• Due to the risk of HIT, institutions now use 0.9% normal saline as a flush for heparin-lock IV ports.
• Heparin flushes, at 100 units/mL, remain in use for central catheters.

Warfarin Sodium (Coumadin)

• Warfarin is a commonly prescribed oral anticoagulant.
• It requires proper monitoring of the prothrombin time (PT)/international normalized ratio (INR).
• A normal INR, without warfarin, is 0.8 to 1.2.
• A therapeutic INR with warfarin: ranges from 2 to 3.5, depending on drug use (atrial fibrillation, thromboprevention, prosthetic heart valve).
• Warfarin:
  • Dietary considerations
  • Variations in certain genes (CYP2CP and VKORC1)
  • Age considerations
  • Maintenance dose determined by the INR
  • Natural health product cautions

Antiplatelet Drugs

• Examples of antiplatelet drugs:
  • Aspirin
  • Clopidogrel bisulfate (Plavix)
  • Prasugrel (Effient)
  • Treprostinil (Remodulin)
  • Abciximab (ReoPro)
  • Eptifibatide (Integrilin)
  • Tirofiban (Aggrastat)
  • Anagrelide hydrochloride (Agrylin)
  • Dipyridamole (Aggrenox, Persantine).

Antiplatelet Drugs: Mechanism of Action

• Prevent platelet adhesion.
• Indications: Antithrombotic effects.
• Adverse effects can be serious due to risk for bleeding, vary based on drug

Aspirin

• Aspirin is available in many prescription and nonprescription drug combinations.
• The use of aspirin in children and adolescents experiencing flu-like symptoms is uniquely contraindicated.
• This is due to it being associated with Reye's syndrome.
• Reye's syndrome is a rare, acute, and potentially fatal condition.
• Reye's syndrome involves the liver and central nervous system (CNS).

Clopidogrel Bisulphate

• Clopidrogel bisulphate (Plavix) is a most widely used medication.

Thrombolytic Drugs

• Thrombolytic drugs break down (lyse) preformed clots in the coronary arteries.
• Older drugs:
  • Streptokinase and urokinase
• Current drugs:
  • Alteplase (Activase)
  • Tenecteplase (TNKase)

Thrombolytic Drugs: Mechanism of Action

• Activate the fibrinolytic system to quickly break down clots in the blood vessel.
• Activate plasminogen which converts to plasmin to lyse thrombus, proteolytically.
• Mimics the body's own process of clot destruction.

Thrombolytic Drugs: Indications

• Acute myocardial infarction.
• Arterial thrombolysis.
• DVT.
• Shunt or catheter occlusion.
• Pulmonary embolism.
• Acute ischemic stroke.

Thrombolytic Drugs: Adverse Effects

• Internal intracranial and superficial.
• Nausea, vomiting, hypotension, hypersensitivity, anaphylactoid reactions.
• Cardiac dysrhythmias can be dangerous.

Antifibrinolytic drugs

• Prevent the lysis of fibrin, promoting clot formation.
• Used for the prevention and treatment of excessive bleeding when related to hyperfibrinolysis or surgical complications.
• Treatment of hemophilia A or type I von Willebrand's disease with desmopressin
• Aprotinin (Artiss, Trasylol), tranexamic acid (Cyklokapron), and desmopressin acetate (DDAVP).
• Adverse effects are uncommon, mild, and include rare reports of thrombotic events.
• Dysrhythmia, orthostatic hypotension, bradycardia, dizziness, abdominal cramps, and diarrhea.

Nursing Implications

• Assess patient history (medication and allergies), contraindications, vitals, lab values, drug interactions and bleeding conditions.
• Intravenous heparin doses are usually double-checked with another nurse.
• Ensure that subcutaneous doses are given subcutaneously and not intramuscularly.
• Subcutaneous doses should be given in areas of deep subcutaneous fat.
• Rotate administration sites.
• Avoid administering subcutaneous doses within 5 cm of the umbilicus, abdominal incisions, open wounds, scars, drainage tubes, stomas, or areas of bruising or oozing.
• Do not aspirate subcutaneous injections or massage the injection site.

Heparin

• IV doses may be given as bolus or IV infusions.
• Anticoagulant effects are immediate.
• Laboratory values (aPTT) are checked daily to monitor coagulation effects.
• Protamine sulphate is an antidote for excessive coagulation.

Low Molecular Weight Heparins

• Administer subcutaneously in the abdomen and rotate injection sites.
• Protamine sulphate is used as an antidote in case of excessive anticoagulation.

Warfarin

• The treatment may be started while still on heparin until PT/INR levels indicate adequate anticoagulation.
• It takes several days until the therapeutic effect.
• Lab values like PT/INR are monitored regularly.
• Vitamin K is the antidote.

Herbal Considerations For Warfarin Users

• Several herbal products have potential interactions, which may increase instances of bleeding.
• Capsicum pepper, garlic, ginger, ginkgo, St. John's wort, and feverfew.

Patient Education

• Importance of regular laboratory testing.
• Know the Signs of abnormal bleeding.
• Measures to prevent bruising, bleeding, and tissue injury.
• Wear a medical alert bracelet.
• Avoid foods high in vitamin K (tomatoes, dark leafy green vegetables).
• Consulting the physician before taking other drugs or over-the-counter products.

Antiplatelet Medications

• Concerns and teaching tips as like anticoagulants.
• Consider adverse reactions and monitor for abnormal bleeding.

Monitoring Thrombolytic Medications

• Follow strict manufacturer's guidelines for preparation and administration.
• Monitor the IV site and for bleeding, redness or pain.
• Monitor for bleeding from gums, mucous membranes, nose, and injection sites.
• Decreased blood pressure, restlessness, increased pulse rates can be signs of internal bleeding.