Anticoagulant Drugs, Thrombolytic Drugs, and Drugs for Bleeding Disorders PDF

Anticoagulant Drugs, Thrombolytic Drugs, and Drugs for Bleeding Disorders Christine McCulley, PharmD [email protected] Wayne Parker, PharmD Learning Objectives 1. Explain the molecular mechanism of action of each drug in each drug class. 2. Describe the anticoagulant and fibrinolytic actions of...

Anticoagulant Drugs, Thrombolytic Drugs, and Drugs for Bleeding Disorders Christine McCulley, PharmD [email protected] Wayne Parker, PharmD Learning Objectives 1. Explain the molecular mechanism of action of each drug in each drug class. 2. Describe the anticoagulant and fibrinolytic actions of these drugs. 3. Describe the routes of administration and elimination processes of the drugs of each class. 4. Describe the main adverse effects of the drugs of each class. 5. Describe the laboratory tests used to detect overdose toxicity of anticoagulants. 6. Describe the clinically important drug interactions of the drugs of each class with special reference to the oral anticoagulant drug interactions. 7. Describe the main contraindications of the drugs of each class.. 8. Describe the use of anticoagulants and fibrinolytic drugs in unstable angina, myocardial infarction, vascular thromboembolism and stroke. 9. Describe the use of coagulation factors and antifibrinolytic drugs in bleeding disorders. Drugs for coagulation disorders Antiplatelet drugs - Aspirin, clopidogrel, ticagrelor, prasugrel, cangrelor, eptifibatide, tirofiban, dipyridamole, cilostazol, vorapaxar Anticoagulants Parenteral Oral Fibrinolytic drugs - Heparin, low molecular weight heparin (enoxaparin, dalteparin), fondaparinux, argatroban, bivalirudin - Warfarin, rivaroxaban, apixaban, edoxaban, dabigatran - Alteplase, tenecteplase, reteplase Drugs for bleeding disorders Coagulation factors; Drugs that - Factor concentrates, Vitamin K, Desmopressin increase synthesis/release of coagulation factors Inhibitors of fibrinolysis - Tranexamic acid, Aminocaproic acid Medication Overview Plasminogen Activators Inhibition of Clotting Factor Synthesis Inhibition of Clotting Factors Direct Thrombin Inhibitors Inhibitors of Fibrinolysis Heparin Xa selective below this line Streptokinase Urokinase Alteplase Reteplase Tenecteplase Fibrinolytic Warfarin (COUMADIN) (PO) Enoxaparin Dalteparin Fondaparinux Rivaroxaban Apixaban Edoxaban Betrixaban Bivalirudin Argatroban Aminocaproic acid Tranexamic acid Dabigatran (PO) PO “DOACs” in red Anticoagulant Stop bleeding Normal Clotting Process 1. Endothelial injury and formation of the platelet plug. 2. Propagation of the clotting process by the coagulation cascade. sequential activation of a series of proenzymes or inactive precursor proteins (zymogens) to active enzymes, resulting in significant stepwise response amplification 3. Termination of clotting by antithrombotic control mechanisms. 4. Removal of the clot by fibrinolysis. The site of clot formation (artery or vein) and the rate of blood flow also have important effects on clot composition. Coagulation cascade Prothrombin = Factor II Thrombin = Factor IIa TF = tissue factor Extrinsic (tissue factor activated) and intrinsic (activated by factors in blood) converge to a common pathwayà factor Xa Coagulation cascade, simplified Tissue factor exposed at a wound interacts with factor VIIa and initiates clotting by two pathways: (1) – Activation of factor X to factor Xa (the extrinsic ten-ase complex). (2) – Conversion of factor IX to factor IXa, which activates factor X to factor Xa (the intrinsic tenase complex). (3) – Thrombin also activates factor XI to factor XIa, which can lead to further generation of factor IXa; it serves as an amplification pathway required during severe hemostatic challenges. Pathological Thrombi Review Arterial thrombi Composed primarily of platelets, although they also contain fibrin and occasional leukocytes. Generally, occur in areas of rapid blood flow (i.e., arteries) and are typically initiated by spontaneous or mechanical rupture of atherosclerotic plaques followed by aggregation of platelets (dyslipidemias, atherosclerosis, and coronary heart disease, and acute coronary syndrome). Venous thrombi Found primarily in the venous circulation and are composed almost entirely of fibrin and erythrocytes. Have a small platelet head and generally form in response to either venous stasis or vascular injury after surgery or trauma. The areas of stasis prevent dilution of activated coagulation factors by normal blood flow. Big Picture – Selection of Agent The selection of an antithrombotic agent is influenced by the type of thrombus to be treated: The anticoagulants heparin, low-molecular-weight heparins (LMWHs), factor Xa inhibitors, direct thrombin inhibitors and warfarin are used in the treatment and prevention of both arterial and venous thrombi. (PE and DVT treatment and prevention, MI treatment, ischemic stroke prevention in NVAF, anticoag for mechanical heart valves) Drugs that alter platelet function (e.g., aspirin, clopidogrel), alone and/or in combination with anticoagulants, are used in the prevention of arterial thrombi. (ischemic stroke prevention, MI prevention). Also a component of MI treatment Also can be used for VTE prevention (venous thrombi) post-ortho surgery as an alternative to anticoagulant in certain patients Fibrinolytic (aka thrombolytic) agents are used for rapid dissolution of thromboemboli, during MI, acute ischemic stroke, PE, DVT (rarely) – clot busters. Used for short term, emergency management of clots to “break them up” Big Picture Therapeutic anticoagulation with a parenteral anticoagulant is often short term and transitioned to longer term anticoagulation with an oral agent. Some conditions have indications for anticoagulant and/or antiplatelet therapy E.g., ACS treatment (both), VTE prophylaxis post-total hip or knee replacement (either/or, depends) Must use evidence-based guidelines, patient factors, medication factors, and an analysis of the risk of thrombosis vs bleeding risk to guide choices In general, bleeding risk is greatest with fibrinolytics > anticoagulants > antiplatelets Organizing anticoagulants by route of adminstration Parenteral anticoagulants UFH = unfractionated heparin LMWH = low molecular weight heparin: enoxaparin and dalteparin Fondaparinux (used for HIT treatment or for VTE treatment/prophylaxis in patients with history of HIT) Argatroban (used for HIT treatment or for ACS in patients with hx of HIT) Bivalrudin (used for ACS in patients with hx of HIT) Oral anticoagulants Warfarin DOACs Dabigatran (direct thrombin inhibitor) Apixaban (Factor Xa inhibitor, commonly used) Rivaroxaban (Factor Xa inhibitor, commonly used) Edoxaban (Factor Xa inhibitor; not used as often) Heparin, aka UFH Heparin- heterogeneous mixture of large, sulfated, negatively charged mucopolysaccharides with a mean of 45 saccharide units, mean molecular weight of 15,000 daltons Endogenously produced by mast cells Heparin, as used for medication, is isolated from porcine or bovine intestine UFH = unfractionated heparin MOA: a high affinity pentasaccharide sequence on heparin binds with antithrombin III (ATIII), the complex enhances ATIII activity Resulting in inhibition of thrombin, factor Xa, IXa, XIa, XIIa and thus decreased clotting, and also reduced platelet aggregation by reducing thrombin’s actions on platelets Mechanism of Action Heparin – accelerates antithrombin neutralization of BOTH thrombin and factor Xa LMWHs (enoxaparin, dalteparin) are more selective inhibitors of factor Xa (thrombin inhibition requires the larger heparin molecule). Note: LMWHs do not inactivate thrombin, only factor Xa Semisynthetic, derived from heparin, 1/3 the molecular weight Fondaparinux: synthetic pentasaccharide Fondaparinux with high specificity to factor Xa (rate increased 300 fold) – more specific than LMWH Pharmacological Effects of Heparin The anticoagulant effect of a fixed dose of heparin is variable (due to individual differences in plasma concentration of neutralizing plasma proteins). High doses of heparin tend to decrease platelet aggregation. Unclear to what extent this effect contributes to heparin-induced bleeding Heparin has a direct anticoagulant activity (can inhibit clotting in vitro, as in heparinized tubes for laboratory blood collection) Heparin “resistance” may occur, requiring higher dose levels of heparin to produce a therapeutic effect. Heparin resistance can be due to: 1) High concentrations of heparin binding proteins in plasma, (heparin resistance is often encountered in acutely ill patients or in patients with malignancy). 2) Antithrombin III deficiency, a rare, hereditary, autosomal dominant disorder. Remember: heparin and LMWHs need antithrombin to form the complex first before inactivating the clotting factors (heparin can’t work without antithrombin III) Therapeutic Uses of Heparin Treatment of PE and DVT = VTE treatment Prevention of PE and DVT = VTE prophylaxis Acute Coronary Syndrome- Treatment of acute MI Prevents clotting in extracorporeal circulation devices (ECMO) FYI- There are also “heparin flushes” for IV catheter and “A-line heparin” for arterial line patency (LOWER concentrations, NOT appropriate to be used therapeutically for a clot) Many concentrations of vials, bags, syringes, etc. are available. Need to be aware due to the potential for dosing errors. Heparin LMWH (e.g., enoxaparin) Fondaparinux -NOT orally bioavailable -LOW Vd ~4L (does not leave vasculature, does not cross the placenta) -Rapidly metabolized by reticuloendothelial system, zero order saturable enzymatic inactivation -either continuous IV infusion for treatment or SC BID/TID for prophylaxis -t1/2 = 60-90 minutes (up to 150 minutes at higher doses) GREATER PREDICTABILITY OF AC AND PK -once daily or BID dosing -decreased binding to macrophages or endothelial cells leads to longer t1/2 (4 hours) GREATER PREDICTABILITY OF AC AND PK -once daily dosing -weight based dosing Adverse Effects Bleeding, Thrombocytopenia, HIT Osteoporosis with long term use Bleeding, Thrombocytopenia, HIT (to a lesser extent than heparin) Bleeding, Does NOT cause HIT Route of administration IV (continuous), SC SC, IV (Most commonly SC; IV is for STEMI if bolus indicated) SC Monitoring activated partial thromboplastin time (aPTT) or antiFactor Xa activity *Monitoring is REQUIRED for IV infusion (hospital protocols, etc) *baseline level needed Hgb/Hct, platelet count No routine monitoring of level -may consider anti-Xa level in certain patients/scenarios (extreme weights, pregnancy, renal impairment, etc) No routine monitoring Protamine sulfate IV Protamine sulfate IV Pharmcokinetics A - absorption D - distribution M - metabolism E - excretion Reversal -Renal elimination- dose adjust for renal impairment, inc risk of bleeding in renally impaired. -Renal eliminationdose adjust for renal impairment, inc risk of bleeding in renally impaired. Contraindicated in CrCl 2g/day Potentiation, INR increase CYP enzyme induction Carbamazepine, phenobarbital, phenytoin, rifampin, azathioprine, St. John’s Wort, long term alcohol consumption Inhibition, INR reduction Pharmacodynamic NSAIDs, aspirin, 2nd/3rd gen cephalosporins, gingko, other anticoagulants, fibrinolytics Potentiation (little INR effect) Absorption Cholestyramine, sucralfate Inhibition, INR reduction Foods (or supplements) containing vitamin K- leafy greens, spinach, kale, broccoli, brussel sprouts, beef liver, etc. Increased vitamin K intake could reduce warfarin anticoag effect Reduced vitamin K intake potentiates warfarin anticoag effect Consistent vitamin K intake is recommended (OK to eat these foods but do not suddenly change intake) Warfarin has variable effects based on patient factors Acute decompensated heart failure with hepatic congestion Hepatic dysfunction End stage renal disease Elderly Hypermetabolic state, such as acute illness or hyperthyroidism Also, thyroid hormones inc catabolism of clotting factors, antithyroid drugs decrease catabolism of clotting factors Poor nutrition status Genetic polymorphisms of CYP2C9 and VKORC1 Adverse effects of warfarin Bleeding (It can occur at any site and is related to dosage, length of therapy, patient’s underlying disorder and concomitant use of other drugs.) Skin and tissue necrosis (rare, but it can be very serious. It is associated with local thrombosis and seems related to warfarin-induced inhibition of the anticoagulant protein C) Cholesterol microembolization (rare, but it can be very serious. It is due to enhanced release from atherosclerotic plaques. It can cause many syndromes related to vascular occlusion including infarction in various organs, gangrene, and Purple Toe syndrome) Fetal toxicity: it includes abortion, fetal bleeding and a characteristic pattern of malformations called fetal warfarin syndrome (the drug is classified pregnancy risk category X by FDA = CONTRAINDICATED). Must test for pregnancy before initiating warfarin in females. Therapeutic Uses of Warfarin Note: Warfarin costs less than DOACs, so this may play a role in selection VTE treatment VTE prophylaxis (as a secondary prevention, not primary) Stroke prophylaxis in atrial fibrillation Reduce risk of thromboembolism in patients with mechanical heart valves DOACs are not currently recommended in patients with mechanical heart valves or mod-severe mitral stenosis Reversal – there are guidelines and protocols depending on INR and bleeding Vitamin K: oral or IV diluted and infused slowly over at least 20 min 4 Factor PCC (Kcentra, Balfaxar) or alternatively, fresh frozen plasma, for major bleeding or reversal for emergent procedures (in combination with IV vitamin K) DOACs Direct Oral Anticoagulants You may also hear “Novel” Oral Anticoagulants (NOACs) Argatroban Oral Factor Xa Inhibitors Apixaban (Eliquis) Rivaroxaban (Xarelto) Edoxaban (Savaysa) Betrixaban Oral Direct Thrombin Inhibitor Dabigatran Boxed Warnings for all: (1) Premature discontinuation of any oral anticoagulant increases the risk of thrombotic events. (2) Epidural or spinal hematomas have occurred in patients treated with (insert DOAC name) who are receiving neuraxial anesthesia or undergoing spinal puncture. Not recommended for patients with mechanical heart valves or moderate to severe mitral stenosis. Not recommended for pregnant or breastfeeding patients. Advantages (compared to warfarin) Fixed dosing Dosing is still complicated because it differs by indication – difficult to memorize, utilize drug references Fewer drug interactions, though still several clinically significant interactions More predictable pharmacokinetic properties Fewer dietary interactions Less frequent monitoring DOACs Warfarin Dosing Fixed Variable Routine Lab Monitoring No Yes Drug interactions Few Many Food interactions Few Yes Reversal agent Yes, except edoxaban Yes Cost Expensive Cheap Bridging No Yes Therapeutic uses of DOACs Prevention of thromboembolism in non-valvular atrial fibrillation (NVAF) à Anticoagulant CHA2DS2-VASc score to risk stratify and determine need for anticoag AND evaluate for bleeding risks DOACs preferred over warfarin (if no mechanical heart valve or severe rheumatic mitral stenosis) 2023 – aspirin, either alone, or in combination with clopidogrel, is not recommended as an alternative to anticoagulant for NVAF in the guidelines (still see in practice?) VTE treatment VTE prophylaxis See chart on next slide FDA Indications by DOAC Indication Dabigatran Rivaroxaban Apixaban Edoxaban NVAF Yes Yes Yes Yes VTE treatment Yes* Yes Yes Yes* VTE recurrent risk reduction Yes Yes Yes No VTE prophylaxis after knee or hip surgery Yes, hip only Yes Yes No VTE prophylaxis in adults hospitalized for acute medical illness No Yes No No Peripheral Artery Disease No Yes No No *Dabigatran and edoxaban REQUIRE parenteral anticoagulation for 5-10 days PRIOR TO initiation for VTE treatment. This is not the same as concomitant bridging of warfarin with a parenteral anticoagulant. Dabigatran (Pradaxa): oral direct thrombin inhibitor Prodrug lacking anticoagulant activity that is converted in vivo to the active dabigatran, a specific, reversible, direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin Parenteral anticoagulant required prior to initiation for VTE treatment P-gp (P-glycoprotein efflux pump transporter) substrate, 80% renally eliminated Not metabolized by CYP450 enzymes Drug interaction with P-gp inhibitors, such as dronedarone and ketoconazole Adverse effects: Dyspepsia is common, bleeding Reversal agent: idarucizumab (Praxbind) IV Apixaban (Eliquis): Oral Factor Xa Inhibitor Renal, weight, age dose adjustment in NVAF indication only. Do not adjust the dose for VTE treatment. If 2 out of 3 conditions met, adjust dose Age >= 80, weight = 1.5 Metabolized by CYP3A4, P-gp substrate, 27% cleared by kidney - less renal clearance than other DOACs Strong dual CYP3A4 and P-gp inhibitors or inducers interact the most (systemic ketoconazole, itraconazole, posaconazole, or ritonavir) Reversal agent: andexanet alfa (Andexxa) Rivaroxaban (Xarelto): Oral Factor Xa Inhibitor Take doses of 15 mg or greater with food for better oral bioavailability Renal dose adjustment for NVAF Can adjust for CrCl 15-50 ml/min, less than 15 ml/min not recommended Not recommended in CrCl < 30 ml/min for VTE treatment Metabolized by CYP3A4, P-gp substrate, 36% cleared by kidney Strong dual CYP3A4 and P-gp inhibitors or inducers interact the most (systemic ketoconazole, itraconazole, posaconazole, or ritonavir) Reversal agent: andexanet alfa (Andexxa) Edoxaban (Savaysa): Oral Factor Xa Inhibitor Parenteral anticoagulant required prior to intiation for VTE treatment Contraindicated in CrCl > 95 ml/min for NVAF due to inferior data compared to warfarin in this subgroup Renal dose adjustment 50% cleared by kidney, P-gp substrate No approved reversal agent Specific Reversal Agents for Bleeding Heparin Protamine sulfate (1 mg protamine neutralizes 100 units heparin; max dose 50 mg) - Due to the short t1/2 of IV heparin, consider amount of heparin administered in last 2.5 hours. - For subcut, consider amount in 12 hours prior. Low Molecular Protamine sulfate (1 mg protamine for every 1 mg enoxaparin; max dose 50 mg) Weight Heparin Fondaparinux No specific agent, but rVIIa (NovoSeven RT) or activated PCC (FEIBA) may be used for ICH Argatroban None, but very short half life (stop infusion) Bivalrudin None, but very short half life (stop infusion) Warfarin Vitamin K (plus 4F-PCC (Kcentra, Balfaxar) for life threatening bleeding) Apixaban andexanet alfa (Andexxa) Rivaroxaban andexanet alfa (Andexxa) Edoxaban No approved reversal, but data suggests andexanet alfa will reverse edoxaban Dabigatran Idarucizumab (Praxbind) Thrombolytic Cryoprecipitate, but if not available, tranexamic acid or aminocaproic acid Fibrinolytics/Thrombolytics Overview of the Fibrinolytic System Tissue plasminogen activator(tPA) is released from endothelial cells ↓ In the blood tPA is inhibited by circulating inhibitors and exerts little effect on circulating plasminogen ↓ Plasminogen that is bound to fibrin is activated by tPA and is converted to plasmin ↓ Plasmin catalyzes the proteolytic digestion of fibrin remodeling the thrombus and limiting the extension of thrombosis. Fibrinolytic Drugs “The Clot Busters” Drugs and chemistry Streptokinase is a protein secreted by several species of streptococci that can bind and indirectly activate human plasminogen. Not available in US. Non fibrin specific, immunogenic. Urokinase also called urokinase-type plasminogen activator (uPA), is a serine protease that activates plasminogen. Not available in US. Non fibrin specific. Alteplase is a recombinant human tissue plasminogen activator (rtPA) with good fibrin specificity. ++ Reteplase is a third generation nonglycosylated deletion mutant of alteplase with a longer half life and less fibrin specific binding than alteplase. + Tenecteplase is a third generation genetically modified form of alteplase with alterations in the protein structure at 3 sites, which prolongs the half life and allows greater binding affinity for fibrin. +++ Mechanism of action Act by converting plasminogen into active plasmin. Massive activation of plasminogen causes a “systemic lytic state” in which hemostasis is impaired. Dissolve the fibrin clot. Tissue plasminogen activators (alteplase, reteplase and tenecteplase) preferentially activate plasminogen bound to fibrin. Not totally “fibrin specific”, and fibrin specificity is lost at higher doses. At clinical doses, however, less fibrinogen degradation took place than with nonspecific activators. tPA clearly opened coronary arteries more rapidly than nonspecific activators and this is likely why its use improved mortality rates. Fibrinolytics Streptokinase (no longer marketed in US; used in Europe) Acts on both bound and free plasminogen (not clot specific) depleting circulating plasminogen and factors V and VIII Would you expect to have more bleeding with streptokinase? Is antigenic (derived from B-hemolytic streptococci) May cause a problem if recent past use (body will see as antigen and attack) or past infection à streptococci antibodies may decrease activity Alteplase (rtPA), reteplase, tenecteplase Clot specific, acting mainly on fibrin-bound plasminogen No allergy problems (recombinant form of human tPA) Alteplase may be used to clear occluded venous catheter, but the product and dose is different for this indication- “Cathflo activase” is NOT appropriate for systemic clot treatment 44 Clinical Features of Fibrinolytics The main factor in effectiveness is TIME. Alteplase and tenecteplase are the most commonly used agents currently Therapeutic Uses: Acute Ischemic Stroke Initiate within 4.5 hours of symptom onset or last known well- TIME DEPENDENT, if patient meets eligibility criteria STEMI (as an alternative to primary PCI) Acute high risk, massive PE (i.e., presence of hypotension/hemodynamic instability) Risk/benefit analysis due to the risk of serious bleeding. Complications include bleeding (clot busters), possible intracerebral hemorrhage. Cryoprecipitate, aminocaproic acid, and tranexamic acid are possible antidotes in excessive bleeding For catheter occlusion, low dose alteplase used – dwells in catheter and is aspirated back out, NOT infused into patient. 45 Adverse effects Pharmacokinetics Oral bioavailability: 0 (always administered IV) Bleeding (most common in cerebral vessels) due to: Lysis of fibrin at sites of vascular injury The systemic lytic state. The systemic formation of plasmin destroys coagulation factors (mainly fibrinogen, but also V and VIII) Hypersensitivity reactions (mainly fever,1-4%) Contraindications and precautions Any active internal bleeding or hemorrhagic disorder. Recent severe trauma or major surgery (within past two weeks). Cerebrovascular accident within the past two months. Any active intracranial process (tumors, aneurysms, etc.). Active malignancy. Suspected aortic dissection. Severe hypertension ( >180/110 mm Hg). Pregnancy Therapeutic Uses Acute myocardial infarction (> 60% decrease in mortality if given within 3 hrs.) Pulmonary thromboembolism. Ischemic stroke Antiplasmin drugs Drugs Aminocaproic acid is a lysine analog that binds to plasminogen and plasmin, blocking both the conversion of plasminogen to plasmin and the binding of plasmin to target fibrin. The drug is thereby a potent inhibitor of fibrinolysis and can reverse states associated with excessive fibrinolysis. Tranexamic acid (TXA) is a more potent analog of aminocaproic acid NEJM, 1998; 339: 245-251 Adverse effects Intravascular thrombosis Myopathy with rhabdomyolysis (rare). Contraindicated in active clot Therapeutic uses Given perioperatively to prevent intraoperative blood loss and transfusion. TXA can be IV or topical at site of bleeding. Mucosal bleeding, heavy menstrual bleeding, epistaxis Bleeding due to fibrinolytic therapy Adjunct to prevent bleeding in patients with hemophilia Drugs for Bleeding Disorders Note: Drugs that reverse bleeding generally have a risk of thrombotic events. Fresh Frozen Plasma Use: trauma, massive transfusion, severe liver disease, disseminated intravascular coagulation (DIC), bleeding due to a factor deficiency when a specific clotting factor is not available, bleeding due to a vitamin K antagonist or other anticoagulant when a prothrombin complex concentrate is not available Derived from whole blood and frozen, contains all of the coagulation factors and proteins present in the original unit of blood Generally not recommended for bleeding due to warfarin or other anticoagulants, unless prothrombin complex concentrate (PCC) or specific antidote is not available Cryoprecipitate and Fibrinogen Concentrate Uses: congenital fibrinogen deficiency, trauma and massive transfusion, DIC, liver disease, kidney disease, postpartum hemorrhage, some cardiac surgeries NOT used in: bleeding due to thrombocytopenia, anticoagulants, or platelet dysfunction Cryoprecipitate: composed of the insoluble coagulation factors that precipitate out after FFP is thawed, centrifuged, and pooled. Provides fibrinogen, factor VIII, XIII, VWF, fibronectin Risk of transfusion complications For disorders of specific clotting factors (i.e., von Willebrand disease & hemophilia A or B), those clotting factor concentrates are preferred. Cryoprecipitate would only be used when those are unavailable. Fibrinogen concentrate: prepared from pooled human plasma, undergoes purification and lyophilization to inactivate microorganisms Contains only fibrinogen Preferred over cryoprecipitate for congenital fibrinogen deficiency (more specific) More expensive than cryoprecipitate Four-factor prothrombin complex concentrate (PCC) Brand names: Kcentra, Balfaxar Provides vitamin K-dependent coagulation factors (II, VII, IX, and X) as well as protein C and protein S Used for: life threatening hemorrhage associated with vitamin K antagonist (warfarin, labeled indication) or direct factor Xa inhibitor or direct thrombin inhibitor (off label) For example, if specific antidote for the DOAC is unavailable at the institution or it does not exist When given for warfarin, administer PCC + vitamin K IV These products contain heparin and are contraindicated in patients with a history of HIT von Willebrand disease Von Willebrand Factor concentrate, IV Plasma derived or recombinant May also be given Factor VIII in combination with VWF Desmopressin (DDAVP) – short term for minor bleeding/before invasive procedures in type 1 von Willebrand disease Causes release of endogenous VWF from storage sites in endothelial cells, but tolerance develops after a few days Increases plasma levels of von Willebrand factor, and factor VIII Tranexamic acid or epsilon aminocaproic acid, IV or topical; prevent fibrinolysis of clot, especially useful for bleeding in uterus, nose, or oropharynx. Alternative only if no VWF concentrate: cryoprecipitate Hemophilia A Hemophilia B Deficiency in factor IX (factor 9) Prophylaxis Deficiency in factor VIII (factor 8) Prophylaxis Emicizumab (Hemlibra) subcutaneous injection (t1/2 = 4-5 weeks) Monoclonal antibody that binds factor IXa and X, substituting for the role of factor VIII in hemostasis Cost barrier Intravenous Factor VIII replacement therapy Plasma-derived, recombinant, or recombinant with extended half life Treatment of bleeding Factor replacement Desmopressin (DDAVP)- short term for minor bleeding/before invasive procedures in patients who have previously demonstrated a response Increases plasma levels of von Willebrand factor, and factor VIII Intravenous Factor IX replacement therapy Plasma-derived, recombinant, or recombinant with extended half life Treatment of bleeding Factor replacement Prothrombin complex concentrates (PCC) – contain factor IX among others, not first line Future/investigational: gene therapy ($$$$) NovoSeven RT Recombinant, activated factor VIIa (factor 7a) Replaces deficient activated coagulation factor VII, which complexes with tissue factor and may activate coagulation factor X to Xa and factor IX to IXa. Used for: bleeding in hemophilia patients with inhibitors Patients with hemophilia can develop an “inhibitor” = an antibody directed against infused factor. With inhibitors, can no longer use standard factor replacement to treat bleeding or to provide prophylaxis against bleeding. Vitamin K (phytonadione) Uses: Reversal agent (“antidote”) for warfarin, a“vitamin K antagonist” Newborn – single dose IM as part of routine newborn order set, prophylaxis to prevent vitamin K deficient bleeding Vitamin K deficiency without liver disease; off label: coagulopathy of liver disease Vitamin K for warfarin reversal Oral route has more predictable absorption, full reversal observed in 24-48 hours Preferred over IV for patients without severe bleeding IV route for serious bleeding (*in combo with PCC) or needs emergent procedure requiring reversal, full reversal observed in 12-24 hours (PCC works in ~30 min) NOT IV push! MUST be diluted in 50 mL bag and infused slowly over ~ 20 minutes Boxed Warning: IV or IM can cause fatal hypersensitivity reaction including anaphylaxis SC or IM not recommended due to variable absorption (also potential for hematoma with IM) Clinical pearl: when warfarin is resumed after treatment with vitamin K, it takes longer than usual for INR to return to therapeutic level ALERT: US Boxed Warning Hypersensitivity reactions with IV and IM use. INR Bleeding Management Supratherapeutic, but < 4.5 None Lower or omit VKA dose(s) Consider/resume at adjusted dose when INR therapeutic 4.5-10 None Omit next 1-2 doses Resume at adjusted dose when INR therapeutic 4.5-10 At risk of bleeding Omit doses of VKA Consider vitamin K 1-2.5 mg PO > 10 None Any Minor bleeding Hold VKA Vitamin K PO 2.5 – 5 mg Resume at adjusted dose when INR therapeutic Any No bleeding, rapid reversal required Hold VKA Vitamin K 5-10 mg / 50 mL 0.9% sodium chloride IV via slow infusion Any Major or lifethreatenin g Hold VKA Vitamin K 10 mg / 50 mL 0.9% sodium chloride IV via slow infusion 4F-PCC IV