8 - Hematologic Therapies

Editors: Susla, Gregory M.; Suffredini, Anthony F.; McAreavey, Dorothea; Solomon, Michael A.; Hoffman, William D.; Nyquist, Paul; Ognibene, Frederick P.; Shelhamer, James H.; Masur, Henry

Title: Handbook of Critical Care Drug Therapy, 3rd Edition

Copyright 2006 Lippincott Williams & Wilkins

> Table of Contents > Chapter 8 - Hematologic Therapies

Chapter 8

Hematologic Therapies

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TABLE 8.1. Blood Component Therapies

Preparation	Indications	Dosage	Comments
Whole blooda,b,c,d	Acute massive blood loss Increases O2 carrying capacity Increases intravascular volume	Volume of 1 unit is approximately 500 ml (450 ml blood plus anticoagulant) with hematocrit of 38%	RBCs and plasma After storage, few if any platelets and no factors V or VIII No major advantage over component therapy
Packed red blooda,b,c,d,e	Acute massive blood loss Increases O2 carrying capacity Increases intravascular volume	Volume of 1 unit is approximately 250 ml with hematocrit of 65% to 70%	1 unit increases hematocrit by approximately 3% Leukocyte-poor blood prevents fever by lowering exposure to HLA and other antigens In emergency (risk of exsanguination) group O negative blood can be given. After 2 4 units of O negative blood, subsequent transfusions during the acute episode should continue with O negative to prevent hemolysis
Plateletsa,b,c	Bleeding due to thrombocytopenia or abnormal platelet function Post-op bleeding, platelets <100,000/mm3 Bleeding patient, platelets <50,000/mm3 Prophylaxis, platelets <20,000/mm3f	Volume of 1 unit is approximately 50 ml Usual transfusion 6 8 units Final volume approximately 300 ml	ABO compatibility desirable but not necessary 1 unit raises platelet count approximately 5,000 7,000/cu mm Potential complications: fever, sepsis, DIC, uremia, allo- or autoantibodies If alloimmunization present (poor 1 h posttransfusion count), HLA match can improve platelet survival; IVIG may also be useful May need anti-D IgG if Rh negative and given Rh positive platelets
Granulocytesa,b,c,d	<500 granulocytes/mm3 Fever, progressive infection despite antibiotics, hypoplastic marrow Qualitative function abnormalities (e.g., chronic granulomatous disease)	Volume of usual unit 300 500 ml with 0.5 2 1010 cells	Hematocrit approximately 10% to 20% Fever, chills, dyspnea, leukoagglutination reactions common Questionable efficacy in neutropenia/sepsis and most other clinical situations
DIC, disseminated intravascular coagulation; HLA, human leukocyte antigen; IVIG, IV immunoglobulin; RBC, red blood cells aPotential for infectious disease transmission. bPotential for alloimmunization. cPotential for transfusion reaction.
dRecipient's Blood Group		Transfused Blood Compatibility
O		O
A		A or O
B		B or O
AB		AB, A, B, or O
eTyping (ABO and Rh compatible) alone results in 99.8% chance of compatible transfusion, requires 5 10 minutes screen (testing recipients serum against common antigens associated with transfusion reactions) results in 99.94% chance of a compatible transfusion; requires 45 minutes to 1 hour major cross match (tests recipients serum against donor's RBCs) results in 99.95% chance of compatibility; >1 hour to perform. fProphylaxis in an afebrile patient, not on antibiotics, with no invasive procedures planned, who is not bleeding or has stable platelet counts >10,000/cu mm; may elect to transfuse at a higher platelet count in patients who are febrile, on antibiotics, or have rapidly falling counts.

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TABLE 8.2. Clotting Component Preparations

Preparation	Indications	Dosage	Comments
Fresh frozen plasmaa	Replace multiple factor deficiency in bleeding patient (e.g., severe liver disease, DIC, reversal of warfarin, dilutional coagulopathy after massive transfusions) After transfusion of 10 units PRBCs in patient with excessive bleeding Bleeding in any patient with elevated PT or aPTT, prolonged thrombin time, or fibrinogen <100 mg/dl Antithrombin III deficiency requiring heparin therapy C1-esterase deficiency with life-threatening laryngeal edema	Volume of 1 unit is approximately 250 ml	Usual replacement 1 2 units 1 unit has near normal amounts of all coagulation factors and approximately 400 mg fibrinogen Adequate hemostasis achieved with factor levels of approximately 30% normal 2 units increase levels of factors by approximately 20% ABO compatibility desirable but not necessaryb 1 ml FFP contains 1 unit of each coagulation factor
Cryoprecipitatea	Hypofibrinogenemia (<100 mg/dl) Hemophilia A Von Willebrand disease Factor XIII deficiency Uremic bleeding DIC	6 10 units in 250 ml q8 10h	Each 10 40 ml bag contains 250 mg fibrinogen, approximately 100 units factor VIII procoagulant and von Willebrand factor, and 75 units factor XIII Does not contain factors II, VII, IX, or X
Recombinant activated coagulation factor VII (rFVlla)	Bypass inhibitors to FVIII and factor IX in hemophilia A and B, congenital factor VII deficiency Off-label use: Surgical or traumatic bleeding with acquired FVII deficiency Warfarin-associated bleeding Coagulopathy of severe liver dysfunction Management of acute intracerebral hemorrhage	90 g/kg IV bolus, may be repeated 90 120 g/kg IV bolus, may be repeated q2h alternatively 15 30 g/kg IV q12h (warfarin) 2 120 g/kg IV (hepatic coagulopathy)	Binds tissue factor and activated platelets at site of injury, promotes conversion of prothrombin to thrombin Generally does not cause systemic thrombosis Reports of venous thrombosis, myocardial infarction, cerebral sinus thrombosis in patients treated with rFVlla but cause and effect unclear
Recombinant human factor VIII	Hemophilia A	Major surgery or life threatening hemorrhage; antihemophilic factor 100% (50 IU/kg) repeat q6 12h until healing complete or threat resolvedc	Several preparations available, some with human albumin (theoretical infectious risk)
Factor VIII (plasma derived)	Hemophilia A	Major trauma, surgery or life-threatening hemorrhage, required peak pre- and postsurgery level 80% to 100% (40 50 IU/kg), administer q6 24h until healing completec Refractory bleeding due to inhibitor (<50 Bethesda units/mL) 100 150 porcine units/kg IV	If bleeding not controlled with adequate dose, test for inhibitor, if titers elevated consider antihemophilic factor (porcine)
Factor IX complexa (prothrombin complex concentrate)	Hemophilia B Factor IX deficiency Warfarin overdose Factor X deficiency Hemophilia A (factor VIII inhibitors) Factor VIII deficiency (Proplex T only) Factor II deficiency	Major trauma or surgery, levels of factor IX needed 25% to 50%, initial load <75 U/kg, repeat q18 30h prn measured factor IX levelsd For warfarin overdose, give 15 U/kg	Contains factors II, VII, IX, and X Thromboembolic problems are common with administration; 5 10 units heparin added to each ml of reconstituted complex Patients with liver disease or antithrombin III deficiency should not receive complex Fresh frozen plasma is usually preferred because of clotting problems with factor IX complex; primarily used to control bleeding from warfarin overdose or factor II, VII, IX, or X deficiencies
Purified factor IX concentrate	Hemophilia B Factor IX deficiency	Units required = body weight 1 unit/kg desired factor IX increase (in % of normal)	20-fold purer than prothrombin complex Essentially no factors II or VII; <10 units factor X per 100 units factor IX For serious hemorrhage, factor IX should be increased to 30% to 50%; for surgery, factor IX should be maintained at 30% to 50% for 1 wk postoperatively
Recombinant factor IX	Hemophilia B	Major surgery, trauma or life-threatening hemorrhage, circulating factor IX activity required 50% to 100% (see empiric dosing in comments) duration of therapy 7 10 d	Empirical dosing's body weight (kg) desired % increase in plasma factor IX 1.2 IU/kg
Antithrombin III concentratea	Congenital antithrombin III deficiency (level <75% of normal)	Dosage units = [desired - baseline level AT-III(%)] wt (kg)	Dosage must be individualized 1 IU/kg raises level of AT-III by 1% to 2% Levels should be measured before and 30 min after dose After 1st dose, level should be >120% of normal and then maintained at >80% of normal with q24h dosing If administering heparin, lower dose after administering concentrate to prevent excessive bleeding
Fibrin glue (fibrinogen concentrate)	Use with topical thrombin as sealant for vascular grafts, plastic surgery, neurosurgery, bronchopleural fistula	1 unit	Recipient may make antibody to bovine thrombin, leading to false prolongation of coagulation values; glue should not be injected blindly because arterial clots may occur
aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; PRBC, packed red blood cells; PT, prothrombin time aPotential for infectious disease transmission.
bRecipient Blood Group		Transfused Plasma Compatibility
O		O, A, B, AB
A		A, AB
B		B, AB
AB		AB
cDose (IU factor VIII) for rFVIII or plasma-derived FVIII = body weight (kg) 0.5 IU/kg desired factor VIII increase (%). dTo raise blood level % (factor IX complex): (a) determine plasma volume = wt (kg) 70 ml/kg (adult) [1-Hct (in decimals)]; (b) determine number of units needed = desired - actual level plasma volume (mL).

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TABLE 8.3. Hematologic Growth Factors

Agent/Indications	Dosage	Comments
Epoetin Alfa (Erythropoietin Human Glycoform )
To correct anemia of chronic renal failure	Initial: 50 100 U/kg IV or SC 3 /wk Maintenance: 25 units/kg IV or SC 3 /wk	Switch to maintenance when hematocrit >30% Ensure adequate iron stores Maintenance dose can range from 12.5 525 units/kg 3 /wk, adjusted by increments of 10 25 units/kg Most frequent adverse effects in chronic renal failure (e.g., hypertension, seizures) are related to the rate and extent of increase in erythrocyte count and hematocrit
Cancer chemotherapy (nonmyeloid malignancies)	150 units/kg IV/SC 3 wk 8 wk Maintenance 300 units/kg 3 wk	Use if baseline serum erythropoietin level is less than 200 mU/mL
HIV disease	Initial: 100 units/kg IV or SC 3 /wk 8 wk then increase dose by 50 100 units/kg every 4 8 wk until adequate response	Indication: serum erythropoietin <500 mU/ml Increase dose after 8 wk
Darbepoetin
Anemia associated with chronic renal failure, cancer	0.45 g/kg IV or SC q w, can be adjusted at 4-w intervals by 25% Decrease dose by 25% if hemoglobin approaches 12 g/dL or increases by greater than 1 g/dL in 2-wk period	Half-life 2 3 times longer than epoetin alfa Clinical equivalent to epoetin alfa Preferred for outpatient therapy rather than inpatient therapy; long half-life offers no advantage for inpatient therapy May increase blood pressure in chronic renal failure Rapid increase in hemoglobin (>1 g/dL in a week) increases risk of vascular access thrombosis, stroke, myocardial infarction
Filgastrim (Granulocyte-Colony Stimulating Factor, G-CSF)
To decrease risk of infectious complications of febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive therapy	5 10 g/kg SC qd 2 wk	Dosage regimens may vary with investigational protocols May be given until absolute neutrophil count reaches 10,000/cu mm Side effects: fever, bone pain, headache, rash
To accelerate myeloid recovery after chemotherapy and autologous bone marrow transplantation	5 10 g/kg IV over 30 min or 1 20 g/kg SC qd 2 4 wk	Administration continued until absolute neutrophil counts greater than 1000/cu mm 3 d, then dose reduced
HIV-associated or drug-induced neutropenia	60 g/kg IV over 30 min or 1 20 g/kg SC qd 2 4 wk
Pegfilgastrim
Prevention of febrile neutropenia in patients with nonmyeloid malignancies	6 mg SC injection	Pegylated granulocyte colony stimulating factor which delays renal clearance Preferred for outpatient therapy rather than inpatient therapy; long half-life offers no advantage for inpatient therapy Side effects similar to filgastrim Increase risk of chemotherapy-related myelosuppression if given 14 d before and 1 d after each chemotherapy cycle Do not use if weight <45 kg
Sargramostim (Granulocyte/Macrophage-Colony Stimulating Factor, GM-CSF)
Myeloid reconstitution after autologous bone marrow transplantation	250 mg/M2 IV over 2 h qd 21 d	Side effects include capillary leak syndrome, flulike syndrome
Failure or engraftment delay in autologous bone marrow transplantation	250 mg/M2 IV over 2 h qd 14 d	Repeat in 7 d if engraftment has still not occurred; a third course of 500 mg/M2/d for 14 d may be tried after another 7 d off therapy
IV, intravenous; SC, subcutaneous

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TABLE 8.4. Transfusion Reactions Therapy

Complication	Etiology	Management
Urticaria, pruritus	Antibodies to donor plasma protein (mild)	Interrupt transfusion; give diphenhydramine 25 100 mg PO or IV; if problem resolves, resume transfusion
Febrile nonhemolytic reactions (fever, chills, urticaria, agitation, headache, dyspnea, and/or palpitations)	Antibodies to donor plasma proteins, leukocytes or platelets, rarely bacterial contamination	Stop transfusion Check for clerical errors Return blood to blood bank with fresh blood and urine samples to check for hemoglobin, bilirubin, and haptoglobin Antipyretics Leukocyte-poor blood as alternative
Acute hemolytic reaction (agitation, confusion, chest pain, chills, fever, tachycardia, flank pain, shock, hematuria, and/or hemorrhage)	Antibodies to red cell antigens	Stop transfusion and return blood to blood bank with fresh blood and urine samples to check for hemoglobin, bilirubin, and haptoglobin Antipyretics Leukocyte-poor blood as alternative Supportive care Maintain urine output with furosemide, mannitol; alkalinize urine
Anaphylaxis (anxiety, chest pain, wheezing, shock)	Antibodies to donor plasma protein (severe), especially congenital IgA deficiency (total IgA or IgA subclass deficiency)	Stop the transfusion Epinephrine 0.3 ml (1:1,000) SC or, if reaction is severe (e.g., shock), 0.5 1.0 ml (1:10,000) IV push Support circulation Oxygen Bronchodilators See Table 11.2
Ig, Immunoglobin; IV, intravenous; PO, by mouth; SC, subcutaneous

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TABLE 8.5. Immune Globulin Preparations

Preparation	Indications	Dosage	Comments
Cytomegalovirusa (CMV) immune globulin	For attenuation of primary CMV disease associated with kidney transplantation (i.e., CMV seronegative transplant recipient who receives kidney from CMV seropositive donor)	150 mg/kg IV within 72 hrs of transplant, then 100 mg/kg at 2, 4, 6, 8 wk after transplant, then 50 mg/kg at 12 and 16 wk after transplant	IgG preparation (5% to 6% solution) with standardized amount of antibody to CMV from pooled adult human plasma Infusion rate: 15 mg/kg/h for 15 min; if no adverse reactions, then 30 mg/kg/h for 15 min; then increase to maximum infusion rate of 60 mg/kg/h (volume not to exceed 75 ml/h)
	Prophylaxis of CMV disease (seropositive donor to seronegative recipient) in liver, heart, lung, or pancreas transplantation	150 mg/kg IV within 72 hrs of transplant, then 150 mg/kg at 2, 4, 6, 8 wk after transplant, then 100 mg/kg at 12 and 16 wk after transplant	CMV prophylaxis in organ transplants (other than kidney) use with ganciclovir If patient develops nausea, back pain, or flushing during infusion slow rate or temporarily stop infusion
	Severe CMV pneumonia	400 mg/kg IV with ganciclovir on days 1, 2, 7 or 8 followed by 200 mg/kg CMV-IVIG on days 14 and 21	Discontinue if blood pressure falls or anaphylaxis Can precipitate and worsen renal insufficiency Aseptic meningitis may occur within 2 48 h of therapy
Hepatitis B immune globulina	Passive immunity for individuals exposed to hepatitis B virus or HBsAg-positive material Postexposure prophylaxis following percutaneous bites, direct mucous membrane contact, ingestion, or intimate contact	0.06 ml/kg or 3 5 ml IM	Administer within 24 h but not later than 7 d after exposure Derived from plasma from individuals with high HBsAb titers (10% to 18% protein) Should be combined with active immunization with hepatitis B vaccine at separate site if not previously vaccinated May be repeated 1 mo later in known vaccine nonresponders
Immune serum globulinsa (ISG)	IM immune globulins are used to provide passive immunity for susceptible individuals exposed to infectious diseases when no vaccine is available or there is insufficient time for active immunization.		16% solution of immune globulins May cause local pain and tenderness at the injection site for several days
	Hepatitis A	0.02 ml/kg IM	As soon as possible and within 2 wk of exposure
	Non-A, non-B hepatitis	0.06 ml/kg IM	As soon as possible
	Measles (rubeola)	0.25 ml/kg IM (maximum 15 ml) for normal host; 0.5 ml/kg IM for immunosuppressed host	Measles virus vaccine live within 72 h of exposure is preferred Use IgIM when vaccine contraindicated (<1 y of age, pregnancy, immunocompromised) Not given concurrently with live measles virus vaccine
	Rubella (1st trimester exposure)	0.55 ml/kg IM	Efficacy in preventing disease is poor
	Varicella zoster	0.06 0.12 ml/kg IM	Alternative to Varicella-zoster Ig
IV immuno-globulina (IVIG)	Congenital agammaglobulinemia or hypogammaglobulinemia Idiopathic thrombocytopenic purpura	100 200 mg/kg monthly Refer to manufacturers' instructions	5% to 6% solution Contraindicated in patients with selective IgA deficiencies; however, some preparations are low in IgA and can be used
	Kawasaki syndrome	400 mg/kg/d 4 d or 2 g/kg 1 dose	Most adverse reactions are related to the infusion rate (i.e., anaphylaxis and hypotension)
	Patients refractory to platelet transfusions who are bleeding or need surgery	400 mg/kg/d 4 d or 2 g/kg 1 dose	Specific infusion rates according to manufacturers' instructions
Rh immune globulina	Block immune response in obstetrics to small amounts of Rh incompatible blood exposure during delivery, ectopic pregnancy, or abortion When Rh positive blood components are given to Rh negative recipients of childbearing age	50 300 mg IM	50 mg dose is protective for abortion, miscarriage, ectopic pregnancy, vaginal hemorrhage, or abdominal trauma during first 12 wk of pregnancy 300 mg dose is given to Rh negative mothers after exposure to 15 ml fetal blood caused by delivery, abortion, or ectopic pregnancy, or after amniocentesis
Rh0-D immune globulin IVa	To prevent Rh isoimmunization in Rh-negative women exposed to Rh-positive fetal red blood cells at 28 weeks gestation, at term, and after invasive intrauterine procedures such as amniocentesis	300 g IV at 28 weeks and 102 g IV at delivery	Preparation is IgA-depleted and unlikely to cause anaphylactic reaction in women with IgA deficiency and anti-IgA antibodies Vial should not be shaken because it can damage protein and cause aggregate formation that increases risk of adverse reaction
	Treatment of ITP in Rh positive patient who has not had a splenectomy	25 50 g/kg IV initial dose, then maintenance therapy with 25 60 g/kg IV	For ITP, hemolysis is the dose-limiting toxicity Hgb decrease >2 g/dl in 5% to 10% In ITP, fever can be treated with acetaminophen, diphenhydramine, or prednisone If Hgb <10, reduced dose (25 40 g/kg) should be given Frequency and dose of maintenance therapy determined by clinical response, including platelet counts, red cell counts, Hgb, and reticulocyte levels
Tetanus immune globulin (TIG)a	Prophylaxis	250 units IM (standard) 500 units IM (severe exposure or delayed administration)	Used in conjunction with active immunization with tetanus toxoid (separate site) in individuals with less than 3 doses of tetanus toxoid or if immunization status unknown TIG does not interfere with immune response to tetanus toxoid
	Treatment of tetanus	3,000 6,000 units IM	Used in treatment of tetanus in conjunction with antibiotics, sedation, and supportive care
Varicella-zoster immune globulin (VZIG)a	Prophylaxis after exposure of immunodeficient patient to varicella zoster (See comments)	125 units/10 kg body weight IM, max dose 625 U (5 vials), min dose 125 U	Purified human immune globulin (5%) High risk patients: immunocompromised state, pregnant women, neonates, premature infants Antiviral treatment (acyclovir) can be considered for adolescents and adults if illness occurs Investigational new drug available under expanded access protocol (FFF Enterprises, Temecula, CA, 24h telephone [phone]). Requires informed consent and possibly local IRB approval
Rabies immune globulin (RIG)a	Pre-exposure immunization	RIG not recommended for pre-exposure immunization	Pre-exposure immunization with human diploid cell rabies vaccine (HDCRV, 1 ml/dose IM on d 0, 7, 21, and 28 or 0.1 ml/dose intradermally on d 0, 7, 21, and 28) does not eliminate the need for postexposure prophylaxis
	Postexposure immunization	20 IU/kg IM previous immunization 1 ml/dose IM on d 0 and 3	Should always include both immunization with RIG and vaccination (HDCRV, 1 ml/dose IM on d 0, 3, 7, 14, and 28) Patients with adequate rabies antibody titer should receive only the vaccine RIG may be given up to the 8th day after the 1st dose of vaccine is given
HDCRV, human diploid cell rabies vaccine; Hgb, hemoglobin; Ig, immunoglobulin; ITP, idiopathic thrombocytopenia purpura; IV, intravenous; ISG, immune serum globulin aPotential for infectious disease transmission.

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TABLE 8.6. Venous Thrombosis Prophylaxis

Drug	Indication	Dosage	Comments
Dextran sulfate	High-risk surgery patients at risk for thromboembolism	Dextran 40 (10% solution) 500 ml IV q3d during prolonged bedrest	More costly than other antithrombotic agents Inhibits platelet function and fibrin polymerization Contraindicated in established venous thromboembolism and in patients with heart failure or dextran hypersensitivity No more effective than warfarin or heparin in general surgery patients
Heparin sodium	Venous thrombosis (general) Venous thrombosis (perioperatively for most abdominal, thoracic, or urologic procedures)	Fixed low dose 5,000 U SC q8 12h Fixed low dose 5,000 U SC 2 h prior to surgery, then 5,000 U SC q8 12h 5 7 d, or Continuous infusion    1 U/kg/h at surgery, then for 3 5 d after surgery
	Maintaining patency of indwelling venous catheters	1 ml (10 100 U/ml) after each use of catheter or q4 8h	Withdraw at least 1 ml from catheter prior to flush
Dalteparin sodium	For prevention of postoperative deep vein thrombosis in patients undergoing abdominal surgery who are at moderate to high riska,b,c of thromboembolic complications	Moderate high riska,b: 2,500 units daily deep SC (not IM) 1 2 h prior to surgery, then qd for 5 10 d High-very high riskb,c: initial dose 5,000 units SC prior to surgery or 2,500 units 1 2 h prior to surgery, followed 12 h later by 2,500 units SC After initial dose, 5,000 units SC qd 5 10 d	Low molecular weight heparin, porcine derived, each mg = 156.25 anti-Factor Xa International Units Dosage adjustment and routine monitoring of coagulation parameters are not necessary At recommended doses does not affect platelet aggregation fibrinolysis, prothrombin time, thrombin time, activated partial thromboplastin time Pharmacology differs from heparin or other low molecular weight heparins and is not interchangeable on a unit-for-unit basis Dosage adjustments in renal and hepatic disease have not been established; use with caution Use with care in patients receiving oral anticoagulants and/or platelet-aggregation inhibitors
Enoxaparin sodium	For prevention of postoperative deep-vein thrombosis in patients undergoing hip replacement surgery	30 mg deep SC bid, initial dose given as soon as possible after surgery but not more than 24 h postoperatively Given for 7 10 d	Low molecular weight heparin; porcine-derived Daily monitoring of the therapeutic effect is not necessary during therapy if laboratory indices of coagulation are normal prior to hip surgery At recommended doses, does not affect platelet aggregation or global-clotting tests (PT, aPTT) Pharmacology differs from heparin or other low molecular weight heparins and is not interchangeable on a unit-by-unit basis Adjust dose in renal disease Dosage adjustment in hepatic disease has not been established Use with care in patients receiving oral anticoagulants and/or platelet-aggregation inhibitors
Fondaparinux	Prevention of deep venous thrombosis after hip fracture surgery or hip replacement	2.5 mg daily SC, usually started 4 8 h postoperatively and treated for 5 9 d	Synthetic heparin analog that increases factor Xa inhibition without neutralizing thrombin Does not bind platelet factor IV, does not cause immune-mediated thrombocytopenia No effect on PT, aPTT time, bleeding time, or platelet function Renal clearance Not recommended if creatinine clearance <30 mL/min, platelets below 100,000/ L, or weight <50 mg Bleeding most common adverse effect especially if given less than 6 h after surgery
Warfarin
Therapy and prophylaxis	Venous thrombosis and pulmonary embolism	10 15 mg PO qd 2 5 d, then 2 10 mg PO qd Coagulation end point for therapy: 1.3 1.5 control PT (INR 2 3)d	Indirect anticoagulant; alters synthesis of vitamin K dependent coagulation factors II, VII, IX, and X; use for follow-up anticoagulation after heparin Requires 2 7 d of therapy to deplete coagulation factors and to initiate anticoagulant effect; should overlap with heparin therapy by 4 5 d Multiple drug interactions (see Table 13.2) Cautions: (a) hemorrhage: if minor, hold and reduce dose; if moderate or severe, reverse with phytonadione, fresh frozen plasma, factor IX complex and/or rFVIIa (Table 8.2); (b) necrosis of skin or other tissues (especially in females and in protein C deficiency): treat with phytonadione and heparin
	Rheumatic mitral valve disease if history of systemic embolism, or paroxysmal or chronic atrial fibrillation, or sinus rhythm with left atrium diameter >5.5 cm if recurrent systemic embolism despite adequate warfarin	INR target 2.5 (range 2.0 3.0) INR target 2.5 (range 2.0 3.0) and aspirin PO 80 100 mg/d or INR 2.5 3.5 and dipyridamole PO 400 mg/d or clopidogrel
	Mitral valvuloplasty	Warfarin for 3 wks prior to procedure and 4 wks after the procedure. INR target 2.5 (range 2.0 3.0)
	Mitral valve prolapse with documented but unexplained TIA with systemic embolism, chronic or paroxysmal atrial fibrillation, or recurrent TIAs despite aspirin therapy	Aspirin 50 162 mg/d INR target 2.5 (range 2.0 3.0)
	Mitral annular calcification with non-calcific embolism and associated atrial fibrillation	INR target 2.5 (range 2.0 3.0)
	Aortic valve disease		Low incidence of systemic embolism unless concomitant mitral valve disease, atrial fibrillation, or history of systemic emboli
	Aortic valve disease with mobile aortic atheromas and aortic plaques >4mm by TEE	Consider warfarin therapy
	Prosthetic heart valves/mechanical heart valves	All patients with mechanical heart valves should receive warfarin Unfractionated heparin or LMWH should be used until the INR is stable and therapeutic for 2 consecutive days
	St. Jude Medical bileaflet valve (aortic position)	INR target 2.5 (range 2.0 3.0)
	Tilting disk valves and bileaflet mechanical valves (mitral position)	INR target 3.0 (range 2.5 3.5)
	CarboMedics bileaflet valve or Medtronic Hall tilting disk mechanical valves (aortic position, normal left atrium size, sinus rhythm)	INR target 2.5 (range 2.0 3.0)
	Mechanical valve and additional risk factors (atrial fibrillation, myocardial infarction, left atrial enlargement, endocardial damage, low ejection fraction)	INR target 3.0 (range 2.5 3.5) with low dose aspirin, 75 100 mg/d
	Caged ball or caged disk valves	INR target 3.0 (range 2.5 3.5) with low dose aspirin, 75 100 mg/d
	Mechanical valves with systemic thromboembolism despite therapeutic INR	INR target 3.0 (range 2.5 3.5) with low dose aspirin, 75 100 mg/d
	Mechanical valves in whom warfarin must be discontinued	LMWH or aspirin 80 100 mg/d
	Bioprosthetic valve replacement	Heparin or LMWH until INR stable for 2 consecutive days
	First 3 months after valve insertion
	mitral position	Warfarin INR target 2.5 (2.0 3.0 range)
	aortic position	Warfarin INR 2.5 target (2.0 3.0 range) or aspirin 80 100 mg/d
	bioprosthetic valves with a history of systemic embolism	Warfarin for 3 to 12 months
	bioprosthetic valve with evidence of left atrial thrombus at surgery	INR target 2.5 (range 2.0 3.0)
	Bioprosthetic valve with atrial fibrillation; long-term treatment	INR target 2.5 (range 2.0 3.0)
	Bioprosthetic valves with sinus rhythm; long-term treatment	Aspirin 75 100 mg/d
	PFO and atrial septal aneurysm with unexplained systemic embolism or TIAs and venous thrombosis, or pulmonary embolism	INR target 2.5 (2.0 3.0 range) until venous interruption or closure of PFO
	Antithrombotic therapy in atrial fibrillation		Risk factors for thrombosis are: previous TIA or stroke, hypertension, heart failure, diabetes, clinical coronary artery disease, mitral stenosis, prosthetic heart valves, or thyrotoxicosis
	if age < 60 y with no risk factorsd	Aspirin 325 mg/d
	if age < 60 y with heart disease and no risk factors	Aspirin 325 mg/d
	if age > 60 y with no risk factors	Aspirin 325 mg/d
	if age > 60 y with diabetes or coronary disease	INR 2.0 3.0 with optional addition of aspirin 81 162 mg/d
	if heart failure ejection fraction <.35, thyrotoxicosis, hypertension	INR 2.0 3.0
	if age > 75 y, especially women, with or without risk factors	INR 2.0 3.0
	with cardioversion if atrial fibrillation more than 2 d in duration	INR 2.0 3.0 for 3 w before elective cardioversion and then continued for 4 weeks
	Infective endocarditis		Continue anticoagulant therapy because of high frequency of systemic thromboembolism but increase risk of intracranial hemorrhage
	in patients with mechanical prosthetic valves
	Nonbacterial thrombotic endocarditis	Heparin therapy (see above)
	with systemic or pulmonary emboli
	Disseminated cancer with aseptic vegetations	Full dose unfractionated heparin
aPTT, activated partial thromboplastin time; INR, International Normalized Ratio; ISI, International Sensitivity Index; IV, intravenous; IM, intramuscular; PFO, patent foramen ovale; PO, by mouth; PT, prothrombin time; SC, subcutaneous; TIA, transient ischemic attacks; TEE, transesophageal echo Recommendations based in part on 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:3(Suppl):457S 482S. aPatients at risk for thromboembolic complications who are undergoing abdominal surgery are 40 years of age, obese, or in whom surgical procedure requires general anesthesia greater than 30 minutes in duration. bAdditional risk factors include malignancy, history of deep-venous thrombosis, or pulmonary embolism. cOther risk factors: prolonged immobility or paralysis, varicose veins, heart failure, myocardial infarction, fractures of the pelvis, hip, or leg, possibly high-dose estrogen therapy, and hypercoagulable states. dThe International Normalized Ratio (INR) is used to monitor warfarin therapy. The INR is intended to standardize prothrombin time (PT) reporting by minimizing the variability that can result from differences in the sensitivity of the thromboplastin reagent used to perform the PT test. The sensitivity of the thromboplastin reagent is measured by the ISI, which is referenced to a World Health Organization (WHO) reference standard. The INR is calculated as follows: (patient PT/mean normal control)ISI. The INR adjusts for differences in sensitivity of the thromboplastin reagent and reflects the result that would be obtained with the WHO reference thromboplastin.

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TABLE 8.7. Anticoagulant Therapy

Drug	Indication	Dosage	Comments
Heparin sodium	Acute pulmonary embolism Proximal deep venous thrombosis Acute myocardial infarction Acute arterial occlusion Cerebral embolism or transient ischemic attack Embolism associated with mitral valve disease and/or atrial fibrillation	80 U/kg IV load and then 18 U/kg/h maintenance infusion	Measure aPTT at 6 h, then adjust per weight-based dosing (see table below) (aPTT 1.5 2.5 control) Follow hematocrit, platelet count, and fecal occult blood See also Table 4.11, re: anticoagulation and thrombolytic therapy Start warfarin therapy on day 1 if long-term anticoagulation anticipated, then stop heparin after 4 7 d of joint therapy and INR 2 3 without heparin (see below) With acute MI, begin with or after rtPA therapy and administer with aspirin (325 mg PO qd) Nondose-related thrombocytopenia occurs with bovine lung heparin (15%) and porcine intestinal heparin (5%); when thrombocytopenia develops with one preparation, it may be useful to switch to the other; discontinue heparin if platelet count <100,000/cu mm; heparin is rarely associated with thrombosis (usually arterial) and irreversible in vivo platelet aggregation (white clot syndrome)
	Continuous arteriovenous or venovenous hemofiltration	Bolus 15 25 U/kg IV, then 5 15 U/kg/h, follow aPTT (35 45 sec) or maintain ACT 150 200 s	Dose individualized for patients who are critically ill or who have preexisting coagulopathy
Enoxaparin	Deep venous thrombosis Treatment-inpatient with and without pulmonary embolism -outpatient treatment in patients without pulmonary embolism	1 mg/kg/dose SC q12h or 1.5 mg sid	Start warfarin within 72 h and continue enoxaparin until INR is between 2.0 3.0 (usually 7 d) Renal impairment Clcr <30 ml/min 1mg/kg SC qd Not approved for dialysis patients
	Unstable angina Percutaneous coronary interventions Acute coronary syndrome	1 mg/kg SC q12h in conjunction with aspirin 100 325 mg PO sid
Dalteparin	Acute treatment of unstable angina or non-Qwave MI	120 IU/kg SC q12h for 5 8 d with concurrent aspirin therapy	Dosage adjustment and routine monitoring of anticoagulation not necessary
Argatroban	Heparin-induced thrombocytopenia	Initial dose (normal hepatic function) 2 g/kg/min IV adjusted to keep aPTT 1.5 3 times normal If hepatic dysfunction present, start 0.5 g/kg bolus and increase infusion to 30 g/kg/min	Direct-thrombin inhibitor Steady state anticoagulated effect after 1 3 h, monitored by aPTT Decrease dose with hepatic dysfunction aPTT returns to normal within 2 h of discontinuation 10% to 15% incidence of hematuria, allergic reactions dyspnea/cough, or rash No adjustment for renal failure Conversion to warfarin, no load, start at expected daily dose
	Percutaneous intervention	Start 25 g/kg/min and administer bolus of 350 g/kg over 3 5 min with goal of ACT >300 s If ACT <300 s, give 150 g/kg bolus and increase infusion to 30 g/kg/min If ACT >450 sec, decrease infusion to 15 g/kg/min
Lepirudin	Heparin-induced thrombocytopenia	Initial dose (if normal renal function) 0.4 mg/kg IV bolus (15 20 s) followed by continuous infusion at 0.15 mg/kg/h	Direct thrombin inhibitor Monitor aPTT 4 h after infusion starts (range 1.5 2.5 ratio) If aPTT is below target, increase infusion by 20%, if aPTT is too high, decrease infusion by 50% Repeat aPTT after any dosing change
	Concomitant use with thrombolytic therapy	Initial dose 0.2 mg/kg IV bolus (15 20 s) followed by continuous infusion at 0.1 mg/kg/h	All patients with Clcr <60 or serum Cr >1.5 mg/dL require dosage reduction Dosing with renal failure:-Clcr 45 60 mL/min, Scr 1.6 2.0 mg/dL; 50% std infusion rate or 0.075 mg/kg/h-Clcr 30 44, Scr 2.1 3.0; 30% std infusion rate or 0.045 mg/kg/h-Clcr 15 29, Scr 3.1 6.3; 15% std infusion rate or 0.0225 mg/kg/h-Clcr <15, Scr >6.0 avoid or stop infusion Over dosage with life threatening bleeding, blood transfusion and hemofiltration or dialysis with high flux dialysis membrane, e.g., AN 69, may be useful
Tinzaparin	Treatment of acute symptomatic deep venous thrombosis with or without pulmonary embolism in conjunction with warfarin	175 anti-Xa IU/kg SC qd, duration of therapy at least 6 d while warfarin therapy initiated	Low molecular weight heparin derived from porcine heparin Decreased clearance with severe renal failure, use with caution
Bivalirudin	IV anticoagulation, alternative to heparin in patients with unstable angina or undergoing percutaneous coronary intervention	1 mg/kg bolus IV then 2.5 mg/kg/h IV for 4 h, then 0.2 mg/kg/h for 14 20 h Alternative 0.75 mg bolus IV, then 1.75 mg/kg/h for duration of procedure, then D/C	Hirudin derivative, direct thrombin inhibitor Use in conjunction with aspirin Not associated with immune thrombocytopenia
Body Weight-Based Dosing of IV Heparin
Initial Dose: 80 U/kg load then 18 U/kg/h maintenance with aPTT at 6 h
aPTT	Dose Change U/kg/h	Additional Action	Next aPTT
<35 s (1.2 control)	+4	Rebolus with 80 U/kg	After 6 h
35 45 s (1.2 1.5 control)	+2	Rebolus with 40 U/kg	After 6 h
46 70 s (1.5 2.5 control)	0	0	Within first 24 h, check every 6 h, then daily
71 90 s (2.3 3.0 control)	-2	0	After 6 h
>90 s (>3 control)	-3	Stop infusion 1 h	After 6 h
ACT, activated clotting time; aPTT, activated partial thromboplastin time; INR, International Normalized Ratio; IV, intravenous; MI, myocardial infarction; PO, by mouth; SC, subcutaneous

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TABLE 8.8. Preoperative and Postoperative Anticoagulation

Indication for Patients Who Are Taking Oral Anticoagulants	Before Surgery	After Surgery
Acute venous thromboembolism
Month 1	IV heparina	IV heparina
Months 2 and 3	No changeb	IV heparin
Recurrent venous thromboembolismc	No changeb	SC heparin
Acute arterial embolism
Month 1	IV heparin	IV heparind
Mechanical heart valve	No changeb	SC heparin
Nonvalvular atrial fibrillation	No changeb	SC heparin
aA vena caval filter should be considered if acute venous thromboembolism has occurred within 2 weeks or if the risk of bleeding during intravenous heparin therapy is high. bIf patients are hospitalized, subcutaneous heparin may be administered, but hospitalization is not recommended solely for this purpose. cThe term refers to patients whose last episode of venous thromboembolism occurred more than 3 months before evaluation but who require long-term anticoagulation because of a high risk of recurrence. dIntravenous heparin should be used after surgery only if the risk of bleeding is low.

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TABLE 8.9. Reversal of Anticoagulants

Agent	Indications	Dosage	Comments
Heparin Reversal
Protamine	Heparin overdose or heparin-associated hemorrhage	Dose required decreases with elapsed time after heparin discontinued 0 29 min: 1 1.5 mg protamine/100 U heparin 30 60 min: 0.5 0.75 mg/100 U heparin >120 min: 0.25 0.375 mg/100 U heparin Infuse protamine slowly IV, rate not to exceed 50 mg in 10 min (50 mg protamine in 5 ml sterile water = 10 mg/ml)	If heparin was given SC, some clinicians load with protamine 25 50 mg IV and then infuse calculated dose over 8 16 h Monitor effect with ACT or aPTT Can cause hypotension, bradycardia, dyspnea, allergic reactions Relatively contraindicated in diabetics who have received NPH insulin because of risk of hypersensitivity
	Reversal of extracorporeal heparinization	1.5 mg protamine/100 U of heparin
Fresh frozen plasma			See Table 8.2
Hemostasis
Aminocaproic acid	Treatment of life-threatening hemorrhage from systemic hyperfibrinolysis and urinary fibrinolysis (e.g., cardiac surgery, portacaval shunt, abruptio placenta, liver transplantation, prostatectomy)	4 5 g IV infusion over 1 h, then 1 g/h for 8 h or until hemorrhage controlled PO dose same as IV dose	Can be used with heparin to treat selected cases of DIC Do not exceed 30 g/d Adverse effects: muscle necrosis with prolonged administration, cardiac myocyte injury, intrarenal or ureteral thrombosis Reduce dose in renal, cardiac, or hepatic disease
Conjugated estrogens	Hemorrhage associated with uremia	0.6 mg/kg/d 5 d	Infuse over 30 min Effects last 7 14 d
Desmopressin (DDAVP)	Hemorrhage associated with uremia Hemophilia A von Willebrand disease Cardiac surgery	0.3 g/kg qd	Infuse over 30 min Effects last 8 12 h Side effects: facial flushing, conjunctival erythema, headache, blood pressure reduction, tachycardia
Recombinant activated coagulation factor VII (rFVlla)	Warfarin-associated bleeding	15 30 g/kg IV q12h (warfarin)	Binds tissue factor and activated platelets at site of injury, promotes conversion of prothrombin to thrombin Generally does not cause systemic thrombosis Reports of venous thrombosis, myocardial infarction, cerebral sinus thrombosis in patients treated with rFVlla but cause and effect unclear
Topical thrombin	Hemostasis (when oozing from capillaries and small venules is visible and accessible)	General: 100 U/ml applied topically Profuse bleeding: 1,000 2,000 U/ml applied topically	Final concentration is a function of indication for use
Tranexamic acid	To reduce or prevent hemorrhage in patients with hemophilia; reduce need for replacement therapy after dental extraction	Immediately before surgery, 10 mg/kg IV then 25 mg/kg PO 3 4 /d for 2 8 d	Competitive inhibitor of plasminogen activation and at higher concentration noncompetitive inhibitor Contraindicated in patients with acquired defective color vision and subarachnoid hemorrhage; if patients are going to be treated for more than several days, a full ophthalmologic examination is required Dose adjusted for moderate to severe renal failure
ACT, activated clotting time; aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; IV, intravenous; NPH, neutral protamine Hagedorn; PO, by mouth; SC, subcutaneous

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TABLE 8.10. Antiplatelet Drugs

Drug	Indication	Dosage	Comments
Aspirin	Prevention of strokes and transient ischemic attacks; prevention and treatment of MI Adjunct with thienopyridine in PCI	81 325 mg PO qd	Inhibits platelet conversion of arachidonic acid to thromboxane for 5 7 d after exposure Enteric-coated preparations may be better tolerated by some patients 5% to 45% of patients with coronary artery disease may be relatively resistant to antiplatelet effects
Dipyridamole	Used in combination with warfarin for post-operative thromboembolic complications of cardiac valve replacement	75 100 mg PO qid
Clopidogrel	Acute coronary syndrome PCI including the prevention of myocardial infarct poststent placement	300 600 mg PO then 75 mg PO qd Initiated 2 6 h prior to PCI	A thienopyridine that inhibits adenosine diphosphate receptor-mediated platelet activity Often used in combination with aspirin Thrombotic thrombocytopenia purpura rare
Glycoprotein IIb/IIIa Inhibitors
Abciximab	Adjunctive therapy for PCI including angioplasty, stent placement Unstable angina pending PCI	10 60 min prior to PCI 0.25 mg/kg IV bolus then 0.125 mcg/kg/min IV (max 10 mcg/min) for 18 24 h concluding 1 h after PCI	Fab fragmented of chimeric antibody to GP IIb/IIIa receptor Binds both activated and nonactivated platelets Reverse effects with platelet transfusions
Eptifibatide	Acute coronary syndrome Adjunctive therapy for PCI	Immediately prior to PCI 180 mcg/kg IV bolus 2 10 min apart, then 2 mcg/kg/min IV for 12 24 h	Binds GP IIb/IIIa receptor of activated platelets only, effects not reversed by platelet transfusion Reduce dose in renal failure Single bolus used in patients with ACS
Tirofiban	Acute coronary syndrome but may be continued through later PCI	Prior to PCI (for acute coronary syndrome) 0.4 mcg/kg/min for 30 min, then 0.1 mcg/kg/min for 12 24 h post-PCI	Similar to eptifibatide Partially metabolized by liver Reduce dose in renal failure
MI, myocardial infarction; PCI, percutaneous coronary interventions; PO, by mouth; TIA, transient ischemic attack

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TABLE 8.11. Declotting Catheters Procedures

Drug	Dosage	Duration	Comments
Thrombolytics			All agents may be effective in occlusions due to fibrin clots Indications include complete catheter occlusion and the inability to withdraw blood Should be administered locally in clotted port or ports of catheter; after indicated dwell time duration, the drug should be aspirated from the catheter with a syringe; assessment of catheter patency should then occur catheter should not be flushed to avoid systemic administration of the drug
Alteplase	2 mg/ml and instill volume equal to internal volume of the catheter	Allow to stand for 0.5 1 h prn
Other Agents
Ethanol 70%	1 2 ml or equal to the internal volume of the catheter	Allow to stand for 20 min prn	Useful for occlusions caused by drugs or fat emulsion
Hydrochloric acid 0.1 N	0.2 1 ml or equal to the internal volume of the catheter	Allow to stand for 0.5 1 h prn	Useful for occlusions caused by drugs or fat emulsion; calcium, phosphorus, and mineral salts
Sodium bicarbonate 8.4%	0.25 3 ml, or equal to the internal volume of the catheter	Allow to stand for 15 min prn	Useful for occlusions caused by phenytoin

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TABLE 8.12. Heparin-Induced Thrombocytopenia^a

Clinical Condition		Platelet Count Monitoring
Therapeutic-dose UFH		qod until day 14 or until UFH stopped
Postoperative antithrombosis prophylaxis with UFH, postoperative cardiac surgery receiving UFH or LMWH		qod between day 4 14 or until UFH stopped
Medical or obstetric patient with prophylactic-dose UFH, postoperative patients receiving prophylactic-dose LMWH, postoperative patients receiving intravascular catheter UFH flushes, medical or obstetric patient receiving LMWH after first receiving UFH		Every 2 3 days from day 4 14 or until heparin stopped
Medical/obstetrical patients receiving LMWH only, medical patients receiving intravascular catheter UFH flushes		No routine platelet monitoring
Diagnosis
HIT antibody (high titer anti-platelet factor 4) formation or washed platelet activation assay and unexplained platelet count fall:
Usually >50% even if nadir >150 109/L    May occur 5 14 days after initiating heparin therapy    Rapid-onset HIT where counts fall within 24 hours of starting heparin after recent heparin exposure (within past 100 days)
or Skin lesions at heparin injection sites or Acute systemic reaction such as chills, cardiorespiratory distress after IV heparin bolus (obtain platelet count immediately) or Venous or arterial thrombosis.
Treatment
Direct thrombin inhibitors
Lepirudin	With or without 0.4 mg/kg IV bolus, infusion rate 0.15 mg/kg/h IV	Treatment of thrombosis complicating HIT Monitor aPTT 1.5 2.0 times baseline Renal excretion
Argatroban	2 g/kg/min (no bolus) HIT undergoing PCI IV bolus of 350 g/kg then 25 g/kg/min IV	Prevent and treat HIT-associated thrombosis Anticoagulation during angioplasty Increases INR Hepatobiliary excretion
Bivalirudin	0.15 0.20 mg/kg/h IV (no bolus)	Anecdotal experience in HIT Anticoagulation during PCI Monitor aPTT 1.5 2.5 times baseline
HIT, heparin-induced thrombocytopenia; INR, International Normalized Ratio; IV, intravenous; LMWH, low molecular weight heparin; PCI, percutaneous coronary intervention; UFH, unfractionated heparin (*Adapted from the 7th ACCP Conference on Antimicrobial and Thrombolytic Therapy. Chest 2004;126:Supplement.)