Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

HEPARIN

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Heparin is an anionic sulfated glycosaminoglycan mucopolysaccharide with anticoagulant activity and normally found in mast cells. It is a heterogenous mixture of proteins of various sizes.

Specific Substances

    1) Calcium heparin
    2) Hepariini
    3) Heparinum natricum
    4) Heparina
    5) Heparino
    6) Heparinkalcium
    7) Heparinum
    8) Heparinum calcium
    9) Heparyna
    10) Sodium heparin
    11) Soluble heparin (heparin sodium)
    12) CAS 9005-49-6 (Heparin)
    13) CAS 37270-89-6 (Heparin calcium)
    14) CAS 9041-08-1 (Heparin sodium)

Available Forms Sources

    A) FORMS
    1) Heparin is available (with benzyl alcohol or preservative free) in the United States as (Prod Info heparin sodium IV, subcutaneous injection, 2010; Prod Info heparin lock flush solution injection, 2006; Prod Info Heparin sodium in 5% dextrose IV injection, 2009):
    a) INJECTION SOLUTION: 1000 Units/mL, 2500 Units/mL, 5000 Units/mL, 10,000 Units/mL, 5000 Units/0.5 mL, 20,000 Units/mL
    b) IV SOLUTION: 1 Units/mL. 2 Units/mL, 10 Units/mL, 100 Units/mL, 2000 Units/mL
    2) In February 2008, the United States Food and Drug Administration (FDA) announced that Baxter has voluntarily recalled all of their heparin sodium injection multi-dose, single-dose vials and heparin lock flush products. The only Baxter heparin-containing products that will remain on the market are large volume pre-mix parenteral solutions containing 200 units of heparin/100 mL in 500-mL and 1000-mL total volume bags (US Food and Drug Administration, 2008).
    a) In a public health advisory released by the FDA in 2008, serious adverse events including severe hypotension and allergic or hypersensitivity-type reactions (ie, oral swelling, nausea, vomiting, sweating, shortness of breath) have been reported with higher bolus doses of heparin. Most heparin infusions were prepared from multiple-dose vials manufactured by Baxter Healthcare Corporation, although several cases were attributed to bolus injections prepared from several single-dose vials. Most events typically occurred within minutes of receiving the heparin bolus, and a delayed response has not been excluded (US Food and Drug Administration, 2008).
    B) USES
    1) Heparin is used for the prophylaxis and/or treatment of venous thrombosis, pulmonary embolism, atrial fibrillation with embolization, chronic consumptive coagulopathies (disseminated intravascular coagulation), and peripheral arterial embolism. It is also used as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures, and in blood specimens for laboratory purposes (Prod Info heparin sodium IV, subcutaneous injection, 2010).
    2) Heparin lock flush solution is used to maintain patency of vascular access devices for intermittent or infusion therapy (Prod Info heparin lock flush solution injection, 2006).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Heparin is used for the prophylaxis and/or treatment of venous thrombosis, pulmonary embolism, atrial fibrillation with embolization, chronic consumptive coagulopathies (disseminated intravascular coagulation), and peripheral arterial embolism. It is also used as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures, and to maintain patency of vascular access devices for intermittent or infusion therapy.
    B) PHARMACOLOGY: Heparin sodium, a glycosaminoglycan, inhibits the mechanisms that induce the clotting of blood and the formation of stable fibrin clots at various sites in the normal coagulation system. When heparin sodium is combined with antithrombin III (heparin cofactor), thrombosis is blocked through inactivation of activated factor X and inhibition of prothrombin's conversion to thrombin. This also prevents fibrin formation from fibrinogen during active thrombosis.
    C) TOXICOLOGY: At low doses, heparin combines with antithrombin III (heparin cofactor). This complex then inactivates activated factor X, thereby inhibiting the conversion of prothrombin to thrombin. With larger doses, heparin combines with antithrombin III to inactivate factors IX, X, XI, and XII and thrombin and prevent the conversion of fibrinogen to fibrin. HEPARIN-INDUCED THROMBOCYTOPENIA (HIT): Type I HIT is a minor decrease in platelet count attributed to the direct interaction between heparin and circulating platelets. The pathophysiology of type II HIT is multifactorial, but the primary factor mediating cellular activation is the generation of anti-heparin-platelet factor 4 complex antibodies. Most patients with HIT produce IgG antibodies against complexes of platelet factor 4 (PF4) and heparin. PF4 is found on the surface of endothelial cells and stored within the alpha granules of platelets. The antibody-PF4-heparin complex activates platelets, generating platelet-derived procoagulant microparticles, thereby initiating thrombin generation and provoking a hypercoagulable state.
    D) EPIDEMIOLOGY: Heparin is commonly prescribed, but overdoses are rare.
    E) WITH THERAPEUTIC USE
    1) The most common complication observed with heparin therapy is bleeding (9% to 45%; common sites are gastrointestinal tract, skin, urinary tract, and pulmonary and cardiovascular systems). Cardiovascular collapse may occur with significant hemorrhage or cardiac tamponade. Heparin-induced thrombocytopenia (HIT) is an acquired hypercoagulability syndrome caused by the antibody-mediated reaction. It is characterized by thrombocytopenia and a high risk for venous or arterial thrombosis, also referred to as heparin-induced thrombocytopenia and thrombosis (HITT). The overall incidence of HIT has been as high as 30% (type I HIT 2% to 25% and type II HIT 1% to 3%). The following thromboembolic events may occur: deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, and gangrene of the extremities that may lead to amputation. The following adverse effects have also been reported with heparin administration: hypotension, hematoma, ecchymoses, skin necrosis, reversible transaminase elevations, hypersensitivity reactions, eczema, generalized urticaria, hyperkalemia, chemosis, and hyphema.
    F) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. The main sign of heparin overdose is bleeding. Patients may experience epistaxis, hematuria, tarry stool, easy bruising, or petechial formation, followed by frank bleeding.
    0.2.20) REPRODUCTIVE
    A) Heparin is classified as FDA pregnancy category C. Numerous studies have reported on the maternal and fetal outcomes associated with heparin use during pregnancy. Studies in which heparin has been given IV and subQ, have generally reported normal deliveries with no maternal or fetal bleeding and no other complications. In earlier studies, increased rates of abnormal pregnancies and fetal outcomes were reported with heparin therapy, but these may have been due to maternal comorbidities rather than the heparin itself.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturers do not report any carcinogenic potential for heparin sodium in humans.

Laboratory Monitoring

    A) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    B) Monitor CBC with platelets, aPTT, PT or INR, and bleeding time in patients with evidence of bleeding or following a significant exposure.
    C) Monitor vital signs, renal function and hepatic enzymes in symptomatic patients.
    D) Monitor for signs and symptoms of heparin-induced thrombocytopenia and thrombosis (HITT), including deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, or gangrene of the extremities; delayed HITT could occur up to several weeks after the discontinuation of heparin therapy.
    E) In one case of heparin overdose in a bleeding neurosurgical patient, thromboelastography (TEG) was used at the point-of-care to guide heparin reversal before emergency surgical procedures. Since TEG results are more rapidly available than standard coagulation studies, this may be more useful to guide protamine reversal in patients requiring emergent heparin reversal.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor for bleeding. Manage mild hypotension with IV fluids. If hypotension persists, treat patients with vasopressors.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat patients with severe bleeding with protamine sulfate. Transfusions of packed red blood cells and fresh frozen plasma may be indicated in addition to protamine sulfate. In patients with strongly suspected or confirmed heparin-induced thrombocytopenia (HIT), with or without thrombosis, discontinue heparin and start an alternative, nonheparin anticoagulant (lepirudin, argatroban). Treat severe hypotension with fluids (and transfusion if hypotension is secondary to bleeding), add vasopressors if necessary. An anaphylactoid or anaphylactic reaction may require aggressive airway management and support.
    C) DECONTAMINATION
    1) Decontamination is not indicated; heparin is only available parenterally.
    D) AIRWAY MANAGEMENT
    1) Assess airway; endotracheal intubation may be required in patients with intracranial bleeding, severe hemoptysis, or acute allergic reaction.
    E) ANTIDOTE
    1) PROTAMINE: If the bleeding tendency is severe or if massive amounts of heparin have been administered, treatment with protamine sulfate may be indicated.
    a) DOSES: ADULTS: 1 mg IV for every 100 units of heparin remaining in patient; if 30 minutes have elapsed since the injection of heparin, one-half the dose may be sufficient. Protamine sulfate should be given by slow intravenous administration over a 10 minute period (not to exceed 50 mg) to avoid the risk of severe adverse reactions such as hypotension and bradycardia. Dosing of protamine sulfate should be guided by anticoagulation studies. CHILDREN: The Seventh American College of Chest Physicians (ACCP) Antithrombotic and Thrombolytic Therapy Consensus Guidelines state that protamine sulfate can be considered for use in children if rapid reversal of heparin activity is required (eg, heparin-induced bleeding). If it has been less than 30 minutes since the last dose of heparin therapy, the recommended dose of protamine is 1 mg given IV for every 100 units. If 30 to 60 minutes have elapsed since last dose of heparin therapy, protamine 0.5 to 0.75 mg IV should be given for every 100 units of heparin received. If 60 to 120 minutes have elapsed since the last dose of heparin, protamine 0.375 to 0.5 mg IV should be given per every 100 units of heparin received. If more than 120 minutes have elapsed since the last dose of heparin, protamine 0.25 to 0.375 mg IV should be given per every 100 units of heparin received. The maximum dose of protamine sulfate is 50 mg, and can be administered in a concentration of 10 mg/mL not exceeding 5 mg/minute.
    F) HEPARIN-INDUCED THROMBOCYTOPENIA
    1) In patients with strongly suspected or confirmed heparin-induced thrombocytopenia (HIT), with or without thrombosis, discontinue heparin and start an alternative, non-heparin anticoagulant (lepirudin, argatroban). LEPIRUDIN: ADULTS: 0.4 mg/kg (maximum 44 mg) IV bolus, at a concentration of 5 mg/mL, is administered slowly (eg, over 15 to 20 seconds) followed by a continuous infusion of lepirudin at a rate of 0.15 mg/kg/hr (maximum initial infusion dose of 16.5 mg/hr) for 2 to 10 days or longer if clinically needed. According to the American College of Chest Physicians (ACCP) guidelines, the initial lepirudin IV infusion should not exceed 0.1 mg/kg/hour (mg/kg/hr). Initial bolus dose is recommended either to be omitted or, in case of perceived life- or limb-threatening thrombosis, be given at 0.2 mg/kg. ARGATROBAN: The recommended initial dose is 2 mcg/kg/min administered as a continuous infusion. Dose can be adjusted as clinically indicated, not exceeding 10 mcg/kg/min, until the steady-state aPTT is 1.5 to 3 times the initial baseline value (not to exceed an aPTT of 100 seconds). CHILDREN: initial, 0.75 mcg/kg/min continuous IV infusion; adjust in increments of 0.1 to 0.25 mcg/kg/min to achieve aPTT of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). In the absence of any prospective comparative clinical trials, the choice between lepirudin and argatroban usually is based on their different elimination mechanisms. Lepirudin is cleared by the kidneys, so it is preferred in patients with liver disease. Argatroban is cleared by the liver, so it is preferred in patients with renal insufficiency. Other agents such as bivalirudin, danaparoid (not available in the United States), and fondaparinux have also been used in patients with HIT.
    G) ACUTE ALLERGIC REACTION
    1) MILD to MODERATE effects: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE Effects: Administer oxygen, aggressive airway management may be necessary. Administer antihistamines, epinephrine, corticosteroids as needed. Treatment includes IV fluids and ECG monitoring.
    H) ENHANCED ELIMINATION
    1) Efforts to enhance elimination are not indicated as heparin is rapidly removed from the body. Some data indicate that heparin is not dialyzable and its half-life is unchanged by hemodialysis.
    I) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with heparin overdose should be evaluated and monitored until symptoms resolve. Patients can be discharged when laboratory values are stable with no evidence of bleeding.
    2) ADMISSION CRITERIA: Patients with severe symptoms (eg, anaphylaxis, hemorrhage) should be admitted to an intensive care setting.
    J) PITFALLS
    1) When managing a suspected heparin overdose, the possibility of multi-drug involvement should be considered.
    K) PHARMACOKINETICS
    1) TMAX: SubQ, 2 to 4 hours; metabolism: hepatic and reticulo-endothelial system. Protein binding is extensive to low density lipoprotein, globulins (including the alpha-globulin antithrombin III) and to fibrinogen. Vd: Average 0.060 L/kg. Heparin is primarily distributed into the blood. Approximately 80% of a dose of heparin is recovered in the urine 8 hours after IV injection, mostly in the form of inorganic sulfate.
    L) DIFFERENTIAL DIAGNOSIS
    1) Bleeding diathesis: Disseminated intravascular coagulation, Vitamin K deficiency, rattlesnake envenomation, congenital bleeding disorders (hemophilia, von Willebrand’s disease), or coumadin overdose. Thrombocytopenia: Caused by other drugs, vitamin B12 or folic acid deficiency, hereditary syndromes, leukemia. Thromboembolic events: Includes other agents (e.g. oral contraceptives) or disorders such as a history of deep vein thrombosis, superficial thrombophlebitis, trauma, soft tissue injury, immobility, or cellulitis. Hypotension: Hypovolemia (other causes), antihypertensive agents.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Heparin sodium injection vials contain various strengths of heparin (eg, 10,000 Units/1 mL). Fatal hemorrhages have been reported in children when 1-mL heparin sodium injection vials were confused with 1-mL "catheter lock flush" vials. Three of 5 neonates died within 3 days of receiving heparin overdose (a single dose vial of 10,000 Units/mL instead of a single dose vial of 10 Units/mL). An 8-month-old infant developed a hematoma and bleeding from injection sites 2 hours after receiving 20,000 Units (3636 Units/kg) of heparin IM. Following protamine therapy and a transfusion, he recovered gradually.
    B) THERAPEUTIC DOSE: Varies by indication. ADULTS: IV: Up to 40,000 Units/24 hours; SubQ: Up to 20,000 Units every 8 to 12 hours. CHILDREN: IV: Up to 20,000 Units/m(2)/24 hours.

Clinical Effects

Summary Of Exposure

    A) USES: Heparin is used for the prophylaxis and/or treatment of venous thrombosis, pulmonary embolism, atrial fibrillation with embolization, chronic consumptive coagulopathies (disseminated intravascular coagulation), and peripheral arterial embolism. It is also used as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures, and to maintain patency of vascular access devices for intermittent or infusion therapy.
    B) PHARMACOLOGY: Heparin sodium, a glycosaminoglycan, inhibits the mechanisms that induce the clotting of blood and the formation of stable fibrin clots at various sites in the normal coagulation system. When heparin sodium is combined with antithrombin III (heparin cofactor), thrombosis is blocked through inactivation of activated factor X and inhibition of prothrombin's conversion to thrombin. This also prevents fibrin formation from fibrinogen during active thrombosis.
    C) TOXICOLOGY: At low doses, heparin combines with antithrombin III (heparin cofactor). This complex then inactivates activated factor X, thereby inhibiting the conversion of prothrombin to thrombin. With larger doses, heparin combines with antithrombin III to inactivate factors IX, X, XI, and XII and thrombin and prevent the conversion of fibrinogen to fibrin. HEPARIN-INDUCED THROMBOCYTOPENIA (HIT): Type I HIT is a minor decrease in platelet count attributed to the direct interaction between heparin and circulating platelets. The pathophysiology of type II HIT is multifactorial, but the primary factor mediating cellular activation is the generation of anti-heparin-platelet factor 4 complex antibodies. Most patients with HIT produce IgG antibodies against complexes of platelet factor 4 (PF4) and heparin. PF4 is found on the surface of endothelial cells and stored within the alpha granules of platelets. The antibody-PF4-heparin complex activates platelets, generating platelet-derived procoagulant microparticles, thereby initiating thrombin generation and provoking a hypercoagulable state.
    D) EPIDEMIOLOGY: Heparin is commonly prescribed, but overdoses are rare.
    E) WITH THERAPEUTIC USE
    1) The most common complication observed with heparin therapy is bleeding (9% to 45%; common sites are gastrointestinal tract, skin, urinary tract, and pulmonary and cardiovascular systems). Cardiovascular collapse may occur with significant hemorrhage or cardiac tamponade. Heparin-induced thrombocytopenia (HIT) is an acquired hypercoagulability syndrome caused by the antibody-mediated reaction. It is characterized by thrombocytopenia and a high risk for venous or arterial thrombosis, also referred to as heparin-induced thrombocytopenia and thrombosis (HITT). The overall incidence of HIT has been as high as 30% (type I HIT 2% to 25% and type II HIT 1% to 3%). The following thromboembolic events may occur: deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, and gangrene of the extremities that may lead to amputation. The following adverse effects have also been reported with heparin administration: hypotension, hematoma, ecchymoses, skin necrosis, reversible transaminase elevations, hypersensitivity reactions, eczema, generalized urticaria, hyperkalemia, chemosis, and hyphema.
    F) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. The main sign of heparin overdose is bleeding. Patients may experience epistaxis, hematuria, tarry stool, easy bruising, or petechial formation, followed by frank bleeding.

Heent

    3.4.2) HEAD
    A) WITH THERAPEUTIC USE
    1) ALOPECIA: Delayed transient alopecia has been reported (Prod Info heparin sodium IV, subcutaneous injection, 2010).
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CHEMOSIS: Reversible corneal opacification, hyperemia of the iris, conjunctival chemosis, and transient intraocular pressure elevation were noted with subconjunctival injection of heparin (Grant & Schuman, 1993).
    2) HYPHEMA was reported with intravenous heparin (Grant & Schuman, 1993).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) EPISTAXIS occurred in less than 1% of patients receiving therapeutic doses of heparin (Walker & Jick, 1980).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension was reported in neonates who inadvertently received heparin (Schreiner et al, 1978). Cardiovascular collapse occurred within minutes of an IV bolus (Ansell et al, 1986).
    b) In a public health advisory released by the United States Food and Drug Administration (FDA) in 2008, serious adverse events including severe hypotension and allergic or hypersensitivity-type reactions (ie, oral swelling, nausea, vomiting, sweating, shortness of breath) have been reported with higher bolus doses of heparin. Most heparin infusions were prepared from multiple-dose vials manufactured by Baxter Healthcare Corporation, although several cases were attributed to bolus injections prepared from several single-dose vials. Most events typically occurred within minutes of receiving the heparin bolus, and a delayed response has not been excluded (US Food and Drug Administration, 2008).
    B) PERICARDIAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cardiac tamponade was reported in a 34-year-old woman with renal failure that had been induced by systemic lupus erythematosus (SLE). She required hemodialysis during which heparin was given intravenously (at a loading dose of 100 units followed by a continuous infusion of 500 units/hour). The patient developed shock approximately 30 minutes after beginning dialysis and died, despite cessation of dialysis and fluid infusion. Postmortem examination revealed accumulation of blood (approximately 600 mL) in the pericardial sac. It is believed that the patient developed vasculitis from reactivation of her SLE, and heparin administration prompted bleeding from the vasculitic vessels (Leung et al, 1990).
    C) VENOUS THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) HEPARIN-INDUCED THROMBOCYTOPENIA AND THROMBOSIS: Venous thrombosis, pulmonary emboli, and thrombocytopenia were reported in a 59-year-old woman who received low-dose heparin line flushes (6000 units over 5 days) after a hepatectomy (Rizzoni et al, 1988).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Respiratory distress was described in neonates who inadvertently received heparin via indwelling umbilical artery catheter or with IV line flushing (Schreiner et al, 1978).
    B) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Pulmonary edema has been reported during therapeutic use; however, a definite cause-effect relationship was not established (Ahmed & Nussbaum, 1981).
    C) HEMOTHORAX
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hemothorax occurred in a 33-year-old man who received continuous heparin infusion (of unreported dose) for a suspected pulmonary embolism (Morecroft & Lea, 1988).
    D) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 67-year-old man developed severe dyspnea and wheezing 3 hours after receiving a heparin bolus (5000 units) followed by an infusion (1000 units/hr). Physical examination revealed rhonchi throughout the lungs. After stopping heparin, the patient recovered with albuterol, aminophylline, and prednisolone (Savas et al, 1997).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Femoral neuropathy occurred in a 69-year-old man after receiving 25,000 units of subQ heparin twice daily andphenprocoumon (Olesen, 1989).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Significant reversible elevations in serum transaminases have been reported in up to 95% of patients receiving heparin (Prod Info heparin sodium IV, subcutaneous injection, 2010; Monreal et al, 1989; Dukes et al, 1984).
    b) Elevations of hepatic transaminase plasma activity generally occur without an increase in bilirubin or alkaline phosphatase (Hardman et al, 1996; Amerena et al, 1990).
    c) Cholestatic hepatitis was reported in a 54-year-old man after treatment with unfractionated heparin. The patient was found to have bilateral pulmonary emboli several days after surgery. He was initially given heparin calcium 5000 international units every 12 hours, but 3 days later, due to continuing chest pain and confirmation of the emboli, he was started on heparin sodium 1000 international units/hour. Five days later, acenocoumarol 4 mg/day was added to therapy. Meanwhile hepatic enzyme concentrations were rising, reaching a peak on day 11 (aspartate aminotransferase 514 units/L, alanine aminotransferase 1111 units/L, alkaline phosphatase 936 units/L, and gamma-glutamyltransferase 151 units/L). Heparin was withdrawn, the patient received oral anticoagulation therapy, and liver enzyme levels normalized within 90 days (Manfredini et al, 2000).
    d) Elevations in liver enzymes (alanine transaminase and aspartate transaminase) occurred in 59% of patients receiving bovine heparin and 27% receiving porcine heparin. Abnormal transaminase levels were correlated with male sex and higher baseline enzyme values. In most cases, transaminase levels returned to normal after withdrawal of heparin (80%), whereas transaminase levels normalized in 20% of patients during continued treatment. In addition, LDH concentrations were abnormal in 36% of patients. No cases of hepatic dysfunction were observed (Dukes et al, 1984a).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Hematuria was noted in 2% of nonsurgical patients in one study (Walker & Jick, 1980).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: The cumulative risk of bleeding for all doses, modes, and frequencies of heparin administration among 2656 patients was 9.2%, with peak incidence of bleeding at 3 days (Walker & Jick, 1980).
    1) The frequency of bleeding complications was 45% among patients treated within 6 days after total joint replacement, and this declined to 15% among those treated more than a week after arthroplasty (Patterson et al, 1989).
    b) SITES: The occurrence of hemorrhage in patients receiving therapeutic heparin is often related to preexisting medical conditions or invasive procedures. The most common types of bleeding in nonsurgical patients are melena (2.9%), hematoma (2.4%), hematuria (2%), and ecchymosis (1.2%). Epistaxis, hematemesis, and intracranial or pulmonary hemorrhage each occur in less than 1% (Walker & Jick, 1980).
    c) DOSE: In a study of 2656 patients, a dose-response relationship was noted for the risk of bleeding in nonsurgical patients. The incidence of minor and major bleeding episodes with doses of 12.5 units/kg/hour or greater was 3.2 and 2.6 times greater, respectively, compared with doses of less than 12.5 units/kg/hour (Walker & Jick, 1980).
    1) The rate of hemorrhagic complications was 4.9% when the dose was less than 50 units/kg/dose and 17.2% when more than 100 units/kg/dose was given (Walker & Jick, 1980).
    2) Excessive hemorrhage, in volume of blood loss, has been reported with inadvertent anticoagulation using heparin flushes (less than 500 units/day) for maintaining the patency of arterial and venous catheters (Harrington & Hufnagel, 1990; Passannante & Macik, 1988).
    d) ROUTE: A review of randomized studies showed that toxicity was related to the dose rather than the route of administration (Gilman et al, 1990).
    1) Other studies have shown a relationship between major bleeding episodes and intermittent injections of heparin, compared with continuous infusions of heparin (presumably due to the higher transient peaks after bolus injections) (Amerena et al, 1990).
    e) DURATION: The risk of hemorrhage increases with the duration of heparin therapy. The risk of bleeding after 7 days was 9.1% compared with approximately 20% after 3 weeks (Walker & Jick, 1980).
    f) PREDISPOSING CONDITIONS/FACTORS associated with an increased risk of minor bleeding while receiving heparin include aspirin use, underlying morbid condition, and female sex. The risk for major bleeding also increased with patient's age (especially among women), alcohol consumption, and renal failure (Walker & Jick, 1980).
    1) An HIV-positive man with cachexia and mild liver dysfunction developed a massive hemorrhage after receiving subQ heparin (5000 units twice daily). Following supportive care and protamine therapy, he recovered (Hudcova & Talmor, 2009).
    g) CASE REPORTS/SERIES
    1) CASE SERIES: Ten stroke patients with no predisposing factors for hemorrhage developed intracerebral hemorrhage on heparin therapy. Eight events occurred less than 72 hours after the time heparin was started, and 7 of the patients had activated partial thromboplastin times more than double the that of control patients (Babikian et al, 1989).
    2) Cord compression due to a spinal epidural hematoma was reported in a 49-year-old man who received short-term streptokinase and continuous heparin therapy for acute coronary artery occlusion (Mustafa & Gallino, 1988).
    2) WITH POISONING/EXPOSURE
    a) The main sign of heparin overdose is bleeding. Patients may experience epistaxis, hematuria, tarry stool, easy bruising, or petechial formation, followed by frank bleeding (Prod Info heparin sodium IV, subcutaneous injection, 2010).
    b) ADULTS
    1) Surreptitious IM self-administration of 700 mg heparin was reported in a 24-year-old nurse. Eight hours later, bleeding from puncture wounds was noted. Laboratory values included a prothrombin time of 29 seconds, partial thromboplastin time 380 seconds (control 31 seconds), and normal platelet count. Administration of protamine sulfate 50 mg IV restored normal coagulation (Martin et al, 1970).
    2) ADULT: A 51-year-old obese woman underwent a surgery to remove an intracranial hemangiopericytoma. The day after the surgery, she developed pulmonary embolism and was treated with IV continuous unfractionated heparin (50,000 Units/24 hours after a bolus dose of 50 Units/kg). She developed bleeding from different puncture wounds 12 hours later and heparin infusion was discontinued. A blood sample revealed heparin concentration of 4.5 Units/mL using an anti-Xa heparin assay. At this time, she developed right-sided hemiplegia and impaired consciousness. A head CT scan revealed an intracranial hematoma at the operation site. Thromboelastography (TEG) was used to guide heparin reversal. After normal coagulation was stored, an emergency procedure for intracranial hemorrhage was performed. Following further supportive care, including repeated administration of protamine, her coagulation tests gradually normalized. She was treated with subcutaneous enoxaparin (40 mg) 2 days after surgery and she was discharged 2 months later (Figueiredo et al, 2013).
    c) PEDIATRIC
    1) Heparin sodium injection vials contain differing strengths of heparin (eg, 10,000 units/1 mL). Fatal hemorrhages have been reported in children when the wrong type of vial was chosen: 1-mL heparin sodium injection vials were confused with 1-mL "catheter lock flush" vials (Prod Info heparin sodium IV, subcutaneous injection, 2010).
    2) CASE REPORT: An 8-month-old infant developed a hematoma and bleeding from injection sites 2 hours after receiving heparin 20,000 units (3636 units/kg) IM. Protamine was given repeatedly (187 mg over 32 hours), and 100 mL of citrated blood was transfused. No further bleeding was noted after 12 hours of therapy; however, capillary coagulation times remained abnormal for 31 hours (Pachman, 1965).
    3) CASE SERIES: One study reported 3 cases of inadvertent heparin administration to neonates. In one case, heparin (5 mL of 10,000 units/mL) was used to flush an umbilical artery catheter. Bleeding, respiratory distress, and hematuria were noted. Bleeding ceased immediately following exchange transfusion. In the second case, heparin (2 mL of 1000 units/mL) was administered to flush an IV line. No bleeding occurred and coagulation studies normalized 2 hours after the administration of protamine sulfate 10 mg. In the last case, heparin (0.5 mL of 1000 units/mL) was given to flush an IV line. Mild bleeding occurred but resolved without therapy (Schreiner et al, 1978).
    4) One study reported a case of inadvertent administration of heparin 8620 units/kg to a neonate via an umbilical catheter. Four hours later, excessive bleeding from sites of skin puncture was noted, and the patient's thrombin time was more than 200 seconds. He was treated with Polybrene and packed cell transfusion and recovered. The half-life of heparin was 50.8 hours (Glueck et al, 1965).
    5) A neonate developed intra-abdominal hemorrhage and bleeding from injection sites 17 hours after receiving heparin 8000 units (2666 units/kg). Despite treatment with protamine sulfate (total dose, 25.4 mg), the infant died of complications. The half-life of heparin was 45.8 hours (Galant, 1967).
    B) HEPARIN-INDUCED THROMBOCYTOPENIA WITH THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Heparin-induced thrombocytopenia (HIT) is an acquired hypercoagulability syndrome caused by an antibody-mediated reaction. It is characterized by thrombocytopenia and a high risk for venous or arterial thrombosis, also referred to as heparin-induced thrombocytopenia and thrombosis (HITT). The overall incidence of HIT has been as high as 30% (type I HIT 2% to 25% and type II HIT 1% to 3%). HIT has similar incidence in children but has a less severe outcome. The clinically severe form of HIT is caused by an immunologic reaction that potentially can develop from exposure to any dose of heparin, including incidental exposure through heparin-coated catheters and heparin flushes used to maintain an intravenous line (Prod Info heparin sodium IV, subcutaneous injection, 2010; Menajovsky, 2005; Schmugge et al, 2002; Warkentin & Kelton, 2001; Stephan et al, 2000; Brieger et al, 1998; Harrington & Hufnagel, 1990; Becker & Miller, 1989; Bell, 1988).
    b) TYPES: HIT occurs in 2 distinctive types, HIT type I and HIT type II (Menajovsky, 2005).
    1) TYPE I HIT: Type I HIT causes a minor decrease in platelet count attributed to the direct interaction between heparin and circulating platelets (Brieger et al, 1998). This type occurs in 2% to 25% of patients, 2 to 15 days after the initiation of full-dose heparin therapy, and usually presents with a platelet count between 50,000 to 100,000/mcL (Harrington & Hufnagel, 1990; Becker & Miller, 1989; Bell, 1988). Since the thrombocytopenia is mild and transient, heparin may be continued without undue risk of bleeding (Harrington & Hufnagel, 1990; MacLean et al, 1990; Becker & Miller, 1989)
    2) TYPE II HIT: Type II HIT, commonly referred to simply as HIT, is a more severe IgG antibody-mediated thrombocytopenia. It develops in 1% to 3% of patients following heparin therapy. This form is associated with potentially devastating thromboembolic sequelae in 30% to 80% of cases. Platelet counts typically drop to 30,000 to 50,000/mm(3) (Menajovsky, 2005; Warkentin & Kelton, 2001; Stephan et al, 2000; Brieger et al, 1998).
    a) The typical presentation of type II HIT begins at least 5 days, and up to 3 weeks, after exposure to heparin. Platelet counts begin to fall about 5 to 10 days after starting heparin therapy (Warkentin & Kelton, 2001; Brieger et al, 1998). HIT may manifest sooner if the patient has had previous heparin exposure, and manifestations can take longer (Menajovsky, 2005; Brieger et al, 1998). Because HIT is an immunologic reaction, it can be provoked by even incidental exposures to heparin (eg, IV line flushes) (Menajovsky, 2005). It may also occur weeks after heparin has been discontinued (Brieger et al, 1998).
    b) PATHOPHYSIOLOGY: The pathophysiology of type II HIT is multifactorial, but the primary factor mediating cellular activation is the generation of anti-heparin-platelet factor 4 complex antibodies (Fabris et al, 2000). Most patients with HIT produce IgG antibodies against complexes of platelet factor 4 (PF4) and heparin. PF4 is found on the surface of endothelial cells and stored within the alpha granules of platelets. The antibody-PF4-heparin complex activates platelets, generating platelet-derived procoagulant microparticles, thereby initiating thrombin generation and provoking a hypercoagulable state (Menajovsky, 2005; Cines et al, 2004).
    c) COMPLICATIONS: Severe HIT, combined with thrombosis (HITT), has been associated with occasional cases of deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, and gangrene of the extremities that may lead to amputation (Prod Info heparin sodium IV, subcutaneous injection, 2010; Bell et al, 1976; Ramirez-Lassepas et al, 1984; Silver et al, 1983).
    d) INCIDENCE: A prospective cohort analysis showed that the incidence of HIT in medical patients given unfractionated heparin subQ for prophylaxis was 1.4% (n=360). However, 3 of the 5 patients (60%) who developed HIT also experienced other thromboembolic complications, including fatal ischemic stroke, bilateral deep venous thrombosis followed by fatal acute myocardial infarction, and acute lower limb arterial occlusion (Girolami et al, 2003). In another study, 6 of 18 patients (33%) with carotid thrombosis occurring after carotid endarterectomy had heparin-induced coagulation disorders (Atkinson et al, 1988).
    e) WHITE CLOT SYNDROME, platelet-fibrin thrombi which appear macroscopically pale white, may be present in HITT (MacLean et al, 1990; Arthur et al, 1985). In a series of 10 patients with white clot syndrome, mortality was 50%, and major limb amputations were done in 20% (Stanton et al, 1988).
    f) PROGNOSIS: With HIT, the platelet count usually reverts to normal within days or weeks and the pathogenic HIT antibodies disappear within weeks or a few months (Warkentin et al, 2008).
    1) Six of 21 (28.5%) thrombocytopenic patients (average platelet count of 46,857/mm(3)) died after receiving heparin following cardiovascular surgery. The high mortality rate was attributed to complications of the thrombocytopenia and delayed diagnosis (Glock et al, 1988)
    g) DELAYED-ONSET: Twelve patients reported symptoms of HITT that began on an average of 9 days (range from 5 to 19 days) after withdrawal of heparin therapy. Each patient with delayed-onset HITT showed higher IgG antibody titers and greater heparin-dependant and heparin-independent platelet activation as compared with controls (Warkentin & Kelton, 2001).
    h) DIFFERENTIAL DIAGNOSIS: The differential diagnosis of HITT includes sepsis, other drug-induced thrombocytopenias, disseminated intravascular coagulation, bone marrow hypoplasia, hypersplenism, uremia, and immune thrombocytopenia (MacLean et al, 1990; Miller, 1989).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Local irritation, erythema, mild pain, hematoma, or ulceration have been reported following deep subQ injections of heparin sodium (Prod Info heparin sodium IV, subcutaneous injection, 2010). Ecchymosis, pruritus, urticaria, and eosinophilia have also been reported (Schey, 1989; Barbaccia et al, 1984; Walker & Jick, 1980).
    b) Eczematous plaques (a delayed hypersensitivity reaction) have been noted at subQ injection sites. These appeared 4 to 14 days after the start of the heparin therapy and did not progress to necrosis (Bircher et al, 1990; Guillet et al, 1989; Klein et al, 1989).
    c) CASE REPORT: A generalized exanthem, believed to be an immediate type I reaction, occurred in a 65-year-old woman with acute retinal necrosis who had been given heparin 5000 units subQ twice daily (Patrizi et al, 1989).
    B) SKIN NECROSIS
    1) WITH THERAPEUTIC USE
    a) Skin necrosis and tender erythematous nodules (panniculitis) at the sites of subQ heparin injections have been ascribed to the complications of heparin-induced thrombocytopenia (Nogueira et al, 1997; Amerena et al, 1990; Fowlie et al, 1990; MacLean et al, 1990; Rongioletti et al, 1989; Cohen et al, 1988; Hartman et al, 1988; Stricker et al, 1988; Young, 1988).
    1) Skin reactions develop 6 to 14 days after the initiation of heparin therapy and are associated more frequently with bovine heparin (Amerena et al, 1990).
    2) Given its association with thrombosis and increased mortality, the onset of skin reactions warrants prompt discontinuation of heparin and close monitoring for thrombocytopenia and platelet-aggregating antibodies (Amerena et al, 1990).
    3) It has been theorized that dermal necrosis is caused by heparin-mediated thrombosis in the microvasculature, which also leads to thrombocytopenia (Tonn et al, 1997).
    b) CASE REPORTS
    1) A 36-year-old woman receiving subQ heparin after a cesarean section developed edema, redness, and pain at the injection site. The next day, a necrotic lesion developed that required skin grafting. No thrombocytopenia or thrombotic complications were present (Christiaens & Nieuwenhuis, 1996).
    2) A 30-year-old woman with a protein S deficiency developed an injection site ulceration 3 days after receiving subQ heparin. A biopsy showed epidermal necrosis. The ulcer gradually resolved following topical corticosteroid treatment (Libow et al, 1997).
    3) A 57-year-old woman developed dark red macular lesions on both thighs following 8 days of subQ heparin administration. Thrombocytopenia was not present. Following symptomatic treatment, the lesions gradually resolved over a 3-month period (Khan & Watson, 2000).
    C) CALCINOSIS CUTIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 28-year-old woman with oligoanuric renal failure related to HIV nephropathy developed calcinosis cutis after receiving subQ injections of calcium-containing heparin. She presented with widespread enlarged peripheral lymph nodes, diarrhea, ascites, and pancytopenia, related to disseminated tuberculosis. Her laboratory findings revealed elevated serum creatinine 839 mcmol/L (normal range, 35 to 100 mcmol/L), hypercalcemia 1.57 mmol/L (normal range, 2.2 to 2.6 mmol/L); hyperphosphatemia 2.76 mmol/L (normal range, 0.9 to 1.5 mmol/L); and calcium-phosphate product 4.33 (normal range, 1.9 to 3.9). The woman was treated with repeated hemodialysis and antimycobacterial antibiotics. On the right arm and thighs, she developed 2-cm wide subQ nodules which were well-palpable, firm, erythematous, and slightly painful. A morphological analysis revealed crackled and violaceous deposits in the dermis and in the collagenous septa of the subQ tissue. An electron microscopy showed hard deposits which were located in extracellular areas. The patient had several subQ injections of calcium-containing heparin on the thighs and also on the right upper arm. A whitish material that was suspected to be calcium was later transepidermally removed. The calcium-containing heparin was discontinued, and the patient's renal function and calcium-phosphate balance improved. Her skin lesions gradually healed over 5 weeks (Boccara et al, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) OSTEOPOROSIS
    1) WITH THERAPEUTIC USE
    a) Spontaneous bone fractures due to osteoporosis have been described following chronic heparin use (15,000 units or more daily for 3 to more than 6 months), especially in pregnant women (Prod Info heparin sodium IV, subcutaneous injection, 2010; Tuneu et al, 1985; Ahmed & Nussbaum, 1981; Amerena et al, 1990; Dahlman et al, 1990; Hardman et al, 1996; Silber & Olund, 1989; Griffith et al, 1965).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) INCREASED THYROXINE LEVEL
    1) WITH THERAPEUTIC USE
    a) Increased free plasma thyroxine has been reported with heparin use (Laji et al, 2001; HSDB , 1990).
    b) CASE REPORTS: Abnormally high levels of free thyroid hormones were associated with administration of therapeutic doses of tinzaparin or unfractionated heparin in 4 case reports. In all cases, thyroid-stimulating hormone concentrations were within the normal range. After discontinuation of heparin or tinzaparin, serum free thyroxine and tri-iodothyronine concentrations returned to normal. The mechanism was postulated to be the displacement of thyroid hormones from their binding sites by heparin-induced elevation of free fatty acid (Laji et al, 2001).
    B) ADRENAL CORTICAL HYPOFUNCTION
    1) WITH THERAPEUTIC USE
    a) Suppression of aldosterone secretion occurs to a variable extent in the majority of patients treated with heparin. It is manifested by natriuresis, potassium retention, and increased plasma renin activity (Prod Info heparin sodium IV, subcutaneous injection, 2010; Amerena et al, 1990).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Generalized hypersensitivity reactions manifested by chills, fever, urticaria, asthma, rhinitis, lacrimation, headache, nausea and vomiting, pruritus and burning, especially on the plantar side of the feet, have been reported following heparin administration (Prod Info heparin sodium IV, subcutaneous injection, 2010; Schey, 1989).
    b) Eczema occurred as a delayed hypersensitivity reaction to subQ calcium heparinate given to women with venous leg ulcers (Guillet et al, 1989; Klein et al, 1989).
    c) CASE REPORT: A generalized exanthem, believed to be an immediate type I reaction, occurred in a 65-year-old woman with acute retinal necrosis who was receiving subQ heparin 5000 units twice daily (Patrizi et al, 1989).
    B) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylactoid reactions, including shock, have been reported following heparin administration (Prod Info heparin sodium IV, subcutaneous injection, 2010).
    1) CASE SERIES: Fatal cardiovascular collapse was described in 3 patients who received IV heparin. Onset of symptoms occurred within 2 to 15 minutes. Cardiac arrest was preceded by anaphylaxis-like symptoms (respiratory distress, dyspnea). All had previous exposure to heparin (Ansell et al, 1986).
    2) CASE REPORT: Difficulty breathing, shock, cyanosis, extreme apprehension, and inaudible heart sounds occurred within 3 minutes of administration heparin sodium 50 mg IV in a 71-year-old man with a history of long-standing seasonal rhinitis and asthma. Two weeks prior to this reaction, the patient was administered heparin sodium 100 mg by IV injection without incident. Skin and passive transfer tests were positive for the beef heparin preparation used and negative for pork heparin (Bernstein, 1956).

Reproductive

    3.20.1) SUMMARY
    A) Heparin is classified as FDA pregnancy category C. Numerous studies have reported on the maternal and fetal outcomes associated with heparin use during pregnancy. Studies in which heparin has been given IV and subQ, have generally reported normal deliveries with no maternal or fetal bleeding and no other complications. In earlier studies, increased rates of abnormal pregnancies and fetal outcomes were reported with heparin therapy, but these may have been due to maternal comorbidities rather than the heparin itself.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS, RATS: No teratogenic effects were reported in rats and rabbits administered IV heparin at a dose of 10,000 units/kg/day (approximately 10 times the maximum human dose, based on body weight), during organogenesis (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Prod Info heparin sodium in 5% dextrose intravenous injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Heparin is classified as FDA pregnancy category C (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Prod Info heparin lock flush intravenous injection solution, 2010; Prod Info heparin sodium in 5% dextrose intravenous injection, 2014).
    2) Heparin should only be administered to a pregnant woman if clearly needed (Prod Info heparin lock flush intravenous injection solution, 2010), and the potential benefit to the mother outweighs the potential fetal risk (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Prod Info heparin sodium in 5% dextrose intravenous injection, 2014).
    3) Heparin and low-molecular-weight heparins (LMWHs) are currently the anticoagulants of choice for pregnant patients at risk or requiring treatment for venous thrombosis (Ginsberg et al, 2001).
    B) PLACENTAL TRANSFER
    1) Heparin does not cross the placenta (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Prod Info heparin lock flush intravenous injection solution, 2010; Prod Info heparin sodium in 5% dextrose intravenous injection, 2014).
    C) MATERNAL AND FETAL EFFECTS
    1) In earlier studies, increased rates of abnormal pregnancies and fetal outcomes were reported with heparin therapy, but these may have been due to maternal comorbidities rather than the heparin itself (Ellenhorn & Barceloux, 1988).
    2) Excessive maternal deaths, fetal loss, premature deliveries, and neonatal deaths occurred more frequently with patients on heparin rather than with coumarin derivatives (Ellenhorn & Barceloux, 1988).
    3) A review of the literature argues that the underlying maternal disease, rather than the heparin, accounts for the increased rate of adverse outcomes (Ginsberg & Hirsh, 1989).
    4) Maternal hemorrhage is the most common maternal complication. However, incidence is still low with heparin doses of 5000 Units twice daily (Ginsberg & Hirsh, 1989).
    D) PREMATURE DELIVERY
    1) CASE REPORT: A 32-year-old pregnant woman with DVT delivered a normal infant prematurely at 28 weeks while on continuous heparin (Brabeck, 1987).
    E) THROMBOCYTOPENIA
    1) Heparin-induced thrombocytopenia (HIT) is an immune, IgG-mediated condition that occurs rarely in patients treated with unfractionated heparin or, less commonly, low-molecular-weight heparins (Warkentin et al, 1995). The incidence of thrombocytopenia in pregnant patients has been reported to be 4% (Fausett et al, 2001), which compares to an estimated incidence of 3% in nonpregnant patients (Warkentin et al, 1995).
    F) TOXIC EPIDERMAL NECROLYSIS
    1) CASE REPORT: A mother who received IV heparin at a dose of 1000 Units/hour for venous thrombosis during the last 2 weeks of pregnancy delivered a full-term male neonate with toxic epidermal necrolysis (Leung, 1985).
    G) LACK OF EFFECT
    1) Numerous studies have reported on the maternal and fetal outcomes associated with heparin use during pregnancy. Studies in which heparin has been given IV and subQ, have generally reported normal deliveries with no maternal or fetal bleeding and no other complications. Such studies have used various dosing methods for heparin, including fixed subcutaneous doses, and adjusted subQ and IV doses based on target aPTT (Dahlman et al, 1989; Brabeck, 1987; Tawes et al, 1982).
    H) ANIMAL STUDIES
    1) RABBITS, RATS: Early resorptions were observed in rats and rabbits administered IV heparin at a dose of 10,000 units/kg/day (approximately 10 times the maximum human dose, based on body weight), during organogenesis (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Prod Info heparin sodium in 5% dextrose intravenous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Heparin is not excreted into human breast milk (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Prod Info heparin lock flush intravenous injection solution, 2010; Prod Info heparin sodium in 5% dextrose intravenous injection, 2014).
    2) Exercise caution when administering heparin to a woman who is breastfeeding (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Prod Info heparin sodium in 5% dextrose intravenous injection, 2014).
    3) If possible, preservative-free heparin sodium injection is recommended when administered to a nursing woman; benzyl alcohol present in maternal serum is likely to be excreted into human milk and absorbed by the breastfed infant (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturers do not report any carcinogenic potential for heparin sodium in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturers do not report any carcinogenic potential for heparin sodium in animals (Prod Info heparin sodium IV, subcutaneous injection, 2010).

Genotoxicity

    A) At the time of this review, the manufacturer does not report any mutagenic potential for heparin sodium (Prod Info heparin sodium IV, subcutaneous injection, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    B) Monitor CBC with platelets, aPTT, PT or INR, and bleeding time in patients with evidence of bleeding or following a significant exposure.
    C) Monitor vital signs, renal function and hepatic enzymes in symptomatic patients.
    D) Monitor for signs and symptoms of heparin-induced thrombocytopenia and thrombosis (HITT), including deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, or gangrene of the extremities; delayed HITT could occur up to several weeks after the discontinuation of heparin therapy.
    E) In one case of heparin overdose in a bleeding neurosurgical patient, thromboelastography (TEG) was used at the point-of-care to guide heparin reversal before emergency surgical procedures. Since TEG results are more rapidly available than standard coagulation studies, this may be more useful to guide protamine reversal in patients requiring emergent heparin reversal.
    4.1.2) SERUM/BLOOD
    A) COAGULATION STUDIES
    1) ACTIVATED PARTIAL THROMBOPLASTIN TIME (aPTT): The most reproducible and frequently used monitoring tool for assessment of anticoagulation with heparin is the activated partial thromboplastin time (aPTT). Thromboembolism is prevented by "therapeutic" values of 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value (Prod Info heparin sodium IV, subcutaneous injection, 2010; Basu et al, 1972). The activated partial thromboplastin time is a global indicator of the balance between activators and inhibitors of the intrinsic pathways of plasma coagulation. It cannot distinguish between the effects of heparin and various clotting factor deficiencies. Normal adult values range from 28 to 42 seconds (Evans et al, 1986).
    2) BASELINE DETERMINATION: There is a large interpatient variability in anticoagulant response to heparin as evaluated by the aPTT. Similar doses of heparin may lead to 12-fold variations in aPTT. The baseline aPTT accounts for most of the variability and should be determined prior to initiating therapy (Bjornsson & Wolfram, 1982).
    3) Other coagulation tests (prothrombin time (PT), thrombin time (TT), and activated coagulation time (ACT)) have been used for monitoring heparin effects.
    a) THROMBIN TIME (TT): Thrombin time measures Factor IIa conversion of fibrinogen to fibrin. Normal adult values range from 13 to 20 seconds. Therapeutic heparin therapy results in a thrombin time of 50 to 100 seconds at a 1:4 dilution (Evans et al, 1986).
    b) ACTIVATED COAGULATION TIME (ACT): The activated coagulation time is less sensitive to effects of low heparin concentrations, but is a global test that can be performed rapidly at the bedside. Normal adult values are 80 to 130 seconds, with therapeutic heparinization at 150 to 190 seconds (Evans et al, 1986).
    B) THROMBOELASTOGRAPHY (TEG)
    1) Since TEG results are more rapidly available than standard coagulation studies, this may be more useful to guide protamine reversal in patients requiring emergent heparin reversal. In one case of heparin overdose in a bleeding neurosurgical patient, thromboelastography was used at the point-of-care to guide heparin reversal before emergency surgical procedures (Figueiredo et al, 2013).
    a) CASE REPORT: A 51-year-old obese woman underwent a surgery to remove an intracranial hemangiopericytoma. The day after the surgery, she developed pulmonary embolism and was treated with IV continuous unfractionated heparin (50,000 Units/24 hours after a bolus dose of 50 Units/kg). She developed bleeding from different puncture wounds 12 hours later and heparin infusion was discontinued. A blood sample revealed heparin concentration of 4.5 Units/mL using an anti-Xa heparin assay. At this time, she developed right-sided hemiplegia and impaired consciousness. A head CT scan revealed an intracranial hematoma at the operation site. Thromboelastography (TEG) was used to guide heparin reversal. Protamine was administered using the first result of TEG analysis while standard coagulation tests were still not available. After normal coagulation was restored, an emergency procedure for intracranial hemorrhage was performed. Following further supportive care, including repeated administration of protamine guided by TEG, her coagulation tests gradually normalized. She was treated with subcutaneous enoxaparin (40 mg) 2 days after surgery and she was discharged 2 months later (Figueiredo et al, 2013).
    C) LABORATORY INTERFERENCE
    1) Over 0.1 mL of heparin left in a syringe for each 3 to 4 mL of arterial blood drawn may alter the results of an ABG, causing a decrease in pCO2, HCO3, and base excess (Ellenhorn & Barceloux, 1988; Kirshon & Moise, 1989).
    D) HEPARIN-INDUCED THROMBOCYTOPENIA
    1) The main diagnostic criteria for heparin-induced thrombocytopenia (HIT) include the presence of HIT antibodies, in association with a decrease in platelet count of greater than 50% (from the highest platelet count during the 2-week period following the start of heparin therapy or to levels less than 150 X 10(9)/L) and current or recent exposure to heparin. Thus, serial platelet counts in patients treated with heparin are essential for the early diagnosis and management of HIT (Warkentin et al, 2008; Menajovsky, 2005). Complications due to HIT may occur before a drop in platelet count. A diagnosis of HIT may also be made in a patient with HIT antibodies who has thrombosis, heparin-induced skin lesions, or an acute systemic reaction following an IV bolus of heparin (Warkentin et al, 2008).
    2) A CBC with peripheral smear, coagulation studies, and disseminated intravascular coagulation (DIC) screen should also be obtained to rule out the presence of HIT-associated DIC. A peripheral blood film examination usually reveals only reduced platelets. However, some HIT patients have evidence of DIC with RBC fragments (schistocytes) or even nucleated RBCs (normoblasts) (Warkentin, 2005).
    4.1.3) URINE
    A) URINALYSIS
    1) Urinalysis should be obtained for detection of hematuria.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Examine sputum and stool for the presence of blood.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms (eg, anaphylaxis, hemorrhage) should be admitted to an intensive care setting.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All patients with heparin overdose should be evaluated and monitored until symptoms resolve. Patients can be discharged when laboratory values are stable with no evidence of bleeding.

Monitoring

    A) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    B) Monitor CBC with platelets, aPTT, PT or INR, and bleeding time in patients with evidence of bleeding or following a significant exposure.
    C) Monitor vital signs, renal function and hepatic enzymes in symptomatic patients.
    D) Monitor for signs and symptoms of heparin-induced thrombocytopenia and thrombosis (HITT), including deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, or gangrene of the extremities; delayed HITT could occur up to several weeks after the discontinuation of heparin therapy.
    E) In one case of heparin overdose in a bleeding neurosurgical patient, thromboelastography (TEG) was used at the point-of-care to guide heparin reversal before emergency surgical procedures. Since TEG results are more rapidly available than standard coagulation studies, this may be more useful to guide protamine reversal in patients requiring emergent heparin reversal.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not indicated; heparin is only available parenterally.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Refer to the PARENTERAL EXPOSURE section of treatment recommendations.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Efforts to enhance elimination are not indicated as heparin is rapidly removed from the body. Some data indicate that heparin is not dialyzable and its half-life is unchanged by hemodialysis (Guha, 1973; Cameron et al, 1972).
    B) EXCHANGE TRANSFUSION
    1) Exchange transfusion was reported to be successful in stopping hemorrhage in a neonate given a massive amount of heparin (Schreiner et al, 1978).
    2) Plasma exchange was successful in 4 patients with heparin-induced thrombocytopenia (Bouvier et al, 1988).

Abstracts

Case Reports

    A) ADULT
    1) Subcutaneous injection of 3704 units/kg of heparin and simultaneous oral ingestion of warfarin 2000 mg by a 45-year-old man resulted in over-anticoagulation (prothrombin time more than 2 minutes, normal platelet count) without clinical bleeding. One day after the overdose, protamine sulfate, factor II, IX, and X infusion, and IV vitamin K were given and the patient gradually recovered completely (Hackett et al, 1985).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Heparin sodium injection vials contain various strengths of heparin (eg, 10,000 Units/1 mL). Fatal hemorrhages have been reported in children when 1-mL heparin sodium injection vials were confused with 1-mL "catheter lock flush" vials. Three of 5 neonates died within 3 days of receiving heparin overdose (a single dose vial of 10,000 Units/mL instead of a single dose vial of 10 Units/mL). An 8-month-old infant developed a hematoma and bleeding from injection sites 2 hours after receiving 20,000 Units (3636 Units/kg) of heparin IM. Following protamine therapy and a transfusion, he recovered gradually.
    B) THERAPEUTIC DOSE: Varies by indication. ADULTS: IV: Up to 40,000 Units/24 hours; SubQ: Up to 20,000 Units every 8 to 12 hours. CHILDREN: IV: Up to 20,000 Units/m(2)/24 hours.

Therapeutic Dose

    7.2.1) ADULT
    A) HEPARIN LOCK FLUSH IV SOLUTION
    1) MAINTAIN PATENCY OF IV INJECTION DEVICE: Fill the entire device with sufficient quantity of 10 units/mL or 100 units/mL; solution is replaced with each use of device (Prod Info heparin lock flush intravenous injection solution, 2010).
    B) HEPARIN SODIUM IV, SUBQ INJECTION SOLUTION
    1) BLOOD TRANSFUSION ANTICOAGULATION : 400 to 600 units/100 mL whole blood (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).
    2) CARDIAC SURGERY TOTAL PERFUSION: 150 to 400 units/kg IV (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).
    3) THERAPEUTIC ANTICOAGULATION WITH FULL-DOSE HEPARIN:
    a) INTERMITTENT IV INJECTION: 10,000 units as IV bolus followed by 5000 to 10,000 units IV every 4 to 6 hours (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).
    b) CONTINUOUS IV INFUSION: 5000 units as IV bolus followed by 20,000 to 40,000 units/24 hours for infusion (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).
    c) SUBQ INJECTION: 333 units/kg subQ, followed by 250 units/kg subQ every 12 hours, using a different injection site each time to prevent hematomas (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).
    4) INTRAVASCULAR VIA EXTRACORPOREAL DIALYSIS: 25 to 30 units/kg initial dose followed by 1500 to 2000 units/hour infusion (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).
    5) LOW-DOSE POSTOPERATIVE THROMBOEMBOLISM PROPHYLAXIS: 5000 units subQ 2 hours before surgery and 5000 units subQ every 8 to 12 hours for 7 days or until fully ambulatory (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).
    7.2.2) PEDIATRIC
    A) HEPARIN LOCK FLUSH SOLUTION
    1) The safety and efficacy of heparin of 10 or 100 units/mL lock flush solution have not been established in pediatric patients (Prod Info heparin lock flush intravenous injection solution, 2010).
    B) HEPARIN SODIUM
    1) LOADING DOSE
    a) INFANT TO OLDER CHILDREN: Dosage range: 50 to 150 units/kg depending on indication (maximum 5000 units). IV bolus over 10 minutes, followed by continuous infusion dosed according to age (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Monagle et al, 2008; Roach et al, 2008; deVeber et al, 1998; Andrew et al, 1994).
    MAINTENANCE DOSE
    b) LESS THAN 1 YEAR OF AGE: 25 to 30 units/kg/hour (Prod Info heparin sodium, intravenous subcutaneous injection, 2013); average, 28 units/kg/hour continuous IV infusion (Moharir et al, 2010; Monagle et al, 2008; Roach et al, 2008; Andrew et al, 1994).
    c) CHILDREN 1 YEAR OF AGE AND OLDER: 18 to 20 units/kg/hour continuous IV infusion (Prod Info heparin sodium, intravenous subcutaneous injection, 2013; Moharir et al, 2010; Monagle et al, 2008; Roach et al, 2008; Andrew et al, 1994).
    d) OLDER CHILDREN: 18 units/kg/hour continuous IV infusion (Monagle et al, 2008; Roach et al, 2008). Older children may need less heparin similar to weight-adjusted adult dosage (Prod Info heparin sodium, intravenous subcutaneous injection, 2013).

Minimum Lethal Exposure

    A) Heparin sodium injection vials contain various strengths of heparin (eg, 10,000 Units/1 mL). Fatal hemorrhages have been reported in children when 1 mL heparin sodium injection vials were confused with 1 mL "catheter lock flush" vials (Prod Info heparin sodium IV, subcutaneous injection, 2010).
    B) NEONATES: Three of 5 neonates died within 3 days of receiving heparin overdose (a single dose vial of 10,000 Units/mL instead of a single dose vial of 10 Units/mL) (Roesler et al, 2009).
    C) NEONATE: A neonate developed intraabdominal hemorrhage and bleeding from injection sites 17 hours after receiving 8000 Units (2666 Units/kg) of heparin. Despite treatment with protamine sulfate (total dose, 25.4 mg), the infant died of complications. The half-life of heparin was 45.8 hours (Galant, 1967).

Maximum Tolerated Exposure

    A) In a study of 2656 patients, a dose-response relationship was noted between heparin and the risk of bleeding in non-surgical patients. The incidence of minor and major bleeding was 3.2 and 2.6 times greater, for heparin doses of 25 Units/kg/hr compared to doses of less than 12.5 Units/kg/hr (Walker & Jick, 1980).
    B) ADULT: Subcutaneous injection of 3704 Units/kg of heparin and simultaneous oral ingestion of 2000 mg of warfarin in a 45-year-old man resulted in over-anticoagulation (prothrombin time more than 2 minutes, normal platelet count) without clinical bleeding. One day after the overdose, protamine sulfate, factor II, IX, and X infusion, and IV vitamin K were given and the patient gradually recovered completely (Hackett et al, 1985).
    C) ADULT: A 51-year-old obese woman underwent a surgery to remove an intracranial hemangiopericytoma. The day after the surgery, she developed pulmonary embolism and was treated with IV continuous unfractionated heparin (50,000 Units/24 hours after a bolus dose of 50 Units/kg). She developed bleeding from different puncture wounds 12 hours later and heparin infusion was discontinued. A blood sample revealed heparin concentration of 4.5 Units/mL using an anti-Xa heparin assay. At this time, she developed right-sided hemiplegia and impaired consciousness. A head CT scan revealed an intracranial hematoma at the operation site. Thromboelastography (TEG) was used to guide heparin reversal with protamine. After normal coagulation was restored, an emergency procedure for intracranial hemorrhage was performed. Following further supportive care, including repeated administration of protamine, her traditional coagulation tests gradually normalized. She was treated with subcutaneous enoxaparin (40 mg) 2 days after surgery and she was discharged 2 months later (Figueiredo et al, 2013).
    D) NEONATE: One study reported a case of inadvertent administration of heparin, 8620 Units/kg, to a neonate via an umbilical catheter. Four hours later, excessive bleeding from sites of skin puncture was noted, and the patient's thrombin time was more than 200 seconds. He was treated with Polybrene and packed cell transfusion and recovered. The half-life of heparin was 50.8 hours (Glueck et al, 1965).
    E) INFANT: An 8-month-old infant developed a hematoma and bleeding from injection sites 2 hours after receiving 20,000 Units (3636 Units/kg) of heparin IM. Protamine was given repeatedly (187 mg over 32 hours), as well as a transfusion of 100 mL of citrated blood. No further bleeding was noted after 12 hours of therapy; however, capillary coagulation times remained abnormal for 31 hours (Pachman, 1965).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) There is a wide range in sensitivity (as measured by aPTT) to a given plasma heparin concentration between different patients. Plasma levels of 0.4 Unit/mL have resulted in changes in aPTT of 11 to 57 seconds (Cipolle et al, 1981).
    2) In one study, the mean heparin dose required to produce an aPTT of about twice baseline was 13.9 Units/kg/hr in one study (Cipolle et al, 1981).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) HEPARIN
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1900 mg/kg (RTECS, 2006)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 500 mg/kg (RTECS, 2006)
    3) LD50- (ORAL)RAT:
    a) 1950 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SUMMARY: Heparin sodium, a glycosaminoglycan, inhibits the mechanisms that induce the clotting of blood and the formation of stable fibrin clots at various sites in the normal coagulation system. When heparin sodium is combined with antithrombin III (heparin cofactor), thrombosis is blocked through inactivation of activated Factor Xa and inhibition of prothrombin's conversion to thrombin. This also prevents fibrin formation from fibrinogen during active thrombosis (Prod Info heparin sodium IV, subcutaneous injection, 2010).
    B) ANTICOAGULANT EFFECTS
    1) At low-doses, heparin combines with antithrombin III (heparin cofactor). This complex then inactivates activated factor Xa, thereby inhibiting the conversion of prothrombin to thrombin (Ellenhorn & Barceloux, 1988; S Sweetman , 2000).
    2) With larger doses, heparin combines with antithrombin III to inactivate factors IX, X, XI, XII, and thrombin and prevent the conversion of fibrinogen to fibrin (Ellenhorn & Barceloux, 1988; S Sweetman , 2000).
    3) Heparin also inhibits the activation of factor XIII (fibrin stabilizing factor) and prevents the formation of a stable fibrin clot (S Sweetman , 2000).
    4) Heparin can decrease thrombin-induced platelet agglutination (Hardman et al, 1996; HSDB , 2000).

Toxicologic Mechanism

    A) THROMBOCYTOPENIA
    1) Heparin-induced thrombocytopenia (HIT) is an acquired hypercoagulability syndrome caused by the antibody-mediated reaction. It is characterized by thrombocytopenia and a high risk for venous or arterial thrombosis, also referred to as heparin-induced thrombocytopenia and thrombosis (HITT). Type I HIT is a minor decrease in platelet count attributed to the direct interaction between heparin and circulating platelets. The pathophysiology of type II HIT is multifactorial, but the primary factor mediating cellular activation is the generation of anti-heparin-platelet factor 4 complex antibodies. Most patients with HIT produce IgG antibodies against complexes of platelet factor 4 (PF4) and heparin. PF4 is found on the surface of endothelial cells and stored within the alpha granules of platelets. The antibody-PF4-heparin complex activates platelets, generating platelet-derived procoagulant microparticles, thereby initiating thrombin generation and provoking a hypercoagulable state (Menajovsky, 2005; Cines et al, 2004; Fabris et al, 2000; Brieger et al, 1998).
    B) OSTEOPOROSIS
    1) The cause of heparin-induced osteoporosis is unknown. Heparin may complex with calcium and thus potentiate the effects of parathyroid hormone on osteoclast function or it may increase chondroitin sulfate and collagenase activity causing accelerated bone absorption (Amerena et al, 1990).
    C) HYPOALDOSTERONISM
    1) Short-term heparin therapy causes reversible suppression of 18-hydroxylase activity. Prolonged therapy may cause atrophy of zona glomerulosa (Amerena et al, 1990).
    D) LIPEMIC PLASMA CLEARING
    1) Lipoprotein lipase released by heparin into the circulation hydrolyzes triglycerides to glycerol and free fatty acids (Hardman et al, 1996; S Sweetman , 2000).

Physicochemical

Physical Characteristics

    A) White or pale-colored amorphous powder that is nearly odorless and is soluble in saline solution and water and insoluble in alcohol, benzene, acetone, chloroform, and ether (Budavari, 1989; Lewis, 1997).

Ph

    A) HEPARIN SODIUM: 5 to 7.5 (Prod Info heparin sodium IV, subcutaneous injection, 2010)

Molecular Weight

    A) HEPARIN, COMMERCIAL: 15,000 daltons (average) (Amerena et al, 1990)
    B) HEPARIN, NATURAL: At least 75,000 daltons (Amerena et al, 1990)

References

General Bibliography

    1) Ahmed SS & Nussbaum M: Development of pulmonary edema related to heparin administration. J Clin Pharmacol 1981; 21:126-128.
    2) Amerena J, Mashford ML, & Wallace S: Adverse effects of anticoagulants. Adverse Drug React Acute Poisoning Rev 1990; 9:1-36.
    3) Andrew M, Marzinotto V, Massicotte P, et al: Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res 1994; 35(1):78-83.
    4) Ansell JE, Clark WP Jr, & Compton CC: Fatal reactions associated with intravenous heparin (letter). Drug Intell Clin Pharm 1986; 20:74-75.
    5) Arthur CK, Isbister JP, & Aspery EM: The heparin induced thrombosis - thrombocytopenia syndrome (H.I.T.T.S.): a review. Pathology 1985; 17:82-86.
    6) Atkinson JLD, Sundt TM, & Kazmier FJ: Heparin-induced thrombocytopenia and thrombosis in ischemic stroke. Mayo Clin Proc 1988; 63:353-361.
    7) Aull L, Chao H, & Coy K: Heparin-induced hyperkalemia. DICP 1990; 24:244-246.
    8) Babikian VK, Kase CS, & Pessin MS: Intracerebral hemorrhage in stroke patients anticoagulated with heparin. Stroke 1989; 20:1500-1503.
    9) Barbaccia JC, Perry WR, Dellatore C, et al: Comparison of low-dose subcutaneous heparin calcium and heparin sodium on ecchymosis formation. Clin Pharmacokinet 1984; 3:184-186.
    10) Basu D, Gallus A, & Hirsh J: A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287:324-327.
    11) Becker PS & Miller VT: Heparin-induced thrombocytopenia. Stroke 1989; 20:1449-1459.
    12) Beermann B & Lahnborg G: Pharmacokinetics of heparin in healthy and obese subjects and in combination with dihydroergotamine. Thromb Haemost 1981; 45:24-26.
    13) Bell WR, Tomasulo PA, & Alving BM: Thrombocytopenia occurring during the administration of heparin. Ann Intern Med 1976; 85:155-160.
    14) Bell WR: Heparin-associated thrombocytopenia and thrombosis. J Lab Clin Med 1988; 3:600-605.
    15) Bernstein IL: Anaphylaxis to heparin sodium: report of a case, with immunologic studies. JAMA 1956; 161:1379-1381.
    16) Bircher AJ, Fluckiger R, & Buchner SA: Delayed-type hypersensitivity to subcutaneous heparin. Contact Dermatitis 1990; 23:264.
    17) Bjornsson TD & Wolfram KM: Intersubject variability in the anticoagulant response to heparin in vitro. Eur J Clin Pharmacol 1982; 21:491-497.
    18) Boccara O, Prost-Squarcioni C, Battistella M, et al: Calcinosis Cutis: A Rare Reaction to Subcutaneous Injections of Calcium-Containing Heparin in Patients With Renal Failure. Am J Dermatopathol 2009; epub:epub.
    19) Bouvier JL, Lefevre P, & Villain Ph: Treatment of serious heparin-induced thrombocytopenia by plasma exchange: report on 4 cases. Thromb Res 1988; 51:335-336.
    20) Brabeck MC: Ambulatory management of thromboembolic disease during pregnancy with continuous infusion of heparin. JAMA 1987; 257:1790-1791.
    21) Brieger DB, Mak KH, Kottke-Marchant K, et al: Heparin-induced thrombocytopenia. J Am Coll Cardiol 1998; 31(7):1449-1459.
    22) Brooks JC: Noncardiogenic pulmonary edema immediately following rapid protamine administration. Ann Pharmacother 1999; 33:927-930.
    23) Budavari S: The Merck Index, 11th ed, Merck & Co, Inc, Rahway, New Jersey, 1989.
    24) Busch EH, Ventura HO, & Lavie CJ: Heparin-induced hyperkalemia. South Med J 1987; 80:1450-1451.
    25) Cameron JS, Fitzgerald D, & Youssef AK: Heparin 35S removal in anephric patients undergoing regular dialysis. Proc Eur Dial Transplant Assoc 1972; 9:614-617.
    26) Christiaens GCM & Nieuwenhuis HK: Heparin-induced skin necrosis. N Engl J Med 1996; 335:715.
    27) Cines DB, Bussel JB, McMillan RB, et al: Congenital and acquired thrombocytopenia. Hematology (Am Soc Hematol Educ Program) 2004; 0:390-406.
    28) Cipolle RJ, Seifert RD, & Neilan BA: Heparin kinetics: variables related to disposition and dosage. Clin Pharmacol Ther 1981; 29:387-393.
    29) Cohen GR, Hall JC, & Yeast JD: Heparin-induced cutaneous necrosis in a postpartum patient. Obstet Gynecol 1988; 72:498-499.
    30) Cola C & Ansell J: Heparin-induced thrombocytopenia and arterial thrombosis: alternative therapies. Am Heart J 1990; 119:368-374.
    31) Dager WE & White RH: Pharmacotherapy of heparin-induced thrombocytopenia. Expert Opin Pharmacother 2003; 4:919-940.
    32) Dager WE & White RH: Treatment of heparin-induced thrombocytopenia. Ann Pharmacother 2002; 36:489-503.
    33) Dahlman T, Lindvall N, & Hellgren M: Osteopenia in pregnancy during long-term heparin treatment: a radiological study postpartum. Br J Obstet Gynaecol 1990; 97:221-228.
    34) Dahlman TC, Hellgren MS, & Blombeck M: Thrombosis prophylaxis in pregnancy with use of subcutaneous heparin adjusted by monitoring heparin concentration in plasma. Am J Obstet Gynecol 1989; 161(2):420-5.
    35) Dang CH, Durkalski VL, & Nappi JM: Evaluation of treatment with direct thrombin inhibitors in patients with heparin-induced thrombocytopenia. Pharmacotherapy 2006; 26(4):461-468.
    36) Dawes J & Papper DS: Catabolism of low-dose heparin in man. Thromb Res 1979; 14:845-860.
    37) Deitcher SR, Topoulos AP, Bartholomew JR, et al: Lepirudin anticoagulation for heparin-induced thrombocytopenia. J Pediatr 2002; 140(2):264-266.
    38) Dukes GE, Sanders SW, & Russo J: Transaminase elevations in patients receiving bovine or porcine heparin. Ann Intern Med 1984; 100:646-650.
    39) Dukes GE, Sanders SW, Russo J, et al: Transaminase elevations in patients receiving bovine or porcine heparin. Ann Intern Med 1984a; 100:646-650.
    40) Edes TE & Sunderrajan EV: Heparin-induced hyperkalemia. Arch Intern Med 1985; 145:1070-1072.
    41) Edes TE: Heparin-induced hyperkalemia. Postgrad Med J 1990; 87:104-106.
    42) Ellenhorn MJ & Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning, Elsevier, New York, NY, 1988.
    43) Ellison N, Ominsky AJ, & Wollman H: Is protamine a clinically important anticoagulant? A negative answer. Anesthesiology 1971; 35:621-629.
    44) Estes JW & Poulin PF: Pharmacokinetics of heparin: distribution and elimination. Thromb Diath Haemorrh 1975; 33:26-37.
    45) Estes JW: Clinical pharmacokinetics of heparin. Clin Pharmacokinet 1980; 5:204-220.
    46) Evans WE, Schentag JJ, & Jusko WJ: Applied Pharmacokinetics, 2nd ed, Applied Therapeutics, Spokane, WA, 1986.
    47) Fabris F, Ahmad S, Cella G, et al: Pathophysiology of heparin-induced thrombocytopenia: clinical and diagnostic implications--a review.. Arch Pathol Lab Med 2000; 124:1657-1666.
    48) Fabris F, Luzzatto G, Stefani PM, et al: Heparin-induced thrombocytopenia. Haematologica 2000a; 85:72-81.
    49) Fausett M, Vogtlander M, Lee R, et al: Heparin-induced thrombocytopenia is rare in pregnancy. Am J Obstet Gynecol 2001; 185(1):145-52.
    50) Figueiredo S, Vigue B, Benhamou D, et al: Emergency reversal of heparin overdose in a neurosurgical patient guided by thromboelastography. Br J Anaesth 2013; 111(2):303-304.
    51) Fowlie J, Stanton PD, & Anderson JR: Heparin-associated skin necrosis. Postgrad Med J 1990; 6:573-575.
    52) Frame JN, Mulvey KP, & Phares JC: Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med 1989; 111:946-947.
    53) Galant SP: Accidental heparinization of a newborn infant. Am J Dis Child 1967; 114:313-319.
    54) Genton E: Guidelines for heparin therapy. Ann Intern Med 1974; 80:77-82.
    55) Gilman AG, Rall TW, & Nies AS: The Pharmacological Basis of Therapeutics, 8th ed, Pergamon Press, New York, NY, 1990.
    56) Ginsberg JS & Hirsh J: Anticoagulants during pregnancy. Am Rev Med 1989; 40:79-86.
    57) Ginsberg JS, Greer I, & Hirsh J: Use of antithrombotic agents during pregnancy. Chest 2001; 119(1 Suppl):122S-131S.
    58) Girolami B, Prandoni P, Stefani PM, et al: The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood 2003; 101:2955-2959.
    59) Glock Y, Szmil E, & Boudjema B: Cardiovascular surgery and heparin induced thrombocytopenia. Int Angiol 1988; 7:238-245.
    60) Glueck HI, Light IJ, & Flessa H: Sodium heparin administration to a newborn infant. JAMA 1965; 191:159-160.
    61) Gonzalez-Martin G, Diaz-Molinas MS, Martinez AM, et al: Heparin-induced hyperkalemia: a prospective study. Int J Clin Pharmacol Ther Toxicol 1991; 29:446-450.
    62) Gram J, Mercker S, & Bruhn HD: Does protamine chloride neutralize low molecular weight heparin sufficiently?. Thromb Res 1988; 52:353-359.
    63) Grant WM & Schuman JS: Toxicology of the Eye, 4th ed, Charles C Thomas, Springfield, IL, 1993.
    64) Griffith GC, Nichols G Jr, & Asher JD: Heparin osteoporosis. JAMA 1965; 193:85-88.
    65) Guha A: Heparin kinetics in uremia. Proc Am Soc Nephrol 1973; 45.
    66) Guillet G, Delaire P, & Plantin P: Eczema as a complication of heparin therapy. J Am Acad Dermatol 1989; 20:1130-1132.
    67) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 1990; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    68) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    69) Hackett LP, Ilett KF, & Chester A: Plasma warfarin concentrations after a massive overdose. Med J Aust 1985; 142:642-643.
    70) Hardman JG, Limbird LE, & Molinoff PB: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, McGraw-Hill, New York, NY, 1996.
    71) Harenberg J & Heene DL: Pharmacology and special clinical applications of low-molecular-weight heparins. Am J Hematol 1988; 29:233-240.
    72) Harrington L & Hufnagel JM: Heparin-induced thrombocytopenia and thrombosis syndrome: a case study. Heart Lung 1990; 19:93-99.
    73) Hartman AR, Hood RM, & Anagnostopoulos E: Phenomenon of heparin-induced thrombocytopenia associated with skin necrosis. J Vasc Surg 1988; 7:781-784.
    74) Hirsh J, Bauer KA, Donati MB, et al: Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(6 Suppl):141S-159S.
    75) Holland CL, Singh AK, & McMaster PRB: Adverse reactions to protamine sulfate following cardiac surgery. Clin Cardiol 1984; 7:157-162.
    76) Hudcova J & Talmor D: Life-threatening hemorrhage following subcutaneous heparin therapy. Ther Clin Risk Manag 2009; 5(1):51-54.
    77) Hull R, Delmore T, & Carter C: Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306:189-194.
    78) Khan Z & Watson DK: Heparin-induced skin necrosis. Br J Obstet Gynecol 2000; 107:1315-1316.
    79) Kirshon B & Moise KJ Jr: Effect of heparin on umbilical arterial blood gases. J Reprod Med 1989; 34:267-269.
    80) Kiser TH & Fish DN: Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction. Pharmacotherapy 2006; 26(4):452-460.
    81) Klein GF, Kofler H, & Wolf H: Eczema-like, erythematous, infiltrated plaques: a common side effect of subcutaneous heparin therapy. J Am Acad Dermatol 1989; 21:703-707.
    82) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    83) Kondo LM, Wittkowsky AK, & Wiggins BS: Argatroban for prevention and treatment of thromboembolism in heparin-induced thrombocytopenia. Ann Pharmacother 2001; 35:440-451.
    84) LaMonte MP, Brown PM, & Hursting MJ: Stroke in patients with heparin-induced thrombocytopenia and the effect of argatroban therapy. Crit Care Med 2004; 32:976-980.
    85) Laji K, Rhidha B, John R, et al: Abnormal serum free thyroid hormone levels due to heparin administration. Q J Med 2001; 94:471-473.
    86) Leung A: Toxic epidermal necrolysis associated with maternal use of heparin. JAMA 1985; 253:201.
    87) Leung WH, Lau CP, & Wong CK: Fatal cardiac tamponade in systemic lupus erythematosus - a hazard of anticoagulation. Am Heart J 1990; 119:422-423.
    88) Lewis RJ: Hawley's Condensed Chemical Dictionary, 13th ed, John Wiley & Sons, Inc, New York, NY, 1997.
    89) Libow LF, DiPreta EA, & Dyksterhouse DL: Cutaneous heparin necrosis in a patient with heterozygous protein S deficiency. Cutis 1997; 59:242-244.
    90) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    91) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    92) Lowenstein E, Johnston WE, & Lappas DG: Catastrophic pulmonary vasoconstriction associated with protamine reversal of heparin. Anesthesiology 1983; 59:470-473.
    93) Lubenow N, Eichler P, Lietz T, et al: Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost 2005; 3(11):2428-2436.
    94) MacLean JA, Moscicki R, & Bloch KJ: Adverse reactions to heparin. Ann Allergy 1990; 65:254-259.
    95) Manfredini R, Boari B, Regoli F, et al: Cholestatic liver reaction and heparin therapy (letter). Arch Intern Med 2000; 160:3166.
    96) Manzano L, Yebra M, & Vargas JA: Plasmapheresis in heparin-induced thrombocytopenia and thrombosis (letter). Stroke 1990; 21:1236.
    97) Marciniak E: Binding of heparin in vivo and in vitro to plasma proteins. J Lab Clin Med 1974; 84:344-356.
    98) Martin CMM, Engstrom PF, & Barrett O Jr: Surreptitious self-administration of heparin. JAMA 1970; 212:475-476.
    99) Matsuo T, Yamada T, & Yamanashi T: Anticoagulant therapy with MD805 of hemodialysis patient with heparin-induced thrombocytopenia. Thromb Res 1990; 58:663-666.
    100) Matthai WH, Hursting MJ, Lewis BE, et al: Argatroban anticoagulation in patients with a history of heparin-induced thrombocytopenia. Thromb Res 2005; 116(2):121-126.
    101) McAvoy TJ: The biologic half-life of heparin. Clin Pharmacol Ther 1979b; 25:372-379.
    102) McDonald MM, Jacobson LJ, & Hay WW: Heparin clearance in the newborn. Pediatr Res 1981; 15:1015-1018.
    103) Menajovsky LB: Heparin-induced thrombocytopenia: clinical manifestations and management strategies. Am J Med 2005; 118(Suppl 8A):21-30.
    104) Miller ML: Heparin-induced thrombocytopenia. Cleve Clin J Med 1989; 56:483-490.
    105) Moharir MD, Shroff M, Stephens D, et al: Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study. Ann Neurol 2010; 67(5):590-599.
    106) Monagle P, Chalmers E, Chan A, et al: Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(6 Suppl):887S-968S.
    107) Monagle P, Chan A, Massicotte P, et al: Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl):645-687.
    108) Monreal M, Lafoz E, & Salvador R: Adverse effects of three different forms of heparin therapy: thrombocytopenia, increased transaminases, and hyperkalemia. Eur J Clin Pharmacol 1989a; 37:415-418.
    109) Monreal M, Lafoz E, Salvador R, et al: Adverse effects of three different forms of heparin therapy: thrombocytopenia, increased transaminases, and hyperkalaemia. Eur J Clin Pharmacol 1989; 37:415-418.
    110) Morecroft JA & Lea RE: Haemothorax - a complication of anticoagulation for suspected pulmonary embolism. Br J Clin Pract 1988; 42:217-218.
    111) Mustafa MH & Gallino R: Spontaneous spinal epidural hematoma causing cord compression after streptokinase and heparin therapy for acute coronary artery occlusion. South Med J 1988; 81:1202-1203.
    112) Nand S & Robinson JA: Plasmapheresis in the management of heparin-associated thrombocytopenia with thrombosis. Am J Hematol 1988; 28:204-206.
    113) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    114) Nogueira PCK, Giuliani C, & Rey N: Calcifying panniculitis in a child after renal transplantation. Nephrol Dial Transplant 1997; 12:216-218.
    115) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    116) Olesen LL: Femoral neuropathy secondary to anticoagulation. J Int Med 1989; 226:279-280.
    117) Orlando MP, Dillon ME, & O'Dell MW: Heparin-induced hyperkalemia confirmed by drug rechallenge. Am J Phys Med Rehabil 2000; 79:93-96.
    118) Pachman DJ: Accidental heparin poisoning. Am J Dis Child 1965; 110:210-212.
    119) Passannante A & Macik BG: Case report: the heparin flush syndrome: a cause of iatrogenic hemorrhage. Am J Med Sci 1988; 296:71-73.
    120) Patrizi A, Di Lernia V, & Patrone P: Generalized reaction to subcutaneous heparin. Contact Dermatitis 1989; 20:309-310.
    121) Patterson BM, Marchand R, & Ranawat C: Complications of heparin therapy after total joint arthroplasty. J Bone Joint Surg 1989; 71-A:1130-1134.
    122) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    123) Product Information: COUMADIN(R) oral tablets, IV injection, warfarin sodium oral tablets, IV injection. Bristol-Myers Squibb Company, Princeton, NJ, 2007.
    124) Product Information: Heparin sodium in 5% dextrose IV injection, Heparin sodium in 5% dextrose IV injection. B Braun Medical Inc, Irvine, CA, 2009.
    125) Product Information: REFLUDAN(R) IV injection, lepirudin (rDNA) IV injection. Bayer Healthcare Pharmaceuticals Inc, Wayne, NJ, 2006.
    126) Product Information: argatroban IV injection, argatroban IV injection. Encysive Pharmaceuticals Inc, Houston, TX, 2008.
    127) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    128) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    129) Product Information: heparin lock flush intravenous injection solution, heparin lock flush intravenous injection solution. APP Pharmaceuticals, LLC (per DailyMed), Schaumburg, IL, 2010.
    130) Product Information: heparin lock flush solution injection, heparin lock flush solution injection. Syrex, Neptune, NJ, 2006.
    131) Product Information: heparin sodium IV, subcutaneous injection, heparin sodium IV, subcutaneous injection. APP Pharmaceuticals, LLC, Schaumburg, IL, 2010.
    132) Product Information: heparin sodium in 5% dextrose intravenous injection, heparin sodium in 5% dextrose intravenous injection. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2014.
    133) Product Information: heparin sodium, intravenous subcutaneous injection, heparin sodium, intravenous subcutaneous injection. Pfizer Labs (per DailyMed), New York, NY, 2013.
    134) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    135) Product Information: protamine sulfate IV injection, protamine sulfate IV injection. APP Pharmaceuticals LLC, Schaumburg, IL, 2008.
    136) RTECS: Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2006; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    137) Ramirez-Lassepas M, Cipolle RJ, & Rodvold KA: Heparin-induced thrombocytopenia in patients with cerebrovascular ischemic disease. Neurology 1984; 34:736-740.
    138) Rizzoni WE, Miller K, & Rick M: Heparin-induced thrombocytopenia and thromboembolism in the postoperative period. Surgery 1988; 103:470-476.
    139) Roach ES, Golomb MR, Adams R, et al: Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke 2008; 39(9):2644-2691.
    140) Roesler R, Ward D, & Short M: Supporting staff recovery and reintegration after a critical incident resulting in infant death. Adv Neonatal Care 2009; 9(4):163-171.
    141) Rongioletti F, Pisani S, & Ciaccio M: Skin necrosis due to intravenous heparin. Dermatologica 1989; 178:47-50.
    142) S Sweetman : Martindale: The Complete Drug Reference. Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    143) Savas MC, Benekli M, & Akcay A: Heparin-associated refractory bronchospasm (letter). Ann Pharmacother 1997; 31:253.
    144) Sax NI & Lewis RJ: Dangerous Properties of Industrial Materials, 7th ed, Van Nostrand Reinhold Co, New York, NY, 1989.
    145) Schey SA: Hypersensitivity reactions to heparin and the use of new low molecular weight heparins (letter). Eur J Haematol 1989; 42:107.
    146) Schmidt OH & Lang W: Heparin-induced thrombocytopenia with thromboembolic arterial occlusion treated with recombinant hirudin (letter). N Engl J Med 1997; 337:1389.
    147) Schmugge M, Risch L, Huber AR, et al: Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients. Pediatrics 2002; 109:E10.
    148) Schreiner RL, Wynn RJ, & McNulty C: Accidental heparin toxicity in the newborn intensive care unit. J Pediatr 1978; 92:115-116.
    149) Sherman DS, Kass CL, & Fish DN: Fludrocortisone for the treatment of heparin- induced hyperkalemia. Ann Pharmacother 2000; 34:606-610.
    150) Silber M & Olund A: Successful outcome of pregnancy complicated by giant myoma and severe heparin-induced osteopenia. Gynecol Obstet Invest 1989; 28:51-52.
    151) Silver D, Kapsch DN, & Tsoi EKM: Heparin-induced thrombocytopenia, thrombosis, and hemorrhage. Ann Surg 1983; 198:301-306.
    152) Smoot EC, Marx A, Weiman D, et al: Recognition, diagnosis, and management of heparin-induced thrombocytopenia and thrombosis. Plast Reconstruct Surg 1999; 103:559-565.
    153) Smythe MA, Stephens JL, Koerber JM, et al: A comparison of lepirudin and argatroban outcomes. Clin Appl Thromb Hemost 2005; 11(4):371-374.
    154) Spinler SA & Dager W: Overview of heparin-induced thrombocytopenia. Am J Health Syst Pharm 2003; 60 (Suppl 5):S5-S11.
    155) Stanton PE Jr, Evans JR, & Lefemine AA: White clot syndrome. South Med J 1988; 81:616-620.
    156) Stephan F, Cheffi MA, Kaplan C, et al: Autoantibodies against platelet glycoproteins in critically ill patients with thrombocytopenia.. Am J Med 2000; 108:554-560.
    157) Stricker H, Lammle B, & Furlan M: Heparin-dependent in vitro aggregation of normal platelets by plasma of a patient with heparin-induced skin necrosis: specific diagnostic test for a rare side effect. Am J Med 1988; 85:721-724.
    158) Tawes RL Jr, Kennedy PA, Harris EJ, et al: Management of deep venous thrombosis and pulmonary embolism during pregnancy. Am J Surg 1982; 144(1):141-5.
    159) Tonn ME, Schaiff RA, & Kollef MH: Enoxaparin-associated dermal necrosis: a consequence of cross-reactivity with heparin-mediated antibodies. Ann Pharmacother 1997; 31:323-326.
    160) Tuneu A, Moreno A, & de Moragas JM: Cutaneous reactions secondary to heparin injections. J Am Acad Dermatol 1985; 12:1072-1077.
    161) US Food and Drug Administration: FDA Approves Updated Warfarin (Coumadin) Prescribing Information. US Food and Drug Administration. Rockville, MD. 2007. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html.
    162) US Food and Drug Administration: Important Warnings and Instructions for Heparin Sodium Injection (Baxter). US Food and Drug Administration. Beltsville, MD. 2008a. Available from URL: http://www.fda.gov/cder/drug/advisory/heparin.htm.
    163) US Food and Drug Administration: Recall of Heparin Sodium Injection and Heparin Lock Flush Solution (Baxter). US Food and Drug Administration. Rockville, MD. 2008. Available from URL: http://www.fda.gov/cder/drug/infopage/heparin/public_health_update.htm.
    164) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    165) Walker AM & Jick H: Predictors of bleeding during heparin therapy. JAMA 1980; 244:1209-1212.
    166) Warkentin TE & Kelton JG: Delayed onset-heaprin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135:502-506.
    167) Warkentin TE & Kelton JG: Heparin and platelets. Hematol Oncol Clin North Am 1990; 4:243-264.
    168) Warkentin TE & Kelton JG: Heparin-induced thrombocytopenia. Ann Rev Med 1989; 40:31-44.
    169) Warkentin TE, Greinacher A, Koster A, et al: Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:340S-380S.
    170) Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.. N Engl J Med 1995; 332:1330-1335.
    171) Warkentin TE: Heparin-induced thrombocytopenia and its treatment. J Thrombosis Thrombolysis 2000; 9:S29-S35.
    172) Warkentin TE: Heparin-induced thrombocytopenia: diagnosis and management. Circulation 2004; 110(18):454-458.
    173) Warkentin TE: Limitations of conventional treatment options for heparin-induced thrombocytopenia. Sem Hematol 1998; 35 (Suppl 5):17-25.
    174) Warkentin TE: New approaches to the diagnosis of heparin-induced thrombocytopenia. Chest 2005; 127(Suppl 2):35S-45S.
    175) Weiler JM, Freiman P, & Sharath MD: Serious adverse reactions to protamine sulfate: are alternatives needed?. J Allergy Clin Immunol 1985; 75:297-303.
    176) Winsor HM & Freeman M: An investigation of routes of administration of heparin other than injection. Am J Med 1964; 37:408-416.
    177) Young E: Allergy to subcutaneous heparin. Contact Dermatitis 1988; 19:152-153.
    178) deVeber G, Chan A, Monagle P, et al: Anticoagulation therapy in pediatric patients with sinovenous thrombosis: a cohort study. Arch Neurol 1998; 55(12):1533-1537.