Antithrombin III (Human) and HepFlush

• Generic Name: antithrombin iii
• Dosage Forms: n.a.
• Other Brand Names: Thrombate III

Short-term replacement therapy for prevention or treatment of thromboembolism in selected patients with congenital antithrombin III deficiency at high risk for thromboembolism (i.e., those undergoing surgical or obstetrical procedures) or those with thromboembolism. Has been designated an orphan drug by FDA for this use.

Confirm congenital antithrombin III deficiency based on clear family history of venous thrombosis and decreased endogenous plasma antithrombin III concentrations; exclude acquired antithrombin III deficiency.

Thromboprophylaxis (e.g., with unfractionated heparin, low molecular weight heparin) throughout pregnancy recommended by the American College of Chest Physicians (ACCP) and other clinicians in women with congenital antithrombin III deficiency. ACCP and other clinicians recommend discontinuance of heparin or low molecular weight heparin thromboprophylaxis prior to labor followed by postpartum anticoagulation with warfarin. Follow-up replacement therapy with antithrombin III in women with congenital deficiency suggested by some clinicians, initiated prior to or on day of delivery and continued postpartum. Has been used in combination with unfractionated heparin after delivery in such patients.

Management of venous thromboembolism in patients with congenital antithrombin III deficiency generally similar to that in other patients (i.e., conventional anticoagulation with unfractionated heparin, low molecular weight heparin, or fondaparinux followed by warfarin). Short-term therapy with antithrombin III suggested by some clinicians when unacceptable risks of bleeding exist with conventional anticoagulation.

Role of antithrombin III as adjunctive therapy to unfractionated heparin in patients with congenital antithrombin III deficiency and thromboembolism not clearly defined. (See Interactions.) Used to overcome unfractionated heparin resistance (e.g., IV heparin dosage >35,000–40,000 units daily required to achieve aPTT ≥1.5 times control value) in such patients. Use of antithrombin III also suggested by some clinicians in patients with severe thrombosis or breakthrough thrombosis despite anticoagulation.

Has been used in a limited number of neonates with congenital antithrombin III deficiency. (See Pediatric Use under Cautions.)

• Generic Name: heparin
• Dosage Forms: n.a.
• Other Brand Names:

  Hep-Pak, Heparin Lock flush, Hep-Pak CVC, Hep-Lock, Heparin Sodium ADD-Vantage, HepFlush

Treatment of DVT and PE.

Recommended by the American College of Chest Physicians (ACCP) as an appropriate choice of anticoagulant for initial treatment of acute proximal DVT or PE.

LMWHs or fondaparinux generally preferred over heparin for initial treatment of acute venous thromboembolism; however, heparin may be preferred in patients with renal impairment. IV heparin also may be preferred over sub-Q therapies in patients with PE in whom thrombolytic therapy is being considered or if there is concern about adequate sub-Q absorption.

After full-dose heparin therapy, warfarin or an LMWH generally is administered as follow-up anticoagulant therapy for ≥3 months in adults with venous thromboembolism.

Thromboprophylaxis in General Surgery

Prophylaxis of postoperative DVT and PE in patients undergoing general (e.g., abdominal) surgery who are at risk of thromboembolism.

ACCP recommends pharmacologic (e.g., low-dose heparin) and/or nonpharmacologic/mechanical (e.g., intermittent pneumatic compression) methods of thromboprophylaxis in patients undergoing general surgery, including abdominal, GI, gynecologic, and urologic surgery, according to the patient’s risk of thromboembolism and bleeding. In general, pharmacologic prophylaxis is recommended in patients with high (and possibly moderate) risk of venous thromboembolism who do not have a high risk of bleeding, while mechanical methods are suggested in patients who require thromboprophylaxis but have a high risk of bleeding.

If pharmacologic prophylaxis is indicated in patients undergoing general surgery, ACCP states that an LMWH or low-dose heparin is preferred.

ACCP states that the same recommendations for use of antithrombotic agents in general surgery patients can be applied to patients undergoing bariatric, vascular, and plastic/reconstructive surgery.

Thromboprophylaxis in Cardiac Surgery

Mechanical methods of prophylaxis generally recommended in patients undergoing cardiac surgery; however, ACCP states that low-dose heparin may be considered in cardiac surgery patients with a complicated postoperative course.

Thromboprophylaxis in Neurosurgery

Has been used for prevention of venous thromboembolism in patients undergoing craniotomy; however, benefits may be outweighed by possible increased risk of intracranial hemorrhage. ACCP states that the addition of low-dose heparin to a mechanical method of prophylaxis may be considered in patients at very high risk of thromboembolism (e.g., those undergoing craniotomy for malignant disease) once adequate hemostasis established and risk of bleeding decreases.

Also may be considered as a possible addition to mechanical prophylaxis in high-risk patients undergoing spinal surgery (e.g., those with malignancy or those undergoing surgery with a combined anterior-posterior approach) once adequate hemostasis established and risk of bleeding decreases.

Thromboprophylaxis in Thoracic Surgery

Prevention of postoperative DVT and PE in patients undergoing major thoracic surgery.

Pharmacologic thromboprophylaxis (e.g., low-dose heparin) recommended by ACCP in patients undergoing thoracic surgery who are at high risk of venous thromboembolism, provided risk of bleeding is low.

Thromboprophylaxis in Major Orthopedic Surgery

Has been used for prevention of DVT and PE in patients undergoing total hip-replacement surgery, total knee-replacement surgery, or hip-fracture surgery.

ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method) in all patients undergoing major orthopedic surgery because of high risk of postoperative venous thromboembolism; continue thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.

Among several antithrombotic agents (e.g., LMWH, fondaparinux, low-dose heparin, warfarin, aspirin) recommended for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery, ACCP states LMWHs generally preferred; may consider alternative agents when an LMWH is not available or cannot be used.

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy and safety of the drugs in addition to other logistics and compliance issues.

Thromboprophylaxis in Selected Medical Conditions

Used for prevention of DVT and PE in acutely ill hospitalized medical patients and in those with medical conditions associated with a high risk of thromboembolism (e.g., cancer).

In general, pharmacologic thromboprophylaxis recommended only in patients considered to be at high risk of venous thromboembolism.

ACCP recommends anticoagulant prophylaxis (e.g., low-dose heparin) in acutely ill, hospitalized medical patients at increased risk of thrombosis who are not actively bleeding and do not have an increased risk of bleeding. Continued thromboprophylaxis suggested for 6–21 days until full mobility is restored or hospital discharge.

Low-dose heparin also suggested by ACCP for pharmacologic thromboprophylaxis in critically ill patients (e.g., those in an intensive care unit [ICU]) who are not actively bleeding and do not have risk factors for bleeding.

Risk of venous thromboembolism is particularly high in patients with cancer. Use of low-dose heparin suggested by ACCP in cancer (solid tumors) outpatients who have additional risk factors for thromboembolism, provided risk of bleeding is low.

Thromboprophylaxis in Trauma

Low-dose heparin may be used for thromboprophylaxis in patients with major trauma. For major trauma patients at high risk of venous thromboembolism, including those with acute spinal cord injury, traumatic brain injury, or spinal surgery for trauma, ACCP suggests the use of both a pharmacologic and mechanical method of prophylaxis, unless contraindications exist.

Thromboembolism During Pregnancy

Has been used for prevention and treatment of venous thromboembolism during pregnancy; however, an LMWH generally is recommended by ACCP because of a more favorable safety profile.

Complications of Pregnancy

Has been used in combination with low-dose aspirin for prevention of recurrent pregnancy loss in women with antiphospholipid antibodies (APLA) syndrome.

Also has been used with aspirin (often combined with immune globulin) for prevention of venous thromboembolism and early pregnancy loss in women who have undergone in vitro fertilization.

Venous Thromboembolism in Pediatric Patients

Has been used for treatment and secondary prevention of venous thromboembolism in neonates and children; venous thromboembolism usually occurs secondary to an identifiable risk factor (e.g., presence of central venous access device) in such patients.

Recommendations regarding use of antithrombotic therapy in children generally based on extrapolation from adult guidelines.

In children with central venous catheters (or umbilical venous catheters) who experience venous thromboembolism, ACCP recommends removal of catheter if no longer functioning or required; at least 3–5 days of therapeutic anticoagulation suggested prior to removal. If such catheters must remain in place, ACCP suggests anticoagulant therapy until catheter is removed.

Cardioversion of Atrial Fibrillation/Flutter

Has been used to reduce the risk of stroke and systemic embolism in patients undergoing electrical or pharmacologic cardioversion for atrial fibrillation or atrial flutter.

Therapeutic anticoagulation with heparin may be used in patients in whom prolonged anticoagulation (e.g., with warfarin for ≥3 weeks) prior to cardioversion is not necessary or not possible; in these situations, heparin or an LMWH generally is administered at the time of transesophageal echocardiograph (TEE) or at presentation (for those with atrial fibrillation ≤48 hours) just prior to cardioversion.

In patients with hemodynamic instability who require urgent cardioversion, ACCP suggests administration of IV heparin or an LMWH prior to cardioversion, if possible; however, such anticoagulant therapy must not delay any emergency intervention.

Thromboembolism Associated with Prosthetic Heart Valves

Used during conversion to maintenance warfarin therapy to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical heart valves.

ACCP suggests bridging anticoagulation (administration of an LMWH in either prophylactic or therapeutic dosages or IV heparin in prophylactic dosages) during the early postoperative period after insertion of a mechanical heart valve until patient is stable on warfarin therapy.

Also may be used for bridging anticoagulation in patients with a mechanical heart valve in whom therapy with warfarin must be temporarily discontinued (e.g., for major surgery). ACC and AHA state that perioperative use of heparin should be considered for noncardiac surgery, invasive procedures, or dental procedures in patients with prosthetic heart valves who are at high risk for thrombosis without oral antithrombotic therapy (e.g., those with any mechanical mitral valve or a mechanical aortic valve with additional risk factors).

Used for thromboprophylaxis in pregnant women with prosthetic mechanical heart valves. (See Thromboembolism During Pregnancy under Dosage and Administration.)

Renal Vein Thrombosis

Renal vein thrombosis is the most common cause of spontaneous venous thromboembolism in neonates. Although use of anticoagulant therapy in patients with renal vein thrombosis is controversial, heparin is suggested by ACCP as a possible treatment option in selected neonates.

Arterial Thromboembolism

Used to reduce the extent of ischemic injury in patients with acute arterial emboli or thrombosis; however, ACCP states formal studies demonstrating improved outcomes have not been conducted.

In patients with limb ischemia secondary to arterial emboli or thrombosis, immediate systemic anticoagulation with heparin to prevent thrombotic propagation is suggested by ACCP.

Prophylaxis during cardiac catheterization via an artery in neonates and children. If femoral artery thrombosis occurs following cardiac catheterization, therapeutic-dose IV heparin is recommended, followed by subsequent conversion to an LMWH or continued treatment with heparin to complete 5–7 days of therapeutic anticoagulation.

Thromboembolism Associated with Cardiac and Arterial Vascular Surgery

Prevention of activation of the coagulation mechanism during arterial and cardiac surgery.

A nonheparin anticoagulant (e.g., bivalirudin) may be used in place of heparin in patients with acute heparin-induced thrombocytopenia (HIT) or subacute HIT (platelets have recovered, but HIT antibodies still present) who require urgent cardiac surgery. Because HIT antibodies are transient, ACCP states that short-term use of heparin may be appropriate in patients with a remote (>3 months) history of HIT and no detectable antibodies who require cardiac surgery.

Disseminated Intravascular Coagulation

Treatment of acute and chronic consumptive coagulopathies, including disseminated intravascular coagulation.

Thrombosis Associated with Indwelling Venous or Arterial Devices

Maintenance of patency of indwelling peripheral or central venipuncture devices designed for intermittent injections and/or blood sampling.

ACCP suggests use of heparin flushes as an option for primary thromboprophylaxis of central venous access devices in children.

In neonates and children with peripheral arterial catheters, ACCP recommends continuous IV infusion of heparin (in low concentrations) via the catheter for prophylaxis. Also may consider use of heparin for treatment if symptomatic catheter-related thromboembolism occurs.

In neonates with umbilical arterial catheters, ACCP also suggests thromboprophylaxis with low-dose heparin via the catheter to maintain patency.

ST-Segment-Elevation MI (STEMI)

Used in combination with antiplatelet agents (e.g., aspirin) during and after successful coronary artery reperfusion (e.g., thrombolytic agents) for prevention of ischemic complications of STEMI (e.g., death, reinfarction, stroke).

The American College of Cardiology Foundation (ACCF) and AHA state that patients with STEMI undergoing thrombolytic therapy should receive an anticoagulant (e.g., heparin, enoxaparin, fondaparinux) for ≥48 hours, and preferably for the duration of the index hospitalization, up to 8 days or until revascularization is performed. Enoxaparin is preferred over heparin if extended anticoagulation (>48 hours) is necessary.

Acute Ischemic Complications of PCI

Used to reduce the risk of thrombotic complications in patients undergoing PCI. Used in conjunction with aspirin and other standard therapy (e.g., GP IIb/IIIa-receptor inhibitors, P2Y12 receptor antagonists).

Use of a parenteral anticoagulant is recommended in patients undergoing PCI to prevent thrombus formation during the procedure. IV heparin is recommended by AHA, the American College of Cardiology Foundation (ACCF), and the Society for Cardiovascular Angiography and Interventions (SCAI) as an appropriate choice of anticoagulant.

Non-ST-Segment-Elevation Acute Coronary Syndromes (NSTE ACS)

Reduction in the risk of acute cardiac ischemic events (death and/or MI) in patients with NSTE ACS (unstable angina or non-ST-segment-elevation MI [NSTEMI]).

Used concurrently with aspirin and/or other standard therapy (e.g., nitrates, β-adrenergic blocking agents [β-blockers], P2Y12 receptor antagonists).

Initial parenteral anticoagulants with established efficacy in patients with NSTE ACS include enoxaparin, heparin, bivalirudin (only in patients managed with an early invasive strategy), and fondaparinux.

In patients who will undergo CABG, if heparin is already being administered, continue during surgery. If patient is receiving other anticoagulants (enoxaparin, fondaparinux, or bivalirudin), discontinue other anticoagulant and use heparin during CABG.

In patients in whom conservative medical therapy is selected as a postangiographic management strategy, recommendations for continued antiplatelet and anticoagulant therapy generally are based on the presence of CAD.

Treatment of Cerebral Venous Sinus Thrombosis

May be used for treatment of acute cerebral venous sinus (sinovenous) thrombosis in adults. May convert to oral anticoagulant therapy once patient is stabilized.

Recommended by ACCP as an option for initial anticoagulation in children with cerebral venous sinus thrombosis without substantial intracranial hemorrhage. Also has been suggested for use in such children with substantial hemorrhage.

Acute Ischemic Stroke

Heparin anticoagulants (i.e., LMWH or heparin) have been used for thromboprophylaxis in selected patients with acute ischemic stroke; those with additional risk factors for venous thromboembolism are more likely to benefit.

ACCP suggests thromboprophylaxis with an LMWH (in prophylactic dosages), sub-Q heparin, or intermittent pneumatic compression in patients with acute ischemic stroke and restricted mobility; LMWH is preferred over heparin.

Prophylactic-dose heparin usually initiated within 48 hours of onset of stroke and continued throughout hospital stay until patient regains mobility; do not administer within the first 24 hours after thrombolytic therapy.

Also has been used for initial management of acute arterial ischemic stroke in children until dissection and embolic causes have been excluded.

In children with acute arterial ischemic stroke secondary to non-Moyamoya vasculopathy, ACCP recommends ongoing antithrombotic therapy (e.g., heparin) for 3 months.

Heparin may be considered in neonates with a first episode of arterial ischemic stroke associated with a documented cardioembolic source.

Perioperative Management of Antithrombotic Therapy

Used in the perioperative management of patients who require temporary interruption of long-term warfarin therapy for surgery or other invasive procedures.

ACCP suggests perioperative use of an LMWH or IV heparin (bridging anticoagulation) in selected patients with venous thromboembolism, atrial fibrillation, or mechanical prosthetic heart valves depending on their risk of developing thromboembolism without warfarin therapy.

In general, bridging anticoagulation is suggested in such patients who are considered to be at particularly high risk of venous thromboembolism without oral anticoagulant therapy.

Anticoagulant in Blood Transfusions, Blood Samples, and Other Procedures

Used as an in vitro anticoagulant in blood transfusions.

Used for anticoagulation during extracorporeal circulation and dialysis procedures.