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Antithrombotic and Thrombolytic Therapy in Children and Neonates - ACCP Guidelines



  •  Antithrombotic Doses
    • Unfractionated Heparin
    • Low Molecular Weight Heparin
    • VKA
    • Aspirin
  • Primary Antithrombotic Prophylaxis - Neonates and Children
    • Central Venous Access Device (CVAD)
    • Modified Blalock-Taussig Shunt
    • Norwood Procedure
    • Peripheral Arterial Catheters in situ
    • Bilateral Cavopulmonary Shunts
    • Fontan Surgery
    • Endovascular Stents
    • Cardiomyopathy
    • Primary Pulmonary Hypertension
    • Biological Prosthetic Heart Valves
    • Mechanical prosthetic heart valves
    • Ventricular Assist Device (VAD) Placement
    • Umbilical Artery Catheter (UAC)
    • Cardiac Catheterization via an Artery
    • Hemodialysis
  • Venous Thromboembolism Treatment - Neonates
    • Central Venous Access Device (CVAD)
    • Modified Blalock-Taussig Shunt
    • Norwood Procedure
    • Peripheral Arterial Catheters in situ
    • Umbilical Artery Catheter (UAC)
    • Cardiac Catheterization via an Artery
  • Venous Thromboembolism Treatment - Children
    • Idiopathic, secondary and recurrent venous thromboembolism
    • Central Venous Access Device (CVAD)
    • Cancer
    • Antiphospholipid antibodies (APLA)
    • Femoral Artery Thrombosis
    • Peripheral Arterial Catheters
    • Structural Venous Abnormalities
    • Central Venous Access Device (CVAD)
    • Cerebral Sinovenous Thrombosis (CSVT)
    • Kawasaki Disease
    • Acute Ischemic Stroke (AIS)

Each recommendation is graded by the ACCP with a strength of recommendation of 1 or 2, with the quality of the underlying methodology assigned a grade of A, B, or C [2]:

Strength of Recommendation
Grade 1Strong (ie, benefits clearly do or do not outweigh risks, burdens, and costs)
Grade 2Weak (ie, benefits closely balanced with risks, burdens, and costs)

Quality of Underlying Methodology
ARandomized controlled trials (RCTs) and observational studies with very large effects
BDowngraded RCTs or upgraded observational studies
CObservational studies and RCTs with major limitations

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ANTITHROMBOTIC DOSES

Unfractionated Heparin (UFH)
  • Initiate UFH with bolus not greater than 75 to 100 units/kg; withhold or reduce if significant bleeding risk (Grade 2C).
  • Titrate UFH dose to achieve target anti-Xa activity range of 0.35 to 0.7 units/mL, or APTT range correlating to the anti-Xa range, or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C).
  • Avoid long-term use in children (Grade 2C).

Unfractionated Heparin Doses
Loading dose: 75 units/kg IV over 10 minutes
Initial Maintenance dose: (age less than 1 year) 28 units/kg/hr; (age greater than 1 year) 20 units/kg/hr
Adjust to maintain aPTT of 60 to 85 seconds (an anti-Xa level of 0.35 to 0.7 units/mL)
Obtain blood sample for aPTT 4 hours after administration of the loading dose and every change in the infusion rate
When aPTT is therapeutic, perform daily CBC and aPTT
Key: aPTT=activated partial thromboplastin time

Low Molecular Weight Heparin (LMWH)
  • Neonates or children receiving once- or twice daily therapeutic LMWH, monitor to target anti-Xa activity range of 0.5 to 1 unit/mL in a sample taken 4 to 6 hours after subQ injection or 0.5 to 0.8 units/mL in a sample taken 2 to 6 hours after subQ injection (Grade 2C).

LMWH Doses in Pediatric Patients
DrugWeightAgeTreatment, initialProphylaxis, initial
reviparinless than 5 kgNA150 units/kg/dose every 12 hours50 units/kg/dose every 12 hours
greater than 5 kgNA100 units/kg/dose every 12 hours30 units/kg/dose every 12 hours
enoxaparinNAless than 2 months1.5 mg/kg/dose every 12 hours0.75 mg/kg/dose every 12 hours
NAgreater than 2 months1 mg/kg/dose every 12 hours0.5 mg/kg/dose every 12 hours
dalteparinNAall129 +/- 43 units/kg/dose every 24 hours92 +/- 52 units/kg/dose every 24 hours
tinzaparinNA0 to 2 months275 units/kg
NA2 to 12 months250 units/kg
NA1 to 5 years240 units/kg
NA5 to 10 years200 units/kg
NA10 to 16 years175 units/kg
NA = not applicable

VKA
  • Initial dose: 0.2 mg/kg orally
  • Titrate to a target INR of 2.5 (range 2 to 3) except in prosthetic cardiac valves (follow adult clinical guidelines) (Grade 2C)

Aspirin
  • Antiplatelet therapy in children, aspirin 1 to 5 mg/kg/day (Grade 2C).

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PRIMARY THROMBOPROPHYLAXIS - NEONATES AND CHILDREN

Central Venous Access Device (CVAD):
  • Neonates
    • To maintain CVAD patency: unfractionated heparin via continuous infusion 0.5 units/kg/hr (Grade 1A), or intermittent local thrombolysis (Grade 2C)
    • Blocked CVAD: local thrombolysis (Grade 2C)
  • Children
    • Flush CVAD with normal saline or heparin or intermittent recombinant urokinase to maintain patency (Grade 2C)
    • Routine systemic thromboprophylaxis NOT recommended in children with a short- or medium-term central venous line (Grade 1B)
    • Long-term home total parenteral nutrition: vitamin K antagonists (VKAs) suggested (target INR 2.5, range 2 to 3), except in the setting of prosthetic cardiac valves (see below) (Grade 2C)
    • Blocked CVADs: tissue plasminogen activator (tPA) or recombinant urokinase suggested to restore patency (Grade 2C); second dose suggested if patency not restored 30 minutes following local thrombolytic instillation; investigate to rule out CVAD-related thrombosis if patency not restored after 2 doses (Grade 2C)

Modified Blalock-Taussig Shunt:
  • Intraoperative unfractionated heparin (UFH) followed by either aspirin 1 to 5 mg/kg/day or no further antithrombotic therapy suggested over prolonged low molecular weight heparin (LMWH) or vitamin K antagonists (VKAs) (Grade 2C)

Norwood Procedure:
  • Intraoperative unfractionated heparin (UFH) followed by either aspirin 1 to 5 mg/kg/day or no further antithrombotic therapy suggested over prolonged low molecular weight heparin (LMWH) or vitamin K antagonists (VKAs) (Grade 2C)

Peripheral Arterial Catheters in situ:
  • UFH recommended through the catheter, preferably by continuous infusion of 5 units/mL at 1 mL/hr (Grade 1A)

Bilateral Cavopulmonary Shunts:
  • Postoperative UFH suggested (Grade 2C)

Fontan Surgery:
  • Aspirin 1 to 5 mg/kg/day or therapeutic UFH suggested after Fontan surgery, followed by VKA therapy (target INR 2.5, range 2 to 3) (Grade 1C)

Endovascular Stents:
  • UFH perioperatively suggested (Grade 2C)

Cardiomyopathy:
  • VKA therapy suggested (target INR 2.5, range 2 to 3), starting no later than their activation on a cardiac transplant waiting list (Grade 2C)

Primary Pulmonary Hypertension:
  • VKA therapy suggested when other medical therapy commences (Grade 2C)

Biological Prosthetic Heart Valves: follow relevant recommendations from adult population

Adult population recommendations for bioprosthetic heart valves [3]:

Aortic Bioprosthetic Heart Valves:
  • Sinus rhythm with no other indications for VKA therapy: aspirin 50 to 100 mg daily in patients in the first 3 months (Grade 2C)

Transcatheter Aortic Bioprosthetic Heart Valves:
  • Aspirin 50 to 100 mg daily plus clopidogrel 75 mg/day in the first 3 months (Grade 2C)

Mitral Bioprosthetic Heart Valves:
  • VKA (target INR 2.5, range 2 to 3) for the first 3 months after valve insertion (Grade 2C)

Any Bioprosthetic Valve Long-term Therapy
  • 3 months postoperative: aspirin therapy in patients with normal sinus rhythm (Grade 2C)

Mechanical prosthetic heart valves: follow relevant recommendations from adult population with respect to the intensity of anticoagulation therapy

Adult population recommendations for mechanical heart valves [3]:

Bridging Therapy
  • Prophylaxis with unfractionated heparin prophylactic dose or low molecular weight heparin prophylactic or therapeutic dose until stable on VKA therapy (Grade 2C)

Long-term Therapy
  • VKA therapy (Grade 1B)

Mechanical Aortic Valve:
  • VKA therapy: target INR 2.5 (range 2 to 3) suggested over lower targets (Grade 2C) and suggested over higher targets (Grade 1B)

Mechanical Mitral Valve:
  • VKA therapy: target INR 3 (range 2.5 to 3.5) suggested over lower INR targets (Grade 2C)

Mechanical Heart Valve in both Aortic AND Mitral position:
  • Target INR 3 (range 2.5 to 3.5) suggested over target INR 2.5 (range 2 to 3) (Grade 2C)
  • Low bleeding risk: add antiplatelet such as low-dose aspirin 50 to 100 mg/day to the VKA therapy (Grade 1B)
  • VKA is recommended over antiplatelet agents (Grade 1B)

Mitral Valve Repair
  • Valve repair with prosthetic band in normal sinus rhythm: antiplatelet therapy for the first 3 months (Grade 2C)

Aortic Valve Repair
  • Aspirin 50 to 100 mg per day (Grade 2C)

Ventricular Assist Device (VAD) Placement:
  • UFH (target anti-factor Xa 0.35 to 0.7 units/mL or activated partial thromboplastin time correlating to anti-factor Xa target range or protamine titration range of 0.2 to 0.4 units; mL (Grade 2C)) starting between 8 and 48 hours following VAD implantation suggested, in the absence of bleeding (Grade 2C). When initiating UFH, boluses should not be greater than 75 to 100 units/kg and be withheld or reduced if there is significant bleeding risks (Grade 2C). Avoid longterm use of UFH in children (Grade 2C)
  • Antiplatelet therapy with either aspirin 1 to 5 mg/kg/day and/or dipyridamole suggested to commence within 72 hours of VAD placement (Grade 2C)
  • Wean from UFH to either LMWH (target anti-factor Xa 0.5 to 1 unit/mL) or VKA (target INR 3, range 2.5 to 3.5) once clinically stable and until transplanted or weaned from VAD (Grade 2C)

Umbilical Artery Catheter (UAC):
  • Neonates
    • UAC placement: a high position is suggested over a low position (Grade 2B)
    • To maintain patency: prophylaxis with low-dose UFH infusion (heparin concentration 0.25 to 1 unit/mL- total heparin dose 25 to 200 units/kg/day) via the UAC is suggested (Grade 2A)

Cardiac Catheterization via an Artery:
  • IV UFH prophylaxis recommended (Grade 1A), with a bolus dose of 100 units/kg (Grade 1B); further UFH therapy is suggested in prolonged procedures (Grade 2B)
  • Aspirin is NOT recommended (Grade 1B)

Hemodialysis:
  • Routine use of VKAs or LMWH suggested for thromboprophylaxis related to central venous lines or fistulas (Grade 2C)
  • UFH or LMWH to maintain circuit patency suggested (Grade 2C)

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ANTITHROMBOTIC AND THROMBOLYTIC TREATMENT - NEONATES

Central Venous Access Device (CVAD) or Umbilical Artery Catheter (UAC) related venous thromboembolism in neonates:
  • CVAD or Umbilical Artery Catheter (UAC) associated with confirmed thrombosis: remove, if possible, after 3 to 5 days of anticoagulation (Grade 2C)
  • Initial anticoagulation or supportive care with radiologic monitoring suggested (Grade 2C); subsequent anticoagulation recommended if extension of the thrombus occurs during supportive care (Grade 2C)
  • Suggested anticoagulation (Grade 2C):
    • LMWH once or twice daily, adjust to achieve target anti-factor Xa level of 0.5 to 1 unit/mL in sample taken 4 to 6 hours following subQ injection, or 0.5 to 0.8 units/mL in sample taken 2 to 6 hours after subQ injection, or
    • UFH for 3 to 5 days, adjust to achieve anti-factor Xa level of 0.35 to 0.7 units/mL or activated partial thromboplastin time correlating to anti-factor Xa target range or protamine titration range of 0.2 to 0.4 units/mL (Grade 2C) followed by LMWH (Grade 2C)
  • Duration of anticoagulation: 6 weeks to 3 months suggested (Grade 2C)
  • For CVAD or UVCs still in place upon completion of anticoagulation: a prophylactic dose of anticoagulation is suggested to prevent recurrent VTE until the CVL/UVC is removed (Grade 2C)
  • Thrombolytic therapy:
    • NOT recommended unless major vessel occlusion is causing critical compromise of organs or limbs (Grade 2C)
    • If thrombolysis is required: use of tissue plasminogen activator (tPA) is suggested, administer plasminogen prior to starting therapy (Grade 2C)

Renal Vein Thrombosis (RVT)
  • Neonates or children with unilateral RVT in the absence of renal impairment or extension into the inferior vena cava (IVC): supportive care with monitoring of the renal vein thrombosis (RVT) for extension, or anticoagulation with UFH/LMWH or LMWH in therapeutic doses suggested for 6 weeks to 3 months (Grade 2C)
  • Unilateral RVT that extends into the IVC: anticoagulation with UFH/LMWH or LMWH suggested for 6 weeks to 3 months (Grade 2C)
  • Bilateral RVT with various degrees of renal failure: anticoagulation with UFH/LMWH or initial thrombolytic therapy with tPA suggested, followed by anticoagulation with UFH/LMWH (Grade 2C)

Femoral Artery Thrombosis
  • Therapeutic doses of IV UFH recommended (Grade 1B) for at least 5 to 7 days (Grade 2C); may convert to LMWH if thrombolysis or surgery is not required for a total duration of 5 to 7 days of treatment (Grade 2C)
  • Neonate patients with limb or organ-threatening (via proximal extension) femoral artery thrombosis who do not respond to initial UFH therapy and who have no contraindications: thrombolytic therapy recommended (Grade 1C)
  • Neonate patients with imminent limb or organ death who have a contraindication to thrombolytic therapy: surgical intervention suggested (Grade 1C)

Peripheral Arterial Catheters
  • Neonates with a peripheral arterial catheter-related thromboembolism:
    • Immediate removal of the catheter suggested (Grade 2B)
    • UFH anticoagulation with or without thrombolysis, or surgical thrombectomy and microvascular repair with subsequent heparin therapy (Grade 2C)

Cerebral Sinovenous Thrombosis (CSVT)
  • Without significant intracranial hemorrhage (ICH): anticoagulation suggested, initially with UFH or LMWH and then with LMWH for at least 6 weeks and up to 3 months (Grade 2C)
  • With significant hemorrhage: either anticoagulation or radiologic monitoring of the thrombosis suggested at 5 to 7 days, anticoagulate if thrombus propagation is seen (Grade 2C)

Acute Ischemic Stroke (AIS)
  • First AIS, in the absence of a documented ongoing cardioembolic source: anticoagulation or aspirin NOT recommended (Grade 2C)
  • First AIS, in the presence of a documented ongoing cardioembolic source: anticoagulation with UFH or LMWH (Grade 2C)
  • Recurrent AIS: anticoagulant or aspirin therapy suggested (Grade 2C)

Homozygous Protein C Deficiency
  • Administration of either 10 to 20 mL/kg fresh frozen plasma every 12 hours or protein C concentrate 20 to 60 units/kg until resolution of clinical lesions (Grade 1A)
  • Long term VKA therapy (Grade 1C), LMWH (Grade 1C), protein C replacement (Grade 1B), or liver transplantation (Grade 2C)

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ANTITHROMBOTIC AND THROMBOLYTIC TREATMENT - CHILDREN

Venous Thromboembolism (VTE)

First episode
  • Anticoagulation recommended with either UFH or LMWH (Grade 1B), treat initially for at least 5 days (Grade 1B)
  • Patients who will subsequently receive VKAs: begin oral therapy as early as day 1, continue UFH/LMWH until day 6 or later until the INR exceeds 2 (Grade 1B)

Idiopathic thromboembolism:
  • Duration of anticoagulation: for 6 to 12 months (Grade 2C)

Secondary thrombosis with a resolved risk factor:
  • Duration of anticoagulation: at least 3 months (Grade 2C)

Secondary thrombosis with ongoing, but potentially reversible, risk factors (eg, active nephrotic syndrome or ongoing L-asparaginase treatment):
  • Continue anticoagulation in either therapeutic or prophylactic doses until the risk factor has resolved (Grade 2C)

Recurrent idiopathic thrombosis:
  • Treat indefinitely with VKA therapy (target INR 2.5, range 2 to 3) (Grade 1A)

Recurrent secondary thromboembolism with an existing, reversible risk factor:
  • Anticoagulate until the risk factor has resolved, but for at least 3 months (Grade 2C)

Central Venous Access Device (CVAD) :
  • If a CVAD is nonfunctioning or no longer required: removal is recommended (Grade 1B), with at least 3 to 5 days of anticoagulation prior to its removal (Grade 2C)
  • If a CVAD is required and functioning: anticoagulate the patient and keep the CVAD in situ (Grade 2C)
  • First CVAD-related DVT: initially manage as for secondary thromboembolism above; after the first 3 months of therapy, prophylactic doses of VKAs (INR range 1.5 to 1.9) or LMWH (anti-factor Xa level range 0.1 to 0.3 units/mL) are suggested until CVAD removal (Grade 2C)
    • If recurrent thromboembolism occurs during prophylactic therapy: continue therapeutic doses until CVL removal but for at least 3 months (Grade 2C)

Life- or Limb-threatening Venous Thromboembolism:
  • Thrombolysis suggested for life- or limb-threatening thrombosis only (Grade 2C)
  • Thrombolysis with a pathologic deficiency of plasminogen, supplementation with plasminogen recommended (Garde 2C)
  • Systemic or catheter-directed thrombolysis recommended
  • Thrombectomy suggested and initiation of anticoagulation suggested following thrombectomy (Grade 2C)

Thrombolytic therapy:
  • Routine thrombolytic therapy NOT recommended in children with VTE (Grade 2C)
  • If thrombolytic therapy is used, plasminogen supplementation is suggested in the presence of physiologic or pathologic deficiencies of plasminogen (Grade 2C)

Inferior vena cava (IVC) filter:
  • Children with a contraindication to anticoagulation who have a lower-extremity VTE and who weigh more than 10 kg: placement of a temporary IVC filter is suggested (Grade 2C)
    • Remove as soon as possible if thrombosis is not present in the basket of the filter, and when the risk of anticoagulation decreases (Grade 2C)
    • Anticoagulate as appropriate as soon as the contraindication for anticoagulation resolves (Grade 1B)

Cancer:
  • Manage VTE as per general management of VTE in children; LMWH is suggested for the treatment of VTE for at least 3 months until the precipitating factor has resolved (Grade 2C)

Antiphospholipid antibodies (APLA):
  • Manage VTE as per general management of VTE in children

Femoral Artery Thrombosis:
  • Therapeutic doses of IV UFH recommended (Grade 1B) for at least 5 to 7 days (Grade 2C); may convert to LMWH if thrombolysis or surgery is not required for a total duration of 5 to 7 days of treatment (Grade 2C)
  • Pediatric patients with limb or organ-threatening (via proximal extension) femoral artery thrombosis who do not respond to initial UFH therapy and who have no contraindications: thrombolytic therapy recommended (Grade 1C)
  • Pediatric patients with imminent limb or organ death who have a contraindication to thrombolytic therapy: surgical intervention suggested (Grade 1C)

Peripheral Arterial Catheters:
  • Children with a peripheral arterial catheter-related thromboembolism:
    • Immediate removal of the catheter suggested (Grade 2B)
    • UFH anticoagulation with or without thrombolysis, or surgical thrombectomy and microvascular repair with subsequent heparin therapy (Grade 2C)

Structural Venous Abnormalities:
  • First episode, anticoagulation recommended with subsequent percutaneous or surgical interventions consideration (Grade 2C)
  • Recurrent VTE, indefinite anticoagulation unless percutaneous or surgical interventions can be performed (Grade 2C)

Central Venous Access Device (CVAD) :
  • Right atrial thrombosis related to CVAD, remove CVAD suggested (Grade 2C)
  • Mobile, larger than 2 cm, right atrial thrombosis: anticoagulation with appropriately timed CVAD removal and consider surgical intervention or thrombolysis (Grade 2C)
  • Blocked CVAD: use a tissue plasminogen activator or recombinant urokinase to restore patency (Grade 2C); give a second dose if patency not restored after at least 30 minutes; if still no effects, rule out CVAD-related thrombosis using radiologic imaging (Grade 2C)

Cerebral Sinovenous Thrombosis (CSVT):
  • Without significant ICH: anticoagulation recommended, initially with UFH or LMWH and then with LMWH or VKA for at least 3 months (Grade 1B); if radiologic recanalization of CSVT is incomplete or if ongoing symptoms are present after 3 months, an additional 3 months of anticoagulation is suggested (Grade 2C)
  • With significant hemorrhage: anticoagulation or radiologic monitoring of the thrombosis suggested at 5 to 7 days, anticoagulate if thrombus propagation is seen (Grade 2C)
  • Severe CSVT in children who have no improvement with initial UFH treatment: thrombolysis, thrombectomy, or surgical decompression suggested (Grade 2C)
  • With potentially recurrent risk factors (eg, nephrotic syndrome, L-asparaginase therapy): prophylactic anticoagulation suggested during times of risk factor recurrence (Grade 2C)

Kawasaki Disease
  • High-dose aspirin (80 to 100 mg/kg/day during the acute phase for up to 14 days) recommended initially as an antiinflammatory agent, followed by lower doses (1 to 5 mg/kg/day for 6 to 8 weeks) for its antiplatelet effects (Grade 1B)
  • IV gamma globulin (single dose of 2 grams/kg) recommended within 10 days of symptom onset (Grade 1A)
  • Moderate or giant coronary aneurysms following Kawasaki disease: warfarin (target INR 2.5, range 2 to 3) suggested in addition to low-dose aspirin as primary thromboprophylaxis (Grade 2C)
  • Giant aneurysms and acute coronary artery thrombosis, suggest thrombolysis or acute surgical interventions (Grade 2C)

Acute Ischemic Stroke (AIS)
  • With or without thrombophilia: initial therapy with UFH, LMWH, or aspirin until dissection and embolic causes excluded (Grade 1C), then daily aspirin prophylaxis for at least 2 years (Grade 2C)
  • Thrombolysis (tPA) or mechanical thrombectomy NOT recommended outside of research protocols (Grade 1C)
  • AIS secondary to cardioembolic causes: anticoagulation with LMWH or VKAs for at least 3 months (Grade 2C)
  • AIS secondary to cardioembolic causes with demonstrated right-to-left shunts (eg, patent foramen ovale): Surgical closure of shunt (Grade 2C)
  • AIS secondary to dissection: anticoagulation with LMWH or VKAs for at least 6 weeks (Grade 2C); evaluate radiologically for stenosis and evidence of recurrent ischemic events
  • AIS secondary to non-Moyamoya vasculopathy: initial treatment with UFH, LMWH, or aspirin for at least 3 months (Grade 1C); ongoing antithrombotic treatment as determined by repeat cerebrovascular imaging
  • AIS secondary to Moyamoya: initial therapy, treat with aspirin (Grade 2C); refer to an appropriate center to be assessed for revascularization

References: 

1. Monagle P, Chan AK, Goldenberg NA, et al: Antithrombotic Therapy in Neonates and Children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2 suppl):e737S-e801S.
PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
PubMed Article: http://www.ncbi.nlm.nih.gov/...

2. Guyatt GH, Norris SL, Schulman S, et al: Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141(2 Suppl):53S-70S.
PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
PubMed Article: http://www.ncbi.nlm.nih.gov/...

3. Whitlock RP, Sun JC, Fremes SE, et al: Antithrombotic and Thrombolytic Therapy for Valvular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2 suppl):e576S-e600S.
PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
PubMed Article: http://www.ncbi.nlm.nih.gov/...

- Drug Consults, Micromedex Online, Accessed 17/01/2019