Pharmacy Program

Delivering Integrated Care and Cost Management

The IHTC works collaboratively with payors to optimize care. We ensure that the patients and families we serve have access to care and therapies, thereby helping to contain costs and reduce both bleeding events and utilization of resources.

The IHTC Pharmacy’s ability to purchase clotting factor through the Public Health Service 340B discount program and our overall pricing structure benefit payors and patients by dispensing clotting factor at significantly reduced prices.

Treatment of Thrombosis

Once a patient is diagnosed with thrombosis, anticoagulants are used to decrease the ability of the blood to clot. The commonly used anticoagulants include:

  • Unfractionated heparin (UFH)
  • Low molecular weight heparin (LMWH)
  • Warfarin (Coumadin®)
  • Fondaparinux

Unfractionated Heparin (UFH)
UFH’s major anticoagulant effect is through inactivation of thrombin and activated factor X (FXa) via an antithrombin (AT)-dependent mechanism. Heparin binds to AT via a high-affinity pentasaccharide that is found on approximately one-third of heparin molecules. To inhibit thrombin, heparin must bind to both the thrombin and to AT; binding directly to FXa is not required for its inhibition. Heparin molecules with fewer than 18 saccharides lack the required chain length to bridge between thrombin and AT and therefore cannot inhibit thrombin. In contrast, very small heparin fragments that contain the pentasaccharide sequence can inhibit factor Xa via AT. By inactivating thrombin, UFH not only prevents fibrin formation but also inhibits thrombin-induced activation of platelets and of factors V and VIII.1

UFH is usually the treatment of choice immediately after the diagnosis of thrombosis. It can also be used to prevent the occurrence of thrombosis. UFH has a short half-life, ~40 minutes. It can be given intravenously as a continuous infusion or subcutaneously. Therapeutic efficacy of anticoagulation with UFH is monitored by the APTT test. To achieve adequate anticoagulation, the APTT value is maintained between 60 and 80 seconds. Frequent monitoring is required to maintain the therapeutic efficacy of UFH. Specific treatment algorithms are available for UFH dose adjustments. After the initial treatment, anticoagulation may be transitioned to a low molecular weight heparin or warfarin (Coumadin®) for continued therapy.

Low Molecular Weight Heparin (LMWH)
LMWH is a category of medications that includes drugs such as enoxaparin (Lovenox®) and tinzaparin (Innohep®). LMWH is used for both the treatment and prevention of thrombosis. It is derived from UFH. The half-life of LMWH is ~12 hours. LMWH is administered via subcutaneous injection. One or two injections per day may be prescribed. Laboratory monitoring of blood levels is not always required. In special patient population including children or pregnant women, LMWH is monitored by measurement of an anti-FXa assay. Specific treatment recommendations are available based upon LMWH management algorithms. LMWH is used commonly during pregnancy for the prevention of thrombotic complications. Since the effective anticoagulant action of LMWH occurs within 2 to 3 doses, it is also used as a “bridging” therapy when a patient is initiated on an oral anticoagulant such as warfarin (Coumadin®), as these oral agents require several days (~5-7 days) to achieve an adequate level of anticoagulation.

Warfarin (Coumadin®)
Warfarin (Coumadin®) is most commonly administered orally in tablet form. Warfarin affects clotting by interference with the vitamin K pathway. The vitamin K pathway is a hepatic post-translational modification that occurs for normal production of the vitamin K dependent clotting factors, including factors II, VII, IX, and X, required to allow normal clot formation. Interference of this pathway leads to a decrease in the function of these clotting factors, resulting in a decreased ability to generate thrombin and hence anticoagulation. Each person may require a different dose of Coumadin. In addition, Coumadin has interactions with medications and is also affected by the daily dietary vitamin K content consumed (green leafy vegetables contain vitamin K), so frequent monitoring is required to ensure that the Coumadin dose is safe and effective. You can refer your patients to the IHTC’s section on food interactions with Coumadin® [link to Coumadin Interactions with Food] for a review of the nutritional considerations associated with Coumadin therapy.

Coumadin is by far the most commonly used anticoagulant as it is administered orally. Coumadin commonly requires 3 to 7 days to achieve an adequate anticoagulant effect. Therefore, patients initiated on Coumadin therapy require some form of heparin for additional coverage to assure adequate anticoagulation. This therapy is termed “bridging anticoagulation.” Anticoagulation with Coumadin is monitored via INR testing. The frequency of INR monitoring is individualized and dependent on the consistency of INR values and other patient dependent variables. Monitoring may be required weekly to monthly.

After a DVT, a person will often be treated with an anticoagulant such as Coumadin for approximately 6 months. The total duration of treatment for a thrombotic episode is based on variables such as the presence of a precipitating event, severity of the clot, patient age, and identified underlying risk factors such as a coagulation factor abnormality. Length of anticoagulation is both evidence-based and individualized to achieve optimal outcome. Coumadin should not be used during pregnancy.

Treatment of Antiphospholipid Antibody Syndrome (APS)

Patients who persistently test positive for either a lupus anticoagulant or anticardioplipin antibodies (ACA) and have a thrombotic history appear to be at increased risk for recurrent thrombosis (~50% over a 5-year period). Treatment is reserved for patients who have clinical evidence of antiphospholipid antibody syndrome (APS). If an individual initially experiences a venous thrombotic event, the subsequent recurrence is typically venous. The intensity of oral anticoagulation (INR 2 to 3) required to suppress venous recurrence remains controversial. In general, patients with APS should be treated more aggressively with oral anticoagulants (high intensity) with an INR goal of 2.5 to 3.5.2 Treatment of patients with transiently positive ACA or a lupus anticoagulant is not required.

The following table lists many of the anticoagulants that are currently available.

ANTI-
COAGULANT
HALF-LIFE PRIMARY EXCRETION MODE ANTI-
COAGULANT
ACTION
THERAPEUTIC
ANTICOAGULATION
DOSE
ANTICOAGULATION MONITORING REVERSAL AGENTS*
PEDIATRICS ADULT
VITAMIN K ANTAGONIST
Warfarin (Coumadin®) 42 hours Liver Inhibits vitamin K
mediated gamma-
carboxylation of
Factor II, VII, IX, X
Loading dose: 0.2
mg/kg, PO

Maintenance
dose: 0.1 mg/kg
(max dose: 5
mg), PO

Loading dose: 5-10
mg PO
(NOT necessary)

Maintenance dose:
5-10 mg daily, PO

INR Vitamin K1
(Antidote);
PCC;
rFVIIa (NovoSeven®);
FFP
HEPARIN DERIVATIVES
Unfractionated Heparin 90 minutes (range: 1-2 hours) Majority reticuloen-dothelial
system (faster clearance); Liver
Anti-thrombin mediated inhibition of thrombin & factor Xa Loading dose:
50-75 U/kg, IV

Maintenance, CI:
< 1 year: 28 IU/kg/hr
>1 year: 20 IU/kg/hr

Loading dose:
50-75 IU/kg, IV

Maintenance, CI:
12-18 IU/kg/hr, IV

APTTMay also use:
ACT
Anti factor-Xa
(Heparin level)
Protamine sulfate
(Antidote),
rFVIIa
(NovoSeven®)
Low Molecular Weight Heparin: Enoxaparin (Lovenox®), Dalteparin (Fragmin®), Tinzaparin (Innohep®) Single dose: 4.5 hours
Repeat dosing: 7 hours
Renal Anti-thrombin mediated inhibition of factor Xa < 2 months: 1.5-2
mg/kg/dose, SC
BID

>2 months-12
years: 1.5
mg/kg/dose SC BID

1 mg/kg/dose, SC,
q12 hr; 1.5 mg/kg daily, SC
Typically no
monitoring requiredAnti-factor Xa
(heparin level) using
drug specific curve
Protamine sulfate
(Partial antidote),
rFVIIa(NovoSeven®)
Xa-INHIBITORS
Fondaparinux:
(Arixtra®)
17-21 hours Renal Anti-thrombin
mediated inhibition
of factor Xa
0.15 mg/kg,
SC,QD
< 50 kg: 5 mg,
SC, daily
50-100 kg: 7.5 mg,
SC, daily
>100 kg: 10 mg
daily
Typically no
monitoring required
Anti-factor Xa
(Calibrated with
Arixtra curve)
rFVIIa (NovoSeven®)
DIRECT THROMBIN INHIBITORS
Bivalirudin: (Angiomax®) 25 minutes Enzymatic cleavage Direct inhibition of thrombin Loading dose:
0.25 mg/kg, IV
Maintenance, CI:
0.07±0.16 mg/kg/hour
PCI
Loading dose: 0.75 mg/kg,
IV
Maintenance, CI:
1.75 mg/kg/hr, IV

Unstable angina
Load: 0.1 mg/kg
Maintenance: 0.25
mg/kg/hr

APTT, TCT, ACT Desmopressin
Acetate;
Cryoprecipitate;
Antifibrinolytics:
EACA (Amicar®);
Tranexamic acid
Argatroban® 40-50 minutes Biliary, Liver Direct inhibition
of thrombin
Loading dose:
65-250 mg/kg, IV
CI:0.5-15
mg/kg/hr, IV
Loading dose: None

Maintenance, CI:
0.5-2.0 mg/kg/hr, IV

APTT Desmopressin
Acetate;
Cryoprecipitate;
Antifibrinolytics:
EACA (Amicar®);
Tranexamic acid
Lepirudin
(recombinant
hirudin,
Refludan®)
80 minutes Renal Direct inhibition
of thrombin
Loading dose: Not
recommended

Maintenance, CI:
0.1 mg/kg/hr

Loading dose:
0.4 mg/kg

Maintenance, CI:
0.15 mg/kg/hr, IV

APTT,
Ecarin clotting time,
Chromogenic
Lepirudin assay
Desmopressin
Acetate;
Cryoprecipitate;
Antifibrinolytics:
EACA (Amicar®);
Tranexamic acid
* Reversal Agents: Table includes agents that do not have an indication for reversal of antithrombotic agents.

Treatment of Heparin-Induced Thrombocytopenia (HIT)
Direct thrombin inhibitors are specifically indicated and licensed for treatment of heparin-induced thrombocytopenia (HIT), and include lepirudin (Refludan®), and Argatroban®. In addition, the only low molecular weight heparin that can be utilized in this setting is danaparoid (Orgaran®). Other LMWHs are not an alternative anticoagulant after the diagnosis of HIT is confirmed.

Long-Term Management of Thrombosis and Thrombophilia
Management of inherited thrombophilia encompasses the treatment of acute thromboembolic events, primary prophylaxis in asymptomatic individuals, and secondary prophylaxis of post-thrombotic recurrence. In general, thrombotic episodes do not occur in a continuous fashion except in individuals who are homozygous deficient for proteins C or S. Lifelong prophylaxis, therefore, should not be considered for asymptomatic patients not exposed to risk factors. This approach is considered impractical due a variety of issues including –

  • Cost of lifelong anticoagulation and associated monitoring
  • Therapeutic adherence
  • Lack of documented target anticoagulation levels in this setting, and
  • Long-term risk of bleeding associated with anticoagulation.

Currently, there is no definitive mechanism to identify those asymptomatic affected individuals who are destined to develop a thrombosis. However, prophylactic measures should be utilized in asymptomatic individuals during those situations that place them at increased risk for thrombosis.

Concomitant risk factors for development of thrombosis include the following:

  • Pregnancy, oral contraceptives, puerperium
  • Hormone replacement therapy
  • Malignancy
  • Surgery/trauma
  • Dehydration
  • Sepsis
  • Immobility
  • Fractures
  • Congestive heart failure
  • Increasing age
  • Chronic inflammatory states
  • Air travel

For more detailed information on many of these risk factors, see the IHTC’s webpage on Acquired Causes of Thrombosis.

References

  1. Hirsh J, et al. Mechanism of action and pharmacology of unfractionated heparin. Arterioscler Thromb Vasc Biol. 2001;21:1094-1096.
  2. Crowther M, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome N Engl J Med. 2003;349:1133-1138.
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