Suggested Coagulation Therapy

Suggested testing when suspect diagnoses is:

Coagulation Test Names that Are Confusing

Is it Factor V or Factor V Leiden?

Factor V is rarely ordered

• The most common purpose for ordering the factor V activity assay is to help with the differential diagnosis of liver disease.
• The factor V assay is also ordered to establish the presence of an inherited factor V deficiency. These are very rare and are associated with severe bleeding in infancy.

Factor V Leiden is ordered often

The factor V Leiden mutation is present in 3-8% of Caucasians and Hispanics and confers a 2- to 8-fold risk of thrombosis (80-fold when homozygous). The factor V Leiden mutation test is usually ordered as part of a profile that includes antithrombin (AT, ATIII), protein C (PC), protein S (PS), factor VIII (for elevated factor VIII), prothrombin 20210 mutation, and lupus anticoagulant (LAC).

When the factor V Leiden mutation assay is ordered, the laboratory first performs the activated protein C resistance (APCR) assay, which is an effective screen. The factor V Leiden mutation molecular test is only performed when the APCR ratio is less than 1.8.

Is it Factor X or Anti-Xa?

Factor X is rarely ordered

The factor X assay is used mostly to diagnose congenital factor X deficiency, a very rare disorder that causes severe bleeding beginning in infancy.

Anti-Xa is ordered often

The anti-Xa test (anti-factor Xa, or anti-activated factor X) is used to monitor heparin therapy. It may be ordered to monitor standard, unfractionated heparin when the activated partial thromboplastin time (APTT) cannot be used, such as when the patient has the lupus anticoagulant. The anti-Xa test is the only test that works for monitoring low molecular weight heparin such as Lovenox or synthetic heparin such as Danaparoid.

Warfarin (Coumadin®)

Indications for Warfarin

• Treatment of arterial and venous thrombosis to prevent clot propagation
• Prevention of thromboembolic disease in thrombophilia, atrial fibrillation, mechanical heart valves, and high-risk surgery
• Treatment may be short or long term.

Mechanism of action for warfarin

• Prevents the vitamin K dependent gamma-carboxylation of factors II, VII, IX, and X, proteins C and S, slowing thrombin production

Dosage of warfarin

• 0.5mg-12.5mg/day with no loading dose. Must be monitored due to unpredictable half-life.
  Affected by many drugs and dietary variation.
• Requires 2-7 days to reach therapeutic or prophylactic levels. To achieve immediate anticoagulation, begin with heparin.

Laboratory monitoring: The INR

• PT generates the international normalized ratio (INR) by this formula:

INR = (Patient PT/MRI PT) ISI

Where…

PT = prothrombin time in seconds

MRI = geometric mean of reference interval

ISI = international sensitivity index supplied by reagent manufacturer

Target INRs

• Most therapy and prophylaxis: INR 2.0-3.0
• Post-MI and mechanical heart valves: INR 2.5-4.5

Laboratory monitoring sequence

• Daily until INR is therapeutic twice at least 24 hours apart
• Twice a week for 2 weeks, then once a month until therapy is complete

Unfractionated Heparin (UFH)

Indications for UFH

• Treatment of arterial and venous thrombosis to prevent clot propagation.
• Prevention of thromboembolic disease in atrial fibrillation, mechanical heart valves, and high-risk surgery.

Mechanism of action

• Increases the inhibitory effect of antithrombin on the serine proteases thrombin, IXa, Xa, XIa, and XIIa with greatest effect upon thrombin
• UFH clearance varies by individual and requires routine monitoring

Usual dosage

• 80 U/kg bolus, 8 U/kg/h IV started concurrently with warfarin
• Discontinue after 5 days if the INR has been therapeutic for at least 24 hours

Laboratory monitoring: TAPTT

• Assay 4-6 hours after bolus dosage and every 12-24 hours thereafter; if dose adjustment is needed, 6 hours after changing IV infusion
• Normal therapeutic range: 61-90 seconds.
• High therapeutic range: 91-110 seconds.

Laboratory monitoring: platelet count

• Check PLT count daily to detect heparin induced thrombocytopenia (HIT)
• If count drops 50%, consider HIT, withdraw heparin, start alternative anticoagulant, order confirmatory test for HIT

Overdose of UFH

• Stop heparin and monitor APTT. Heparin half-life is approximately 30 minutes. If bleeding is severe, consider protamine sulfate (1 mg/100 units heparin in circulation)
• FFP does not reverse heparin effect

Heparin-induced Thrombocytopenia with Thrombosis (HIT)

From 1-5% of patients receiving unfractionated heparin develop HIT. An antibody to heparin-bound platelet factor 4 (PF4) that activates platelets causes HIT. HIT is a major source of morbidity and mortality, and must be rigorously guarded against. Daily platelet counts throughout and following heparin therapy are the primary defense. A 30-50% decrease, even when the count remains within the normal range, may signal the onset of HIT. Laboratory confirmation consists of an immunoassay for the anti-heparin-PF4 antibody. This assay requires several hours and yields a relatively high false positive rate, thus is considered confirmatory but not diagnostic. When the clinical suspicion is high, heparin should be replaced with one of the direct thrombin inhibitors Lepirudin or Argatroban, until the clinical situation is elucidated.

Low Molecular Weight Heparin (LMWH)

Indications for LMWH

• Prevention or treatment of thromboembolic disease

Mechanism of action

• Increases the inhibitory effect of antithrombin on the serine proteases thrombin and Xa with greatest effect upon Xa
• LMWH clearance is predictable and requires little monitoring in uncomplicated thrombosis.

Dosage for Enoxaparin (Lovenox ®)

• Prophylaxis: 40 mg SC once a day (for morbidly obese may need 60mg)
• Treatment: 1 mg/kg q12h

Laboratory monitoring of LMWH

• Use chromogenic anti-Xa heparin assay; TAPTT/APTT is not useful for LMWH or pentasaccharide
• Assay not necessary in uncomplicated treatment situation
• Assay needed for infants, children, obese or underweight patients, or those with renal disease, long-term treatment, pregnancy, or unexpected bleeding or thrombosis
• Target for prophylaxis: 0.2 to 0.45 anti-Xa IU/ml.
• Target for therapy: 0.45-0.7 anti-Xa IU/ml.
• Platelet count once a day
• If count drops 50%, consider HIT, withdraw LMWH, switch to Argatroban or Lepirudin
• Assay should be drawn 4 hours after bolus.

Direct Thrombin Inhibitors (DTIs): Argatroban and Lepirudin

DTI indications

• Substitute for heparin when HIT is suspected or confirmed. Even when HIT's only manifestation is thrombocytopenia and heparin is stopped, risk of thrombosis in subsequent 30 days approaches 50% unless alternative anticoagulant is used.

DTI dosages

• Lepirudin (Refludan ®): 0.4 mg/kg slowly IV, then 0.15 mg/kg continuous infusion for 2-10 days depending on indication.
• Argatroban: 2 µg/kg/min IV.

DTI half-lives

• Lepirudin: 20 minutes
• Argatroban: 39-51 minutes

Laboratory monitoring of DTIs

• TAPTT is used to prevent bleeding or thrombosis
• Lepirudin: collect blood four (4) hours after initial dosage, adjust dosage to TAPTT 1.5-3.0 x mean of reference interval.
• Argatroban: collect blood two (2) hours after initial dosage, adjust dosage to TAPTT 1.5-3.0 x mean of reference interval.
• Lepirudin accumulates in kidney failure.
• Argatroban accumulates in liver failure.
• Do not start in patients with TAPTT longer than 2.5 x mean of reference interval
• In HIT, warfarin may be introduced when platelet count starts to increase but DTIs should be continued until platelet count normalizes. After 4-5 days of warfarin, if platelet count is normal and PT is therapeutic, stop DTI for a few hours and recheck INR. If between 2-3, it is safe to discontinue DTI.
• Continue with once daily TAPTT or more often if there is renal impairment.

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