Page 2443 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 149 Antithrombotic Drugs 2181

should be avoided during pregnancy, particularly during the first problems, warfarin is rarely used in pregnancy, particularly in the
trimester. first and third trimesters. Instead, heparin, LMWH, or fondaparinux
can be given during pregnancy for prevention or treatment of
Bleeding thrombosis.
At least half of the bleeding complications with warfarin occur when Warfarin does not pass into the breast milk. Consequently, war-
the INR exceeds the therapeutic range. Bleeding complications may farin can safely be administered to nursing mothers.
be mild, such as epistaxis or hematuria, or more severe, such as ret-
roperitoneal or gastrointestinal bleeding. Life-threatening intracranial Special Problems
bleeding also can occur. Patients with a lupus anticoagulant or those who need urgent or
To minimize the risk of bleeding, the INR should be maintained elective surgery present special challenges. Although observational
in the therapeutic range. In asymptomatic patients whose INR is studies suggested that patients with thrombosis complicating the
between 3.5 and 4.5, warfarin should be withheld until the INR antiphospholipid antibody syndrome required higher-intensity war-
returns to the therapeutic range. If the INR is over 4.5, a therapeutic farin regimens to prevent recurrent thromboembolic events, two
INR can be achieved more rapidly by administration of low doses of recent randomized trials demonstrated that targeting an INR of 2.0
sublingual vitamin K. to 3.0 is as effective as higher-intensity treatment and produces less
Patients with serious bleeding need treatment that is more aggres- bleeding. Monitoring warfarin therapy can be problematic in patients
sive. These patients should be given 5 to 10 mg of vitamin K by slow with antiphospholipid antibody syndrome if the lupus anticoagulant
intravenous infusion. Additional vitamin K should be given until the prolongs the baseline INR.
INR is in the normal range. Treatment with vitamin K should be If patients receiving long-term warfarin treatment require an
supplemented with prothrombin complex concentrate to replace the elective invasive procedure, warfarin can be stopped 5 days before the
missing vitamin K–dependent clotting factors. 19 procedure to allow the INR to return to normal levels. Those at high
Warfarin-treated patients who experience bleeding when their risk for recurrent thrombosis can be bridged with once- or twice-daily
INR is in the therapeutic range require investigation into the cause subcutaneous injections of LMWH when the INR falls below 2.0.
of the bleeding. Those with gastrointestinal bleeding often have The last dose of LMWH should be given 12 to 24 hours before the
underlying peptic ulcer disease or a tumor. Similarly, investigation of procedure, depending on whether LMWH is administered twice or
hematuria or uterine bleeding in patients with a therapeutic INR may once daily, respectively. After the procedure, warfarin can be restarted.
unmask a tumor of the genitourinary system.
Skin Necrosis Dabigatran
A rare complication of warfarin, skin necrosis usually is seen 2 to 5
days after initiation of therapy. Well-demarcated erythematous lesions The active moiety of dabigatran etexilate, dabigatran targets the active
form on the thighs, buttocks, breasts, or toes. Typically the center of site of thrombin and blocks its procoagulant activities. Dabigatran
the lesion becomes progressively necrotic. Examination of skin inhibits both free and fibrin-bound thrombin.
biopsies taken from the border of these lesions reveals thrombi in the
microvasculature.
Warfarin-induced skin necrosis is seen in patients with congenital Mechanism of Action
or acquired deficiencies of protein C or protein S. Initiation of
warfarin therapy in these patients produces a precipitous fall in Dabigatran etexilate is a prodrug with an oral bioavailability of 6%
plasma levels of proteins C or S, thereby eliminating this important to 7%. Once absorbed, the drug is rapidly biotransformed by esterases
anticoagulant pathway before warfarin exerts an antithrombotic effect to dabigatran, the levels of which peak 1 to 2 hours after oral admin-
through lowering of the functional levels of factor X and prothrom- istration. Dabigatran has a half-life of 12 to 14 hours. About 80% of
bin. The resultant procoagulant state triggers thrombosis. Why the the drug is excreted unchanged by the kidneys (Table 149.8). Potent
thrombosis is localized to the microvasculature of fatty tissues is permeability glycoprotein (P-GP) inhibitors, such as ketoconazole,
unclear. are contraindicated.
Treatment involves discontinuation of warfarin and reversal with
vitamin K, if needed. An alternative anticoagulant, such as heparin
or LMWH, should be given in patients with thrombosis. Protein C Indications
concentrates or recombinant activated protein C can be given to
patients with protein C deficiency to accelerate healing of the skin Dabigatran is licensed for thromboprophylaxis after hip arthroplasty
lesions; fresh frozen plasma may be of value for those with protein S in the United States, and it is licensed for this indication and for
deficiency. Occasionally, skin grafting is necessary when there is thromboprophylaxis after knee arthroplasty in most other countries.
extensive skin loss. Dabigatran also is licensed for stroke prevention in patients with
Because of the potential for skin necrosis, patients with known nonvalvular atrial fibrillation and as an alternative to warfarin for
protein C or protein S deficiency require overlapping treatment with treatment of venous thromboembolism.
a parenteral anticoagulant when initiating warfarin therapy. Warfarin When compared with warfarin in patients with atrial fibrillation,
should be started in low doses in these patients, and the parenteral dabigatran at the 150-mg twice-daily dose was superior for reduction
anticoagulant should be continued until the INR is therapeutic for
at least 2 to 3 consecutive days.
Pregnancy TABLE Comparison of Dabigatran, Rivaroxaban, Apixaban,
Warfarin crosses the placenta and can cause fetal abnormalities or 149.8 and Edoxaban
bleeding. The fetal abnormalities include a characteristic embryopa- Dabigatran Rivaroxaban Apixaban Edoxaban
thy, which consists of nasal hypoplasia and stippled epiphyses. The
risk of embryopathy is highest if warfarin is given in the first trimester Target Thrombin (IIa) Factor Xa Factor Xa Factor Xa
of pregnancy. Central nervous system abnormalities also can occur Active drug No Yes Yes Yes
with exposure to coumarins at any time during pregnancy. Finally, Onset Time (h) 0.5–2 2–4 3–4 1–3
maternal administration of warfarin produces an anticoagulant effect
in the fetus that can cause bleeding. This is of particular concern at Half-life (h) 12–17 5–13 ~12 9–11
delivery, when trauma to the head during passage through the birth Renal excretion (%) 80 33 27 50
canal can lead to intracranial bleeding. Because of these potential