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396 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 397

TABLE 25–3. HAS-BLED Score for Predicting Bleeding Risk considered during the second trimester, but heparin or an LMWH is a
preferable alternative in most situations. Vitamin K antagonists are safe
on Coumadin
during lactation. 44
Variable Points
Hypertension (uncontrolled, systolic 1 point REVERSAL OF ANTICOAGULATION
>160 torr)
Anticoagulation must be reversed for episodes of bleeding, surgery,
Abnormal renal or liver function 1 point each, max 2 trauma, or overdosage. Appropriate interventions for patients with
points excessively prolonged INRs without bleeding include holding warfa-
Stroke (prior history) 1 point rin doses, administering low doses of vitamin K (0.5 to 1.0 mg), and
increasing the frequency of monitoring (Table 25–4). Serious bleeding
45
Bleeding history of predisposition 1 point
and major warfarin overdosage requires factor replacement and larger
Labile INR (<60% time in therapeutic 1 point vitamin K doses that may need to be given intravenously. Four-factor
range) concentrates have been developed and tested for reversal of warfarin.
Elderly (>65 years old) 1 point A large, open-label, prospective phase IIIB noninferiority study in
Drugs/alcohol use (nonsteroidal 1 point for each, max 2 nonsurgical patients on warfarin requiring reversal for major bleed-
antiinflammatory drugs, aspirin, anti- points ing compared fresh-frozen plasma (FFP) to four-factor prothrombin
platelet agents) complex concentrate (PCC) (factors II, VII, IX, X, protein C, and pro-
tein S). Four-factor PCC was as effective in achieving hemostasis as
46
INR, international normalized ratio. plasma (72.4 percent with four-factor PCC vs. 65.4 percent with plasma;
Bleeding rate: 0 points = 0.8%, 1 point = 1.3%, 2 points = 2.2%, absolute difference, 7.1 percent [95 percent confidence interval, −5.8 to
≥3 points = 7.8% 19.9]) and superior to FFP with regards to INR correction within
0.5 hours of infusion (62.2 percent receiving four-factor PCC vs. 9.6
percent receiving FFP; absolute difference, 52.6 percent [95 percent
confidence interval, 39.4 to 65.9]). The rate of adverse events, such as
Several risk models have been developed to predict bleeding risk in death and thromboembolism, was similar between groups.
patients on warfarin. The HAS-BLED score was derived and validated Anticoagulated patients who need invasive procedures represent
in a prospective cohort of more than 6000 patients on warfarin for atrial management problems, and decisions about periprocedural anticoag-
fibrillation (Table 25–3). Variables in this model include hypertension, ulation should be based on balancing the risk of thromboembolism
40
abnormal renal or liver function, stroke, prior bleeding complications, with that of bleeding from the procedure. Evidence-based guidelines
labile INR, age older than 65 years, and drug or alcohol abuse. The for bridging therapy are available, and the topic has been reviewed.
45
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intensity of anticoagulation as reflected by the INR is the most impor- The goal is to reduce the intensity of anticoagulation during and imme-
tant predictor of bleeding risk, which is low in the therapeutic range diately after surgery, while avoiding thromboembolism caused by the
but increases as the INR prolongs further. The cumulative risk of bleed- underlying disease. Generally, the risk of recurrence is greatest in the
ing increases with a longer duration of treatment, whereas the absolute period shortly after an episode of acute thrombosis and declines pro-
risk is greatest early, possibly caused by pathologic lesions present at the gressively over time. If possible, elective surgery and other invasive
time therapy is started.
A rare complication of warfarin therapy is skin necrosis, which
if it occurs usually presents early in the course of anticoagulation.
41
Thrombosis in dermal and subdermal venules is the underlying cause,
and this may be caused by disproportionately rapid reduction in pro- TABLE 25–4. Reversing Warfarin Therapy
teins C and S. Skin necrosis typically begins with burning and tingling Indication Action
at the affected site, which usually involves a region with a large amount INR <6 Lower the dose, consider withholding 1 or
of subcutaneous tissue, such as the breast, buttock, or thigh. Painful more doses
hemorrhagic full-thickness skin infarction may develop, and frequently
will require skin grafting. Other complications from warfarin are rare. Recheck in 3–7 days
Occasional patients report alopecia; hypersensitivity reactions are rare INR 6–10 Lower the dose and withhold 1–3 doses
and are almost uniformly caused by the dye used in the pill rather than Consider administering vitamin K, 1–2 mg
by the warfarin itself. orally
Warfarin use in patients with heparin-induced thrombocytopenia Recheck INR in 24–48 hours
(HIT) may be complicated by limb gangrene caused by occlusive venous
thrombosis; this effect is likely a result of a combination of inadequate INR >10 Withhold doses until INR in desired range
parenteral anticoagulant effect and reduced levels of protein C, in con- and cause of elevation ascertained
cert with relatively preserved levels of factors II and X that are seen early Give vitamin K, 2–4 mg orally
after the initiation of warfarin administration. This complication high- Recheck INR in 24 hours
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lights the need for parenteral anticoagulants to be continued in patients
with HIT until the coagulopathy has largely resolved, as indicated by a Serious bleeding Administer four-factor prothrombin
return of the platelet count to normal or near normal levels. and major overdose complex concentrate if available for rapid
Oral anticoagulation should be avoided in pregnancy because reversal. If four-factor prothrombin com-
plex concentrate not available administer
warfarin crosses the placenta, and exposure during organogenesis in fresh-frozen plasma. Also give 5–10 mg
the first trimester can lead to fetal embryopathy with significant cra- vitamin K intravenously
nial bone malformations. Anticoagulation during pregnancy increases
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bleeding complications, especially later in pregnancy. Warfarin may be INR, international normalized ratio.

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