Page 2553 - Hematology_ Basic Principles and Practice ( PDFDrive )

2276 Part XIII Consultative Hematology

C. Activated protein C (APC) is a major inhibitor of coagulation, HIV-infected patients to VTE. The majority of reported hemostatic
degrading activated coagulation factors VIIIa and Va. Inflammation abnormalities appear to primarily affect the protein C and S inhibi-
can also result in a decrease in functional protein S, the cofactor of tory mechanisms. However, the available studies reporting an
APC, which most likely explains the acquired protein S deficiency increased risk of VTE in HIV disease are only suggestive at present
observed in some HIV-infected patients, with and without because most supporting data come from case reports and one
thrombosis. uncontrolled retrospective study. Larger prospective studies are
An important additional component of the inflammatory state, needed to assess the true relative risk of VTE in HIV-infected indi-
which further contributes to an increased risk of thrombosis, is the viduals and to determine the primary pathogenic mechanisms
inflammation-induced increase in factor VIII coagulant protein. responsible for thrombosis in this population.
Factor VIII levels greater than 1500 units/L (150%) are an indepen-
dent risk factor for idiopathic VTE. A study of 94 HIV-infected
women and 50 HIV-negative controls who were participants in the Management of Venous Thromboembolism With
Women’s Interagency HIV Study documented a progressive pro- HIV Infection
thrombotic state with advancing HIV disease characterized by pro-
gressive decreases in protein S activity associated with a progressive The overall management principles and goals of therapy for VTE are
increase in Factor VIII activity. The decreases in protein S activity the same for people with and without HIV infection, although extra
and reciprocal increases in factor VIII activity closely correlated with caution is needed to anticipate possible drug interactions with
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decreasing CD4 lymphocyte count and were most significant in the HAART, particularly with the use of warfarin. Initial therapy for the
women with clinical AIDS. This study provides evidence for a link patient presenting with deep vein thrombosis and/or pulmonary
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between advancing HIV disease characterized by decreasing CD4 emboli involves the use of either intravenous unfractionated (UF)
lymphocyte count and the development of clinical AIDS with heparin or preferentially subcutaneous low-molecular-weight (LMW)
opportunistic infections and hemostatic changes associated with an heparin. Oral anticoagulants can be started immediately upon achiev-
increased risk for venous thrombosis. This acute and chronic inflam- ing therapeutic heparin levels, and under optimal circumstances
matory state is the most likely pathogenic mechanism for develop- heparin treatment can be completed and the patient discharged from
ment of VTE in HIV-infected individuals. the hospital within 5–7 days. LMW heparin preparations given
subcutaneously without monitoring have been shown to be safe and
effective treatment for VTE and may be preferable because they also
Anticardiolipin Antibodies allow for safe outpatient management. In a meta-analysis of clinical
trials comparing LMW heparin with UF heparin, LMW heparin
It is well established that antiphospholipid antibodies (anticardiolipin preparations were associated with a lower risk of major bleeding
antibodies [ACA] and lupus anticoagulant) are associated with a compared with adjusted-dose intravenous UF heparin.
hypercoagulable state. The incidence of elevated ACA in asymptom- The greatest difficulties in the management of VTE in HIV-
atic HIV disease is reported to be as high as 50% and even higher in infected patients occur with the use of oral anticoagulants. The
patients with clinical AIDS. Recent reports have documented the optimal therapeutic range for oral anticoagulation with warfarin in
presence of ACA in HIV-infected individuals with VTE. However, patients with VTE is a prothrombin time (PT) international normal-
two small studies reported no correlation between high levels of ACA ized ratio (INR) of 2–3. No data suggest that HIV-infected patients
and thrombosis in HIV infection. Because the increased thrombotic require a different degree of anticoagulation. However, most studies
risk associated with the antiphospholipid antibody syndrome is pre- have found that general medical patients managed as outpatients have
dominantly associated with the lupus anticoagulant and β2GP 1, it is a therapeutic INR in only 60% of assays. Although there are no
not surprising that increased ACA alone was not associated with a published data regarding the use of oral anticoagulants in HIV-
significantly increased risk of thrombosis. Thus the contribution of infected patients, individuals receiving HAART appear to have
antiphospholipid antibodies to the development of VTE in HIV greater difficulty in maintaining therapeutic anticoagulation, most
disease remains unknown and will require larger prospective studies likely because of complex drug interactions. With a reported annual
that include assays for the lupus anticoagulant and anti–β2GP risk of major bleeding with oral anticoagulants of 2% to 3% and
antibodies. bleeding-related fatality of 20%, careful PT monitoring of HIV-
infected patients is mandatory. They should be monitored at least
weekly for the first 6 to 8 weeks and should then have their PT
Role of Protease Inhibitors checked every 2 weeks. In patients in whom maintaining therapeutic
levels is difficult, home monitoring using devices approved by the US
Several investigators have found protease inhibitors to be associated Food and Drug Administration may be indicated. Patients who have
with VTE. Sullivan et al. reported that the use of indinavir (Crixivan) significant difficulty maintaining a therapeutic INR or have had
was associated with an increased risk of VTE. In a case series, George bleeding complications caused by poor control of their anticoagula-
29
et al. reported unexplained thrombosis in HIV patients receiving tion can be treated with long-term LMW heparin as has been recom-
protease inhibitors. Abnormalities of glucose metabolism and serum mended for the long-term management of cancer-related VTE. In
lipids are commonly observed with protease inhibitor therapy. These both HIV-infected and HIV-negative patients with malignancies who
include acquired insulin resistance, increased low-density lipoprotein develop VTE, long-term management with LMW heparin appears
cholesterol, and decreased high-density lipoprotein (HDL) choles- to be associated with a significantly lower risk of recurrent VTE.
terol. Insulin resistance is associated with acquired defects in the Drug–drug interactions may also limit the use of the new oral anti-
fibrinolytic system, including increased levels of plasminogen activa- coagulants. Potent inhibitors (lopinavir, ritonavir, indinavir, conivap-
tor inhibitor and tissue plasminogen activator. Similar fibrinolytic tan) or inducers (carbamazepine, rifampin, phenytoin) of Cyp3A4
abnormalities have been observed in patients with documented and P-GP can significantly increase the bleeding risk or conversely
insulin resistance who are treated with protease inhibitors. decrease the efficacy of these agents.
HDL has been shown to significantly enhance the activity of the Oral anticoagulation in the patient with VTE should be
APC complexed with protein S. This APC complex plays an essential maintained for at least 6 months. Patients with unprovoked VTE
role in downregulating thrombin generation. The lipoprotein abnor- who have had major pulmonary emboli, recurrent thromboemboli,
malities associated with the use of protease inhibitors, when combined or underlying inherited or acquired prothrombotic defects may
with other acquired defects in the protein C anticoagulant pathway, benefit from longer courses of oral anticoagulation. However, the
may further depress the anticoagulant activity of the APC complex decision to extend anticoagulation to prevent recurrence of throm-
and subsequently promote increased thrombin generation. Thus bosis must be weighed against the significant risk of bleeding in this
there are a number of pathogenic mechanisms that could predispose population.