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Chapter 140 Hypercoagulable States 2081

in isolation and secondary when it is associated with autoimmune Heparin-Induced Thrombocytopenia
disorders, such as systemic lupus erythematosus or other connective
tissue diseases. Clinical manifestations of APS include one or more A clinicopathologic syndrome, heparin-induced thrombocytopenia
episode of thrombosis, one or more unexplained fetal deaths at 10 or (HIT) is diagnosed on the basis of clinical features and laboratory
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more weeks of gestation, or three or more first-trimester miscarriages detection of HIT antibodies (see Chapter 133). The risk for HIT
(less than 10 weeks of gestation). Placental thrombosis is hypothesized is higher with unfractionated heparin than with low-molecular-weight
to be the root cause of the pregnancy-related complications that heparin (LMWH) and almost never occurs with fondaparinux. HIT
characterize APS. Intrauterine growth retardation, preeclampsia, and is more common in surgical patients than in medical patients and
eclampsia have also been associated with APS. APS can also occur occurs more frequently in women.
with cancer, with some infections, and with drugs, such as phenothi- Typical clinical features of HIT include thrombocytopenia and
azines, phenytoin, hydralazine, or amoxicillin. Thrombosis in APS thrombosis (arterial or venous). Less common features include
patients can be arterial, venous, or placental. necrotic skin lesions at the site of subcutaneous heparin injection,
To make the diagnosis of APS, at least one clinical criterion and acute systemic reactions to heparin, and rarely, DIC. 16,17 Thrombo-
one laboratory criterion must be met. Laboratory diagnosis of APS cytopenia is the most common finding, occurring in 90% of patients.
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requires the presence of LA or ACL on tests taken at least 6 to 12 Typically, the platelet count falls 5 to 10 days after heparin is started.
weeks apart. Tests for LA are well standardized, and a LA is associated However, thrombocytopenia can occur earlier if the patient has been
with a higher risk of thrombosis than ACL. In contrast, there is exposed to heparin in the past 3 months. Rarely, the onset of HIT
considerable variability among laboratory results of ACL tests reflect- can be delayed and occurs several days after stopping heparin.
ing, at least in part, different methods and lack of consensus on what HIT is an autoimmune-like disorder and is caused by heparin-
constitutes a negative or positive test. 12 dependent, platelet-activating antibodies of the IgG subclass. These
The LA is detected using phospholipid-dependent clotting tests. antibodies are directed against neoantigens that are exposed on
Most screening assays are based on the aPTT. aPTT reagents differ platelet factor 4 (PF4) when it forms a complex with heparin. By
in their sensitivity for detection of LA, and many laboratories have binding to FcγII receptors on platelets, these antibodies trigger
adopted less-sensitive aPTT reagents for routine aPTT testing. LA is platelet activation. Activated platelets and platelet-derived micropar-
suspected when the aPTT is prolonged. To explore the cause of the ticles provide an anionic phospholipid surface on which coagulation
prolonged aPTT, patient plasma is mixed with normal plasma and factors assemble and promote thrombin generation. This produces a
the aPTT is again determined (see Chapter 129). If the aPTT remains hypercoagulable state and explains why 30% to 70% of HIT patients
prolonged, an LA is suspected. The diagnosis is confirmed by dem- develop thrombosis.
onstrating that addition of excess hexagonal-phase phospholipid The diagnosis of HIT is supported by assays that capitalize on the
normalizes the aPTT, thereby documenting the phospholipid depen- platelet-activating properties of HIT antibodies. Functional assays,
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dence of the abnormal test result. In addition to the aPTT, a battery such as the platelet serotonin release assay or heparin-induced platelet
of phospholipid-dependent clotting tests is often used for diagnosis activation assay, detect antibody-induced platelet activation in the
of LA. These include the dilute Russell viper venom time and kaolin presence of heparin and are the gold standard for diagnosis of HIT.
clotting time. In contrast, although enzyme immunoassays for detection of antibod-
ACL antibodies are detected using immunoassays. Only ACL of ies against PF4/heparin complexes are more sensitive than functional
medium to high titer and of the IgG or IgM subclass are associated assays, they are less specific because only a small subset of these
with thrombosis, and the risk is higher with antibodies against β 2 antibodies has the capacity to produce HIT. Consequently a negative
glycoprotein-1 than against cardiolipin. For ACL, the amount of IgG immunoassay is useful to exclude the diagnosis of HIT, but a positive
or IgM antibody binding to cardiolipin-coated platelets is expressed test should be confirmed with a functional assay.
in standardized GPL or MPL units, with 1 unit representing the When the diagnosis of HIT is established, heparin must be
cardiolipin-binding capacity of 1 µg/mL affinity-purified antiphos- stopped and an alternative anticoagulant should be given. Options
pholipid antibody from reference sera. The extent of antibody binding include direct thrombin inhibitors (such as argatroban or bivalirudin)
is influenced by both the titer of the antibody and its affinity for or factor Xa inhibitors (such as fondaparinux or danaparoid). Treat-
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cardiolipin. Lack of standardization of ACL assays makes it difficult ment with these agents should be continued until the platelet count
to compare results between laboratories. returns to baseline levels at which point, low-dose warfarin can be
ACL antibodies are found in 3% to 10% of healthy individuals. initiated.
They also are common with certain infections (such as mycobacterial
pneumonia, malaria, or parasitic disorders) and after exposure to
some medications. Often, these antibodies are of low titer and are Cancer and Its Treatment
transient. ACL antibodies are detected in about 30% to 50% of
patients with systemic lupus erythematosus. Of these, 10% to 20% About 25% of patients who present with venous thromboembolism
also have an LA. have cancer. Cancer patients who develop venous thromboembolism
The mechanism by which antiphospholipid antibodies trigger have reduced survival compared with those without this complica-
thrombin generation is unclear. In cell cultures, these antibodies can tion. Patients with brain tumors, pancreatic cancer, and advanced
directly activate endothelial cells and induce the expression of adhe- ovarian, lung, gastrointestinal tract, or prostate cancer have particu-
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sion molecules that can tether tissue factor–bearing leukocytes or larly high rates of venous thromboembolism. Treatment with che-
microparticles onto their surface. Tissue factor can then induce clot- motherapy, hormonal therapy, and biologic agents, such as erythroid
ting in vitro. stimulating agents and antiangiogenic drugs, and surgery further
Antiphospholipid antibodies also have been shown to (a) activate increases the risk for venous thromboembolism. Additional risk
platelets, (b) interfere with the protein C pathway, (c) inhibit anti- factors include indwelling central venous catheters and major
thrombin catalysis by vessel wall heparan sulfate, (d) impair fibrino- abdominal, pelvic, or orthopedic surgery.
lysis, and (e) enhance transmigration of oxidized LDL into the vessel The pathogenesis of thrombosis in cancer patients is multifacto-
wall, thereby promoting atherothrombosis. Whether these mecha- rial in origin and represents a complex interplay among the tumor,
nisms are operative in vivo has yet to be established. patient characteristics, and the host hemostatic system. Tumors can
In contrast to most hypercoagulable states, APS can be associ- initiate coagulation by expressing tissue factor or cysteine proteases
ated with spontaneous arterial thrombosis, as well as with venous on their surface or by shedding tissue factor–bearing microparticles.
thromboembolism. Arterial thrombosis can manifest as a stroke or In addition to its role in coagulation, tissue factor also acts as a
transient ischemic attack. Thrombosis of the sagittal sinus or other cell-signaling molecule that promotes tumor proliferation and spread.
cerebral veins, a form of venous thrombosis, can cause stroke in Patient factors that contribute to venous thromboembolism
these patients. include immobility and venous stasis secondary to extrinsic