Page 2227 - Hematology_ Basic Principles and Practice ( PDFDrive )

1974 Part XII Hemostasis and Thrombosis

TABLE Risk Factors for Heparin-Induced Thrombocytopenia Diagnostic Considerations in the Patient With Limb Ischemia and
133.1 Thrombocytopenia
Heparin type Unfractionated > low-molecular-weight heparin Concurrence of limb ischemia/necrosis and thrombocytopenia sug-
> fondaparinux gests one of several hematologic emergencies:
Patient type Postoperative (major > minor surgery) > medical • Heparin-induced thrombocytopenia. Occlusion of large lower-limb
> obstetric/pediatric arteries by platelet-rich “white clots” is characteristic of heparin-
induced thrombocytopenia (HIT). The major clue is an otherwise
Dose a Prophylactic dose > therapeutic dose > flushes unexplained platelet count fall that begins 5 or more days after
Duration 11–14 days > 5–10 days > 4 days or fewer initiation of heparin. Urgent thromboembolectomy may be limb
b
sparing. Sensitive assays for HIT antibodies give strongly positive
Sex Female > male
results. See subsequent entry for warfarin.
a Importance of heparin dose is uncertain because of confounding effect of • Adenocarcinoma-associated disseminated intravascular
patient type (e.g., postoperative patients tend to receive prophylactic-dose coagulation. Severe venous or arterial thrombosis can develop in
heparin whereas medical patients [e.g., with venous thromboembolism] are patients with metastatic adenocarcinoma who have disseminated
more likely to receive therapeutic-dose heparin); nevertheless, reported intravascular coagulation (DIC). This often occurs within hours
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frequencies of heparin-induced thrombocytopenia (HIT) are relatively high in after stopping heparin. A clinical clue is an otherwise unexplained
patients given postoperative prophylactic-dose heparin.
b Heparin exposure beyond 14 days does not usually increase the risk of HIT rise in platelet count that occurs with initial or repeated heparin
beyond that of an 11- to 14-day exposure. therapy. See next entry for warfarin.
• Warfarin-induced phlegmasia cerulea dolens/venous limb
gangrene. Coumarin anticoagulants, such as warfarin, can
lead to venous ischemia (phlegmasia cerulea dolens) or
venous limb gangrene in patients with DIC caused by HIT or
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adenocarcinoma. Limb loss can occur even though the limb
CLINICAL AND LABORATORY MANIFESTATIONS pulses are palpable.
• Sepsis-associated microvascular thrombosis. Acquired natural
Most patients with HIT have moderate thrombocytopenia; The anticoagulant depletion (e.g., markedly reduced antithrombin
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median platelet count nadir is approximately 60 × 10 /L; for 90% of or protein C levels) can complicate DIC associated with sepsis,
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patients, the platelet count nadir is greater than 20 × 10 /L (Fig. leading to bilateral acral limb ischemia or necrosis involving
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133.3). In the rare patient whose platelet count falls to less than 10 feet and (sometimes) fingers/hands (“symmetric peripheral
gangrene”).
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× 10 /L, there is often evidence of overt DIC, and red cell fragments • Septic embolism. Rarely, infective endocarditis or aneurysmal
and circulating normoblasts may be evident on examination of the thrombosis leads to the constellation of thrombocytopenia and
blood smear. Thrombosis can occur in HIT patients even if there is acute limb ischemia.
a minimal decrease in the platelet count, and even if the platelet count • Antiphospholipid syndrome. Autoimmune thrombocytopenia
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nadir never falls below 150 × 10 /L. 1 and hypercoagulability can interact to produce acute limb
The platelet count fall usually begins 5–10 days after the initiation ischemia and thrombocytopenia in patients with antiphospholipid
of an immunizing heparin exposure and while the patient continues syndrome.
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to receive heparin (typical-onset HIT). Usually the immunizing
trigger is heparin given during surgery (e.g., cardiac or vascular
surgery) or that is started soon after surgery (e.g., thromboprophy-
laxis). Interestingly, starting LMWH thromboprophylaxis before Patients with HIT have an unusual predisposition to develop
elective surgery (as is more frequently done in Europe) is less likely ischemic limb necrosis. Indeed, approximately 5% of such patients
to be associated with antibody formation compared with postopera- develop some degree of limb necrosis necessitating amputation.
tive first-dose administration. 15 Occasionally multiple limbs are involved (see the box on Diag-
HIT is recognized in approximately one-quarter of patients when nostic Considerations in the Patient With Limb Ischemia and
the platelet count fall occurs abruptly after restarting UFH or LMWH Thrombocytopenia).
(rapid-onset HIT). Invariably, such patients have been exposed to
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heparin within the previous 5–100 days, because HIT antibodies
are transient and are only detectable for several weeks after an immu- DIFFERENTIAL DIAGNOSIS
nizing heparin exposure. Consequently, rapid-onset HIT, which is
caused by administration of heparin to a patient with preformed HIT Only approximately 10% of patients who undergo laboratory inves-
antibodies, is strongly associated with recent heparin exposure. tigations for clinically suspected HIT have a serologic profile that
Sometimes, thrombocytopenia occurs several days after a brief supports the diagnosis (i.e., detectable heparin-dependent, platelet-
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exposure to heparin or worsens despite stopping heparin (delayed- activating IgG antibodies that recognize PF4/heparin complexes).
onset HIT). 4,18 On exceptionally rare occasions, a transient pro- The differential diagnosis includes postoperative thrombocytopenia
thrombotic disorder that resembles HIT clinically and serologically (hemodilution/platelet consumption), thrombocytopenia of critical
occurs without an apparent preceding heparin exposure; triggers of illness, and septicemia. Some non-HIT disorders mimic HIT so
so-called “spontaneous HIT syndrome” include knee replacement closely that they warrant the term pseudo-HIT. One example of
surgery (perhaps because of release of heparin-like glycosaminogly- pseudo-HIT is adenocarcinoma-associated DIC, in which the com-
cans from knee cartilage) and infection. 19,20 bination of progressive thrombocytopenia and severe venous limb
HIT is a highly prothrombotic condition: At least 50% of HIT ischemia that occurs during the transitioning of patients from heparin
patients develop thrombosis. 1,11,16 Both venous (deep vein thrombosis (either UFH or LMWH) to warfarin may suggest a diagnosis of
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and/or pulmonary embolism) and arterial (especially aortic and HIT. Another disorder that can mimic HIT is the antiphospholipid
iliofemoral arterial thrombosis, stroke, or myocardial infarction) syndrome: here, thrombocytopenia, thrombosis, and a false-positive
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thrombosis can occur. Other complications include necrotizing skin PF4-dependent enzyme immunoassay (EIA) caused by anti-PF4 (not
lesions at the sites of subcutaneous heparin injection and acute anti-PF4/heparin) antibodies can be present. 22
inflammatory/cardiorespiratory (anaphylactoid) or transient memory
disturbances after intravenous heparin bolus administration to sensi-
tized persons. Unexplained hypotension or abdominal pain in a CLINICAL SCORING SYSTEMS
patient with HIT suggests bilateral adrenal hemorrhagic infarction,
which can lead to acute adrenal failure; the hemorrhagic adrenal The pretest probability of HIT can be estimated using validated
necrosis is the result of adrenal vein thrombosis. 20 scoring systems. The 4Ts system represents a mnemonic that is based