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2176 Part XII Hemostasis and Thrombosis

TABLE Pharmacokinetic and Biophysical Limitations of TABLE Features of Heparin-Induced Thrombocytopenia
149.2 Heparin 149.3
Limitations Mechanism Features Details
Poor bioavailability at low Limited absorption of long heparin Thrombocytopenia Platelet count of 100,000/µL or less or a
doses chains decrease in platelet count of 50% or more
Dose-dependent clearance Binds to endothelial cells Timing Platelet count falls 5–10 days after starting
Variable anticoagulant Binds to plasma proteins whose heparin
response levels vary from patient to patient Type of heparin More common with unfractionated heparin than
Reduced activity in the vicinity Neutralized by platelet factor 4 LMWH
of platelet-rich thrombi released from activated platelets Type of patient More common in surgical patients than medical
Limited activity against factor Reduced capacity of heparin– patients; more common in women than in men
Xa incorporated in the antithrombin complex to inhibit Thrombosis Venous thrombosis more common than arterial
prothrombinase complex factor Xa bound to activated thrombosis
and thrombin bound to platelets and thrombin bound to LMWH, Low-molecular-weight heparin.
fibrin fibrin

within platelet-rich thrombi has the potential to generate thrombin, TABLE Management of Heparin-Induced Thrombocytopenia
even in the face of heparin. Once this thrombin binds to fibrin, it 149.4
too is protected from inhibition by the heparin–antithrombin Stop all heparin
complex. Clot-associated thrombin can then trigger thrombus growth Give an alternative anticoagulant, such as lepirudin, argatroban,
by locally activating platelets and amplifying its own generation bivalirudin, danaparoid, or fondaparinux.
through feedback activation of factors V, VIII, and XI. Further Do not give platelet transfusions.
compounding the problem is the potential for heparin neutralization Do not give warfarin until the platelet count returns to its baseline
by the high concentrations of PF4 released from activated platelets level. If warfarin is administered, give vitamin K to restore the INR
within the platelet-rich thrombus. to normal.
Evaluate for thrombosis, particularly deep vein thrombosis.
Side Effects INR, International normalized ratio.
The most common side effect of heparin is bleeding. Other complica-
tions include thrombocytopenia, osteoporosis, and elevated levels of
transaminases.
performed by quantifying serotonin release when washed platelets
Bleeding. The risk of heparin-induced bleeding increases with loaded with labeled serotonin are exposed to patient serum in the
higher heparin doses. Concomitant administration of drugs that absence or presence of varying concentrations of heparin. If the
affect hemostasis, such as antiplatelet or fibrinolytic agents, increases patient serum contains the HIT antibody, heparin addition induces
the risk of bleeding, as does recent surgery or trauma. Heparin-treated platelet activation and subsequent serotonin release.
patients with serious bleeding can be given protamine sulfate to Management of HIT is outlined in Table 149.4. Heparin should
neutralize the heparin. Protamine sulfate, a mixture of basic polypep- be stopped in patients with suspected or documented HIT, and an
tides originally isolated from salmon sperm, binds heparin with high alternative anticoagulant should be administered to prevent or treat
16
affinity, and the resultant protamine-heparin complexes are then thrombosis. The agents most often used for this indication are
cleared. Typically, 1 mg of protamine sulfate neutralizes 100 U of parenteral direct thrombin inhibitors, such as lepirudin, argatroban,
heparin. Protamine sulfate is given intravenously. Anaphylactoid or bivalirudin, or factor Xa inhibitors, such as fondaparinux or
reactions to protamine sulfate can occur, and drug administration by danaparoid. Oral factor Xa inhibitors, such as rivaroxaban, have been
slow intravenous infusion is recommended to reduce the risk of these used successfully to manage HIT.
problems. Patients with HIT, particularly those with associated thrombosis,
often have evidence of increased thrombin generation that can lead
Thrombocytopenia. Heparin can cause thrombocytopenia. to consumption of protein C. If these patients are given warfarin
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated without a concomitant parenteral anticoagulant to suppress thrombin
process that is triggered by antibodies directed against neoantigens generation, the further decrease in protein C levels induced by war-
on PF4 that are exposed when heparin binds to this protein (Table farin can trigger skin necrosis. To avoid this problem, patients with
149.3). These antibodies, which usually are of the immunoglobulin HIT should be treated with a direct thrombin inhibitor or
G subtype, bind simultaneously to the heparin–PF4 complex and to fondaparinux until the platelet count returns to normal levels. At this
platelet Fc receptors. Such binding activates the platelets and gener- point, low-dose warfarin therapy can be introduced, and the throm-
ates platelet microparticles. Circulating microparticles are prothrom- bin inhibitor or fondaparinux can be discontinued when the antico-
botic because they express anionic phospholipids on their surface and agulant response to warfarin has been therapeutic for at least 2 days.
can bind clotting factors, thereby promoting thrombin generation. HIT also is covered extensively in Chapter 133.
HIT can be associated with thrombosis, either arterial or venous.
Venous thrombosis, which manifests as deep vein thrombosis and/or Osteoporosis. Treatment with therapeutic doses of heparin for over
pulmonary embolism, is more common than arterial thrombosis. 1 month can cause a reduction in bone density. This complication
Arterial thrombosis can manifest as ischemic stroke or acute myocar- has been reported in up to 30% of patients given long-term heparin
dial infarction. Rarely, platelet-rich thrombi in the distal aorta or iliac therapy, and symptomatic vertebral fractures occur in 2% to 3% of
arteries can cause critical limb ischemia. these individuals.
The diagnosis of HIT is established using enzyme-linked assays Studies in vitro and in laboratory animals have provided insights
to detect antibodies against heparin–PF4 complexes or with platelet into the pathogenesis of heparin-induced osteoporosis. These inves-
activation assays. Enzyme-linked assays are sensitive, but they can be tigations suggest that heparin causes bone resorption, both by
positive in the absence of any clinical evidence of HIT. The most decreasing bone formation and by enhancing bone resorption. Thus
specific diagnostic test is the serotonin release assay. This test is heparin affects the activity of both osteoblasts and osteoclasts.