Page 458 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

328 PART 3: Cardiovascular Disorders

heparin therapy is ongoing, the dose of protamine should be based on LMWHs encompass a number of fragments of unfractionated heparin
the approximate half-life of heparin (90 minutes). Since protamine, too, which are on average 5000 daltons in molecular weight. The different
is an anticoagulant, the dose should be calculated to only half-correct the LMWHs have been depolymerized by various means, and thus differ in
estimated circulating heparin. Protamine has been known to cause hypo- their pharmacokinetic and pharmacodynamic properties. One LMWH
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tension, shock, dyspnea, and pulmonary hypertension upon intravenous may not be interchangeable with another. LMWHs achieve excellent
injection. The incidence is reduced by giving the drug very slowly (no bioavailability when given subcutaneously (about 90% of that achieved
more than 50 mg in 10 minutes). A provider should be present as prot- with an equal intravenous dose), have a long half-life (2-4.4 hours),
amine is administered in case of an anaphylactoid reaction. Once heparin correlate well between anticoagulant response and body weight, and
is stopped and stabilization is underway, one may consider alternatives for have equal or better antithrombotic effects than unfractionated hep-
the treatment, including temporary vena caval interruption if appropriate. arin. There have now been numerous trials comparing LMWHs
Thrombocytopenia is a relatively common occurrence in the ICU; ( subcutaneously or intravenously) with unfractionated heparin in both
a recent review cited incident thrombocytopenia complicating 13% DVT and PE. 99-101 In an early meta-analysis pooling the results of over
to 44% of admissions across medical, surgical, and mixed ICUs. 2000 patients, LMWHs appeared superior with regard to venographic
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Thrombocytopenia may also occur as a complication of heparin admin- score improvement, recurrence rate of VTE, and hemorrhage. There
istration, typically occurring after several days of therapy. In large is also a trend towards an all-cause mortality benefit for LMWHs.
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series, roughly 1% to 3% of patients given full-dose intravenous heparin Similarly, a meta-analysis of LMWH compared to unfractionated hepa-
developed thrombocytopenia. Immune heparin–induced thrombo- rin for the treatment of PE found nonstatistically significant decreases
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cytopenia (HIT) is a specific entity whereby IgG antibodies develop in recurrent symptomatic VTE, PE, and bleeding complications. With
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to antigens against the complex formed by platelet factor 4 (PF4) and such data, groups such as the American College of Chest Physicians now
heparin. When strong PF4/heparin–IgG immune complexes form on recommend either a LMWH, intravenous UFH, or the synthetic agent
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platelet surfaces, the result is a strong platelet activation with release of fondaparinux (discussed below) as initial treatment for PE with a grade
platelet intracellular granules, causing a procoagulant microenviron- IA strength of evidence. While monitoring of anticoagulant effect
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ment. 93-95 Thrombocytopenia is less commonly seen with highly purified is not routinely recommended with LMWH, certain patient groups
LMWHs, suggesting that higher-molecular-weight components may be may benefit from following anti-Xa levels (activity against activated
responsible. It is also rare in patients given prophylactic dose heparin. Factor X). These subgroups include patients with either morbid obesity
The incidence of immune HIT is low when studied prospectively, with (>150 kg) or low body mass index (weight, 40 kg); pregnant patients;
just 0.5% to 1% in most studies of ICU patients. Female gender and sur- and those with renal insufficiency or rapidly changing renal function. 25
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gical or trauma patients seem to be at higher risk for its development. 97 Aspects of caring for critically ill patients may limit the full imple-
The diagnosis of HIT can be challenging given the frequency of mentation of LMWH usage in the intensive care unit. Many patients
thrombocytopenia due to competing causes, and the fact that antibod- with critical illness have coincident renal failure, bleeding diatheses, or
ies to heparin, even if platelet activating, may still not be pathologic. need for ongoing invasive procedures, all of which make UFH, which
Multiple tests are available to detect PF4/heparin antibodies, but the can be quickly discontinued and rapidly cleared from the body, prefer-
most specific for pathogenic HIT are the platelet serotonin release assays able. Conversely, certain situations appear to be ideally suited to the use
(SRA) or similar tests for platelet activation. Enzyme immunoassays of LMWH, such as in the long-term treatment of cancer patients with
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to PF4-IgG are also available and highly sensitive, but less specific, with venous thromboembolism. 102,103 As stated, the incidence of heparin-
a positive predictive value as low as 20%. The classic presentation of induced thrombocytopenia (HIT) is lower with LMWH than with UFH,
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HIT has 4 features: a large magnitude Thrombocytopenia, classically although in many trials of LMWH for DVT or PE, the incidence of HIT
50%; suggestive Timing (5-10 days after the introduction of immuniz- was sufficiently low in both arms to preclude a numeric comparison. In
ing dose heparin); arterial or venous Thrombosis; and no alternative orthopedic and surgical studies as well as the initial industry-sponsored
or oTher explanation for thrombocytopenia. These “4 Ts” are the trials of various LMWHs, the incidence of HIT varied between 0% and
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basis for a pretest clinical score which can be helpful in deciding which 0.8% of patients, compared with approximately 3% of patients treated
patients should undergo serologic testing for HIT; a score ≤3 indicates with unfractionated heparin; notably, these trials did not exclusively
a low probability of having platelet-activating HIT antibodies, whereas a use the serotonin—release assay to diagnose HIT, and may have over-
score ≥6 is highly probable, in the range of 50%, for HIT. The onset of estimated its incidence. Antibodies from patients with previous HIT
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thrombocytopenia is usually on the third to 15th day (mean = day 10), cross-react with every commercially available LMWH, however, there-
but can occur after several hours in patients previously sensitized. The fore LMWHs cannot be safely used in a patient known to have HIT. 93
severity of thrombocytopenia is variable (commonly to 50,000/mm ), Alternatives to Heparin: Neither heparin nor LMWH can be used in
3
but can be severe (<5000/mm ). Most patients remain asymptomatic, patients with HIT; furthermore, no safe dosing regimen has been
3
but some suffer major arterial or venous thrombosis, or life-threatening approved for LMWH in the presence of renal failure. Current alterna-
hemorrhage. Rarely, this syndrome is associated with skin bullae which tives to heparin include selective factor Xa inhibitors, direct thrombin
progress to necrosis (“heparin necrosis”), adrenal insufficiency due to inhibitors, and novel oral anticoagulants.
adrenal hemorrhage, or anaphylactoid reactions. Any time heparin is Direct thrombin inhibitors include the hirudin family, first isolated from
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given, it is prudent to measure platelet counts on a daily basis initially. leeches, and the argatroban family of active-site inhibitors. The advantage
An otherwise unexplained drop in platelet count of 30% has been of such agents over UFH is their ability to inhibit fibrin-bound thrombin
suggested as the threshold which should prompt discontinuation of hepa- with a predictable dose response, and their inability to produce heparin-
rin, although there are few data upon which to base this. When immune induced thrombocytopenia. Hirudin and its derivatives, especially lepi-
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HIT is strongly suspected, additional treatment considerations include: rudin and bivalirudin, are potent anticoagulants which have been proven
cessation and avoidance of all heparin products; initiation of a nonheparin more effective than enoxaparin, an LMWH, in the DVT prophylaxis of
alternative anticoagulant, such as the direct thrombin inhibitors lepirudin patients undergoing hip replacement. Lepirudin is excreted by the kid-
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or argatroban or the synthetic Xa inhibitor fondaparinux; avoidance of ney, and must be dose-adjusted for renal function. In addition, because
coumadin until thrombocytopenia resolves; and avoiding “prophylactic” several studies have reported a very high risk for bleeding with lepirudin
platelet transfusions in the absence of bleeding or procedures. 93 (up to 18%) in the treatment of HIT, many feel the approved dose for lepi-
Low-Molecular-Weight Heparin The promise of low-molecular-weight heparins rudin needs to be decreased to 0.05 to 0.10 mg/kg per hour. 106-109 Activated
(LMWHs) include simplicity, with once or twice daily therapy for venous partial thromboplastin time must be monitored with hirudin agents (goal
thromboembolism due to improved bioavailability over heparin, and aPTT 1.5-2.5 times control). While hirudin derivatives are approved for
the lack of required monitoring of anticoagulant effect. As a class, the use in patients with heparin-induced thrombocytopenia, they have not

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