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Iaki R

on 10 April 2013

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A 57-year-old man remains in the hospital after experiencing complications from knee-replacement surgery 7 days ago.

LMWH prophylaxis is initiated on the first postoperative day.

On day 7 left leg swelling, compression US: DVT. Platelets: 300*10^9/L ---> 125*10^9/L.
ELISA: high titer of antibodies PF4–heparin complexes.

The patient has normal renal function.

The physician in the intensive care unit wonders about the best treatment. Clinical Presentation HIT (Heparin Induced Theombocytopenia) HIT is not rare.

It is both simultaneously underrecognized and overdiagnosed. 2 general types of serologic assays:
1) Quantitative direct-binding assays that detect antibodies.
2) Functional assays that detect platelet activation induced by

Heparin-induced thrombocytopenia should be suspected in any patient who is receiving or who has recently received heparin or low-molecular-weight heparin and in whom thrombocytopenia (defined as a decrease in platelet count of ≥50%), thrombosis, or skin necrosis at the heparin-injection sites develops. The relative rarity of heparin-induced thrombocytopenia among all patients with thrombocytopenia contributes to overdiagnosis of the disorder.25 Overdiagnosis may be reduced if testing is restricted to populations with a higher prevalence of disease. To that end, clinical scoring systems have been developed to assess the likelihood of heparin-induced thrombocytopenia, including the 4T score (see Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org)26 and the HIT Expert Probability (HEP) score27 (Table 2 in the Supplementary Appendix). These scoring systems have high negative predictive value but low positive predictive value. Both scores have limitations. The 4T score has modest interobserver agreement,28 whereas the HEP score is complex and has not been prospectively validated.27 A scoring system has been developed for use in patients who have undergone cardiopulmonary bypass surgery, but it too requires validation.29

Two general types of serologic assays are used to diagnose heparin-induced thrombocytopenia: quantitative direct-binding assays that detect antibodies and functional assays that detect platelet activation induced by these antibodies. The direct-binding assays (or enzyme immunoassays) are readily available and measure antibodies binding to PF4–heparin complexes or similar molecules. These tests have a high sensitivity (approaching 100%) but a low specificity.24,30,31 Thus, a negative test essentially rules out the diagnosis, and heparin-based anticoagulants can be used while alternative causes for the thrombocytopenia are sought.9-11 However, false positive results are common, which leads to a potential for overdiagnosis, even with modifications such as grading the relative amount of antibody (by measuring the optical density) and restricting antibody detection to the IgG subclass.30,31 In contrast, functional assays, such as the serotonin-release assay or the heparin-induced platelet-aggregation test, have both a high sensitivity and a high specificity. The use of these tests is limited in clinical practice because of the lack of standardization, limited availability, and long turnaround times.1,2,9,23,32 We think that patients with a high pretest probability (based on clinical experience or the application of a clinical scoring system) and a strongly positive IgG anti-PF4–heparin enzyme immunoassay do not need a functional test to confirm the diagnosis, although this strategy has not been validated in prospective studies. However, in patients who do not have a high clinical probability of heparin-induced thrombocytopenia, the enzyme immunoassay may be misleading and should not be used as the sole diagnostic test.

The most appropriate anticoagulant for use in patients with heparin-induced thrombocytopenia remains uncertain, but on the basis of the biology of the disorder, several attributes can be identified. It must be immediate-acting and capable of interrupting the activated coagulation cascade at the level of thrombin or factor Xa (Figure 2); it should be associated with a low bleeding risk; it should not require monitoring or should be easily monitored; and perhaps most important, the physician should be familiar with its use. These attributes are important because, since it is often overdiagnosed, currently many patients receive treatment for heparin-induced thrombocytopenia even though they do not have this condition.

. Fc-gamma-RIIa Fc-gamma-RIIa Immune complexes Released microparticles Several attributes can be identified as important:
1. Immediate-action and capability of interrupting the activated coagulation cascade
at the level of thrombin or factor Xa.
2. Low bleeding risk.
3. Not requiring monitoring or easily monitored.
4. The physician should be familiar with its use.

These attributes are important because, since it is often overdiagnosed, currently many patients receive treatment for HIT even though they do not have this condition.

Studies evaluating the anticoagulants used for heparin-induced thrombocytopenia have important methodologic limitations, including the use of historical controls, small sample sizes, and inconsistencies in the diagnosis of the disorder. The search for the most appropriate treatment The 5 competitors Paraenteral direct-thromin inhibtors 1 2 3 4 5 Factor Xa inhibitors Argatroban Argatroban - FDA approved indication in the U.S: for the treatment of HIT. - Simple monitoring: direct thrombin inhibitors cause a dose-
dependent increase in the activated partial-thromboplastin time. - Immediate onset of action. A steady-state anticoagulant effect is
achieved within 1 to 3 hours. - Clearance: Hepatobilliary. - Half life: 40 -50 minutes. The anticoagulant effect ends soon after
the drug is discontinued. Rebound hypercoagulability may occur if
the drug is discontinued while a procoagulant state still exists. Desirudin Desirudin - Approved indication: prevention of deep-vein thrombosis after
hip-fracture surgery. Data regarding the use of desirudin in
HIT are limited. - Monitoring: None required. - Fixed subcutaneous dose of 15 or 30 mg per 12 for every 12 hours. - Clearance: Renal. - Half life: 2-3 hours. Bivalirudin Bivalirudin - Bivalirudin has been used as the anticoagulant during cardiac
surgery in patients with active or a recent history of HIT. - Allows simple monitoring by aPTT. - Short half-life (approximately 25 minutes). It is administered
intravenously by continuous infusion. - Clearance: both renally and by enzymatic degradation. Danaparoid Danaparoid - Approved for the management of HIT in Canada,
Japan, Europe, and Australia. - Monitoring is possible for anti-Xa activity. - Clearence: Renal. - Half life: 24h. - Administration: Subcutaneously or intravenously. Fondaparinux - Does not cross placenta. Fondaparinux - Rapidly absorbed (in <30 minutes) after subcutaneous
injection. - Half life time: 17 - 20h. - Routine anti-Xa monitoring, although possible, is not
required. - Clearance: Renal. - Very easy to administer: 5 mg subcutan once daily for
patients <50kg, 7.5 mg for patients 50-100kg and 10 mg
for patients >100kg. Transition to a Vitamin K Antagonist - The article suggests that anticoagulation be continued
for 4 to 6 weeks in patients with isolated HIT and for
3 months in patients with thrombosis. - Early introduction of vitamin K antagonists should be
avoided. - Once the platelet count has returned to a normal level
after an acute episode of HIT warfarin should be
slowly introduced at a dose of 5 mg or less daily and
gradually increased to achieve an international
normalized ratio (INR) between 2 and 3. - Warfarin should overlap with the chosen parenteral
agent for at least 5 days and until the INR is
therapeutic. Current Guidelines - The ACCP (American College of Chest Physicians): weak
recommendations (grade 2C) for the use of argatroban, lepirudin
or danaparoid over other nonheparin anticoagulants in patients
with normal renal function and for argatroban over other
nonheparin anticoagulants in patients with impaired renal
function. - The Hemostasis and Thrombosis Task Force of the British
Committee for Standards in Haematology favored Lepirudin and full-
dose danaparoid. However, argatroban was not available in the
United Kingdom when these recommendations were written. Areas of Uncertainty The most appropriate agent for treating HIT has not been established. 1. "On the basis of emerging data showing
efficacy and lower bleeding risks, our
preference is to use fondaparinux, even
though it is not FDA-approved, in patients
with normal renal function."
2. "We would use argatroban in patients with
impaired renal function."
3. "Agents with short half-lives, including
argatroban, may be preferred in patients who
are likely to require invasive procedures." Research is pending...
A prospective cohort study evaluating the safety and efficacy of the use of rivaroxaban to manage HIT is recruiting patients (ClinicalTrials.gov number, NCT01598168). We think that the use of unfamiliar anticoagulants, which are associated with important bleeding risks, presents one of the biggest challenges to the safe treatment of patients with suspected, presumed, or confirmed HIT. This issue is further compounded because HIT is often overdiagnosed. Very few studies have made direct comparisons between agents, and the quality of evidence supporting the efficacy and safety of the various anticoagulants in these patients is weak. FONDAPRINUX Which agent was chosen by the authors
as the preferable treatment for HIT? Continuing the vitamin K antagonist treatment for 3
months. Overlaping the
administration of
Fondaparinux and the vitamin k antagonist for at least 5 days or until the INR is within therapeutic range
for 2 consecutive days. Advising the patient to avoid
heparin, especially in the
subsequent 3 to 4 months
after the diagnosis of HIT
and to consult with a specialist if heparin is needed
in the future. Heparin immediate
discontinuation and
administration at a dose
of 7.5 mg subcutaneously
once a day. Test for IgG anti-PF4–heparin
antibodies Serotonin-releasing assay Treating the patient Following the platelet count
and starting a vitamin K
antagonist when it has
recovered to at least
150×10^9 per liter. OR 1 2 3 4 5 6 Unfractionated heparin Low-Molecular-Weight heparin Fondaparinux Plateltet activation Nonheparin anticoagulants for HIT John G. Kelton, M.D., Donald M. Arnold, M.D., and Shannon M. Bates, M.D.C.M.

N Engl J Med 2013; 368:737-744 February 21, 2013DOI: 10.1056/NEJMct1206642
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