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Published on 1 January 2008

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How should heparin-induced thrombocytopenia be treated?

teaser

Patients likely to develop acute HIT need further anticoagulation whether or not thrombosis is clinically apparent. Drugs include danaparoid, lepirudin, argatroban, fondaparinux and bivalirudin.

Andreas Greinacher
MD
Senior Consultant, Haemostasis and Transfusion Medicine

Kathleen Selleng
MD
Consultant, Haemostasis and Transfusion Medicine
Institute for Immunology and Transfusion Medicine
Ernst Moritz Arndt University
Greifswald
Germany
E: greinach@
uni-greifswald.de

Heparin-induced thrombocytopenia (HIT) is a prothrombotic immune-mediated complication that occurs with unfractionated heparin (UFH) and to a lesser extent with low molecular weight heparin (LMWH). HIT is one of the most important adverse drug events encountered by
physicians.1 It must be distinguished from other causes of platelet count reduction as it paradoxically induces new thrombosis.2 The fundamental paradox of HIT, that anticoagulant therapy can induce thrombosis, results from a platelet-activating immune response triggered by the interaction of heparin with a specific platelet protein, platelet factor 4 (PF4). Venous thrombotic complications are more common than arterial thrombotic events, but the latter are associated with significant morbidity.
Clinical features of HIT that help distinguish it from other forms of thrombocytopenia include the timing of onset, the severity of thrombocytopenia and the presence of thrombosis or other sequelae. A fall in platelet count associated with HIT typically begins four to 14 days after starting heparin. The severity of thrombocytopenia in laboratory-confirmed HIT (median platelet count 50–70 x 109 / l) is typically less than in other immune thrombocytopenic disorders such as drug-dependent immune thrombocytopenia (platelet counts often < 15 x 109 / l). In some cases (~ 15%), thrombosis can occur even when platelet counts remain above 150 x 109 / l. These features have recently been evaluated as a scoring system (see Table 1).3
[[Table1_14]]
Currently used laboratory tests fall into one of two categories: functional (platelet activation) assays or antigen assays (ie PF4/polyanion immuno­assay). Both are very good at ruling out HIT – that is, they have high negative predictive value. Platelet activation assays such as the serotonin-release assay ([14C]-SRA) and the heparin-induced platelet activation assay (HIPA) have a higher correlation with clinical HIT.4

Treatment of HIT
[[Table2_14]]
Regarding general measures, if there is high clinical suspicion for HIT, such as a platelet count decrease > 50% between days five and 10 of heparin treatment, associated with thrombosis, and for no other obvious reason, all heparin should be stopped, including heparin used for arterial lines, and alternative non-heparin anticoagulant therapy should be initiated promptly. Stopping of heparin alone is insufficient to prevent new thrombosis in HIT. Vitamin K antagonists must not be given in acute HIT as they can induce venous limb gangrene.5
Three drugs are approved for anticoagulation in HIT: danaparoid (heparinoid), lepirudin (bivalent direct thrombin inhibitor), and argatroban (mono­valent DTI) (see Table 2). Additionally, bivalirudin and fondaparinux are rational therapies for HIT, although controlled studies are lacking. No antidote is available for any of the alternative anticoagulants.

Direct thrombin inhibitors for treating HIT
Lepirudin and argatroban are approved for treating HIT. Argatroban and bivalirudin are both approved for anticoagulation during percutaneous coronary intervention (PCI), with the latter agent also having been compared to heparin during cardiopulmonary bypass surgery in small prospective studies in non-HIT patients.6

Lepirudin
Lepirudin is a recombinant bivalent DTI.7 Since the elimination of lepirudin is primarily renal, its dosing must be greatly adjusted downwards in patients with compromised renal function, particularly in elderly and ICU patients. Based on secondary analysis of the prospective lepirudin trials and real-world experience, the approved dosing regimen of lepirudin (bolus of 0.4 mg/kg of bodyweight followed by 0.15 mg/kg/h continuous infusion) is too high.8–11 Therefore, a major reduction in dosing and close aPTT monitoring are strongly recommended. ­Lepirudin should be started in very low dose (0.001–0.01 mg/kg/h), if there is evidence of renal compromise, and 0.10 mg/kg/h if renal function is normal. Other than in life-threatening massive thrombosis, the initial bolus of lepirudin should be omitted.
Lepirudin can induce antibodies in about 40–70% of patients (including cases of re-exposure).12 The antibodies may reduce elimination of lepirudin, thereby prolonging its half-life. Rare anaphylactic reactions to lepirudin have been reported, which can likely be avoided by omitting bolus doses.

Argatroban
Argatroban is a synthetic monovalent DTI.13–15 With a half-life of some 45 minutes, argatroban is eliminated primarily through the liver with minimal renal clearance. Argatroban is approved for prophylaxis and treatment of HIT-related thrombosis and for patients at risk of or with HIT who are under­going PCI. Severely ill patients often have decreased perfusion of the liver, which may require downward dosage adjustment. Therefore, also for this DTI, the approved starting dose (2.0 µg/kg/min) should be reduced to 0.5–1.0 µg/kg/min (and in cases of severe liver impairment even lower), and titrated upwards to reduce the bleeding risk. Argatroban treatment is monitored by aPTT (1.5–3 x baseline); it causes a substantial increase of the INR.

Bivalirudin
Bivalirudin is a bivalent DTI.6 It is cleaved by thrombin. This avoids major drug accumulation in case of either renal and/or hepatic impairment. It is approved for PCI, but not for HIT. In contrast to ­lepirudin, but similarly to argatroban, thrombin inhibition by ­bivalirudin is reversible. The drug has a short half-life of approximately 30 min. Dosing ranges between a continuous infusion of 0.14 mg/kg/h, and in those with renal or combined hepatic and renal dysfunction, of 0.03–0.05 mg/kg/h.16 Monitoring by aPTT is possible; with a target of 2.0 x baseline, ACT with a threshold > 300 sec might also be an option.

Monitoring of DTIs
DTIs are usually monitored by the aPTT. For lepirudin it has been shown that, at higher concentrations, the dose-response curve flattens, and even major changes in plasma levels cause only a minor change in the aPTT. The laboratory should generate its own standard dose-response curve for its PTT reagent using spiked plasma to define the range over which the aPTT reliably reflects changes in the DTI plasma dose.7 At concentrations above this range the ecarin clotting time (ECT) is more reliable for DTI monitoring.
Another important potential source of error in DTI monitoring occurs in patients with low ­prothrombin levels, such as those with disseminated intra­vascular coagulation or hepatic dysfunction or those undergoing warfarin treatment.17 Low prothrombin levels can result in falsely elevated aPTTs in the ­presence of DTIs, prompting inappropriate dose reduction. The ecarin chromogenic assay (ECA) seems to overcome these problems by providing a linear dose-response curve for all DTIs independently of patient`s prothrombin levels.18
The DTIs have different effects on the INR. Whereas lepirudin and bivalirudin have minor effects, argatroban causes substantial INR prolongation and also major artefacts in most functional clotting assays. This can cause interpretative confusion especially in intensive care patients and complicates the transition to vitamin K antagonists. The different effects of the DTIs on the INR are related to their largely differing molar concentrations at therapeutic dose (argatroban 20 times higher than lepirudin).19

Danaparoid
The heparinoid danaparoid is approved for prophylaxis and treatment of thrombosis in patients with HIT in the EU, Australia and Canada.20–25 ­Danaparoid inhibits thrombin generation primarily by anti-
activated factor X (FXa) activity with a half-life of ~ 24 hours. Its bioavailability is nearly 100% after intra­venous (IV) as well as subcutaneous (SC) administration. Dose-response relationship is predictable, monitoring of treatment in therapeutic dose is required in patients with severely impaired renal function, very low or high body weight, life-­threatening thrombosis, unexpected bleeding complications, or in severely ill patients. Like heparin, danaparoid requires antithrombin for its major anticoagulatory effects. Monitoring of danaparoid requires assessing anti-FXa activity. Activated partial thromboplastin time (aPTT), prothrombin time/international normalised ratio (PT/INR), or activated clotting time (ACT) are not appreciably prolonged. There is no antidote for danaparoid.
In vitro cross-reactivity of HIT antibodies with danaparoid seems to be of minor clinical relevance. Treatment can be started without cross-reactivity testing. Clinical signs of cross-reactivity (new thrombosis or persistent thrombocytopenia beyond four days) should prompt investigation for in vitro cross-reactivity and possibly a switch to another anticoagulant.

Vitamin K antagonists in HIT patients
Warfarin requires approximately five days to decrease procoagulant vitamin K-dependent clotting factors to therapeutic levels. The initial effect of ­warfarin, however, is a rapid reduction in the anticoagulant factor protein C, resulting in a temporary drug-induced procoagulant effect. This initial pro­coagulant effect of warfarin is normally compensated for by the overlapping parenteral anticoagulation. Thus, the recent ACCP guidelines recommend:5
●    Not starting warfarin therapy in acute HIT as long as platelet counts remain low, as the procoagulant effects of HIT increase the risk for warfarin-induced protein C hypercoagulability, and microvascular thrombotic complications such as venous limb gangrene.
●    Initiating warfarin only during overlapping alternative anticoagulation and beginning with low, maintenance doses of warfarin (maximum first dose 5mg, phenprocoumon 6 mg).
●    Discontinuing the DTI (or danaparoid) only after a minimum five-day overlap with the DTI and only after the platelet count has reached a stable plateau.

Anticoagulation in extracorporeal circuits and HIT
Danaparoid, argatroban and lepirudin have been used successfully for renal replacement therapy; lepirudin and bivalirudin have been used for on-pump cardiopulmonary bypass surgery. Both danaparoid and lepirudin have long half-lives in case of severe renal impairment. Dose adjustment of ­lepirudin is particularly difficult in the phase of deteriorating or recurring renal function requiring very close monitoring (every 4 h). Argatroban has been used at doses ranging between 0.7–1.7 µg/kg/min for renal replacement therapy, but there are only limited data for use in cardiopulmonary bypass surgery.26

Management of patients with moderate or low clinical likelihood of HIT
How should a patient with moderate or low clinical likelihood of HIT or anamnestic HIT be managed?
The alternative, non-heparin anticoagulants confer significant risk of major bleeding complications, especially in patients in whom the platelet count decrease is caused by factors other than HIT, eg sepsis or disseminated intravascular coagulation (DIC) and where the positive anti-PF4/heparin EIA is only an epiphenomenon. In prospective studies on lepirudin and argatroban and a large compassionate-use danaparoid programme, the risk of major bleeding per treatment day was 1.03% for lepirudin and 0.84% for argatroban in patients with HIT and thrombosis, and 0.97% (lepirudin) and 1.25% ­(argatroban) in patients with isolated thrombo­cytopenia. For ­danaparoid, the rate of major bleeding was 0.89% in patients receiving the drug in therapeutic dose and 0.36% in those receiving it in prophylactic dose.
In patients with a complicated course, thrombocytopenia is rather frequent and HIT is much more frequently suspected than confirmed (ratio ~9 : 1).27 In these patients it is more likely that the platelet count decrease does not reflect a prothrombotic process; therefore, our practice in patients with low or moderate clinical probability for HIT (eg score ≤ 6; see Table 1) and no reason for therapeutic anti­coagulation is to use danaparoid in prophylactic dose (750 U three times a day SC), especially if no acute thrombosis is evident, pending clarification of the diagnosis by laboratory testing for HIT antibodies. This approach bears a comparable risk of bleeding as LMWH in prophylactic dose, has a minimal risk for HIT antibody cross-reactivity, and as this agent is approved for HIT in many countries, may reduce medicolegal risk.
Based on theoretical considerations and favourable case reports, fondaparinux may also be useful in prophylactic dose in this patient population, as there is no cross-reactivity with HIT antibodies in vitro. Furthermore, successful therapeutic anticoagulation with fondaparinux of HIT patients with thrombo­embolic complications has been described. However, the long half-life of this drug (17 h), its renal elimination, and minimal experience in the ICU setting are important considerations.
For patients with a history of HIT who require cardiopulmonary bypass (CPB) surgery, heparin/protamin during CPB is an appropriate treatment, when HIT antibodies are not present.5 Pre- and post-surgery heparin should be strictly avoided and substituted for by an alternative anticoagulant, when therapeutic anticoagulation is indicated.
Finally, HIT is a very litigious area in medicine. If a non-approved alternative anticoagulant is prescribed in a patient with suspected HIT, it is strongly recommended that one obtain informed consent and document why this treatment is favoured over an approved treatment. ■
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