A New Therapeutic Option by Subcutaneous Recombinant Hirudin in Patients with Heparin-induced Thrombocytopenia Type II: A Pilot Study

doi:10.1016/S0049-3848(00)00253-X

Thrombosis Research

Volume 99, Issue 4, 15 August 2000, Pages 325-334

https://doi.org/10.1016/S0049-3848(00)00253-X Get rights and content

Abstract

We prospectively studied 15 patients suffering from acute heparin-induced thrombocytopenia (HIT) type II with $n =10$ and without $n =5$ thromboembolic events and 4 patients with anamnestically known HIT type II recurrently requiring thromboprophylaxis in order to develop new therapeutic strategies by subcutaneous recombinant hirudin administration. Patients with acute venous or arterial thromboembolism were treated with aPTT-controlled intravenous (mean: 19.3 days) followed by subcutaneous r-hirudin (mean: 22.5 days). Patients without thromboembolism were treated with subcutaneous r-hirudin (mean: 25.9 days). Four patients were readmitted to subcutaneous r-hirudin (mean: 32 days). When r-hirudin was administered subcutaneously following intravenous treatment, mean baseline (prior to the injection) and mean peak (1.5–2.5 hours after the injection) aPTT ratios were 1.1 (±0.2) to 1.7 (±0.48) and 2.48 (±0.43) to 2.52 (±0.4) times normal value, respectively. Mean baseline and mean peak ECT ratios were 1.2 (±0.12) to 1.9 (±0.22) and 2.2 (±0.25) to 2.6 (±0.11) times the upper normal value, respectively. When r-hirudin was initially administered subcutaneously, mean baseline and mean peak aPTT ratios were 1.41 (±0.25) to 1.61 (±00.28) and 1.88 (±0.26) to 2.06 (±0.09) times the normal value, respectively. Mean baseline and mean peak ECT ratios were 1.25 (±0.2) to 1.5 (±0.38) and 2.01 (±0.21) to 2.23 (±0.25) times the upper limit of normal, respectively. Patients who received recurrent subcutaneous r-hirudin had mean baseline and peak aPTT values of 1.5 (±0.35) to 1.75 (±0.156) and 2.0 (±0.33) to 2.1 (±0.18) times the normal value, respectively. Mean baseline and peak ECT ratios were 1.3 (±0.26) to 1.65 (±0.09) and 1.94 (±0.256) to 2.7 (±0.23) times the upper limit of normal, respectively. The overall cumulative incidence of r-hirudin antibodies was 12/19 (63%) with a significant accumulation of r-hirudin in antibody-positive patients compared to antibody-negative patients (p<0.05). No patient suffered a new thromboembolic or major bleeding event. Subcutaneous administration of recombinant hirudin provides a long-term thromboprophylaxis regimen in HIT type II patients after passivation of acute thromboembolism.

Section snippets

Patients

Patient recruitment started on June 1, 1997. The clinical diagnosis of HIT type II was made on the basis of severe thrombocytopenia including a decrease in platelets of more than 50% from the initial value during heparin therapy and normalization of the platelet count after discontinuation of heparin therapy [16]. HIT type II was confirmed by a positive heparin-induced platelet aggregation assay [17] and/or heparin-PF4-induced antibody assay [18] and/or C14-serotonin release assay [19] and/or

Results

A total of 24 patients were assigned to receive r-hirudin. Five patients who received intravenous r-hirudin due to acute venous or arterial thromboembolism while HIT type II were excluded by the investigator before subcutaneous r-hirudin administration of various reasons, and were not allocated to the subcutaneous r-hirudin administration. Nineteen patients (10 from group I, 5 from group II and 4 from group III) were evaluable for further analysis. Table 1 shows the characteristics of all

Discussion

Nineteen patients were included in the study. However, four patients were readmitted for diagnostic and/or therapeutic interventions recommending cessation of oral anticoagulation. Three patients were re-included for subcutaneous r-hirudin administration. Surprisingly, 11/15 received LMWH prior to the clinical manifestation of HIT type II. This is in contrast to published data on incidences of HIT type II [24]. It is well documented that the incidence of HIT type II in LMWH-treated patients is

Acknowledgements

We gratefully acknowledge the assistance of Benjamin Simonis in the preparation of the statistical evaluation.

References (39)

B.H. Chong et al.
Heparin-induced thrombocytopeniaeffects of rabbit IgG, and its Fab and Fc fragments on antibody-heparin-platelet interaction
Thromb Res
(1989)
J. Dodt et al.
The complete amino acid sequence of hirudin, a thrombin specific inhibitor
FEBS Lett
(1984)
F. Markwardt
The development of hirudin as an antithrombotic drug
Thromb Res
(1994)
B.I. Eriksson et al.
Prevention of deep-vein thrombosis after total hip replacementdirect thrombin inhibition with recombinant hirudin, CGP 39393
Lancet
(1996)
D. Sheridan et al.
A diagnostic test for heparin-induced thrombocytopenia
Blood
(1986)
L.C. Wang et al.
Determination of heparin-induced IgG antibody by fluorescence-linked immunofiltration assay (FLIFA)
J Immunol Meth
(1999)
J.M. Schlaeppi
Preparation of monoclonal antibodies to the thrombin/hirudin complex
Thromb Res
(1991)
F. Markwardt et al.
Clinicopharmacological studies with recombinant hirudin
Thromb Res
(1988)
T.E. Warkentin
Heparin-induced thrombocytopeniaPathogenesis, Frequency, Avoidance and Management
Drug Safety
(1997)
D.B. Cines et al.
Immune endothelial cell injury in heparin-associated thrombocytopenia
N Engl J Med
(1987)

W.E. Märki et al.

Recombinant hirudingenetic engineering and structure analysis

Sem Thromb Hemost

(1991)

R.B. Wallis

From leeches to man

Sem Thromb Hemost

(1996)

Greinacher A, Janssens U, Berg G, Böck M, Kwasny H, Kemkes-Matthes B, Eicher P, Völpel H, Pötzsch B, Luz M for the...

A. Greinacher et al.

Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopeniaa prospective study

Circulation

(1999)

J. Harenberg et al.

Anticoagulation in patients with heparin-induced thrombocytopenia type II

Semin Thromb Hemost

(1997)

B.I. Eriksson et al.

A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement

NEJM

(1997)

F. Schiele et al.

Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legsa multicentre prospective dose-ranging randomized trial

Thromb Haemost

(1997)

F. Parent et al.

Treatment of severe venous thromboembolism with intravenous hirudin (HBW 023)an open pilot study

Thromb Haemost

(1993)

F. Schiele et al.

A pilot study of subcutaneous recombinant hirudin (HBW 023) in the treatment of deep vein thrombosis

Thromb Haemost

(1994)

Cited by (32)

Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
2012, Chest
Citation Excerpt :
Data supporting the use of lepirudin,168–170 argatroban,171,172 and fondaparinux173–175 to treat HIT during pregnancy are limited to case reports. The advantage of lepirudin is that it can be administered SC (it has been given in doses ranging from 25 mg bid to 125 mg bid; monitored by aPTT 2 h post injection).170,176 However, long-term administration has been associated with the development of antilepirudin antibodies that prolong the drug's effective half-life.
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke.
The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.
Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C).
Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.
Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition)
2008, Chest
Citation Excerpt :
Secretion of either anticoagulant into the breast milk is not a contraindication for breast feeding as GI absorption of danaparoid and fondaparinux is negligible. A few reports describe use of lepirudin during pregnancy,275-278 but this agent can cross the placenta279 and has caused embryopathy in rabbits given high doses of hirudin.280 Further, a zebrafish model reveals that thrombin plays a role in early embryogenesis.281
This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least 150 x 10⁹/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].
Heparin-induced Thrombocytopenia, a Prothrombotic Disease
2007, Hematology/Oncology Clinics of North America
Citation Excerpt :
In a prospective study of 36 patients who had history of HIT, intravenous argatroban provided adequate acute anticoagulation for venous or arterial thrombosis, without major bleeding or thrombotic complications [103]. In a prospective study of 19 patients who had current or previous HIT, subcutaneous lepirudin supported, without thrombotic or bleeding complications, long-term thromboprophylaxis after passivation of acute thromboembolism [112]. Although there has been no prospective, controlled study of bivalirudin in patients who have HIT, retrospective data describing its use in the noninterventional setting [113,114] and a prospective, open-label study in 52 patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI) [115] have been published.
Heparin-induced thrombocytopenia (HIT) is a serious, yet treatable prothrombotic disease that develops in approximately 0.5% to 5% of heparin-treated patients and dramatically increases their risk of thrombosis (odds ratio, 37). The antibodies that mediate HIT (ie, heparin-platelet factor 4 antibodies) occur more frequently than the overt disease itself, and, even in the absence of thrombocytopenia, are associated with increased thrombotic morbidity and mortality. HIT should be suspected whenever the platelet count drops more than 50% from baseline (or to <150 × 10⁹/L) beginning 5 to 14 days after starting heparin (or sooner if there was prior heparin exposure) or new thrombosis occurs during, or soon after heparin treatment, with other causes excluded. When HIT is strongly suspected, with or without complicating thrombosis, heparins should be discontinued, and a fast-acting, nonheparin alternative anticoagulant such as argatroban should be initiated immediately. With prompt recognition, diagnosis, and treatment of HIT, the clinical outcomes and health economic burdens of this prothrombotic disease are improved significantly.
The management of patients with heparin-induced thrombocytopenia who require anticoagulant therapy
2005, Chest
Citation Excerpt :
For these patients, the use of alternative forms of anticoagulation therapy are listed inTables 2,3 and discussed further in the next sections. Studies51,52 using IV argatroban and lepirudin to treat patients with acute HIT with thrombosis have demonstrated successful control of venous thromboembolism. Thus, the substitution of an IV direct thrombin inhibitor for heparin for the treatment of acute venous thromboembolism can be considered for a patient with subacute or remote HIT.
For patients with heparin-induced thrombocytopenia (HIT), reexposure to heparin is generally not recommended. However, these patients are likely to require anticoagulation therapy at some point in the future. During acute HIT, when thrombocytopenia and anti-heparin-platelet factor 4 antibodies (or HIT antibodies) are present, therapy with heparin must be avoided. In patients with subacute HIT, when platelets have recovered but HIT antibodies are still present, therapy with heparin should be avoided. In patients with a remote history of HIT, when HIT antibodies have cleared, heparin reexposure may be safe, although recurrent HIT has been described in some patients. For all of these patients, the use of alternate anticoagulant agents, including direct thrombin inhibitors and anti-Xa agents, is preferable. There is an increasing amount of data supporting the use of these alternative agents in a wide variety of clinical circumstances, including thromboprophylaxis and treatment of acute thrombosis. Except for a few clinical situations, it is generally possible to avoid heparin reexposure in patients with a history of HIT
Heparin-induced thrombocytopenia in intensive care patients
2007, Critical Care Medicine
To summarize new information on frequency of heparin-induced thrombocytopenia (HIT) in patients treated in intensive care units (ICU), developments in the interpretation of assays for detecting anti-PF4/heparin antibodies, and treatment of HIT patients.
All data on the frequency of laboratory-confirmed HIT in ICU patients were included; for laboratory testing of HIT and treatment of patients, this review focuses on recent data that became available in 2005 and 2006.
HIT is a potentially life-threatening adverse effect of heparin treatment caused by platelet-activating antibodies of immunoglobulin G class usually recognizing complexes of platelet factor 4 and heparin. HIT is more often caused by unfractionated heparin than low-molecular-weight heparin and is more common in postsurgical than in medical patients. In the ICU setting, HIT is uncommon (0.3–0.5%), whereas thrombocytopenia from other causes is very common (30–50%). For laboratory diagnosis of HIT antibodies, both antigen assays and functional (platelet activation) assays are available. Both tests are very sensitive (high negative predictive value) but specificity is problematic, especially for the antigen assays, which also detect nonpathogenic immunoglobulin M and immunoglobulin A class antibodies. Detection of immunoglobulin M or immunoglobulin A antibodies could potentially lead to adverse events such as bleeding if a false diagnosis of HIT prompts replacement of heparin by an alternative anticoagulant. For treatment of HIT, three alternative anticoagulants are approved: the direct thrombin inhibitors, lepirudin and argatroban, and the heparinoid, danaparoid (not approved in the United States). Recent data indicate that the approved dosing regimens of the direct thrombin inhibitors are too high, especially in ICU patients.
HIT affects <1% of ICU patients even though 30–50% develop thrombocytopenia. The choice of the optimal alternative anticoagulant depends on patient characteristics. Many ICU patients require lower doses of alternative anticoagulant than those recommended by the manufacturer.
Looking back into the future: Desirudin in acute coronary syndromes and coronary stenting
2011, EuroIntervention

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Original articleA New Therapeutic Option by Subcutaneous Recombinant Hirudin in Patients with Heparin-induced Thrombocytopenia Type II: A Pilot Study

Abstract

Section snippets

Patients

Results

Discussion

Acknowledgements

Thromb Res

FEBS Lett

Thromb Res

Lancet

Blood

J Immunol Meth

Thromb Res

Thromb Res

Heparin-induced thrombocytopeniaPathogenesis, Frequency, Avoidance and Management

Drug Safety

Immune endothelial cell injury in heparin-associated thrombocytopenia

N Engl J Med

Recombinant hirudingenetic engineering and structure analysis

Sem Thromb Hemost

From leeches to man

Sem Thromb Hemost

Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopeniaa prospective study

Circulation

Anticoagulation in patients with heparin-induced thrombocytopenia type II

Semin Thromb Hemost

A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement

NEJM

Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legsa multicentre prospective dose-ranging randomized trial

Thromb Haemost

Treatment of severe venous thromboembolism with intravenous hirudin (HBW 023)an open pilot study

Thromb Haemost

A pilot study of subcutaneous recombinant hirudin (HBW 023) in the treatment of deep vein thrombosis

Thromb Haemost

Original article
A New Therapeutic Option by Subcutaneous Recombinant Hirudin in Patients with Heparin-induced Thrombocytopenia Type II: A Pilot Study