Low molecular weight heparins (LMWHs) have predictable pharmacokinetic characteristics that enable weight-based dosing and obviate the need for laboratory monitoring . However, the pharmacology of LMWH overdose in humans has not been documented. Herein, we report the anticoagulant response measured with different coagulation parameters in a patient who self-administered 360 000 units of dalteparin in an unsuccessful suicide attempt.
A 39-year-old woman with a past history of recurrent venous thromboembolism, who was receiving chronic anticoagulation treatment with dalteparin because of previous warfarin failure, presented to the emergency department 2 h after injecting herself subcutaneously with 20 18 000-unit vials of dalteparin (approximately 4000 units kg–1) as part of a suicide attempt. In addition to the previously documented thrombosis, she had a history of type I diabetes mellitus and probable opiate dependence. On examination, she had a large ecchymosis at the site of injection without any other evidence of hemorrhage. Laboratory investigations on admission showed an activated partial thromboplastin time (APTT) of 214 s (normal 25–37 s) and a prothrombin time (PT) of 21.2 s (normal 10.8–11.9 s). Renal function was normal (creatinine 56 μmol L−1; normal 55–100 μmol L−1), as was the quantification of total human chorionic gonadotropin β-subunit (< 1 IU L−1; normal ≤ 5 IU L−1). Owing to the absence of hemorrhage no protamine was given, and the patient was admitted to the hospital for monitoring.
Blood samples for routine testing were collected in 3.2% (0.109 mol L−1) sodium citrate polypropylene tubes (BD Vacutainer; Becton Dickinson, Franklin Lakes, NJ, USA) and centrifuged at 1500 × g for 20 min at room temperature. Unused remnant plasma samples were recentrifuged at 1500 × g for an additional 20 min at 18–20 °C, and aliquots were frozen at −70 °C until tested. APTT was measured with the use of a synthetic phospholipid-based reagent activated with micronized silica (HemosIL SynthASil; Instrumentation Laboratory, Bedford, MA, USA). PT was measured with the use of a recombinant human thromboplastin with low heparin sensitivity and an international sensitivity index of approximately 1.0 (HemosIL RecombiPlasTin; Instrumentation Laboratory). Both tests were performed on an ACL Top instrument (Instrumentation Laboratory). Commercial calibration plasma (HemosIL Calibration Plasma; Instrumentation Laboratory) and a commercial dalteparin preparation (Fragmin; Pfizer, New York, NY, USA) were used to construct an LMWH calibration curve. Anti-factor (F)IIa and anti-FXa activities were tested with the use of chromogenic assays (Actichrome Heparin anti-fIIa and Actichrome Heparin anti-fXa; American Diagnostica, Stamford, CT, USA) on an ACL 3000 instrument (Instrumentation Laboratory), according to the manufacturer’s specifications. Internal and external quality controls are routinely used in our laboratory as per current provincial standards.
Figure 1 shows the course of coagulation parameters during the patient’s admission. The anticoagulant response reached a peak 10 h after administration of the drug (APTT > 240 s; PT = 24.1 s; anti-FXa activity = 9.0 units mL−1; anti-FIIa activity = 6.0 units mL−1). The APTT-normalized and the anti-FIIa activity returned to < 0.1 units mL−1 (our lower limit of detection) approximately 50 h post-administration, whereas anti-FXa activity returned to < 0.1 units mL−1 80 h post-administration. After further medical and psychiatric evaluations, the patient was discharged from hospital after 4 days, without further complications. The patient provided written informed consent for the publication of her case details.
Information regarding LMWH overdose is scarce. To the best of our knowledge, this is the first study that has comprehensively evaluated the anticoagulant response after a massive (20-fold) overdose of dalteparin in humans. The present case could inform rational management with protamine therapy, should the latter be needed (e.g. in the face of active hemorrhage). Protamine neutralizes heparin by inhibiting both anti-FIIa and anti-FXa activities. Whereas for unfractionated heparin the neutralizing protamine/heparin ratio is well known, in the case of LMWH the neutralizing activity of protamine depends on the molecular size and degree of sulfation of the particular compound . Furthermore, varying anti-FXa/anti-FIIa ratios for the many commercially available LMWHs might also influence protamine efficacy . We found that at the dalteparin dose received by this patient, anti-FIIa activity was > 1.0 units mL−1 for about 40 h, returning to <0.1 units mL−1 around 56 h post-administration, and these changes were more or less paralleled by the APTT. In contrast, anti-FXa activity was still within the therapeutic range after 60 h, and returned to < 0.1 units mL−1 80 h post-administration. Therefore, it is reasonable to assume that: (i) the neutralizing activity of protamine would be more efficient during the initial 24–36 h, during which APTT might be useful to follow the degree of anti-FIIa neutralization; and (ii) protamine might be required for 48–60 h to neutralize anti-FXa activity, which could be followed by standard anti-FXa monitoring. These notions are supported by a previous case report in which a neonate received a 10-fold overdose of enoxaparin, and protamine sulfate was administered with correction of clotting times within 48 h . That report also suggested that thrombin clotting time might be useful for follow-up. A point deserving further comment is the fact that at 23 h post-administration the prolongation of the APTT (225 s) did not parallel anti-FXa or anti-FIIa activities. We believe that there might be two reasons for this: first, it is known that APTT does not necessarily correlate well with anti-FXa (or presumably with anti-FIIa) activity ; and second, at this level of anticoagulation, the relationship between these parameters is most likely non-linear.
Given that anti-FXa neutralization by protamine is much less efficient for LMWH than it is for unfractionated heparin (∼ 50–75% for dalteparin), protamine dose adjustments are needed to decrease the risk of untoward effects or protamine-induced bleeding. Additionally, the pharmacologic differences among the different LMWHs might result in slightly different anticoagulant responses and protamine dose requirements. Finally, it should be stressed that protamine reversal might not be needed if no active bleeding is present.