Lethal paradoxical cerebral vein thrombosis due to suspicious anticoagulant rodenticide intoxication with chlorophacinone

Lethal paradoxical cerebral vein thrombosis due to suspicious anticoagulant rodenticide intoxication with chlorophacinone

Forensic Science International 166 (2007) 85–90 www.elsevier.com/locate/forsciint Lethal paradoxical cerebral vein thrombosis due to suspicious antic...

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Forensic Science International 166 (2007) 85–90 www.elsevier.com/locate/forsciint

Lethal paradoxical cerebral vein thrombosis due to suspicious anticoagulant rodenticide intoxication with chlorophacinone F. Papin a, F. Clarot b,*, C. Vicomte b, J.M. Gaulier c, C. Daubin d, F. Chapon e, E. Vaz b, B. Proust b a Forensic Department, Caen University Hospital, Caen, France Medical Forensic Institute, Rouen University Hospital, Charles Nicolle, Rouen, France c Pharmacokinetic and Toxicology Laboratory, Limoges University Hospital, Limoges, France d Intensive Care Unit, Caen University Hospital, Caen, France e Neuropathology Department, Caen University Hospital, Caen, France b

Received 9 February 2006; received in revised form 4 April 2006; accepted 9 April 2006 Available online 23 May 2006

Abstract Superwarfarin exposure is a growing health problem, described in many countries. The authors report a case of suspicious chlorophacinone poisoning with a problematic diagnosis. They review the literature and discuss particularities of anticoagulant rodenticide intoxication, as well as the apparent contradiction between anticoagulant intoxication and lethal thrombosis. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Rodenticide; Chlorophacinone; Poisoning; Anticoagulant; Cerebral vein thrombosis

1. Introduction Rodenticide intoxication is rare, as these products are no longer used as rodenticide due to its hazardous effects on humans. Nevertheless, these products may still be found in certain garden sheds, and could have a ‘‘criminal’’ use. The authors report a case of suspicious chlorophacinone poisoning with a problematic diagnosis. Particularities of anticoagulant rodenticide intoxication are discussed; usefulness of blood analysis in suspected poisoning or intoxication is underlined. The authors also discuss the physiopathological characteristics of their case, as well as the apparent contradiction between anticoagulant intoxication and lethal thrombosis. 2. Case report A 34-year old woman, farm worker, with no particular previous medical history or medication – with the exception of * Correspondence to: Institut de Me´decine Le´gale, CHU Rouen, Charles Nicolle, 76031 Rouen Cedex, France. Tel.: +33 232888284; fax: +33 232888367. E-mail address: [email protected] (F. Clarot). 0379-0738/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2006.04.003

an oral oestroprogestative contraception – presented in the emergency department with a massive hematuria. On admission, the patient was apyretic and physical examination confirmed macroscopic hematuria and had abdominal pain in the right hypochondral region, which initially occurred 3 days earlier. No particular violence related lesion was observed. The patient was initially treated by analgesics and intravenous NSAIDs. Blood laboratory tests revealed a hyperleucocytosis (12,500/ 3 mm) which resulted in antibiotic treatment and hospitalization for suspected infected renal colitis. The following day, abdominal ultrasonography was performed and revealed pyelo-calicis hyperechogenicity with no dilatation. Moreover, a slight fluid collection was observed medially to the right kidney, and a mobile echogenic residue was also found in the bladder. The patient continued to have pain and hematuria, and at day 4 she suddenly presented convulsive loss of consciousness. She was transferred to the intensive care unit in a comatose state (Glasgow scale 4) and was then sedated, intubated, and ventilated. Initial neurological examination showed hypotonic coma, a non-reactive left mydriasis and rapidly bilateral areactive mydriasis. She was administered 100 mg of mannitol and a CT

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Fig. 1. Initial CT scan show a large left hemisphere haemorrhagic cerebral infarct, a diffuse oedema, a subarachnoid haemorrhage, and a right shifting of the midline structure with a left ventricule disappearance.

scan was performed with no contrast agent (Fig. 1). It revealed an extended left hemisphere haemorrhagic cerebral infarct, associated with diffuse oedema and midline structure shifted to the right. Biological screening revealed a slight anemia (10.3 g/ dl), an increased hyperleucocytosis (19,490/3 mm) and a normal platelet count. Coagulation study showed an unexplained very low prothrombin time (10%) and especially very low levels of Vitamin K dependant factors (II, VII, IX, and X). However, antithrombin III and factor V were normal. Cerebral angiography, performed to assess the brain perfusion state, revealed a thrombosis of the superior longitudinal sinus (SLS) (Fig. 2). Despite intravenous Vitamin K injection and adapted resuscitation, our patient died in an irreversible comatose state, at day 4.

Further subsequent toxicological analysis performed on a serum sample collected during hospitalization, the 4th day before the death, revealed a high level of chlorophacinone: 25.9 mg/L. At autopsy, performed 4 days after death, we found a slight nail and lip cyanosis, pulmonary asphyxia lesion, and a trachea oedema. Moreover, autopsy revealed diffuse haemorrhagic signs (i.e. multiple ecchymosis, visceral haemorrhages, pleural and peritoneal blood collection, diffuse subarachnoid haemorrhage, and renal intracavity haemorrhage). The biological samples collected were sent to the laboratory for forensic toxicological analysis. Macroscopic and histologic examination confirmed a bilateral and diffuse alveolar pulmonary oedema, a multivisceral congestion, and demonstrated a concentric myocardial hypertrophy. Neuropathological examination confirmed SLS thrombosis. It also showed a left frontal region haemorrhagic infarct lesion, a diffuse oedema, and herniation of the fifth temporal circumvolution (Fig. 3). Police investigation was not able to assess the origin of the intoxication, which was not considered as criminal, but accidental or suicidal. 3. Materials and methods Venous blood sample was collected during hospitalization, the fourth day before the death. Initially, blood was taken to perform coagulation tests but extensive toxicological screening (including a chlorophacinone assay) was subsequently performed in a serum sample, due to the diagnostic problems, using high-performance liquid chromatography coupled with diode-array detection (HPLC– DAD). A second toxicological investigations set was performed in a forensic context 4 days after death, on autopsy biological samples (peripheric blood, urine, pleural effusion, and gastric contents). No visceral, particularly liver, analysis was performed.

Fig. 2. Cerebral angiography (via left vertebral artery) shows lack of flow of the superior longitudinal sinus and a capilar ‘‘marshy’’ stasis (left image). Lack of SLS opacification is confirmed by left lateral sinus venography (right image).

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Fig. 3. Macroscopic brain examination confirmed a left frontal haemorrhagic infarct lesion, extended to the caudate nucleus head and the corpus callosum. Examination showed as well a herniation of the 5th temporal circumvolution.

Chlorophacinone assays in serum were performed using a previously published method [1]. This analytical procedure was also applied for chlorophacinone determinations in forensic samples (i.e. blood, urine, and gastric contents) according to the results of a previous analytical validation step in such biological matrix. Briefly, this method, routinely applied for the simultaneous identification and quantitation of 13 hydroxycoumarin and indandione anticoagulant drugs [2] and rodenticides, used a reversed-phase liquid chromatography with diode-array detection technique. Extraction step consisted of an acidic and alkaline liquid–liquid double extraction with diethylether– ether acetate (50:50, v/v). High-performance liquid chromatography was performed using gradient elution with an acetonitrile and phosphate buffer on a Nucleosil C18, 5 mm particle size (150 mm  4.6 mm i.d.) column. Detection and quantitation limits for chlorophacinone were 20 and 50 mg/L, respectively. The standard calibration curve was linear from 50 to 5000 mg/L; within-run precision coefficient of variation (CV) was less than 10%, and between-run precision CV was less than 20%. Table 1 Chlorophacinone levels

Ante mortem samples Post mortem samples

Blood (mg/L)

Urine Urine (mg/L) (mg)

Gastric contents (mg/L)

Gastric contents (mg)

25.9









6.8

0.102

4.8

0.192

9.4

4. Results Toxicological screening revealed ante and post mortem high blood concentration of chlorophacinone (ante mortem toxicological screening was performed on venous peripheral blood; post mortem blood was obtain from subclavian artery). Citalopram and desmethyl diazepam were also discovered, but at therapeutic levels. Post mortem toxicological analyses were also performed in urine (15 mL) and gastric contents (40 mL); results are shown in Table 1. 5. Discussion Rodenticides are the name given to any of the group of toxic substances that are used to kill rodents. Rodenticides are a group of compounds that exhibit markedly different toxicities to humans and rodents. The varieties of rodenticides used over the years are numerous, leading to the popular expression, ‘‘to build a better mousetrap’’. Adults who ingest these substances are most likely individuals attempting suicide; however, poisoning homicides may occur with these agents due to their ready availability. Superwarfarin exposure is a growing health problem [3], described in many countries. In 2002, in U.S.A., according to the Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers (AAPCC), 19,674 human exposures to rodenticides have been reported. According to the 2002 TESS data, anticoagulant rodenticides were associated with 16,822 of rodenticide exposures, but only two lethal intoxications were observed [2]. These cases are

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always reported as accidental exposition, suicide attempts or Mu¨nchausen syndrome [4–8]. At the turn of the century, rodenticides were composed heavy metals such as arsenic, thallium and phosphorus along with red squill and strychnine. This changed in the 1940s as investigators discovered that warfarin could be transformed in bishydroxycoumarin when fungi in moldy sweet clover oxidize coumarin to 4-hydroxycoumarin. Warfarin was quickly adopted as the major rodenticide and in 1940, bishydroxycoumarin was synthesized and used clinically 1 year later as an oral anticoagulant under the American trade name dicumarol. However, rodents resistance to warfarin became prevalent in the 1960s via autosomal dominant gene transmittance [9]. Novel compounds were synthesized to combat rodent resistance, thereby creating a new class of anticoagulants— the superwarfarins [10]. The term superwarfarin refers to a group of compounds, second-generation anticoagulants, which are extremely longacting. These fat-soluble anticoagulants are colorless, tasteless, and odorless compounds [11]. Superwarfarins, as warfarin, inhibit hepatic synthesis of the Vitamin K-dependent coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S. Chlorophacinone stops the synthesis of the active form of Vitamin K1 via inhibition of Vitamin K1–3 epoxide reductase, which blocks coagulation factor synthesis (II, VII, IX, and X) [2,9,12–16]. Superwarfarins are metabolized by hepatic cytochrome P450 isoenzymes to hydroxylated metabolites. It is uncertain that whole metabolites are inactive [9]. Chlorphacinone is an indandione-derivative with a prolonged effect of the superwarfarins family [11]. This anticoagulant is approximately 100 times more potent than warfarin on a molar basis [9]. The half-life of superwarfarin varies from 16 to 69 days compared with 37 h for warfarin [16,17]. The most human toxic form is an oily base (concentration of 2.5 g/ L), which is found in numerous commercial products worldwide. However, this form is no longer sold in France (since 2000) as it has been considered a health hazard. Each Vitamin K-dependent factor differs in its degradation half-life; factor II requires 60 h, factor VII requires 4–6 h, factor IX requires 24 h, and factor X requires 48–72 h. The half-lives of proteins C and S are approximately 8 and 30 h, respectively. As a result, because antivitamin K reduces first the activity of anticoagulant proteins C and S, a hypercoagulable state may be initially induced. Rapid loss of protein C temporarily shifts the balance in favour of clotting until sufficient time has passed for antivitamin K to decrease the activity of coagulant factors [18–21]. Chlorophacinone poisoning induces prolonged prothrombin time (PT), elevated international normalized ratio (INR), extended activated prothromboplasmin time, and decreased Vitamin K-dependent factors levels. Bleeding is the most common clinical feature and may occur from any mucosal site or organ [22–25]. The first haemorrhagic signs usually occur 3– 7 days after intake, depending on the dose ingested, and the substance half-life (from 6 to 23 days), when the body’s

reserves of prothrombin have diminished [2,4,9,12–14,26–30]. Table 2 showed 16 cases of chlorophacinone intoxication described in the literature. 5.1. Our case raises multiple problems First, concerning the origin of the intoxication, which was not (and will probably never been) assessed. Because our patient, and her family, were farm workers, they consequently had access to concentrated rodenticide for professional use. Regarding the elevated blood level of chlorophacinone, it is uncertain that intoxication involved granules, because this volume would have been too bulky to ingest. Only the oil form is known to be sufficiently concentrated to be hazardous, in small quantities, able to be ingested ‘‘accidentally’’. However, an accidental ingestion of oily chlorophacinone would suppose package reconditioning, or a severe neurological state impairment. Suicidal intoxication was considered but our patient had no previous suicidal history, nor psychiatric symptoms. Criminal poisoning was also considered, but police investigations found no arguments in favour of this hypothesis. Second, the coexistence of a haemorrhagic syndrome and an anticoagulant intoxication was initially disturbing. However, the first hypothesis considered was that SLS thrombosis occurred initially and subsequently induced neuropsychiatric impairment. Accidental or suicidal ingestion would have been consequent to these alterations. Nevertheless, our patient’s husband did not described major or sufficient behavioural abnormalities in favour of this hypothesis. In fact, the review of the literature regarding warfarin has explained this apparent contradiction [31–33]. Certain studies involved warfarin levels, monitored by measuring the prothrombin time, which responds to reductions in levels of three Vitamin K-dependent clotting factors (factors II, VII, and X). It has been demonstrated that during the first 48 h of treatment, the anticoagulant effect of warfarin is caused mainly by a reduction in the activity of factor VII, which has a half-life of 6 h. In contrast, the antithrombotic effect of warfarin (which is thought to be caused primarily by a reduction in the activity of factor II) is delayed for as long as 60 h. Therefore, during the first 48 h of therapy, the anticoagulant and antithrombotic effects of warfarin may be unrelated. In addition, because the half-life of the Vitamin K-dependent anticoagulant protein, protein C, is similar to that of factor VII, the early anticoagulant effect of warfarin (which results from reduction of factor VII) could be counteracted by a procoagulant effect (which results from reduction of protein C). Moreover, it has been also demonstrated that greater dose of warfarin was associated with a significantly more rapid decrease in protein C activity (which decreased before levels of factors X and II were substantially reduced). Therefore, the combination of markedly reduced protein C levels and near-normal levels of factors II and X over the first 2 days of warfarin therapy could produce an initial hypercoagulable state. Obviously, it is not possible to study chlorophacinone effects on humans, but it is probably scientifically possible to extrapolate warfarin data to superwarfarins.

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Table 2 Review of the literature (when chlorophacinone blood level or absoption is reported) Reference

# Case

Sex (age (years))

Intoxication reason

Death (Yes/No)

Absorption mode, dose ingested

Symptoms (appearance delay)

Biological tests (appearance delay)

Chlorophacinone blood level, half-life (Hl)

Cutaneous mucous haemorrhage (day 10) None

PT = 0%, APT = 65/32 (day 10) INR = 1.2 (hour 18)

Unknown Unknown

Haematomas, ecchymosis (day 37) None Multiple cutaneous mucous haemorrhage (day 16) Haematuria (day 15)

PT = 92% (hour 1.5)

Unknown

PT = 43% (hour 18) PT = 75% (hour 1.5); hypocoagulability (day 2) PT = 53% (a few hours later) PT = 38% (day 2) PT = 18% (day 2) PT = 65% (day 16)

Unknown Unknown

Dusein et al. [26] Murdoch et al. [30]

1

M (28)

Suicide

N

Oral, Unknown

2

F (37)

Suicide

N

Oral, 625 mg

Chataigner et al. [4]

3

F (79)

Suicide

N

Oral, 375 mg

4 5

M (45) M (18)

Suicide Suicide

N N

Oral, 500 mg Oral, 625 mg

6

M (21)

Suicide

N

Oral, 750 mg

7 8 9

M (54) M (27) M (72)

Suicide Suicide Suicide

N N N

Oral, 750 a` 1500 mg Oral, Unknown Oral, Unknown

10

M (52)

Suicide

N

Oral, 500–1200 mg

11

M (61)

Suicide

N

Oral, 500 mg

12

F (20) ans

Suicide

N

Oral, 250 mg

13

F (60) ans

Suspected suicide

N

Unknown, unknown

14

M (23) ans

Suspected suicide

N

Unknown, unknown

Arditti et al. [12]

15

F (27) ans

Suicide

N

Oral, 625 mg

Lagrange et al. [14]

16

M (33) ans

Suicide

N

Oral, 1875 mg

Burucoa et al. [9]

None None Microscopical haematuria (day 2) Haematuria, haematomas (day 2) Haematuria (day 19); gums bleeding (day 21)

Unknown Unknown Unknown Unknown

PT = 100% (a few hours later) PT < 10% (day 21)

Unknown Unknown

Lumbar pain, macroscopical haematuria (day 7) Macroscopical haematuria, vaginal bleeding, gum bleeding, thigh ecchymosis Abdominal pain, macroscopical haematuria, gum bleeding

Hypocoagulability (day 7)

Day 12: 2 mg/L, Hl: 6.5 days

Hypocoagulability

12.9 mg/L, Hl: 22.8 days

Hypocoagulability

1.2 mg/L, Hl: 11 days

Asthenia, inhalation pneumopathy (hour 80) Nausea (hour 8)

PT < 10%, APT = 44/32 (hour 80)

Hour 80: 43 mg/L, Hl: 7.6 days

PT normal (hour 8)

Hour 8: 27.6 mg/L

INR: international normalized ratio; PT: prothrombin time; APT: anti-prothrombin time.

6. Conclusion In our case, the origin of the intoxication remains unclear, and will probably never elucidated. Physicians and pathologists should bear in mind that any patient presenting with prolonged and/or unexplained hypocoagulability could have ingested superwarfarins, whether or not voluntarily. Moreover, pathologists and forensic practitioner should also keep in mind that thrombosis could paradoxically be related to anticoagulant intoxication, which is more uncommon. Acknowledgment The authors thank Richard Medeiros, Rouen University Hospital, editor, for his valuable advice in editing the manuscript.

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