Dirofilaria immitis is a parasitic filarial nematode responsible for heartworm disease in dogs, which are the definitive host (1). It has a long and complex life cycle involving transmission by a mosquito vector and several molts prior to sexual maturity (2). D. immitis also harbors Wolbachia, a gram-negative bacterium which is required for its reproduction (3). Mature heartworms mainly reside in the caudal pulmonary arteries and may cause physical obstruction, inflammation, and endothelial dysfunction. Wolbachia appears to contribute to immune polarization during infection as well as inflammatory/immunomodulatory activity via surface protein antigens (4). Clinical signs (if any) depend on the severity of disease and duration of infection (3).

In order to eliminate all life stages of the heartworms while minimizing complications, the American Heartworm Society (AHS) has published a detailed management protocol (5). As part of this protocol, adulticide therapy with melarsomine is recommended (5). In many, if not most cases of canine heartworm infection, melarsomine is considered a safe and effective adulticide (5). However, worm death commonly leads to some degree of thromboembolic disease and a number of clinical sequelae have been described (3). Treated dogs must be carefully monitored for adverse cardiopulmonary effects and intense inflammatory reactions (6).

Disseminated intravascular coagulation (DIC) is a recognized complication in heartworm-infected dogs with caval syndrome (7). DIC has also been reported clinically in heartworm-infected dogs following treatment with thiacetarsamide (8, 9) (the predecessor to melarsomine) and with dichlorvos (10). DIC is also listed as a potential complication (occurring in < 1.5%) of dogs treated with melarsomine dihydrochloride on the drug data sheet (11). However, the authors were unable to find any published data on melarsomine-induced coagulopathy or DIC post-treatment with melarsomine in dogs.

The purpose of this report is to describe the diagnosis and treatment of a dog with DIC following melarsomine treatment for D. immitis and to draw attention to a rare but potentially fatal complication of adulticide therapy.

An estimated 9-year-old female intact pit bull-type dog was presented to a veterinary teaching hospital for management of coagulopathy. The dog was initially adopted from a shelter 4 months earlier. At that time, she had seemed to be in good health except for some intermittent coughing. CBC and serum chemistry during a wellness check were unremarkable. Thoracic radiographs performed at that time showed a mild bronchointerstitial pulmonary pattern. A small mass on the ventral abdomen was resected and histopathology identified a low-grade cutaneous hemangiosarcoma (HSA) with mild solar elastosis. Complete excision was confirmed. The patient was presented again 3 days later for a recheck and vaccinations. A point-of-care bidirectional flow ELISA¹ test was positive for D. immitis antigen.

Following confirmation of microfilaremia by a modified Knott test, imidacloprid and moxidectin (Advantage Multi²) was administered (Day 0). The patient was started on doxycycline³ at 10.8 mg/kg PO every 12 h which was continued for 5 weeks at which time another dose of imidacloprid and moxidectin was administered. On Day 59, another dose of imidacloprid and moxidectin was applied and the patient was started on a tapering dose of prednisone⁴ (0.5 mg/kg PO q 12 hrs for 1 week, 0.5 mg/kg PO q 24 hrs for 1 week and then 0.5 mg/kg PO every other day for a further 2 weeks). On Day 60, a 2.5 mg/kg dose of melarsomine⁵ was administered intramuscularly (IM). On Day 91, a second dose of melarsomine was administered IM and a similar tapering course of prednisone dispensed. Imidacloprid and moxidectin was also applied. One day later (Day 92), a third dose of melarsomine was administered IM. Owner history revealed that the dog had been lethargic for 1–2 days after the first melarsomine injection but had returned to normal after this. After the second and third doses of melarsomine, the patient had become lethargic again and was shivering. Since then, she had remained lethargic and inappetant. The patient had been exercise restricted since administration of the third dose of melarsomine (cage rest and short leash walks for toileting).

Seven days after the third melarsomine injection, the patient was presented to her family veterinarian due to right pelvic limb swelling. Some gingival bleeding was also noted. Complete blood count revealed a non-regenerative normocytic, normochromic anemia with a HCT of 0.247 L/L (24.7%; RI 0.387–0.592 L/L [38.7–59.2%]). Thoracic, abdominal and right pelvic limb radiographs were performed and interpreted by a board-certified radiologist. The cardiopulmonary structures and abdomen were considered normal. The superficial soft tissues of the distal right pelvic limb were mildly swollen consistent with edema or cellulitis. The patient was transferred to an emergency facility for ongoing care. On arrival the patient was bright and alert. Several ecchymoses and subcutaneous swellings were noted in addition to swelling of the right hock and crus.

The patient was hospitalized and started on supportive care. Some evidence of active hemorrhage was noted with swelling at venipuncture sites, cutaneous bleeding, and progression of ecchymoses extending to the ventral abdomen. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged beyond the detectable range. The patient was administered vitamin K1⁶ at 1 mg/kg subcutaneously (SQ). The following day the patient's venipuncture sites continued to bleed and while on a short walk outside the hospital, she collapsed. A new intravenous catheter was placed, and a fresh frozen plasma (FFP) transfusion of unknown volume was administered. A post-transfusion PCV was 24% and total plasma protein (TPP) concentration was 69 g/L (6.9 g/dL; RI 6–8 g/dL). PT and aPTT both remained too prolonged to measure. Abdominal ultrasound by a boarded internist revealed a mildly enlarged liver and single splenic nodule but was otherwise unremarkable. The next day the patient was weak, unwilling to ambulate and pale with bounding pulses. Given the patient's unstable condition, she was subsequently transferred to the authors' institution for further diagnostics and treatment.

On physical examination the patient was obtunded. Temperature, heart rate and respiratory rate were 38.0°C (100.5°F; RI 38.1–39.1°C [100.6–102.4°F]), 150/min and 36/min, respectively. The patient weighed 20.7 kg. Mucous membranes were pale with a capillary refill time of 2s. A grade I/VI left apical systolic heart murmur was auscultated. No arrhythmias were appreciated. Femoral pulses were strong, synchronous and symmetrical. There were increased respiratory sounds bilaterally and mild crackles were auscultated. The mammary tissue was thickened, and some milky discharge was expressed from the caudal glands.

This case report details the diagnosis and treatment of a dog with severe coagulopathy consistent with DIC following melarsomine treatment for D. immitis. The patient in this report had been treated according to current AHS guidelines except that she was administered doxycycline for one week longer than the recommended 30 day course (5).

The pathogenesis of DIC involves initiation of coagulation by tissue factor exposure to circulating blood, increased platelet-vessel wall interaction, impaired regulation of coagulation and defective endogenous fibrinolysis (12). Diagnosis of DIC in people and animals is based on the presence of a primary condition known to be associated with DIC along with a compatible clinical picture (12). A veterinary scoring system for DIC has been proposed and is based on elevated aPTT, PT, D-dimers and decreased fibrinogen with a diagnostic sensitivity and specificity of 90.9 and 90.0% (13). The patient in this report fulfilled all criteria. DIC phenotypes have also been defined according to the associated level of fibrinolytic system activation. Hypofibrinolytic type DIC, characterized by strong coagulation activation and suppressed fibrinolysis, may lead to hemorrhage by development of a consumptive coagulopathy (14). Conversely, enhanced-fibrinolytic DIC is caused by excessive fibrinolysis in which the fibrinolytic pathway is upregulated (12), leading to a severe bleeding diathesis (14). Based on the extent of hemorrhage noted in this patient, a combination of consumptive coagulopathy from dysregulated thrombosis and enhanced fibrinolysis may have contributed to the pathogenesis.

DIC is a recognized complication in heartworm-infected dogs with caval syndrome (3). The patient in this report had echocardiographic findings indicative of pulmonary hypertension and adults were present within the right atrium on necropsy. However, the classic constellation of clinical and echocardiographic signs expected with this syndrome such as hemoglobinuria, cardiovascular collapse and right-sided heart failure were not observed (7).

DIC has previously been reported clinically in heartworm-infected dogs following treatment with parasiticides including thiacetarsamide (the predecessor to melarsomine) (8, 9) and dichlorvos (10). The authors of one report suggested massive tissue factor release due to direct damage from the parasite and secondary to ischemia from thromboembolic disease as a potential inciting cause (9). Some procoagulant effects of thiacetarsamide have also been demonstrated in heartworm-negative dogs, suggesting this drug may have some direct effects on coagulation (15).

DIC is listed as a potential complication (occurring in < 1.5%) of dogs treated with melarsomine dihydrochloride on the drug data sheet (11). Lethargy and some degree of discomfort as recognized in the patient in this report are relatively common following its administration. However, the authors were unable to find any published data on melarsomine-induced coagulopathy in dogs. Melarsomine dihydrochloride is an organic arsenical chemotherapeutic agent. The AHS currently recommends using the three-dose melarsomine protocol for all heartworm-positive dogs to increase the efficacy and safety of treatment (5). The exact mode of action of melarsomine on D. immitis is unknown. Adverse reactions observed after treatment with melarsomine may be directly attributable to the medication or may be secondary to worm death or the underlying heartworm disease process (3). If toxicity secondary to melarsomine is suspected, dimercaprol has been reported as an antidote for arsenic toxicity (16). However, dimercaprol does carry a substantial list of side effects and would not have been appropriate in this dog. Ultimately, successful adulticidal treatment in dogs with heartworm disease may inevitably lead to thromboembolism and an intense pro-inflammatory reaction, which conceivably could lead to DIC and/or hyperfibrinolysis (5).

It is also possible that the patient became coagulopathic due to direct effects of the heartworm infection. Pathologic elevations of D-dimers have been demonstrated in dogs with D. immitis infection and seem to be highest in microfilaremic dogs (17, 18). It has been suggested that the nematode could use anticoagulant properties of its antigens to control the formation of blood clots in its immediate intravascular habitat as a survival mechanism (19). D. immitis excretory/secretory antigens have been shown to stimulate the vascular endothelium to enhance the expression of tissue plasminogen activator and urokinase-type plasminogen activator, to activate fibrinolysis via plasminogen activation, to inhibit coagulation factor Xa and to decrease plasminogen activator inhibitor 1 levels (19–21). Wolbachia, the endosymbiont bacteria of filarial nematodes, may also have a role in stimulating plasmin generation on its release from dying filarial nematodes (22). However, this patient had been treated with doxycycline prior to adulticide therapy.

A paraneoplastic cause of DIC is also possible in this patient. Hemostatic derangements in cancer patients may develop via multiple mechanisms. These include inherent abnormalities of tumor microvasculature, invasion into blood vessels and/or tissue factor expression by neoplastic cells (23).

The dog in this report had undergone resection of a cutaneous HSA 4 months prior to presentation and a chemodectoma was recognized on necropsy. HSA is commonly associated with hemostatic abnormalities including DIC (24). However, cutaneous HSA is typically discrete and surgical excision often curative (25). In addition, solar-induced HSA in a ventral location seems to be inherently less aggressive than dermal HSA of other etiology (26). No evidence of HSA in the skin or other organs was found on gross necropsy or histopathology. The authors could not find a report of DIC resulting from chemodectoma which is generally considered relatively benign with a low metastatic potential (27, 28). The most commonly reported adverse effects associated with chemodectoma include altered cardiovascular function caused by the mass effect or, more commonly, local hemorrhage/effusion into the pericardial space (27, 29). The chemodectoma may also have contributed to the coughing reported in this dog (29). No pericardial effusion or arterial invasion was detected on necropsy in this patient but there was some myocardial infiltration and compression of the right ventricle which could have exacerbated pulmonary hypertension and right ventricular dysfunction.

Antifibrinolytic therapy was administered to the patient in this report in an attempt to enhance clot stability and was initiated due to the severity of bleeding. Ideally viscoelastic testing would have been performed to determine if there was any hyperfibrinolytic component to the hemorrhagic diathesis and to help guide therapy. In dogs with hemorrhage due to Angiostrongylus vasorum infection, viscoelastic testing has been utilized to diagnose hypocoagulability and hyperfibrinolysis and to guide therapy with FFP and antifibrinolytic drugs (30, 31). Potential disadvantages to the empirical use of aminocaproic acid include the risk of side effects and the concern that, in general, patients with DIC should not be treated with antifibrinolytic agents. However, in human medicine, patients with DIC that are characterized by a primary hyperfibrinolytic state and who present with severe bleeding may be treated with lysine analogs (32). Overall, antifibrinolytic therapy was considered justified in this patient based on the wide array of described applications and favorable safety profile described in dogs thus far as well as the severity of hemorrhage.

In conclusion, successful adulticide treatment in dogs with significant heartworm disease inevitably leads to thromboembolism and an intense pro-inflammatory reaction which could lead to hyperfibrinolysis and/or DIC. DIC specifically is listed as a potential adverse reaction to melarsomine therapy but is expected to be rare. It is not clear whether DIC directly results from the drug or is secondary to subsequent worm death. Treatment recommendations for hemorrhage associated with DIC include addressing the underlying cause where possible and blood product administration. Antifibrinolytic agents are also indicated in enhanced-fibrinolytic type DIC (32). Sadly, despite all these treatments the coagulopathy in the patient in this report could not be controlled.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

HP and RL contributed toward study design, data collection, and editing. RL is the senior author. KF contributed to editing and data collection. All authors contributed to the article and approved the submitted version.