Treatment of portal vein thrombosis with rivaroxaban in an American cocker spaniel with chronic hepatitis: a case report

Abstract

Anticoagulants are commonly used to treat venous thrombosis. Rivaroxaban, a direct factor Xa inhibitor, is widely used in veterinary medicine to prevent and treat thromboembolism. It has been used to manage portal vein thrombosis (PVT) in humans. As the incidence of PVT with chronic hepatitis (CH) is low in dogs, treatment methods have not been fully established. This case report describes the treatment of a 9-year-old male American cocker spaniel with CH and ascites, possibly due to concurrent PVT, using rivaroxaban. During treatment with rivaroxaban and diuretics, the patient showed improvement in portal hypertension, ascites, and edema. Herein, we report the first case of using rivaroxaban for the management of PVT with CH (treated with glucocorticoids) in a dog.

Rivaroxaban, a direct factor Xa inhibitor, has recently been used in dogs with thromboembolic diseases or thrombotic complications secondary to several diseases [9, 11, 13]. However, its use for the treatment of portal vein thrombosis (PVT) secondary to chronic hepatitis (CH) in dogs has not been reported. PVT occurs mainly in dogs with hypercoagulable conditions such as CH, those undergoing glucocorticoid therapy, those with a congenital portosystemic shunt, and those with protein-losing enteropathy [13]. CH is among the most frequently encountered liver diseases in dogs [8]. In the United Kingdom, CH in dogs has also been reported with a postmortem prevalence of 12% within first-opinion practice settings [17]. The incidence of PVT secondary to CH is estimated to be only 2.2% [5]. Treatment of PVT in dogs has been attempted with anticoagulants, antiplatelets, or thrombolytic agents, including low-dose aspirin, low-molecular-weight heparin, unfractionated heparin, warfarin, and clopidogrel [12]. However, an effective treatment for PVT in dogs has yet to be established. Herein, we report a case of PVT with CH (treated with glucocorticoids) in an American cocker spaniel treated with rivaroxaban and glucocorticoids.

A 9-year-old male American cocker spaniel visited the referring hospital due to loss of appetite, weight loss, vomiting, and dark yellow urine. The patient was suspected of having CH based on clinical test results showing elevated levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), and total bilirubin (T-Bil) and the presence of ascites and jaundice. The blood test results at the referring hospital are shown in Table 1. This table includes data from day −24, where the minus sign (−) indicates days before day 0. Although jaundice improved with glucocorticoid therapy, the patient’s condition remained poor. Therefore, the patient was referred to Kitasato University Veterinary Teaching Hospital. The first day of the visit to our medical center was defined as day 0. Before referral, the patient had already been administered glucocorticoids and diuretics in various dosages for approximately 20 days, and had received medical treatment with oral prednisolone (1.5 mg/kg PO q 48 hr) and furosemide (2 mg/kg PO q 12 hr) during the last week. The patient also received subcutaneous administration of metoclopramide, famotidine, and enrofloxacin at each visit to the referring hospital.

Table 1. The blood test results at the referring hospital.

		RI	Day −24	Day −23	Day −22	Day −20	Day −17	Day −10	Day −3
Biochemistry
	ALB (g/dL)	2.6–4	-	2.5	-	2.6	-	-	-
	GLU (mg/dL)	75–128	103	-	-	107	-	-	-
	ALT (U/L)	17–78	174	177	147	107	164	311	319
	ALP (U/L)	<89	>1,225	>1,225	>1,225	-	>1,225	>1,225	>1,225
	GGT (U/L)	<14	62	66	52	-	53	89	100
	T-Bil (mg/dL)	<0.5	3.7	4.6	4.5	2.1	1.5	1.3	1.4
Hematology
	WBC (/µL)	6,000–17,000	26,600	28,700	-	-	-	-	38,900
	Platelets (103/μL)	200–500	455	481	-	-	-	-	132

RI: reference interval, ALB: albumin, GLU: glucose, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT: γ-glutamyltransferase, T-Bil: total bilirubin, WBC: white blood cell.

On day 0, the patient presented with reduced appetite and fluid intake. Physical examination revealed clinical signs of edema in the right forelimb and lameness. No heart murmurs were detected. Blood tests, thoracic and abdominal radiological imaging, and cardiac and abdominal ultrasonography were performed. Changes in major blood test results, clinical signs, and medication during the treatment period are shown in Table 2. Hepatic dysfunction was suspected based on biochemistry results (increases in ALT, ALP, GGT, total bile acid, and T-Bil levels; Table 2). A complete blood count (CBC) revealed a significant increase in white blood cell count and a decrease in platelet count. Coagulation test results revealed an obvious coagulation disorder, suggesting disseminated intravascular coagulation (DIC; Table 2). Abdominal radiological imaging showed a reduction in liver size. Abdominal ultrasonography suggested coarsening of the liver parenchyma, multiple portosystemic shunts on the caudal side of the left kidney, and dilated splenic vein with decreased flow (i.e., splenic vein thrombosis (SVT)) (Fig. 1A). Abdominal ultrasonography also revealed findings suggestive of PVT. However, due to concerns about the patient’s worsening condition, a detailed evaluation of the portal vein with abdominal ultrasonography could not be performed, and PVT could not be diagnosed. A small amount of ascites was observed. Right heart failure was ruled out by echocardiographic assessment. These findings suggested that the patient had PVT associated with CH, glucocorticoid administration, or both, leading to venous perfusion impairment, such as venous thrombosis, which worsened his condition. We recommended hospitalization, but the owners refused. Therefore, outpatient management was chosen. Rivaroxaban (1 mg/kg PO q 24 hr) was administered as anticoagulant therapy for thrombosis, and furosemide (1 mg/kg PO q 24 hr) was administered at a reduced dose (Table 2). Prednisolone (1.5 mg/kg PO q 48 hr) was continued. A highly digestible and protein-restricted diet, metronidazole (13 mg/kg PO q 12 hr), and ursodeoxycholic acid (5 mg/kg PO q 12 hr) were administered to treat latent hepatic encephalopathy. Follow-up examinations were conducted on days 7, 14, 28, 51, and 79. During follow-up visits, physical examinations, blood tests, and abdominal ultrasonography were performed. Furthermore, on day 7, as an increase in ascites was observed, paracentesis was performed for diagnostic purposes. Although the patient’s weight and ascites increased compared to that at day 0, likely due to the reduction in furosemide dosage, appetite, vitality, platelet levels, and fibrinogen/fibrin degradation products (FDP) improved by day 7, suggesting mitigation of the DIC risk. Based on abdominal fluid analysis, blood tests, and imaging studies, infectious, neoplastic, right heart failure, hypoalbuminemia, and other possible causes of ascites accumulation were ruled out. Consequently, portal hypertension secondary to CH, thrombosis, or a combination of both was determined to be the cause of ascites. To reduce the ascites, we adjusted the diuretic treatment by temporarily increasing the furosemide dose and adding spironolactone, with the goal of eventually tapering furosemide. Furosemide activates the renin-angiotensin system and promotes aldosterone secretion, and portal hypertension is also known to increase aldosterone secretion. Therefore, we introduced the aldosterone antagonist spironolactone to block the effects of aldosterone directly and to reduce its secretion indirectly through a future reduction in the furosemide dosage. The prednisolone dose was tapered. Rivaroxaban, metronidazole, and ursodeoxycholic acid were continued on day 7. Appetite and vitality remained stable by day 14 and thereafter. Edema of the right forelimb disappeared, and abdominal ultrasonography revealed disappearance of ascites on day 14. At this point, a definitive diagnosis of PVT was made based on findings of dilated portal vein with decreased flow using abdominal ultrasonography. Thereafter, medication was adjusted, focusing on gradually tapering prednisolone and furosemide (Table 2). Blood test results showed a marked improvement in liver enzymes and a decrease in T-Bil levels on day 28, with further improvement on day 51. Abdominal ultrasonography demonstrated a reduction in SVT on day 28 and PVT on day 51. The diameter of the SVT decreased from 7.11 mm to 5.92 mm between day 0 and day 28. Additionally, the diameter of the PVT decreased from 10.82 mm to 9.46 mm between day 14 and day 51. The patient’s condition remained stable by day 79. Further, abdominal ultrasonography revealed a marked reduction in the PVT, with the diameter decreasing to 7.12 mm (Fig. 1B). Additionally, the disappearance of splenic venous dilation was confirmed on day 79. Rivaroxaban clearly improved PVT and SVT, accompanied by a reduction in the diameters of the affected veins. Therefore, rivaroxaban may be effective in improving portal hypertension, as well as the associated ascites and edema through thrombus reduction. However, the owners hoped for discontinuation of rivaroxaban and treatment at a referring hospital due to financial and time constraints. Thus, rivaroxaban was replaced with clopidogrel (2.5 mg/kg PO q 24 hr), and prednisolone, spironolactone, and ursodeoxycholic acid were prescribed for 1 month. The patient did not visit any veterinary hospital after day 79 until day 161. Thereafter, the patient was admitted to our hospital on day 161 with symptoms of no appetite, lethargy, vomiting, black diarrhea, and dark yellow urine that had persisted for more than 1 week. Liver failure caused by the progression of CH and gastrointestinal symptoms associated with portal hypertension were suspected, and coagulation test results suggested progression to DIC. The patient died on day 162 in our hospital. Computed tomography (CT) and autopsy were performed after obtaining the owner’s consent. CT revealed splenic and portal vein dilatation (Fig. 2A). Autopsy and histopathological findings included obstructive icteric CH [15] and organized PVT (Figs. 2 and 3).

Table 2. Changes in major blood test results, clinical signs and medication during treatment.

		RI	Day 0	Day 7	Day 14	Day 28	Day 51	Day 79	Day 161
Biochemistry
	TP (g/dL)	5.6–7.5	5.8	4.8	5.3	5.4	5.7	6.6	5.0
	ALB (g/dL)	2.9–3.8	2.4	1.8	2.1	2.1	1.9	2.1	1.4
	GLU (mg/dL)	88–128	117	95	-	-	-	-	106
	CHO (mg/dL)	113–281	345	269	-	-	-	-	76
	ALT (U/L)	15–79	392	557	466	201	67	66	78
	ALP (U/L)	50–316	12,236	10,913	9,676	3,683	719	612	2,285
	GGT (U/L)	4.0–12.0	109.1	112.5	109.8	42.7	5.6	-	17.9
	T-Bil (mg/dL)	0.00–0.13	0.64	0.76	0.37	0.15	0.06	-	8.56
	TBA (µmol/L)	0–22	335	-	-	-	-	-	159.3
Hematology
	WBC (/µL)	5,050–16,760	44,830	28,910	20,270	20,260	18,070	17,610	62,550
	Platelets (103/μL)	148–484	78	107	219	286	275	256	126
Coagulation
	PT (second)	6.0–8.0	10.6	-	-	-	-	-	>75
	APTT (second)	10.0–16.0	36.7	-	-	-	-	-	>220
	Fibrinogen (mg/dL)	86–375	<50	82	-	-	-	-	<50
	FDP (µg/dL)	<5	11.45	6.13	-	-	-	-	101.2
	AT-III (%)	102–156	73.9	21.7	-	-	-	-	57.4
Clinical sign
	Ascites		Slightly	Accumulated	None	None	None	None	Accumulated
	Edema		Positive	Positive	None	None	None	None	None
Medication
	Rivaroxaban (mg/kg q 24 hr)		1.0	1.0	1.0	1.0	1.0	1.0	-
	Furosemide		1.0 mg/kg/day	2.0 mg/kg/day	1.5 mg/kg/day	1.0 mg/kg/day	0.5 mg/kg q 48 hr	0.5 mg/kg q 48 hr	-
	Spironolactone (mg/kg q 12 hr)		-	1.2	1.2	1.2	1.2	1.2	-
	Prednisolone (mg/kg q 48 hr)		1.5	1.0	1.0	0.5	0.5	0.5	-
	Ursodeoxycholic acid (mg/kg q 12 hr)		5.0	5.0	5.0	5.0	5.0	5.0	-
	Metronidazole (mg/kg q 12 hr)		13	13	-	-	-	-	-

RI: reference interval, TP: total protein, ALB: albumin, GLU: glucose, CHO: cholesterol, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT: γ-glutamyltransferase, T-Bil: total bilirubin, TBA: total bile acid, WBC: white blood cell, PT: prothrombin time, APTT: activated partial thromboplastin time, FDP: fibrinogen/fibrin degradation products, AT-III: anti thrombin III.

Fig. 1.

Ultrasonographic findings of thrombus. (A) Splenic vein dilatation and thrombus (white arrowhead) are seen on day 0. (B) Significant reduction in the diameter of portal vein dilatation and thrombus (white arrow) is seen on day 79, with the diameter decreasing to 65% compared to day 14. Bar=10 mm.

Fig. 2.

Autopsy imaging and gross findings at necropsy. (A) Portal vein dilatation and thrombus (white arrow) are seen in the Multi-Planar Reconstruction images of the Computed tomography. Dashed lines indicate portal vein. Liv: liver; St: stomach; Kid: kidney. (B) Liver and gallbladder: Decrease in liver size, irregular and yellowing surfaces of liver (black arrow), and gallbladder enlargement with cholestasis are seen. (C) Portal vein dilatation and thrombus (white arrow) are seen. (D) Multiple shunts (black arrowheads), which appeared to be acquired, near the caudal side of the left kidney are seen.

Fig. 3.

Histopathological findings. (A) Liver: Chronic hepatitis with cholestasis in hepatocytes (black arrowheads), vacuolar degeneration of hepatocyte, and mononuclear cell infiltration is seen. (B) Portal vein thrombosis: Thrombus is mainly composed of fibrin, fibrosis, and pigmentation, and exhibits fibrous adhesion to the blood vessel wall (black arrows).

Although evidence exists for the infectious, metabolic, toxic, and immune causes of CH, most cases of CH in dogs are classified as idiopathic [18]. Histopathological evaluation of the liver is required for the definitive diagnosis of CH [18], but this could not be performed while the dog was alive. The American cocker spaniel is a breed predisposed to CH [1, 8]. Prednisolone has been suggested to be effective against CH in American cocker spaniels [8]. The patient responded to prednisolone therapy. In advanced CH, the liver is often small with an irregular and coarse surface [18]. In this case as well, similar findings were observed in abdominal radiography and ultrasonography. Portal hypertension is a common secondary manifestation of CH in dogs [3]. While the gold standard for diagnosing portal hypertension is the direct measurement of portal venous pressure, this is rarely performed in clinical settings. The presence of intrahepatic portal hypertension is typically inferred from clinical findings (ascites, gastrointestinal hemorrhage, and hepatic dysfunction), imaging findings (acquired portosystemic shunts reduced hepatopetal or hepatofugal portal vein blood flow), and exclusion of other causes [3]. In the present case, portal hypertension was demonstrated by hepatic dysfunction, ascites, and multiple portosystemic shunts, strongly supporting the diagnosis.

Virchow’s triad is widely recognized as the underlying mechanism of thrombosis, consisting of three factors: hemodynamic disruption, intrinsic hypercoagulability, and endothelial damage or dysfunction [10]. In this case, it was considered that the formation of PVT was influenced by multiple factors. Specifically, both CH and glucocorticoids were associated with these factors and may have contributed to the formation of PVT. Based on these factors, thrombosis was suspected as one of the causes of ascites in this patient. Further, in this case, abdominal ultrasonography revealed a suspected thrombus in the splenic and portal veins. CT has a superior sensitivity for detecting PVT in dogs. However, it has been estimated that only 19% of PVT cases can be detected by ultrasonography [16]. Since the patient was suspected of having DIC, we proposed administering a plasma transfusion and performing CT angiography and a liver biopsy for a definitive diagnosis. However, the owners declined these procedures.

A previous study reported that 3.7% of 136 dogs with CH were affected by portal or splenic venous thrombosis [5]. As PVT is rare, an effective treatment method has not yet been established in veterinary medicine. Anticoagulant and/or antiplatelet therapies using low-dose aspirin, low-molecular-weight heparin, unfractionated heparin, warfarin, and clopidogrel have been used for the treatment of PVT in dogs [12]. Anticoagulants are primarily used for venous thrombolysis, whereas antiplatelets target arterial thrombolysis [6]. In humans, guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis reports anticoagulation therapy for symptomatic PVT and for asymptomatic or chronic PVT. The guidance reports that anticoagulation therapy is recommended for symptomatic PVT, whereas for asymptomatic or chronic PVT, conflicting recommendations exist among various societies [4]. In this case, abdominal ultrasonography revealed decreased portal vein flow and multiple shunts, and blood test results showed liver dysfunction, increased FDP, decreased fibrinogen, and decreased platelets, suggesting progressive PVT. Anticoagulant therapy is also considered standard for managing cirrhosis-derived PVT in humans [7]. Additionally, the antiplatelet drug clopidogrel is reportedly ineffective against PVT in dogs, whereas combination therapy with rivaroxaban is effective [13]. Low-molecular-weight heparin administration has been reported to be useful in the long-term management of PVT secondary to CH in American cocker spaniels [14]. However, the efficacy of heparin is reduced due to low AT-III activity. Warfarin carries a risk of bleeding complications and has so far not been shown to improve the prognosis of thrombosis in dogs [2]. It has been reported that rivaroxaban appears safe and well tolerated in dogs [2]. Therefore, we used rivaroxaban for the treatment of PVT. However, it has also been reported that in humans, rivaroxaban is not recommended with significant liver dysfunction [4]; hence, rivaroxaban should be administered with caution in dogs with CH.

In conclusion, the patient’s condition markedly improved following the initiation of rivaroxaban therapy, allowing for a reduction in the diuretics used for ascites management. Additionally, improvements in liver enzymes, reduction in PVT, and a decrease in portal vein diameter were observed. These findings suggest that rivaroxaban might improve some of the portal hypertension by reducing PVT. However, it should also be considered that natural processes, including recanalization, fibrinolysis, and the development of collateral circulation, may have contributed to the reduction in thrombus size. This case report discusses for the first time the use of rivaroxaban in a dog treated for PVT associated with CH and managed with glucocorticoids concurrently.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.