Persistent abdominal pain related to portal vein thrombosis in young adult with sickle cell disease
Authors: Chiara Dal Zotto, Michele Wieczorek, Gabriele Mariottini, Roberto Malagò, Oliviero Olivieri, Lucia De Franceschi
Journal: American Journal of Hematology (2018)

A 35-year-old man with sickle cell disease (SCD, S/β0) was admitted to our emergency department (ED) for right upper quadrant abdominal pain (RUQ) associated with fever (38°C) and jaundice (Charcot's triad; Total Bil. 3.19 mg/dL). Pain was constantly midepigastric, often radiated to the back. Laboratory tests showed increased CRP (93 mg/dL), ALT (71 U/L), and LDH (347 U/L); whereas, AST (32 U/L), γGT (19 U/L), albumin (34.1 g/L), total protein (74.1 g/L), amylase, aPTT, PT were within normal range. CBC documented Hb 8.7 g/dL, circulating erythroblasts 510.000/mm3, WBC 11 800/mm3, PLTs 286 000/ mm3. The collection of patient history revealed: splenectomy at the age of 8 years and cholecistectomy at age of 19 years. He was taking hydroxyurea (20 mg/kg/d) therapy since the age of 17 years due to recurrent pain crisis, requiring hospitalization, and aspirin (100 mg/d) since splenectomy. Two previous episodes of superficial venous thrombosis were reported by the patient. RUQ pain occurs in almost 10% of SCD patients during acute vaso-occlusive crisis (VOC) and it is one of the first three causes of access to the ED admission.1 RUQ pain is generally associated with increased AST/ALT ratio, which rapidly decreases at resolution of the VOC. Although RUQ pain is generally related to VOCs, a wide variety of conditions has been recognized to possibly sustain abdominal pain and jaundice in SCD (Table 1).1-3 However, emergency physician rarely considers other causes of RUQ pain than VOC in SCD subjects (see also Table 1). This might expose SCD patients to the risk of undertreatment or misdiagnosis of RUQ pain and possibly mismanagement. Thus, it is mandatory to discriminate with the patient whether the abdominal pain episode has characteristics similar to previous once experienced by the patients in order to consider causes others than VOCs and to decide a more aggressive diagnostic approach.4 At the admission in the ED, patient VAS pain-score was 7. Multimodal analgesia with tramadol (7.2 mg/kg/d), ketorolac (0.86 mg/kg/d) and metoclopramide associated with intravenous hydration (saline solution 20-30 mL/kg/d) and ceftriaxone (2 g/d) was started.5, 6 Abdominal ultrasound (US) was negative and portal vein velocity was normal at the admission to the ED and at 48 hours after hospitalization. Abdominal-US is generally used to exclude biliary obstruction and/or dilation (intrahepatic, extrahepatic, or both) or to document primary liver disorders, such as infections/abscesses or portal vein disease as well as pancreatic diseases such as acute or chronic pancreatitis or gallstone-related pancreatic disease. However, US does not allow the identification of choledocholithiasis, which requires MR cholangiopancreatography (MRCP). Multidetector Computed Tomography (MDCT) is, overall, the gold standard imaging approach for undifferentiated abdominal pain, especially in presence of fever and nonlocalized symptoms. MDCT can also better delineate complicated biliary disorders, such as gas-forming processes, abscesses, hemorrhage, and perforation, and can be a second-line imaging modality when Abdominal-US fails. MRI, scintigraphy, endoscopic retrograde cholangiopancreatography (ERCP) or MRCP are useful tools in the diagnosis of RUQ disorders but are rarely indicated in acute setting. ERCP is helpful in the setting of gallstone pancreatitis, but in the absence of obstruction or cholangitis is not indicated in the acute or early disease course.7 At 3 days after hospitalization, despite the improvement of liver indices, RUQ pain persisted (VAS pain score: 5) and patient was again febrile with further increase in CRP (153 mg/dL). Antibiotic therapy was modified and piperacillin/tazobactam was started in place of ceftriaxone. MRI and MDCT respectively documented pancreatic edema in the absence of choledolithiasis and portal vein thrombosis (PVT) extended to the inferior and superior mesenteric vein (Figure 1A, B). Imaging is the cornerstone of diagnosis of PVT. US is generally used as the first-line imaging method because of its sensitivity and specificity. Contrast-enhanced ultrasound (CEUS) might be also considered in selected cases only to discriminate whether the occlusion of the portal venous system is caused by a thrombus or extravascular causes, such as tumors. MDCT might be the second most common imaging tool to identify PVT, since it is sensitive and specific (accuracy close to 95%) to detect partial PVT, occlusion of the main portal venous vessels and to map the porto-splenic collaterals. Whenever long-lasting cavernous transformation of the PV might be suspected, MRCP is the technique of choice. Finally, the invasive angiographic approach is reserved for rare cases with equivocal results on noninvasive imaging.8 In SCD, PVT is a rare, life-threatening complication and it has been mainly reported in SCD children as either spontaneous event or after abdominal laparoscopic procedures.9, 10 Noteworthy, PVT is most frequently observed in patients with chronic myeloproliferative disorders, lymphoma, splenomegaly (1450 g in adults), post-splenectomy thrombocytosis (> 650 000/mm3) and after laparascopic surgery. Thus, in SCD patients the persistent abdominal pain in the absence of bilio-pancreatic tract or liver or kidney disease requires a close re-evaluation of the diagnosis, considering to exclude PVT. Recently, Brunson et al. have reported a population-based study showing increased incidence of venous thromboembolism (VTE) associated with increased mortality in SCD patients compared to age matched control population.11, 12 Although limited data are available on the risk for VTE in SCD patients,11, 13 the severity of SCD and the SS and Sβ0 genotypes might represent additional factors to be considered in intensity of clinical management of SCD subjects with recurrent VTE.11, 12 We present here a novel case of young-adult SCD patient with spontaneous PVT and persistent acute abdominal pain. After an extensive multidisciplinary discussion, heparin sodium treatment (400 IU/Kg/24 hours after a bolus of 5,000 IU with range aPTT 1.5-2) was started. Based on the revision of the literature on therapeutic approaches to PVT,14, 15 heparin sodium was stopped and low molecular weight heparin (LMWH) (100 IU/kg/12 hours) was started. Recent studies show that early treatment with intravenous or LMWH prevents extension of PVT and facilitates PV recanalization, in patients with acute PVT in whom cirrhosis and malignancy were specifically excluded.14, 15 These patients may require lifelong anticoagulant therapy (AC) to prevent recurrent thrombotic events.16 Recent guidelines from the European Association for the Study of the Liver (guidelines EASL 2016) indicate the use of LMWH, with a subsequent shift to vitamin K antagonist targeting an INR between 2 and 3 to be continued for at least 6 months in management of noncirrhotic and nonmalignant acute PVT.17 The direct oral anticoagulant drugs (DOACs) has been evaluated in PVT treatment in cirrhotic patients, revealing efficacy and safety equivalent to the traditional anticoagulation approaches.18 However, DOACs are less studied in noncirrhotic patients even if rivaroxaban has led to recanalization of portal branches with no documented complications in a young female with acute PVT occurring in a noncirrhotic liver linked to heterozygosity of factor V-Leiden and prothrombin G20210A gene mutations.19 In SCD, rivaroxaban seems to be promising as treatment of DVT or pulmonary embolism.20, 21 However, further studies with larger sample size are needed to evaluate long-term impact of rivaroxaban in this subset population. Since DOACs might be hepatotoxic and no antidote is available as for warfarin in the setting of bleeding events, special attention and close follow-up is required when rivaroxaban is used in SCD patients, who might present with SCD related liver or kidney diseases. However, preliminary reports available on DOACs in SCD suggest efficacy and safety for rivaroxaban in treatment of DVT or PE in SCD patients. In presence of one of these conditions: (a) thrombosis refractory to anticoagulation approach; (b) evidence of portal hypertension; (c) symptomatic splanchnic venous thrombosis; endovascular techniques should be considered as therapeutic approach, in conjunction with angiography.16 EASL guidelines underline that thrombolytic therapy may get a recanalization rate similar to AC; nevertheless, it is burdened by remarkable procedural risks with possible fatal outcome. When surgical thrombectomy has been analyzed in respect to AC in treatment of PVT, the recanalization rate comes out to be lower and associated with higher mortality.17 Finally, in PVT complicated by intestinal infarction morbidity, mortality and long-term outcome are similar independently from surgical or nonsurgical management.22 Abdominal MDCT at 6 months after PVT diagnosis showed re-canalized thrombosis of PV but the presence of portal cavernoma, which was also documented at 4 months imaging control (Figure 2A,B). In PVT, the follow-up by imaging is crucial to both identify patients, who progress despite the first-line therapy with AC, and to monitor maintenance of patency in patients in whom AC has been stopped. Since PV recanalization generally occurs up to 6 months after starting AC, a follow-up imaging study after 6 months of AC is recommended.17 The imaging follow-up might be carried out by either MDCT or MRI or CDUS whenever technically feasible.6 At 4 months control, our patient was switched from LMWH to rivaroxaban, starting with 15 mg twice a day for 3 weeks, then 20 mg/day up-to the 6 months control. Previous reports on PVT in SCD patients are on pediatric subjects, who were treated with LMWH for 6 months after the diagnosis.9, 10 In our case, the choice to move from LMWH to rivaroxaban was based on patient request for oral AC treatment. In young adults DOACs might be considered since they have a limited impact on patient quality of live avoiding problematics due to long lasting use of heparin, need for continuous laboratory monitoring of warfarin as well as minimal drug-to-drug and food interactions. Finally, the observed development of portal cavernoma is a very rare complication of PVT with limited clinical options.23 In our SCD patient, we plan a 6-12 months imaging follow-up with US combined with doppler for portal cavernoma. SCD is characterized by a perturbation of hemostasis both on steady state and during acute VOCs.12, 24 Clinical manifestation of pro-thrombotic state of SCD include VTE, in situ thrombosis and stroke, associated with a higher risk of thrombotic complications in patients splenectomized or with functional hyposplenism.24-27 Our case suggests that PVT should be considered in making decision process of RUQ pain with jaundice and negative abdominal US in patients with SCD. Limited data are available on PVT in SCD, which may be underestimated since abdominal pain is the main symptom for PVT as well as of uncomplicated VOCs. This deeply impacts patient clinical management and long-term prognosis related to the development of chronic organ complications. In our experience, US combined with Doppler should always be used as first level imaging in RUQ, to explore vein portal system in SCD patients. However, MDCT or MRI, whenever MDCT is contraindicated, should also be considered in SCD patients with severe clinical presentation with persistent abdominal pain in the absence of evidence for bilio-pancreatic tract or liver or kidney disease. Furthermore, MDCT or MRI are required to achieve a thorough characterization of PVT after US-Doppler PVT identification.6 In our patients, the recognized risk factors for VTE are Sβ0 genotype, splenectomy, and previous history for superficial vein thrombosis.11 In SCD, treatment of VTE or deep vein thrombosis (DVT) with anticoagulants is still a gray zone due to the lacking of guidelines or data on large population studies.11, 24 In addition, in SCD the relative high risk of bleeding together with the high risk of recurrent VTE increase the complexity of clinical management of these patients and it is still based on physician decision on single case.11 Applying EASL guidelines to our clinical case, AC should be permanent in cases of pro-thrombotic conditions or in PVT extending to the superior mesenteric vein.17 About the choice of long-term anticoagulant, warfarin or DOACs may represent an option in our patient with SCD. Up to now reports on SCD patients switched from LMWH or warfarin to DOACs have shown a safe profile and they might be considered in patients with favorable bleeding profile. The extended duration of AC in SCD patient behind the complete re-canalization of PVT should be carefully evaluated considering the balance between thrombotic/bleeding risks in SCD subjects. The present case further highlights the requirement of randomized multicentric and multinational studies on VTE and DVT in adult patients with SCD. The authors have no financial relationship relevant to this article. Authors have nothing to disclose.