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Massive Portal and Mesenteric Vein Thrombosis

Short summary

47-year-old male presented with un-provoked portal and mesenteric vein thrombosis that caused persistent radiating pains of upper abdominal quadrants. The examinations found heterozygous factor II mutation, and family survey for the factor II mutation was recommended. The patient started anticoagulant therapy. In the expert's opinion, the main risk factors for portal vein thrombosis are: Prothrombotic disorder, abdominal inflammation, cirrhosis, cancer, abdominal intervention and abdominal infection. Major complications of portal vein thrombosis include ascites, extension of the thrombus, and gastric and esophageal varices.

Patient's questions

1) Do you confirm the current therapy with enoxaparin (10,000 U.I bid)? For how long, as an indication, is it necessary to continue this therapy before passing to oral Warfarin?

2) In the post-heparin phase are there any alternative therapies to oral dicumarolics so as to reduce the associated haemorrhagic risk? Do you think that driving a motorcycle is very dangerous when under therapy with Warfarin? Refusing the intake of the therapy with oral Warfarin, do you think that the risk of thrombosis relapse will be higher?

3) Which is the percentage probability that the thrombus lyses completely, lyses only partially or does not lyse at all?

4) Do you think that the heterozygous factor II mutation found is the only cause of the thrombotic pathology? Do you recommend any further diagnostic examinations? Which do you think is the cause that this genetic-based thrombosis showed up at 47 years and not before?

Medical Background

Male, 47 year old, Italy
Diagnosis: Massive Portal and Mesenteric Vein Thrombosis

On October, 2009, appearance of moderate painful symptomatology at the upper abdominal quadrants level radiated at lumbar level bilaterally and associated to hyperpyrexia mainly at night that reached max 38°C. This clinical picture has initially been interpreted as a viral gastroenteritis also in consideration of the pandemic period he was going through. In spite of the symptomatic therapies administered, the symptoms still continued more or less stable, getting worse, however, in the digestion phase after the meals. The patient, therefore, drastically reduced eating with subsequent weight loss of approximately 8 Kg in 3 weeks; this led to an organic impairment. The symptomatic course showed an ingravescent nature with persistent pains to the upper abdominal quadrants radiated posteriorly in the lumbar region and became so painful that the patient was forced to go to the Emergency Room of San Matteo Hospital in Pavia on 11/2009. There, the first level examinations were carried out consisting in blood chemistry routine tests, electrocardiogram, chest and abdominal radiography. As no current acute event was found, the patient’s discharge was conducted upon pain relieving infusion therapy, first with paracetamol and then with Toradol, reaching a satisfactory symptomatic improvement. It was further agreed together with the hospital doctors to carry out, within the following week, outpatient instrumental examinations among which: esophagogastroduodenoscopy, upper abdomen ultrasound scan and a CAT scan of the upper abdomen with contrast medium. When the patient returned home in the morning, the symptomatology had almost disappeared and he ate a light lunch at 1.00 pm. Starting at 4.00 pm the usual pains reappeared and in the following hours they became so serious that the patient was forced to return to the same Emergency Room he went the evening before.

This time the patient was hospitalized on 11/2009 for tests and necessary care. The following diagnostic exams were carried out:

- Abdominal CAT SCAN with contrast medium (11//2009): “… ascites in perihepatic and perisplenic space, in the parietocolic gutters; massive portal vein thrombosis with extension to the intrahepatic subdivision branches; the peripheral thrombosis progression involves the mesenteric vein and its peripheral subdivision branches, the lineal thrombosis progression reaches the splenic hilus; the corresponding arterial peduncles are, on the contrary, patent; ascites also at the root of the mesentery and in pelvis; the parenchymas show, in hepatic area, parenchymal central hypodensity as per hypoperfusion of segments from V to VIII; no nodular focal lesions; normal the gall bladder and the intra- and extrahepatic bile ducts; absence of pathological abdominal and pelvic adenopathies, regular the bladder; no central and lateral pelvic masses”.

- Abdominal MR with contrast medium (11/2009): “…massive thrombosis of the common trunk of the portal vein and of its intrahepatic branches, that affects signal alteration of the hepatic parenchyma on vascular basis, with apparent saving of the segments VI and VII, is confirmed. Thrombosis of the splenic vein to the hilus and of the upper mesenteric vein and of the colic vessels, its tributaries, is connected. The size of the liver is, on the whole, within normal limits, with hypotrophy of the left lobe and hypertrophy of the I (first) segment. Two biliary cysts at the VIII and II segment, the biggest one of approximately 1 cm. No dilated the intra- and extrahepatic bile ducts, gall bladder in situ, acalculous. Regular the findings involving kidneys, suprarenal glands, spleen and pancreas. No evident pathological lymph nodes tumefactions. Perihepatic and perisplenic effusion in Morrison’s. Pleural effusion bilaterally is observed. Regular for size, course and channeling the abdominal aorta and its main vessels.”

- CEUS (11/19/2009): “ Complete portal vein thrombosis extended to the upper mesenteric vein and to the splenic one. Hepatic steatosis of moderate degree, hepatic hypoecogenic areas (focal steatosis? areas of altered vascularization?), hepatic cysts, slight splenomegalia, sludge of the gall bladder.”

- Chest CAT scan with contrast medium (11/2009): “No pleural or pericardial effusion. No pathological hilar and mediastinal adenopathies. No evident defects of replenishment to be related to acute pulmonary embolism involving the common trunk of the pulmonary artery, of the right and left main arteries and involving the segmental branches bilaterally, assessable up to the very first sub segmental branches. No lesions involving the pulmonary parenchyma neither focal nor diffuse, in particular of suspect oncologic nature; only a minimum parenchymal bundling in the most sloping part of the lingula.” –

Esophagogastroduodenoscopy (11/2009): “…. Diffuse hyperaemia of the gastric mucosa. At the fornix there are findings of initial clusters of varices along the great curve (IGV1) patent pylorus. Regular bulb, the descending duodenum examined down to the second portion is undamaged. Continent cardia. Canalized esophagus, it is observed an initial congestion of the vascular reticulum near the cardia that does not show, at present, presence of varicose veins. The conclusions give evidence of endoscopic picture consistent with erythematous gastropathy and gastric varicose veins (F1).”

- Total body PET scan (11/2009): “ Consistently with the resolution power of the method, no hypercaptation foci referred to hidden neoplasia are appreciated. The only finding worthy of notice is a prevertebral lymph node probably of inflammatory nature.”

- Colonscopy (11/2009): “… endoscopic picture consistent with simple internal hemorrhoids.” Further, the results of the blood chemistry tests performed during the hospitalization are attached.

During the hospitalization the following specialist visits have been carried out:

- Thromboembolic advice (11/2009): “… administering of Enoxaparin 10,000 U.I. aXa/1.0 ml, at a dosage of a prefilled syringe subcutaneously two times a day, every twelve hours. It is advised to carry out close up tests of the platelet count for the possible onset of thrombocytopenia due to heparin. Since anticoagulation will have to continue for an undetermined period of time but for no less than six months, once that possible invasive tests have been carried out and if an associated pathology requiring potentially cytopenia-inducing therapy will be excluded, start administering oral anticoagulant treatment with farfari tab. (at a dosage to maintain the values of INR between 2.0 and 3.0). It is advised to carry out further diagnostic exams aiming at excluding associated pathology and in particular determination of JACK2 in order to exclude myeloproliferative pathology. Thrombophilia screening tests have been carried out, but until now there has been no evidence of thrombophilia: Protein C, protein s, AT, APA, LAC, ACA: within normal limits. Homocysteine is slightly above the normal range; the molecular analysis of Factor II gene and Factor V gene is not available yet. In approximately 3 months it is advised to carry out a follow-up abdominal CAT scan to assess the evolution of thrombosis.”

- Haematological advice (11/2009): “… it is useful to carry out the assessment of the JAK2 mutations; also carry out assessment of peripheral blood smear in order to assess the platelet morphology. Current therapy with enoxaparin is confirmed.”

- Internal medicine advice (11/2009): “… from the examinations carried out the results are: heterozygous factor II mutation, on-going JAK2, no evidences from the hematochemical examinations and of imaging of neoplasia. Once the medical tests have been concluded the patient can be discharged with indication to start an anticoagulant therapy in approximately 1 month. Useful a family survey for the factor II mutation starting from the parents.” At discharge and at present the patient’s conditions are good with complete regression of the algic symptomatology (with the exception of a slight annoyance in the upper abdominal area due to the ingestion of a bit “heavier” food, which is more difficult to digest), patent alvus to faeces and gas.

Therefore, at discharge the following advices have been provided:
- Continue with enoxaparin sodium 10,000 U.I axa/1.0 ml 1 vial subcutaneous every 12 hours for 1 month.
- A following therapy adjustment will be at the responsibility of the thromboembolic centre where the patient will have to go within 1 month to undergo a visit.
- Repeat weekly haemochrome tests in order to exclude the appearance of thrombocytopaenia due to heparin.
- Carrying out of abdominal CAT scan in 3 months to assess the evolution of the clinical picture.
- Recommended chromosomal mapping of the family for the factor II mutation at the reference center.

Medical opinion

In reviewing this case, two main points must be considered:
1) what caused the thrombosis (i.e. local or systemic risk factors)
2) what complications should be anticipated
3) what is the prognosis

From the literature we know that the main risk factors for portal vein thrombosis are: Prothrombotic disorder, abdominal inflammation, cirrhosis, cancer, abdominal intervention and abdominal infection.
Thorough investigation did not unveil the pathology underlying the thrombosis:
- Prothrombotic disorders - Hyperhomocysteinemia – unlikely, levels are only slightly elevated, antiphospholipid syndrome, Protein C deficiency, Protein S deficiency and antitrombin III deficiency – were not found. Polycythaemia vera – awaiting JAK2 mutation analysis, Factor V Leiden mutation – awaiting results, Prothrombin mutation – exists (heterozygote).
Still not excluded - myeloproliferative syndromes and Paroxysmal Nocturnal Hemoglobinuria (PNH).

- Abdominal inflammation – such as: chronic pancreatitis, cholangitis, acute pancreatitis or liver abscesses were not found on multiple imaging studies. Gastroscopy and colonoscopy failed to show signs if inflammatory bowel disease or other intestinal inflammation. However the CT results did tell of hepatic cysts and polycystic liver disease should be excluded.

- Cirhosis – Although imaging studies did not show signs of cirrhosis – liver biopsy should be considered to rule out this possibility

- Cancer - PET-CT did not show signs of occult malignancy. Gastroscopy and colonoscopy also did not show evidence of malignancy.

- Abdominal intervention (i.e. recent surgery) – not relevant for this case

- Abdominal infection – not relevant to this case (according to the information before me)

Of note is the fact that in 13% of portal vein thrombosis cases, the cause is not found.

Major complications of portal vein thrombosis include: ascites – the accumulation of fluid in the abdomen, extension of the thrombus, gastric and esophageal varices which may spontaneously bleed if untreated.

In one case series, after a follow-up of 230 days, re-canalization of the thrombus occurred in about 30% to 45% of the patients treated with long-term anti-coagulants (more than 9 months). Of note is that in patients who were NOT treated with anti coagulants the thrombus re-canalization rate was significantly lower.

The fact that the patient recuperated so well with the anti-coagulation therapy indicates that the thrombus may be re-canalizing already, which is a very good sign.

Regarding the specific questions:
1) Treatment with Enoxaparin (1mg/kg BID) is the treatment of choice. In parallel, treatment with Warfarin should be initiated, up until INR levels are between 2.0 and 3.0. At that time, treatment with Enoxaparin should be stopped.

2) Warfarin is the best proven therapy for such thrombotic states. Other therapies are in the pipeline – but none of them has been proven to be as effective in similar situations.

3) As Warfarin is a strong anti-coagulant, the most common side effect is bleeding. Motorcycle drivers are at risk even with out medications. Adding anti-coagulants puts them at a very high risk of severe and even fatal hemorrhage.

4) In portal vein thrombosis, the aim of therapy is reconstitution of venous blood flow through re-canalization of the clotted vessel (in up to 45% of patients). This may take many months, and even then, the clot rarely disintegrates completely.

5) Prothrombin (factor II) mutation may contribute to the pro-thrombotic state, but it is uncommon that it will cause such massive thrombosis by itself (i.e. with out another risk factor).

6) To finalize the evaluation, I would consider the following:
a. Rule out Factor V Leiden mutation, myelodysplastic syndrome and Paroxysmal Nocturnal Hemoglobinuria
b. Rule out cirrhosis – consider liver biopsy
c. Rule out polycystic liver
d. Repeat abdominal CT angiography after 3 months to evaluate re-canalization and extension of the thrombus
e. Repeat gastroscopy after 3 months to evaluate edema and varices (if exist – consider medical therapy and ligation)