Splenic Artery Thrombosis in a Patient with Prothrombin Gene

Mutation

Jennifer Teeter, D.O.

Mentor: Dr. Kamal D. Tourbaf, M.D.

Virchow’s triad

• The major theory delineating the pathogenesis of thrombosis– Alterations in blood flow– Vascular endothelial injury– Inherited or acquired hypercoagulable state1

Inherited Thrombophilia

• Factor V Leiden mutation

• Prothrombin gene mutation2

• Protein C deficiency

• Protein S deficiency

• Antithrombin deficiency

• MTHFR mutation

Acquired risk factors

• 50% of thrombotic events in patients with inherited thrombophilia are associated with an acquired risk factor– Pregnancy– Surgery– Prolonged bedrest– Malignancy– Trauma– Smoking– Oral contraceptives3

• The majority of thrombosis are venous rather than arterial.

• The majority occur within the lower extremities.

Our Case

• We describe a patient with prothrombin gene mutation and tobacco use causing splenic artery thrombosis and subsequent splenic infarct after abdominal trauma.

History

• 43-year-old Caucasian male presented to the ER with complaints of nausea and vomiting for 3 days.

• In addition, he had left upper abdominal and left flank pain for 1 day.

ROS

• Left lower chest and left upper abdomen bruised 3 weeks prior to presentation after he bumped into a shelf.

• Denies fever, urinary burning or frequency, SOB or changes in bowel habits.

• PMHx: Gout

• PSHx: none

• Meds: none

• Allergies: NKDA

• Social: +tobacco <1ppd X 15 years, denies alcohol or drug use.

• FHx: mother had breast cancer and LE DVT’s

Physical Exam

• Vitals: 133/89 100 20 100.5 100%RA

• 43-year-old caucasian male in moderate distress, A+Ox3

• HEENT: NCAT, EOMI, PERRLA, OMM, clear pharynx

• Neck: no bruits, no thyromegaly

• Heart: RRR S1S2, no murmurs

• Lungs: CTA b/l no w/r/r

PE con’t

• Abdomen: soft, nondistended, +BS, significant LUQ and left flank tenderness with minimal palpation and with deep inspiration. No rebound or guarding.

• Ext: no edema, negative homans

• Neuro: CN II-XII grossly intact, muscle strength, reflexes, sensation intact

• Rectal: heme occult negative

Labs• WBC 15.5 Na 138 Ca 9.3

• HgB 15.7 Cl 100 T. Bili 1.0

• Hct 44.6 K 3.3 D. Bili 0.2

• Plt 188 CO2 29 T. Pro 7.4

• N 77% BUN 11 Alb 4.1

• L 7% Cr 0.9 ALT 29

• M 15% gluc 116 AST 29

• E 2% amylase 67 alk phos 66

• B 0 lipase 22

U/A

• Negative glucose, ketones, leuk. Esterase, nitrites, protein, bilirubin

• + trace blood, few bacteria, 5-10 squamous epithelial cells

EKG• Sinus tachycardia

CT abdomen and pelviswithout contrast

• Subtle stranding involving the superior aspect of the body of the pancreas and around the left adrenal gland

• Left renal cyst

• No evidence of hydronephrosis, renal, ureteral or bladder calculi

CT abdomen and pelviswith contrast

• Enlarged spleen, 15.1 cm, with patchy areas of enhancement. The majority of the spleen does not appear to enhance, suggestive of ongoing splenic infarction.

• The splenic artery also does not enhance, suggestive of thrombosis

• Left renal cyst

Hospital Course

• The patient was followed by a vascular surgeon, a general surgeon and a hematologist.

• He was managed conservatively with IV heparin which was bridged to coumadin.

• His pain was controlled with analgesic medication.

• A cause for the thrombosis was evaluated.

Studies• Lower extremity venous dopplers:

negative for DVT• Normal lower extremity arterial dopplers• 2D echo: left ventricular EF 50%; poor

overall images, normal right ventricular systolic function, mild thickening of aortic valve leaflets.

• TEE with bubble study: normal left and right ventricular systolic function. No evidence of cardiac source of embolism.

Hypercoagulable Workup

• Protein C 114% (71-146%)

• Protein S 105% (74-146%)

• No resistance to activated protein C

• Factor V Leiden negative

• Antithrombin III 94% (81.1-125.9%)

Con’t

• C-ANCA <6 u/ml (negative)

• P-ANCA <6 u/ml (negative)

• Phospholipids 207 mg/dL (151-264 mg/dL)

• Thrombin time 20 sec (16-23 sec)

• No evidence of lupus anticoagulant

• Cardiolipin antibodies normal

Positive Labs• Factor II mutation positive

– Genotype: heterozygous

• + one copy of MTHFR mutation– The presence of one copy has not been associated

with an increased risk for hyperhomocysteinemia or vascular disease.

• CRP 11.300 mg/dL• ESR 74 mm/hr (0-15 mm/hr)• Fibrinogen 660 mg/dL (250-500 mg/dL)• Homocystine 18.3 umol/L (5-15 umol/L)• Factor VIII 209% (50-150%)

Acute gouty attack

• Right second metatarselphalangeal joint during his course of illness.

• Uric acid 6.0 9.3

• Treated with colchicine

Repeat Labs• Fibrinogen 302 mg/dL (250-500 mg/dL)

• Homocystine 14.4 umol/L (5-15 umol/L)

• Factor VIII 147% (50-150%)

• Therefore, it is felt that the initial elevation of this patient’s fibrinogen, homocystine and Factor VIII were due to an acute phase response secondary to the splenic infarction and gouty attack.

• We concluded that this patient’s hypercoagulability is most likely a result of his Factor II mutation.

• In addition, the patient’s abdominal trauma and tobacco use may have played an additive role.

• We recommended long-term anticoagulation and discontinuation of tobacco use.

• Family members, including siblings and children, were advised to be tested for the Factor II mutation.

DISCUSSION

Splenic Infarction

• Acute occlusion of the splenic artery results in infarction of the splenic parenchyma.

• Patients present with left upper quadrant pain, fever, chills, nausea, vomiting, pleuritic chest pain and left shoulder pain5.

Splenic Infarction

• Usually encountered in association with – hematological diseases– Thromboembolic states– Vasculitides: SLE with lupus anticoagulant or

antiphospholipid antibodies5

– Sickle cell disease– Wegener’s granulomatosis– Cocaine abuse6

Splenic Artery• Abnormalitites of the splenic artery,

particularly stenosis and occlusion, are rare types of acquired disorders of splanchnic circulation.

• Etiological factors:– Blunt trauma– liver transplantation surgery or pancreatectomy– torsion of the wandering spleen5,7-8

Splenic Artery Thrombosis

• Thrombosis of the abdominal aorta and splenic artery in antiphospholipid syndrome9

• Thromboembolic process of cardiac origin causing stenosis of the splenic artery10

• Secondary to oral contraceptive use11

• Thromboembolic splenic infarction due to atherosclerosis of the thoracic aorta and splenic artery12

Splenic A. Thrombosis Con’t

• Spontaneous splenic infarction after sumatriptan use13

• DM with atheromatous arteries and thrombosis of the sclerosed splenic artery14

• Asymptomatic splenic artery occlusion in a child discovered with doppler U/S15

• To our knowledge, a case on splenic artery thrombosis in a patient with prothrombin mutation has never been reported.

Thrombophilia• The blood has an increased tendancy to clot• Risk Factors:

– Inherited risk factor– Obesity– Cancer– Inflammatory bowel disease– Antiphospholipid antibodies– Recent surgery– Trauma– Prolonged immobility– Pregnancy– Oral contraceptive use– Hormone replacement therapy16

Thrombophilia Con’t

• Thrombophilia is a prominent risk factor for venous thromboembolism.

• The role of thrombophilia in determining the risk of arterial thrombotic events is less well defined.

Prothrombin• A protein in the blood that is required to

form fibrin which combines with platelets to form blood clots.

• A mutation in the prothrombin gene, also called prothrombin variant, prothrombin G20210A, or factor II mutation, has been associated with a 30% higher plasma prothrombin level and therefore an increased tendency for thrombosis18.

Prothrombin Con’t• Heterozygous or homozygous• Heterozygous mutations are found in about 2%

of the US Caucasian population. • The homozygous form is uncommon, 1/10,000.• Heterozygous prothrombin mutation increases

the risk of developing a DVT by 2-3 times16.• It plays a role in cerebrovascular ischemic

events in those less than 60 years of age. There is conflicting results when evaluating the role of prothrombin gene mutation in acute myocardial infarction19-21.

• Many people with this mutation will never develop a blood clot

• Often, people will have additional risk factors for clot formation.

• If a patient has the prothrombin mutation but has not developed a blood clot, they should be counseled about reducing or eliminating other factors that add to their risk of developing a blood clot in the future16.

• Several studies have shown a correlation between tobacco use and an increased risk for venous thromboembolism22-24.

• A large population-based study investigated the VTE risk following a minor injury and concluded that a minor injury occurring in the preceding 3 to 4 weeks was associated with a 3- to 5-fold increase in DVT risk26.

• Risk factor modification is also important for preventing arterial disease.

• It is likely that, in our patient, his tobacco use and/or abdominal blunt trauma contributed to his development of thrombosis.

Acute gouty attack

• We were unable to find any evidence that gout is an independent risk factor for increased coagulabilty.

• Nevertheless, gout is associated with a number of risk factors for cardiovascular disease including hypertension, obesity, a high alcohol intake and hyperlipidemia.

• In view of the already raised thrombotic risk profile in gout patients as a group, one study showed that the hyperfibrinogenemia was only present during the acute attack of gout, presumably as an acute phase response.

• They concluded that it is unlikely that the hyperfibrinogenemia noted during acute attacks of gout contributed significantly to the chronically raised cardiovascular risk profile of long-term gout patients27.

Acute Phase Response

• Raised fibrinogen, homocystine and factor VIII levels have been recognized as risk factors for thrombosis.

• Although these levels were initially elevated in our patient, they did return to normal limits after the splenic infarction and the resolution of his acute gouty attack.

• We concluded that these elevations were due to the acute phase response and most likely did not play a significant role in the risk of thrombosis in this patient

CONCLUSION• Thrombosis occurs as a result of disruption of blood flow,

vascular endothelial damage and/or a hypercoagulable state.

• A common cause of inherited thrombophilia is prothrombin gene mutation.

• Thrombophilia is a prominent risk factor for venous thromboembolism; however, the risk for arterial events is less well defined.

• There are many reported causes for splenic artery thrombosis and splenic infarction.

• However, we believe we are the first to report a case of splenic artery thrombosis and subsequent splenic infarction in a patient with prothrombin gene mutation and tobacco use who sustained abdominal trauma.

• Although our patient had elevated fibrinogen, homocystine and factor VIII levels, we determined that these were acute phase reactants.

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