Daniela Fodor, Laura Poanta, Delia Jeican. abstract CASE REPORT

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1 CASE REPORTS HYPERHOMOCYSTEINEMIA AND TYPE II PROTEIN S DEFICIENCY - CAUSES OF MULTIPLE ARTERIAL THROMBOSIS Daniela Fodor, Laura Poanta, Delia Jeican REZUMAT Hiperhomocisteinemia este recunoscut\ ca un factor de risc independent pentru ateroscleroz\, dar sunt pu]ine date n literatur\ privind rolul acesteia n trombozele arteriale acute, f\r\ leziuni vasculare preexistente. Prezent\m cazul unei femei de 48 de ani cu antecedente de infarct intestino-mezenteric [i rezec]ie intestinal\. Pe parcursul spitaliz\rii aceasta a prezentat trei episoade de ischemie acut\: dou\ la nivelul intestinului sub]ire (rezolvate chirugical) [i o tromboz\ acut\ a arterei poplitee drepte (tratament conservator). Nu s-au decelat surse emboligene, nici leziuni aterosclerotice. Determin\rile de laborator au stabilit prezen]a hiperhomocisteinemiei [i a tipului II de deficit de protein\ S. Subliniem importan]a determin\rii homocisteinei serice [i a altor factori de risc pentru trombozele arteriale la un pacient cu status trombofilic, mai ales dac\ acesta este t n\r sau trombozele sunt cu localiz\ri neobi[nuite. Cuvinte cheie: hiperhomocisteinemie, deficit proteina S tip II, tromboze arteriale multiple abstract Hyperhomocysteinemia is considered to be an independent risk factor for atherosclerosis, but there is few data regarding its role in acute arterial thrombosis without any previous lesions. We present the case of a 48 years old female with personal history of small bowel infarction and intestinal resection. During the hospitalization she had three acute ischemic episodes: two at small bowel level (surgical resection), and an acute occlusion of the right popliteal artery (medical treatment). There was no embolic source and no atherosclerotic lesions. Laboratory findings showed hyperhomocysteinemia and type II protein S deficiency. We underline the importance of measuring homocysteinemia and other risk factors for arterial thrombosis in a patient with thrombophilic state, especially in a young patient or in thrombosis in unusual place. Key Words: hyperhomocysteinemia, type II protein S deficiency, multiple arterial thrombosis INTRODUCTION Even if the knowledge about the etiology of acquired or inherited thrombotic disorders have evolved a lot in the past years, mainly by elucidating the molecular mechanisms involved in the coagulation and fibrinolysis processes, the Virchow triade, postulated over 150 years ago, regarding the risk factors for thrombotic disorders (abnormalities of the blood flow, blood constituents and the vessel wall) is still valid. Today the investigation of a patient with 2 nd Internal Medicine Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Correspondence to: Daniela Fodor, 2 nd Internal Medicine Clinic, 4 Clinicilor Str., Cluj Napoca, Romania dfodor@umfcluj.ro Received for publication: 02 Nov Revised: 23 Mar single or recurrent episodes of unique or multiple thromboses implies a thorough search of acquired or inherited thrombogenous risk factors. The common coagulation tests are not sufficient anymore in order to explain a thrombotic syndrome. We present the case of a 48 years old female with inherited thrombophilia (hyperhomocysteinemia and type II protein S deficiency) which evolved with multiple arterial thromboses. CASE REPORT M.A., 48 years old, no births in the personal history, was admitted in our hospital because of a two month history of upper abdominal pain, persistent or intermittent, sometimes colicky, not connected with food intake or time of the day, nausea, liquid vomiting or with partial digested food particles, passage of flatus, constipation and weight loss (five kilograms in two months). Daniela Fodor et al 43

2 Past medical history: a year before this admittance she had the symptoms of an acute surgical abdomen which proved to be bowel infarction and she underwent surgery with the resection of 45 centimeters of the small intestine. The histopathology exam: infarction of the entire resected segment and multiple thrombi in the small mesenteric vessels. Physical exam at admission shows pain while palpating the abdomen, more intense in left upper abdominal quadrant and left flank; bowel sounds were present and there were no vascular murmurs on the main arteries. The peripheral arterial pulses were normal. The clinical interpretation was suboclusive syndrome (Konig) possible due to postoperatory obstruction or adherential syndrome. Laboratory findings were: inflammatory syndrome, with elevated sedimentation rate and alpha 2 globulins (60/95 mm/h and 18% respectively), leucocytosis of 11500/mm 3, normal values for total cholesterol, plasma triglycerides and HDL-cholesterol. Upper gastrointestinal tract was investigated endoscopically, which revealed an axial hiatal hernia with stage II esophagitis. Small-bowel enema (enteroclysis) revealed a 20 centimeter segment of small intestine which remained un-distained by the contrast substance and was probably secondary to a chronic, stenotic process. (Fig. 1) Figure 1. Radioscopy-guided barium enema. It is obvious the narrowed bowel segment during the exam (arrow). On Doppler ultrasound examination the inferior mesenteric artery was found to be completely obstructed, while the superior mesenteric artery was only partially obstructed in the proximal part, the thrombosis being of 75% of the lumen. On the fourth day of admittance the patient developed an acute ischemic occlusion of right popliteal artery; Doppler ultrasound revealed a complete occlusion by an acute thrombosis of the popliteal artery with extension of the thrombus in the anterior tibial artery, but without any significant signs of atherosclerotic injury. (Fig. 2) Figure 2. Doppler ultrasound of popliteal region, transversal section. Popliteal artery (AP) fully occluded without color Doppler signal. VP - popliteal vena. Anticoagulants and vasodilators rapidly and significantly improved the symptomatology, without the need an invasive desobstruating intervention. Abdominal arteries arteriography (Fig. 3,4) and of the lower limbs arteries performed only two weeks after the event (due to technical reasons), confirmed the occlusion of the popliteal artery (Fig. 5) and the inferior mesenteric artery, without significant proof of atherosclerotic lesions (plaques), while the superior mesenteric artery was permeable. Three days after arteriography the patient developed another episode of mesenteric infarction, although under anticoagulant therapy. This time, 70 centimeters of necrotic jejunum was resected. Post surgical evolution was unfavorable, so the next day a new surgical intervention was necessary, and this time 45 centimeters of necrotic jejunum was resected, at a distance from the previous intervention. Intraoperatory the thromboses of the small mesenteric arteries was established; no lesions at the inspection of the colon were found. The histopathological exam excluded the vasculitis aspects on the resected segment, showing only the thrombosis of the small mesenteric arteries. (Fig. 6) All the common coagulation tests performed were normal (platelets count, Quick time, partial activated thromboplastine time, antithrombin III, antiphospholipid antibodies); so we had to go further with the investigation for the coagulating and the fibrinolitic processes. Factor V resistance to activated protein C, factor VIII activity, plasma folic 44 TMJ 2007, Vol. 57, No. 1

3 Figure 3. Abdominal angiography. Inferior mesenteric artery is complete thrombosed. There are no atherosclerotic injuries and all the other abdominal vessel are normal. Figure 6. Histopathology from the latest intestinal infarction. Small vessels are thrombosed. The final diagnosis was: Type II protein S deficiency. Hyperhomocysteinemia. Wild type MTHFR C677T genotype. The patient continued with the anticoagulation therapy: first heparin, followed by warfarin, in association with aspirin, folate and vitamin B6 and B12 supplements. Further determination of homocysteine levels was not possible, but clinical evolution was good, without any thrombotic events in the next two years of surveillance. Figure 4. Normal aspect of bilateral iliac arteries on angiography. Figure 5. Right leg angiography. Complete occlusion of right popliteal artery (arrow), without collateral vessels (acute occlusion). acid and plasma vitamin B12 level were all in normal ranges. The study of prothrombin gene variant and of MTHFR (methylenetetrahydrofolate reductase) C677T gene polymorphism showed the presence of wild type. Plasma homocysteine level was elevated µmol/l (risk limit under 12.5 µmol/l), protein S activity was 44% (normal values between 65 and 140%), with normal free protein S antigen level. Discussions The term of thrombophilia or prothrombotic status refers to the cases where acquired or inherited coagulation disorders enhance the susceptibility of developing venous and/or arterial thromboses. 1,2 Multiple factors causing thrombophilia can determine thrombosis in both arterial and venous territory, but according to the etiological factor there is a predominance of either of them. 2-4 (Table 1) Facing an arterial and/or venous thrombotic disorder, the aquired risk factors are the first and the easiest to analyze and identify. In a recurrent thrombotic disorder or when there are other features of thrombotic predisposition (young age and/or unusual sites of thrombosis), further investigation of the coagulation process is needed. Recurrent arterial thrombosis in our patient, at a young age (48 years old), without any signs of atherosclerosis on vascular Doppler ultrasound and angiography, leads to a complete investigation of all inherited and acquired risk factors to explain these episodes. As hyperhomocysteinemia is frequently reported in association with thrombotic events, that was the first risk factor we looked for. 2,5-7 Homocysteine Daniela Fodor et al 45

4 Table 1. Acquired and inherited factors associated with arterial and venous thrombosis. Acquired factors Inherited disorders Arterial thrombosis Atherosclerosis Diabetes mellitus Tobacco smoking Oral contraceptives Polycythemia Thrombocytosis Paroxysmal nocturnal hemoglobinuria Sickle cell anemia Heparin induced thrombocytosis Antiphospholipid syndrome Hyperhomocysteimemia High Lp(a) Prothrombin G20210A mutation Protein S deficiency Venous thrombosis Prolonged immobilization Trauma Surgery Pregnancy, postpartum Oral contraceptives Neoplasia Cancer chemotherapy Antiphospholipid syndrome Antithrombin, protein C, protein S deficiency Factor V resistance to activated protein C Prothrombin G20210A mutation Plasminogen deficiency, t-pa decrease or PAI-1 increase APC-activated protein C; PAI-1 - plasminogen activator inhibitor 1; t-pa tissue plasminogen activator; Lp(a) lipoprotein a. is a sulfur-containing amino acid formed during the metabolism of methionine. Metabolism of homocysteine occurs along two major enzymatic pathways, either remethylation or transsulfuration, which require folate and vitamine B12 or vitamine B6 respectively. 8,9 High plasma homocysteine levels occur in mutations in one of the enzymes involved in homocysteine metabolism. In homozygous patients the elevation is important (over 50 µmol/l) with high risk for myocardic infarction and high morbidity and mortality associated with thromboembolism, stroke, and arterial peripheral thrombosis. Also, increased plasma homocysteine levels may occur if there is not an adequate supply of vitamin B12, folate, or in chronic renal failure cases. These cases are more frequent in adults and produce only mild increases in homocysteine levels. Despite the etiology of the mild or moderate hyperhomocysteinemia (genetic mutation with homozygous or heterozygous forms or nutritional defects), this increase is considered to be an independent risk factor for stoke, ischemic heart disease and peripheral artery disease. 8 Chanarin (cited by ref. 8) showed that for every increase with 5 µmol/l of homocystein levels the relative risk for coronary heart disease increases with 40%. The prospective studies of recurrent cardiovascular events showed that the hazard ratio for a recurrent event increases by 16% with each increase of 5 µmol/l in the serum homocysteine concentration. 10 Also, lowering homocysteine concentrations with folate supplements by 3 µmol/l from current levels reduces the risk of ischemic heart disease by 16%, of deep vein thrombosis by 25%, and of stroke by 24%. 10 There is evidence in vitro and in vivo that homocysteine is an atherogenic determinant that promotes oxidative stress, inflammation, thrombosis, endothelial dysfunction, and cell proliferation. 11 In fact, the effects of elevated homocysteine levels appear to affect both vascular wall structure, and blood coagulation system. Due to the moderate elevation of the homocysteine level and the absence of the atherosclerotic lesions on Doppler and angiographic examination, in our case we considered an associated risk factor explaining the amount and the extent of the thrombotic lesions. A second risk factor which could have explained the thrombotic predisposition in this patient with mild hyperhomocysteinemia was identified as type II protein S deficiency (inherited, so pre-existent to hyperhomocysteinemia). Protein S it is a vitamin K dependent glycoprotein which acts as a cofactor for protein C to inactivate factors Va and VIIIa. In plasma, protein S has two circulating forms: 60% as a covalent complex with β-chain of the complement component C4b binding protein, while the remaining 40% is free. There are three types of protein deficiency: type I characterized by low total and free protein S antigen level; type II characterized by normal free protein S level, but reduced activated protein C cofactor activity and type III, by a selective reduction in free protein S levels. 11,12 Protein S deficiency is a well known risk factor for venous thrombosis, with a 2.4 higher risk for such events including less common sites, like mesenteric or cerebral veins. 13,14 Occasionally, arterial thrombosis can be found. In our case, Doppler ultrasound revealed thrombosis of the superior mesenteric artery which 46 TMJ 2007, Vol. 57, No. 1

5 was not confirmed on arteriography. This could be explained by the lysis of the thrombus after the heparin therapy was initiated, while angiography was performed 2 weeks later. Even though the anticoagulant therapy was administered in proper dosage, it was not efficient on the small branches of superior mesenteric artery as the two successive intestinal infarctions followed. This comes as an argument for the multiple mechanisms involved in thrombus formation in our patient. It is also of interest that the colon was normal on macroscopic examination during surgery, in spite of the fact that the branches of the superior mesenteric artery and further more, the main branch of the inferior mesenteric artery were occluded. The occlusion of inferior mesenteric artery could have been a gradual one, so the collateral vessels could have formed and supplied the involved territory. The involvement of hyperhomocysteinemia as a risk factor for thrombosis in this patient is obvious from the response to the treatment. Two intestinal infarctions had occurred while treated with heparin; but when given vitamin supplements (vitamin B6 and vitamin B12) and folate there were no recurrences during the two year period in which we followed her. Unfortunately it was not possible to repeat the measurement of the homocysteine levels during the vitamin treatment but, based on clinical evolution, we can only assume that the levels returned to normal values. Even though recent studies are questioning the importance of routine measurement of plasma levels of homocysteine and that of treatment with vitamin supplements and folate in order to prevent atherothrombotic diseases, these measures proved to be beneficial in our case. 15 This case is of great interest due to the association between two factors: one of them inherited (protein S deficiency) and the other one acquired (mild hyperhomocysteinemia). The pro-thrombotic activity of the first factor became clinically evident in the presence of the second one. It is possible that if any of the two risk factors were independent, they couldn t have generated such a significant thrombotic process. REFERENCES 1. Girolami A, Simioni P, Scarano L, et al. Venous and arterial trombophilia. Hematologica 1997;82: De Stefano V, Rossi E, Paciaroini K, et al. Screening for inherited trombophilia: indicatins and therapeutic implications. Hematologica 2002;87: League S, Hooper WC. Molecular diagnostics of inheriteed thrombosis. Clin Lab Sci 2005;18(5): Makin A, Silverman SH, Lip GYH. Peripheral vascular disease and Virchow s triad for thrombogenesis. O J Med 2002;95: Bohm G, Al-Khaffaf H. Trombophilia and arterial disease. An up-todate review of the literature for the vascular surgeon. Int Angiol 2003;22(2): D Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood, 1997;90: Stein JM, McBride PE. Hyperhomocysteinemia and atheroclerotic vascular disease: pathophysiology, screening, and treatment. Arch Intern Med 1998;158: Carmel R, Green R, Rosenblatt DS, et al. Update on cobalamine, folate and homocysteine. Hematology Am Soc Hematol Educ Program. 2003:334: Welch GN, Loscalzo J. Mechanisms of Disease: Homocysteine and atherothrombosis. N Engl J Med 1998;338: Wald D, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325: Loscalzo J. Homocysteine trials-clear outcomes for complex reasons. N Engl J Med 2006; 354: Markris M, Leach M, Beauchamp NJ, et al. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood 2000;95: Simmonds RE, Zőller B, Ireland H, et al. Genetic and phenotypic analysis of a large (122 members) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type II plasma phenotypes. Blood. 1997;89: Faioni EM, Valsecchi C, Palla A, et al. Free protein S deficiency is a risk factor for venous thrombosis. Thromb Haemost. 1997;78: Kaul S, Zadeh AA, Prediman K, et al Homocysteine hypothesis for atherothrombotic cardiovascular disease not validated. J Am Coll Cardiol, 2006;48: Daniela Fodor et al 47