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Case Reports Indian Pediatrics 2002; 39:689-692 |
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Deep Vein Thrombosis With Protein C Deficiency |
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M. Jeilani
Deep venous thrombosis is unusual in children. In a large percentage of children (96-98%) a risk factor or an underlying hypercoagulable state can be identified(1,2). We are presenting this case of deep vein thrombosis with protein C deficiency because of its rarity, unusual presentation and the difficulties it posed during management. Case Report A 13 year old boy, the only child of his parents, presented to us in the 3rd week of febrile illness (intermittent moderate to high grade fever). The fever was associated with severe myalgia and neck pain during the 2nd week and increasing pain and swelling of left thigh during the 3rd week. Initial investigations prior to referral had shown a raised ESR (60 mm in 1 hour), positive widal (Salmonella typhi O and H 1 in 200), and normal blood counts. He had been confined to bed during this time, when he received antipyretics, analgesics, prednisolone (5 days), intravenous chloromphenicol (6 days), followed by intravenous crystalline penicillin (3 days). With the commencement of crystalline penicillin, the pain and swelling over the left thigh showed improvement but increased in severity over the next 48-72 hours. At presentation to us, he was a fairly nourished child, alert and mildly febrile. Examination showed mild swelling over left upper thigh, with restricted extension of left hip. There were few pea sized mildly tender lymphnodes in the left inguinal region. With these findings the possibilities considered were leptospirosis, left hip arthritis and left iliopsoas abscess, all of which were ruled out by negative serum dark field microscopy and microscopic agglutation test titre for leptospirosis, normal X-ray of hip and pelvis, and normal abdominal ultrasonogram. Blood culture for enteric and non-enteric organisms did not reveal any growth. Over the next 48 hours of admission he developed pain over the right leg. In view of the diffuse nature of the pain, viral myositis was considered. He was started on non steroidal anti inflammatory drugs to which he showed clinical improvement and hence was discharged after 5 days. The child was readmitted within a week of discharge with recurrence of pain in both legs and mild swelling of both feet. He was afebrile, and had a positive Homans sign in both calf muscles. There were engorged veins over anterior and lateral aspects of abdomen on both sides with filling of blood from below upwards. Rest of the clinical examination including peripheral arterial pulses were normal. With the above features, a diagnosis of bilateral deep vein thrombosis was made. Investigations were performed to asses the extent of involvement and to identify the cause for hyper-coagulability. Venous doppler of both lower limbs showed deep vein thrombosis of ileo-femoro-popliteal veins with minimal flow. Computerized tomographic scan of the abdomen and the pelvis revealed the thrombus to be extending up to the renal segment of inferior vena cava, occupying the posterior aspect as there was no other discernible intra-abdominal pathology. Platelet count, hematocrit, echocardiogram and X-ray chest were normal. Blood levels of antiphospholipid antibodies, anti thrombin III, homocystine and protein S were normal. However Protein C level was significantly decreased (32% of normal). He was managed during the initial four days with intravenous heparin - a loading dose of 75 units/kilogram body weight followed by maintenance intravenous infusion. However, despite increasing the infusion to 30 units/kilogram/per hour the desired prolongation of activated partial thromboplastin time was not achieved. Hence this was discontinued and low molecular weight heparin was instituted at 100 units/kilogram subcutaneously twice daily. In view of the difficulty in monitoring factor X a, this was changed to oral Warfarin in the next two days. This was increased to a maximum of 7.5 mg/day over the next one week. However, the International Normalised Ratio achieved was only 1.2. Considering a possible resistance to Warfarin, Acenocoumarol was commenced with which at dose of 4 mg/day an International Normalized Ratio of 1.62 was achieved. The dose was not further increased as he was doing well with the disappearence of the leg edema, calf muscle pain, and the engorged veins over the abdomen. There were no fresh symptoms. Repeat venous doppler of lower limbs (after 8 weeks of oral anticoagulation) showed complete resolution of the thrombi with full recanalisation and normal flow. Discussion In this boy, the underlying protein C deficiency secondary to an infection, compounded by immobilization and confinement to bed during the initial phase of illness appears to have provoked the onset of the thrombosis. The actual incidence of protein C deficiency in our population is not known. However in a study done at All India Institute of Medical Sciences, Delhi, to determine the pathogenetic factors underlying juvenile deep vein thrombosis in Indians, Activated Protein C - Resistance was found to be the commonest defect. None of the subjects had protein C deficiency(3). The risk factors include past history of deep vein thrombosis or pulmonary edema, recent operation, immbolization, trauma, stroke or acute neurological deficit, presence of cancer, sepsis, greater than 150% ideal body weight, central venous catheter and hyper coagulable state(4). The inherited hypercoagulable states are protein C and S deficiency, activated Protein C resistance, antithrombin III deficiency, dysplasminogenemia, dysfibro-genemia and high levels plasminogen activator inhibitor. The acquired hyper coagulable states include antiphospholipid syndrome, thrombocythemia(1,2), and severe bacterial or viral illness(5). Protein C system constitutes one of the major regulatory system of hemostasis. Protein C is a vitamin K dependent proenzyme synthesized in the liver. On the surface of endothelial cells, thrombin binds to a receptor known as thrombomodulin. This complex is the site for the interaction with protein C. Once bound to this complex, protein C becomes activated (Activated Protein C). Protein S acts as a cofactor in this process. When activated, protein C inhibits factor VIIIa and factor Va (interfering with the two rate limiting steps of coagulation cascade) thus exhibiting its anticoagulant property. Also activated Protein C enhances fibrinolysis through the inhibition of plasminogen activator inhibitor. Hence if there is a deficiency of protein C or if there is a resistance to activated Protein C (which is secondary to factor V leiden mutation), there results a prothrombotic state which in the presence of reduced fibrinolysis leads to clinically manifesting thrombosis(6). Molecular basis of Protein C deficiency has been studied extensively by polymerase chain reaction and single strand conformational polymorphism analysis. A few recurrent defects all occurring at CG dinucleotides were commonly observed indicating that these are hot spots for mutation in the Protein C gene. The more common defects resulting in deficiency include Arg 169 Trp, Arg 286 His, Val 297 Met, Asp 359 Asn substitutions, and Lys 150, G 8857 deletions. Screeing of these recurrent defects by using restriction enzyme cleavage is a rational method(4). There are two modes of inheritance, i.e., the autosomal dominant and recessive traits. In the former, the heterozygotes are symptomatic and in the latter, only the homozygotes are symptomatic. Clinically, persons who have heterozygous protein C deficiency and protein C levels approximately half normal are at risk for venous thromboembolic disease, occasional arterial thrombosis and childhood stroke. In these patients, the onset of symptoms and signs is in the second decade of life(6). Homozygous protein C deficiency manifests as neonatal purpura fulminans. Acquired causes of protein C deficiency include liver disease, DIC, therapy with L-asparaginase and coumarin, and acute severe bacterial or viral illness(57). The management of heterozygous protein C deficient patients with deep vein thrombosis is with heparin anticoagulation - either conventional or low molecular weight. In cases of acute severe protein C deficiency with clinical manifestation of thrombosis, protein C concentrate or fresh frozen plasma therapy is essential(5). There was resistance to both heparin and warfarin during the initial few days of commencement of therapy. Causes like non compliance, malabsorption, known drug interactions, laboratory errors, excess vitamin K in the diet were considered and ruled out. However, as the International Normalised Ratio improved after starting Acenocumarol, with concomitant improvements in symptoms and signs, possible unusual tissue resistance to both heparin and warfarin is presumed as the underlying cause(8,9). In conclusion, protein C deficiency can result in deep vein thrombosis under rare circumstances. Although it is commonly belived that the incidence of deep vein thrombosis in children is less than in adults, it is however possible that the disease is significantly under diagnosed in children because the index of suspicion of pediatric practitioners is low, a substantial number of patients may have no symptoms and deep vein thrombosis screening is not usually performed. Presence of more than two risk factors warrants screening, prompt evaluation and treatment. Contributors: All the authors contributed in the clinical workup of the case, discussion and interpretation of the findings, drafting of the article and final approval of the version to be published. AA will act as the guarantor for the paper. Funding: None. Competing interests: None stated.
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