Renal vein thrombosis and constitutional protein S deficiency

Venous and arterial thrombosis due to a constitutional protein S deficiency is well-known. We report the case of a 36 year-old patient admitted to hospital in 1991 for primary renal vein thrombosis due to a constitutional protein S deficiency of type I. The diagnosis was made by CT scan and angiography. Left nephrectomy, which was made because of doubt with regard to subjacent neoplasm, showed left renal vein thrombosis and multiple renal infarcts. In 1994, after 4 months of discontinuation of oral anticoagulants, the patient presented pulmonary embolism documented by pulmonary scintigraphy and CT scan, partial portal thrombosis and sural thrombophlebitis documented by echography coupled with Doppler. To our knowledge, this is the first reported case of a constitutional protein S deficiency associated with primary renal vein thrombosis.     

Cutaneous necrosis associated with acquired severe protein S deficiency

The incidence of benign lymphoepithelial lesions of the parotid gland in patients afflicted with HIV has increased. Enucleation is a safe and effective procedure that provides the patient with complete removal of the cyst and a low recurrence rate. Enucleation of these parotid cysts should be considered in treating these patients.     

Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group

Protein S is a protein C-dependent and independent inhibitor of the coagulation cascade. Deficiency of protein S is an established risk factor for venous thromboembolism. We have used a strategy of specific amplification of the coding regions and intron/exon boundaries of the active protein S gene (PROS1) and direct single-strand solid phase sequencing, to seek mutations in 35 individuals with phenotypic protein S deficiency. Nineteen point mutations (16 novel) in 19 probands (or relatives of probands) with venous thromboembolism are reported here. Fifteen of the 19 mutations were expected to be causal and included 10 missense mutations (Lys9Glu, Glu26Ala, Gly54Glu, Cys145Tyr, Cys200Ser, Ser283Pro, Gly340Asp, Cys408Ser, Ser460Pro, and Cys625Arg). Three of the 15 mutations resulted in premature stop codons (delete T 635 producing a stop codon at position 126, Lys368stop and Tyr595stop) and two were at intron/exon boundaries (+1 G to A in intron d and +3 A to C in intron j). Of the remaining four mutations, three were within intronic sequence and one was a silent mutation within the coding region and did not alter amino acid composition. In two of the 10 missense mutations, reduced plasma protein S activity compared with antigen level suggested the presence of variant (type II) protein S.     

Partial portal vein and mesenteric vein thrombosis in familial protein S deficiency

Protein S, a vitamin-K dependent glycoprotein is a cofactor of protein-C system, which acts as an inhibitor of the plasmatic coagulation. Protein-S congenital deficiency results in recurrent venous thromboses, atypical locations in portal and mesenteric veins are possible. In our patient the partial thrombosis of the portal vein was diagnosed by computed tomography and angiography. Small bowel ischaemia due to mesenteric vein thrombosis required segmental resection. Post-operatively the patient was heparinized and later phenprocoumon was applied to a long-term therapy.     

A 41-year-old woman with protein S deficiency and diffuse proliferative lupus nephritis: is protein S deficiency associated with a hyperinflammatory response?

A 41-year-old woman with complete protein S (PS) deficiency who developed diffuse proliferative lupus nephritis is reported. She was referred to our hospital with nephrotic syndrome and thrombocytopenia. Her medical history included colorectostomy and amputation of the extremities because of repeated thrombotic episodes during her teens without any evidence of systemic lupus erythematosus. The diagnosis of PS deficiency was made from the patient's clinical course, undetectable serum PS in either the active or inactive form, normal protein C activity, and no evidence of the antiphospholipid syndrome. However, there was no definitive family history. A depressed level of complements and a positive antinuclear acid antibody suggested a diagnosis of systemic lupus erythematosus. The patient had a rapidly progressive course and died of disseminated intravascular coagulation. An autopsy showed generalized thrombotic lesions and diffuse proliferative lupus nephritis on both ordinal light and immunoperoxidase microscopy. Our observations suggest that PS-deficient patients may have a hyperinflammatory response.     

Free protein S deficiency is a risk factor for venous thrombosis

A recent study suggests that protein S deficiency is not a risk factor for venous thrombosis. Since this unexpected finding would have important clinical implications if confirmed, we performed a case-control study with the aim to determine the prevalence of protein S deficiency in patients with thrombosis and in healthy individuals taken from the general population and the relative risk of thrombosis in protein S-deficient patients. Free protein S concentration was measured in 327 consecutive patients with at least one venous thrombotic episode and in 317 age- and sex-matched control individuals. Different normal reference ranges were obtained and adopted for men and women. Protein S deficiency was found in 3.1% (95% CI: 1.5-5.2) of patients and in 1.3% of controls (95% CI: 0.3-2.8). Ten patients and 4 control subjects had protein S deficiency, which determined a relative risk of thrombosis (sex- and age-adjusted odds ratio) of 2.4 (95% CI: 0.8-7.9). When men and women were analyzed separately, the risk was 5.0 (95% CI: 0.6-43.6) and 1.6 (95% CI: 0.4-6.7) respectively. PS-deficient men had more thrombotic episodes than women and later in life. Multivariate analysis established that sex was an independent determinant of the number of episodes, as was age, while PS deficiency was not. However sex and PS deficiency status were both determinants of age at first thrombotic episode.     

New direct assay of free protein S antigen applied to diagnosis of protein S deficiency

Congenital deficiencies of protein S (PS) are associated with thrombophilia. Their characterization and classification have been hampered by the complex physiology of the protein C-protein S system and the poor standardization and reliability of laboratory assays. The free active form of protein S is usually determined by immunoassay using polyclonal antibodies in the plasma supernate after polyethyleneglycol (PEG) precipitation. A new one step ELISA using two monoclonal antibodies specific for distinct epitopes of the free form of protein S has been developed for the direct measurement of free PS in untreated plasma. We have tested two ELISA assays for free PS. One assay was based on the PEG precipitation (Asserachrom PS, Stago, Asnières, France) whereas the other was a one step ELISA assay (Asserachrom free PS, Stago). Values were obtained in 35 PS deficient patients recruited among 500 consecutive patients evaluated by the laboratory for diagnosis of congenital disorders of coagulation. Values were compared to those obtained in 50 patients with no PS deficiency matched for age and sex with the PS deficient patients as well as in 33 normal subjects and in 12 pregnant women. Strong correlation was found between the two tests (r = 0.81, p < 10(-5)) in the entire population (n = 130), as well as in the separate groups. The new one step ELISA was more accurate than the PEG free PS determination. Determination of PS activity and antigens allowed us to separate quantitative and qualitative deficiencies. Among the qualitative deficiencies, isolated decrease in PS activity was the most frequent defect observed (66%). This fact questions the substitution of PS activity assays by the one step antigenic free PS ELISA assay.     

Cerebral sinus thrombosis in a patient with protein S deficiency: a case report

To investigate the role of occupation as a risk factor for hairy cell leukaemia a case-control study on 121 male, hairy cell leukaemia (HCL) patients, and 484 controls matched for age and sex, was conducted. We found significantly elevated risk for HCL among building painters (OR, 5.7; 95% CI, 1.6-20.8; based on six cases and four controls) and construction workers (OR, 3.3; CI, 1.2-9.2; based on seven cases and eight controls). Farming has been suggested as a risk factor in HCL. In this investigation farmers had an OR of 1.2 (CI, 0.6-2.3) and farm workers an OR of 1.5 (CI, 0.8-2.8). However, having ever worked in farming yielded an OR of 1.8 (CI, 1.1-2.9). Having grown up mainly in a rural area gave an OR of 1.4 (CI, 0.9-2.4). UV light has been suggested as a risk factor for non-Hodgkin's lymphoma (NHL). To evaluate the impact of UV exposure, classification of occupations as indoor, outdoor or mixed indoor/outdoor was made. Outdoor and mixed outdoor/indoor work yielded ORs of 2.3 (1.0-4.9) and 1.6 (1.0-2.5), respectively. When the effect of outdoor/indoor or mixed indoor/outdoor work was analysed using a scoring system the OR was 2.0 (CI, 0.9-4.4) for farmers compared with 0.8 (CI, 0.3-1.9) among non-farmers in the highest scoring group. There was no clear correlation between socioeconomic status as defined by the Swedish Socio-Economic Classification (SEI), and the risk of HCL. As many comparisons were made, the possibility of associations occurring by chance can not be excluded.     

Spontaneous coronary artery dissection associated with oral contraceptive use

A 39-year-old woman presented with acute myocardial infarction due to spontaneous dissection of the left anterior descending artery. This was treated conservatively. She had been on combined oral contraceptive pills from the age of 22. Repeat coronary angiography 7 months later revealed spontaneous complete healing.     

Increased thrombosis incidence in a family with an inherited protein S deficiency and a high oxygen affinity hemoglobin variant

Inherited protein S deficiency and the presence of a rare high oxygen affinity hemoglobin variant: Hb Rainier [beta 145 (HC2) Tyr-->Cys] were found in a family. Among 16 studied members, nine were found as carriers of protein S deficiency (type I with decrease of total, free, and activity levels). Six subjects carried the high-affinity hemoglobin variant, which displayed an increase of blood viscosity. Four members combined both abnormalities. Three had thrombotic accidents before the age of 30. We suggest the combination of protein S deficiency and the presence of this hemoglobin variant can lead to a severe primary hypercoagulable state with pathological consequences compared to each genetic defect alone.     

Arterial thrombosis leading to intestinal infarction in a patient with Beh?et's disease associated with protein C deficiency

Beh?et's disease may be a possible cause of both occlusive and aneurysmal arterial involvement as well as recurrent venous thrombosis. A case of Beh?et's disease complicated with vascular involvement leading to intestinal infarction is presented. A 41-yr-old man suffering from Beh?et's disease for 15 yr presented with a 2-day history of severe abdominal pain and bloody diarrhea. Intestinal infarction secondary to thrombosis of the superior mesenteric artery had been diagnosed during surgical exploration 3 yr previously. He was started on anticoagulation with nutritional support. The patient was readmitted with severe diarrhea and malabsorption symptoms 3 yr after intestinal resection. A thrombus located in the posterior wall of the infrarenal portion of aorta was detected by aortography and ultrasonography. Although thrombosis is a relatively common complication of Beh?et's disease caused by vasculitis, protein C deficiency, which is a pertinent laboratory finding in this case, might be a secondary factor in the thrombotic event. This is the first case reported of mesenteric artery thrombosis leading to bowel infarction and abdominal aorta thrombosis associated with protein C deficiency.     

Inhibition of protein S by autoantibodies in patients with acquired protein S deficiency

This study was undertaken to analyze antibodies to protein S (PS) in patients with an acquired PS deficiency. Plasma from symptomatic patients with acquired (n = 14) or congenital (n = 10) PS deficiency and 10 healthy donors was screened for PS antibodies by immunoblotting and for anti-phospholipid antibodies. PS antibodies (IgG) were detected in five of the patients with acquired PS deficiency. These antibodies belonged to the G1 and G4 immunoglobulin subclasses. IgG fractions from the same 5 patients were shown to inhibit PS activity. The inhibition of PS activity by the 5 IgG fractions was shown to be time- and dose-dependent and was abolished following incubation with purified PS, while no effect was found after absorption with cardiolipin micelles. In addition, anticardiolipin monoclonal or human purified antibodies, failed to exert significant PS inhibition. These findings demonstrate that anti-PS antibodies are able to inhibit PS activity and that this is independent of anti-phospholipid antibodies. Given the clinical features of the patients, these antibodies should be regarded as an expression of the broad autoimmune syndrome involving the phospholipid-binding plasma proteins.     

Progressive intracranial occlusive disease associated with deficiency of protein S. Report of two cases

BACKGROUND AND PURPOSE: Deficiency of the free fraction of protein S has been associated with arterial or venous stroke. The pathogenesis of vascular occlusion in patients with protein S deficiency is not known. We present two cases of cerebral infarction and deficiency of protein S in which the subjects had progressive intracranial occlusions. CASE DESCRIPTION: A 16-year-old girl was admitted because of left brain stem infarction and protein S deficiency. Cerebral angiography disclosed stenosis of the right intracranial vertebral artery and occlusion of the left posterior cerebral artery. A second angiogram performed 18 months later disclosed occlusion of the right vertebral intracranial artery. In the second case, a 17-year-old girl was admitted because of left hemispheric cerebral infarction and protein S deficiency. Cerebral angiography showed stenosis of the left anterior cerebral artery, left supraclinoid internal artery, and left middle cerebral artery. A second cerebral angiogram performed 5 months later disclosed occlusion of the left anterior cerebral artery and poor hemispheric perfusion through the left middle cerebral artery. CONCLUSIONS: Based on our cases, we postulate that some patients with prothrombotic states may develop progressive intracranial arterial occlusions, possibly secondary to a permanent thrombogenic stimulus. We suggest routinely searching for prothrombotic states in young patients with intracranial occlusion, especially if the occlusion is progressive and other causes are not obvious.     

Coagulation activation and fibrinolytic imbalance in subjects with idiopathic antiphospholipid antibodies--a crucial role for acquired free protein S deficiency

To explore the coagulation/fibrinolytic balance and its relation with free protein S (f-PS) in subjects with antiphospholipid antibodies (aPLs) outside the setting of autoimmune inflammatory disorders, we carried out a cross-sectional study on 18 thrombotic patients with primary antiphospholipid syndrome and 18 apparently healthy subjects with persistence of idiopathic aPLs. Prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT) and D-Dimer (D-D) were taken as markers of thrombin generation and fibrin turnover. Mean F1 + 2 levels were higher in thrombotic (p = 0.006) and non-thrombotic subjects (p = 0.0001) than in controls as were those of D-D (p < 0.0001 and p = 0.003 respectively). TAT levels did not differ. Lower mean levels of f-PS were found in thrombotic (p = 0.0006) and non-thrombotic subjects (p = 0.002) than in controls. Within both groups, mean F1 + 2 levels were higher in subjects who had low f-PS levels compared to those with normal f-PS levels (p = 0.01). Gender analysed data revealed blunted tPA release (venous occlusion test) in thrombotic females (from 16.80 +/- 0.79 to 21.3 +/- 3.9 ng/nl, NS) but not in thrombotic males (from 18.2 +/- 2.0 to 33.7 +/- 4.9 ng/ml, p=0.01) nor in asymptomatic subjects of either sex. Also, in both patient groups females had higher mean PAI than males (p < 0.0002) and than control females (p < 0.02). Low free protein S was found in 100% of non-thrombotic and in 90% of thrombotic patients with defective fibrinolysis. These data are consistent with increased thrombin generation, accelerated fibrin turnover and fibrinolysis abnormalities also in asymptomatic carriers of aPLs and highlight a central role for acquired f-PS deficiency in the thrombotic tendency of the antiphospholipid syndrome.     

Spontaneous thrombosis of a basilar artery traumatic aneurysm in a child

Traumatic aneurysms are rare and occur most commonly in young adults; however, the relative frequency in the pediatric population is high, owing to the low prevalence of congenital saccular aneurysms in children. Traumatic aneurysms typically involve the anterior circulation, and spontaneous thrombosis is uncommon; hence, surgery is usually necessary. We present a case of a posttraumatic aneurysm in a child that occurred after a fall from a large height and that spontaneously thrombosed.