Association of inherited dysfibrinogenaemia and protein C deficiency in two unrelated families

Summary An inherited association of dysfibrinogenaemia and protein C deficiency was found in three members of the same family. The propositus was a 48-year-old man who suffered from severe and rapidly complicated atherosclerosis of the aorta and lower limbs arteries, which perhaps suggests that the association of these two molecular abnormalities may have enhanced the thrombotic process. The abnormal fibrinogen had a reduced ability to bind thrombin which may be thrombogenic. We found the same inherited association of dysfibrinogenaemia and protein C deficiency in a patient with venous thrombosis. The functional abnormality of the fibrinogen, which could have been responsible for thrombosis, was delayed proteolysis by plasmin. Not only fibrinogen, but also fibrin clots were resistant to plasmic degradation. These observations raise two questions: (1) Is the association of a protein C deficiency with a dysfibrinogenaemia fortuitous or the result of a common mechanism? (2) Is there a link between an increased thrombotic tendency and either both of the defects of haemostasis that we have found, or only one of them?     

Familial dysalbuminaemic hyperthyroxinaemia and inherited partial TBG deficiency: first report

BACKGROUND Abnormalities of the serum thyroid hormone binding proteins are not uncommon but, when properly asessed, they do not present diagnostic difficulties. In contrast, the presence of two inherited defects of thyroid hormone transport, of the type presented in the family described here, may cause a major problem in diagnosis and has not been described previously. METHODS All conventional thyroid function tests were carried out. In addition, thyroid hormone binding to serum proteins was assessed by agarose gel electrophoresis, and thyroxine binding globulin by immunoassays and by immunodiffusion. The affinity of TBG for thyroxine and its maximal binding capacity were assessed by Scatchard analysis. RESULTS Tests carried out on 22 members of the family revealed familial dysalbuminaemic hyperthyroxinaemia in 10 family subjects. All five living siblings of the propositus had familial dysalbuminaemic hyperthyroxinaemia and two tested transmitted this trait to their children and grandchildren. This was not the case with the propositus. Partial thyroxine binding globulin deficiency only, inherited presumably from the propositus' mother, was found in two family members. Both thyroxine binding globulin deficiency and familial dysalbuminaemic hyperthyroxinaemia were detected in the propositus and in his male nephew, masking the typical laboratory abnormalities associated with each of these defects. CONCLUSIONS Coexistence of two inherited defects of thyroid hormone transport proteins produce atypical thyroid function test abnormalities, which can be misinterpreted as thyroid hormone dysfunction.     

Complement factor 2 deficiency: a clinical and serological family study.

Inherited complement deficiencies are associated with a variety of connective tissue diseases. A family with inherited deficiency of complement factor 2 (C2) is described in which two family members with homozygous C2 deficiency developed cutaneous vasculitis and sicca syndrome. The other family members had heterozygous C2 deficiency and each member had the HLA-A25, B18, DR2 (w15) haplotype. The mother had seropositive rheumatoid arthritis. Further studies showed the presence of cryoglobulins, antibodies against endothelial cells, and anticardiolipin antibodies.     

Pathogenetic factors underlying juvenile deep vein thrombosis (DVT) in Indians.

The role of hereditary antithrombotic protein defects in juvenile deep vein thrombosis (DVT) was evaluated. Fifty six young patients (age <45 yr) with doppler-proven DVT were investigated for the presence of resistance to activated protein C (APC-R), lupus anticoagulant (LA), anticardiolipin antibodies and deficiencies of protein C, protein S, ATIII activities. Fifty nine normal healthy individuals served as controls. APC-R was observed to be the commonest defect underlying the Indian DVT as seen in 39.2% of patients followed by elevated ACA (5.3%), PAI (2.8%), presence of LA (2.8%) and reduced ATIII levels (2.8%). None of the subjects had protein C or S deficiency. APC-R was associated with ATIII deficiency in one case, and elevated ACA in two cases. In two subjects, APC-R was associated with elevated PAI levels. Patients with more than one prothrombotic factor had a higher prevalence of pulmonary thromboembolism, suggesting that the thrombogenic potential of APC-R is enhanced by the presence of coexisting hereditary or acquired prothrombotic defect.     

Factor V Leiden and prothrombin gene mutation may predispose to paradoxical embolism in subjects with patent foramen ovale.

The role of paradoxical embolism through patent foramen ovale as a mechanism of cryptogenic stroke is controversial. If a venous source of emboli is relevant, prothrombotic states should be associated with patent foramen ovale and cryptogenic stroke. We assessed the occurrence of several prothrombotic states (factor V Leiden, prothrombin G20210A, deficiencies in protein S, protein C and antithrombin, lupus anticoagulant, anticardiolipin antibodies, elevated factor VIII, resistance to activated protein C) and classical risk factors for venous thrombosis in 57 adult patients with cryptogenic stroke and patent foramen ovale and in 104 matched controls. Prothrombotic states [odds ratio (OR) 2.8; 95% confidence interval (CI), 1.2-6.5; P = 0.021], migraine with aura (OR 4.4; 95% CI 1.8-10.8; P = 0.001) and classical risk factors for venous thrombosis (OR 2.5; 95% CI 1.1-5.7; P = 0.037) were independent risk factors for cryptogenic stroke. In particular factor V Leiden or prothrombin G20210A associated with cryptogenic stroke (P = 0.022) whereas other coagulation abnormalities did not (P = 0.140). Among the patients with prothrombotic states, Valsalva manoeuvre was common at onset of stroke. Our results support the possibility of paradoxical embolism behind strokes in patients with patent foramen ovale.     

Prevalence of inherited prothrombotic abnormalities and central venous catheter-related thrombosis in haematopoietic stem cell transplants recipients

In this prospective study, we assessed the incidence of central venous catheter (CVC)-related thrombosis in haematopoietic stem cell transplant (HSCT) recipients. We determined the contribution of inherited prothrombotic abnormalities in blood coagulation to CVC-related thrombosis in these patients. The study was conducted between May 2002 and September 2004. CVCs were externalized, nontunneled, polyurethane double lumen catheters. Before catheter insertion, laboratory prothrombotic markers included factor V Leiden, the prothrombin gene Gly20210A mutation, plasma antithrombin levels, and protein C and S activity. All patients were systematically examined by ultrasonography just before, or <24 h after, catheter removal, and in case of clinical signs of thrombosis. A total of 171 patients were included during the 28-month study period. Five (2.9%) and three (1.7%) patients had evidence of protein C and protein S deficiency, respectively. Only one patient had an antithrombin deficiency (0.6%). In total, 10 patients (5.8%) were heterozygous for the factor V Leiden mutation, and one patient had heterozygous prothrombin G20210A mutation (0.6%). We observed a CVC-related thrombosis in 13 patients (7.6%). Thrombosis was diagnosed in four out of 20 patients (20%) with a inherited prothrombotic abnormality compared to nine of 151 patients (6%) who did not have a thrombophilic marker (relative risk 3.3 CI 95% 1.1-9.9). Our results suggest that inherited prothrombotic abnormalities contribute substantially to CVC-related thrombosis in HSCT recipients. In view of physicians' reluctance to prescribe prophylactic anticoagulant treatment in these patients, a priori determination of inherited prothrombotic abnormalities may form a basis to guide these treatment decisions.     

Prevalence of inherited thrombophilia in young thrombosis patients from the East Bohemian region.

Venous thromboembolism is a multifactorial disease that is defined by multiple interactions between genetic and environmental components. Inherited thrombophilia may result in a hypercoagulable state that causes an increased tendency to thrombosis. We assessed the prevalence of factor V Leiden, factor II 20210A, antithrombin III, protein C and protein S deficiency, and the presence of antiphospholipid syndrome among 325 thrombosis patients from the East Bohemian region with a first episode of thrombosis under the age of 45 years. The average age of the first thrombotic event was 34 years (age range, 14-45 years). These data are not known yet from this part of the Czech Republic. Factor V Leiden was found in 40%, factor II 20210A in 6%, antithrombin III deficiency in 4%, protein C deficiency in 6%, and protein S deficiency in 11% in this cohort. Lupus anticoagulant was detected in 8% and anticardiolipin antibodies in 6%. Our results confirm the usefulness of thrombophilia work-up in patients with venous thrombosis before the age of 45 years in our region. The diagnosis of inherited thrombophilia is important for further management of these patients.     

Risk factors for thrombosis in nonembolic cerebrovascular disease

Thirty-seven young patients (less than 42 years of age) presenting with sudden onset of idiopathic nonembolic cerebrovascular disease were evaluated for underlying prothrombotic factors. Activated protein C resistance (APC-R) was measured by Dahlback's method and the modified method using factor V-deficient plasma. Activities of antithrombin (AT) III, protein C and S were measured. Anticardiolipin antibody was estimated by ELISA and lupus anticoagulant by kaolin clotting tests. APC-R was the most common defect (21.62%) followed by AT III deficiency and presence of anticardiolipin antibodies (5.6% each). The latter two were present together in one case. It is thus concluded that APC-R is the most common defect underlying idiopathic nonembolic cerebrovascular infarction in young individuals.     

Cerebral-vein thrombosis: retrospective study of twenty seven cases

PURPOSE: Among the locations of venous thrombosis, even if rare, cerebral-vein thrombosis is a severe event with a high mortality rate. No aetiology is found in 20 to 30% of the cases. In recent years, inherited coagulation disorders have been described, as risk factors for venous thrombosis. We report the results of a retrospective study of 27 patients who suffered cerebral-vein thrombosis, in which coagulation abnormalities have been searched for. METHOD: The patients were referred to the haemostasis laboratory of the Henri Mondor hospital between august 1982 and June 1988, after a cerebral-vein thrombosis. The predisposing factors, personal and family history of thromboembolism, clinical presentation, thrombosis location, evolution under treatment and long-term outcome, have been noted. Deficiencies in antithrombine, protein C, protein S, the Factor V Leiden and the G20210A prothrombin-gene mutation, the presence of lupus anticoagulant, of anticardiolipin antibodies as well as a hyperhomocysteinaemia have been searched, either at the initial presentation, or a posteriori. RESULTS: Fourty-one percent of patients had a coagulation abnormality. The prevalence of the different abnormalities was: inherited deficiency in AT 7.4%, in PC 8%, in PS 12.5%, factor V Leiden mutation 12%, G20210A prothrombin-gene mutation 12%. Two patients had combined defects: AT and PC deficiency in one, F V Leiden and F II G20210A mutations in one. e of the patient had lupus anticoagulant. Three patients had a significant rate of anticardiolipin antibodies. Five patients out of eight displayed a moderate hyperhomocysteinaemia. Nothing (past history, age, predisposing factors) distinguished those patients bearing a coagulation disorder from the others. The venous thromboembolic relapse rate of 15 % (4/27 patients). Three of them had an inherited thrombophilic abnormality. CONCLUSION: We recommend an investigation of the haemostasis after every cerebral venous thrombosis.     

Possible homozygous factor VIIR disorder associated with fibrinolytic hyperactivity

A family with inherited factor VII deficiency is described. The propositus is a 9-year-old girl with chronic haemorrhagic history of epistaxis and bleeding after tooth extractions. Her factor VII coagulant activity was less than 3% using rabbit thromboplastin. She had a factor VII antigen level of 50%. Both parents were heterozygous for factor VII deficiency. The father had procoagulant factor VII (VII-C) of 44% and factor VII antigen (VII-Ag) of 74%, and the mother had 54% of factor VII-C and 85% of VII-Ag. Her only brother had normal levels of factor VII-C (100%). Additionally, some abnormalities in the fibrinolytic system were detected both in the propositus and her brother with shortened euglobulin lysis times and increased functional levels of plasminogen activator. To our knowledge, the clinical association of inherited factor VII deficiency and familial fibrinolytic disturbances has not been described so far.     

Patent foramen ovale and prothrombotic markers in young stroke patients.

Patent foramen ovale (PFO) is more frequent in cryptogenic stroke patients than in the general population. The aim of this study was to determine prothrombotic markers regarding PFO in young cryptogenic stroke patients. We prospectively included consecutive cryptogenic stroke patients younger than 55 years. PFO was diagnosed with simultaneous transcranial Doppler and transesophageal echocardiography. We analyzed the following prothrombotic markers: antiphospholipid antibodies (APS), protein C and protein S deficiencies, factor V Leiden FVG1691A, prothrombin gene mutation PTG20210A and coagulation factor XII mutation FXIIC46T. From June 2005 to July 2006 we studied 39 patients, mean age 44.7 +/- 8.6 years, 48.7% men. PFO was detected in 17 patients (43.6%). We found no differences between PFO and non-PFO patients regarding prothrombotic markers: APS (P = 0.851), protein S deficiency (P = 0.851), protein C deficiency (P = 0.249), FVG1691A (P = 0.202), PTG20210A (P = 0.401) or FXIIC46T (P = 0.966). Female gender was the only variable related to prothrombotic markers, independent of PFO (P = 0.001). The only prothrombotic marker related to PFO size (large PFO) was APS (P = 0.043). Large PFO were also related to deep venous thrombosis (P = 0.040) and atrial septal aneurysm (P = 0.010). PFO patients do not present more prothrombotic markers than non-PFO patients, but APS are more frequent in large PFO.     

The occurrence of systemic lupus erythematosus in two kindreds in association with selective IGA deficiency.

The families of two patients with SLE and IgA deficiency were examined. A study of the first patient's family revealed that IgA deficiency was determined by an incompletely penetrant autosomal dominant gene not linked to the HLA locus. Antinuclear antibodies, found in consanguineous and nonconsanguineous relatives were not related to the presence of IgA deficiency or any HLA haplotype. The second patient and his father with antinuclear, anti RBC, and antithyroid auto-antibodies shared an HLA haplotype not present in other sibs. IgA deficiency was not inherited in this family but may have influenced the expression of disease in the propositus or could have resulted from the disease itself.     

Pulmonary embolism and transitory anti-beta2-GPI antibodies in an adult with chicken pox

Anti-beta2-glycoprotein I antibodies are considered as a specific marker for the antiphospholipid syndrome. In contrast to lupus circulating anticoagulant and anticardiolipin (aCL) antibodies, they are usually not found at significant levels in infections. We report a case of pulmonary embolism in an adult with varicella. Transient significant levels of aCL antibodies and of IgM anti-beta2-GPI antibodies were observed. No other prothrombotic factor, including free protein S antigen deficiency, was found. The direct pathogenic role of these transient antibodies on the thrombotic event may then be suspected. They are probably associated with VZV acute infection and are absent two months after varicella.     

Anticoagulant proteins in childhood venous and arterial thrombosis: a review

Thrombotic disease is less frequent in children than in adults, but may result in severe morbidity and mortality. The coagulation system is balanced to provide rapid activation to stop bleeding and appropriate inhibition to prevent unwanted clot extension. It is regulated by fibrinolysis and by three major anticoagulant pathways: the protein C, antithrombin, and tissue factor pathway inhibitor systems. Acquired or inherited abnormalities of coagulation proteins or hemostatic regulatory mechanisms, particularly when combined with dehydration or the presence of indwelling catheters, may pose a high risk for thrombosis. Thrombosis in a child warrants investigation of potential underlying prothrombotic conditions. These include acquired antiphospholipid antibodies or the lupus anticoagulant as well as abnormalities of the inherited anticoagulant factors including protein C, protein S, antithrombin, and Factor V Leiden. Other abnormalities may result in heightened levels of otherwise normal coagulation proteins such as hyperprothrombinemia due to the prothrombin 20210 mutation. A large survey of children with thrombosis indicated that Factor V Leiden, protein C deficiency, and increased lipoprotein(a) were found most commonly. The most severe predisposition occurs with homozygous protein S or protein C deficiency with resultant purpura fulminans in the newborn. The risk of thrombosis in children with heterozygous deficiencies of anticoagulant proteins is not well defined, although it is clear that combined heterozygotes or a combination of an inherited and an acquired defect heightens the risk for thrombosis. Treatment of thrombosis primarily involves a rapidly acting anticoagulant such as heparin or low-molecular-weight heparin to prevent extension, and long-term anticoagulation with warfarin may be instituted to prevent recurrence. Fibrinolytic therapy is infrequently used because of the risk of serious bleeding complications and is reserved for selected cases of arterial thrombosis to initiate rapid reperfusion of ischemic tissue or used in those patients with a large venous thrombosis and pulmonary emboli causing hemodynamic compromise.     

Intra-cardial thrombosis with systemic and pulmonary embolism as main symptoms in a patient with protein S deficiency.

This report describes the unusual occurrence of both left and right atrial thrombosis with peripheral arterial and pulmonary embolism, respectively, as presenting symptoms of congenital protein S deficiency in a 31-year-old man. The coagulation study performed in the coumarin-treated propositus indicated a heterozygous protein S state. The finding of reduced free protein S antigen and protein S activity levels with normal total protein S and C4B-bp levels in five other family members (father, sister, and three relatives on the paternal side) confirmed the inherited nature of the defect. Since there is an increased frequency of arterial thrombosis in patients suffering from protein S deficiency, any case of idiopathic intra-cardial thrombosis requires careful haemostatic screening. In addition, the possibility of intra-cardial thrombosis should be considered in any thromboembolic event seen in inherited protein S deficiency.     

Hypercoagulability states in upper-extremity deep venous thrombosis

Deep venous thrombosis of the upper extremity (DVTUE) is a rare thrombotic disorder that may occur spontaneously but is most often related to predisposing factors, such as an indwelling central venous catheter, malignancy, or exercise. The role of coagulation disorders, i.e., a hypercoagulable state in the pathogenesis of DVTUE is not well known. We have evaluated both genetic and acquired thrombophilia parameters in consecutive patients with DVTUE. A hypercoagulable state was found in 32% of the patients. The most frequent coagulation abnormality was the presence of lupus anticoagulant or anticardiolipin antibodies (27%). Factor V Leiden mutation was detected in two patients, antithrombin deficiency in one, and none of the patients had the prothrombin G20210A gene variant or protein C or S deficiency. The prevalence of coagulation abnormalities was not significantly different in a subgroup of patients with spontaneous DVTUE as compared to those with an obvious predisposing factor, such as an indwelling central venous catheter. We conclude that antiphospholipid antibodies are frequently found in patients with DVTUE. Factor V Leiden mutation, prothrombin 20210A gene variant, protein C deficiency, and protein S deficiency do not seem to play a major pathogenetic role in DVTUE.     

Plasma protein S deficiency in familial thrombotic disease

A family with a history of severe recurrent venous thromboembolic disease was studied to determine if a plasma protein deficiency could account for observed disease. Protein S levels in plasma were determined immunologically using the Laurell rocket technique. The propositus, his mother, his aunt, and his cousin who were clinically affected had 17% to 65% of the control levels of protein S antigen (normal range, 71% to 147%). Since three of these patients were receiving oral anticoagulant therapy, the ratios of protein S to prothrombin, factor X, and protein C in these patients were compared with values for a group of orally anticoagulated controls. These results suggested that protein S is half-normal in all family members with thrombotic disease. Other proteins known to be associated with familial thrombotic disease, including antithrombin III, plasminogen, fibrinogen, and protein C, were normal. Because plasma protein S serves as a cofactor for the anticoagulant activity of activated protein C and because protein C deficiency is associated with recurrent thrombotic disease, it is suggested that recurrent thrombotic disease in this family is the result of an inherited deficiency of protein S.     

A new case of ''type II'' inherited protein S deficiency

Protein S inherited deficiency is associated with high risk of recurrent venous thrombotic disease (Broekmans et al, 1985a, b). Protein S exists as two forms in plasma, either free and functionally active or complexed with C4b-binding protein (C4b BP) and inactive (Dahibäck & Stenflo, 1981). We report here the case of a 26-year-old woman and her brother, 28 years old, both suffering from recurrent venous thrombosis since the age of 20, diagnosed as severe protein S deficiency according to the following data: free protein S: 2.5–3% by ELISA, undetectable by electroimmunodiffusion (BID); total protein S: 13–16% by ELISA, 21–18% by EID, C4b BP: normal levels. Crossed immunoelectrophoresis using anti-protein S antibodies revealed only traces of protein S associated with C4b BP and no free protein S. All these assays were performed in the absence of any anticoagulant therapy. Among the investigated relatives, less severe protein S deficiency was observed in three children of the propositus: total protein S levels ranging from 41% to 50% (EID), 40–53% (ELISA); free protein S levels ranging from 16% to 18% (EID), 10–12% (ELISA); normal C4b BP levels. Crossed immunoelectrophoresis revealed traces of free protein S but a significant amount of protein S associated with C4b BP. From these results, we consider, according to Comp's classification (Comp et al, 1986a), that the propositus and her brother are the second case of protein S deficiency type II to be reported in the literature while her children belong to the type I category.     

Glucose 6-phosphate dehydrogenase deficiency and red cell membrane defects: additive or synergistic interaction in producing chronic haemolytic anaemia

Summary. We have investigated two unrelated patients with congenital haemolytic anaemia in both of whom we found a combination of hereditary spherocytosis (HS) and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Segregation of the two defects was documented in both families, who had different molecular abnormalities for both HS and G6PD deficiency. In one family the propositus had a reduced level of spectrin and G6PD Seattle (282Asp His). In the other family the propositus had a band 3 abnormality and was heterozygous for G6PD Mediterranean (188Ser Phe). From a comparison of clinical and haematological findings in family members with either or both abnormalities we conclude that in one case the two defects exhibited a synergistic effect, resulting in a severe chronic haemolytic anaemia; whereas in the other the association was simply additive.     

Acquired protein C deficiency in a patient with primary antiphospholipid syndrome. Relationship to reactivity of anticardiolipin antibody with thrombomodulin

A 16-year-old boy had recurrent venous thromboses and pulmonary thromboembolism that caused him pulmonary hypertension. He also had livedo reticularis, thrombocytopenia and high titer IgG antiphospholipid (cardiolipin) antibodies. In the absence of clinical and laboratory evidence of SLE, he was considered to have a primary antiphospholipid syndrome. Coagulation studies revealed a functional deficiency of protein C although it was present in normal antigenic amounts. Since both his parents had normal functional and antigenic protein C findings, his deficiency was considered acquired. The reactivity of the anticardiolipin antibodies could be decreased in a dose dependent fashion when preincubated with increasing amounts of thrombomodulin, a protein required for protein C activation at the endothelial cell membrane. This interaction of antiphospholipid antibodies with thrombomodulin may help explain the occurrence of thrombosis in some patients with antiphospholipid antibodies, despite the behavior in vitro of these antibodies as circulating anticoagulants.