Thrombosis in congenital deficiencies of AT III, protein C or protein S: a study of 44 children

Abstract. Congenital deficiency in coagulation inhibitors is a cause of hereditary thrombotic disease. The severity of symptoms is variable and depends on the type of deficit. In this paper, 44 children suffering from deep venous thrombosis, with a mean age of 5 years, were studied. A search for Lupus anticoagulant (LA) and coagulation inhibitor deficiency showed: 3/44 cases (6.8%) had protein S deficiency, 2/44 cases (4.5%) had protein C deficiency, 1/44 cases (2.3%) had deficiencies in both protein C and S; no cases of AT III deficiency and LA was positive in 2/44 cases (4.5%). Only 1 case of APC resistance out of 13 studied was found. Four family studies were performed and confirmed the congenital origin of the disorder.     

Further evidence that activated protein C resistance can be misdiagnosed as inherited functional protein S deficiency

Summary. A recent report that activated protein C (APC) resistance interferes with functional protein S (PS) assays prompted us to re-investigate two pedigrees previously diagnosed as having functional PS deficiency. APC resistance was demonstrated in all individuals with apparent functional PS deficiency. The latter diagnosis was shown to be due to the assay being non-linear, functional protein S becoming normal at higher dilutions. This observation, taken in conjunction with results of in vitro recovery studies with purified PS, leads us to conclude that APC resistance was the primary disorder in both pedigrees. The misdiagnosis of APC resistance as functional PS deficiency can be prevented by performing the PS assay at several dilutions, including concentrations lower than those recommended by PS assay manufacturers. Subjects previously diagnosed as having functional PS deficiency should be re-investigated for APC resistance.     

Roles of protein C, protein S, and antithrombin III in acute leukemia

Protein C, protein S, and antithrombin III were measured in 35 patients with acute leukemia (13 with AML and 22 with ALL). Low levels of proteins C and S were present in 15 (42.9%) and 20 (57.1%) patients, respectively, and 6 patients had low levels of antithrombin (ATIII). Seven patients also had DIC at presentation. There were no significant differences in the levels of protein C, protein S, and ATIII in patients with or without DIC. Twenty patients were available for re-evaluation at the end of induction therapy. The low levels of protein C and ATIII found at diagnosis had risen to normal levels at the end of the induction therapy, while low =levels of protein S remained in 75% of the patients. One patient with low protein C at presentation developed myocardial infarction on day 15, and another patient died of progressive neuropathy. No other thrombotic manifestations were seen. Whether the low protein C, protein S, or antithrombin levels predispose patients with acute leukemia to thrombosis in the absence of DIC is not known.     

Inferior vena cava thrombosis in a child with nephroblastoma and combined deficiency of antithrombin III and free protein S

Summary A 31/2-year-old girl developed thrombosis of the inferior caval and renal veins several weeks after complete resection of a nephroblastoma. Her mother had suffered from pulmonary embolism at the age of 18 years. Familial antithrombin III deficiency and persistently lowered free protein S levels in the proposita were found. It is assumed that the combination of these two regulatory defects of hemostasis contributed to the early occurrence of this severe thrombotic event.     

Resistance to activated protein C in unselected patients with arterial and venous thrombosis

Four hundred and ninety-three consecutive patients referred for arterial or venous thrombosis were screened for congenital and acquired abnormalities of blood coagulation predisposing to thrombosis, and were compared to 341 age- and sex-matched controls. The aim of the study was to determine the prevalence and clinical characteristics of resistance to activated protein C (APC), a defect shown to have different prevalences in different ethnic groups and to be associated with an increased risk of thrombosis. Seventy-three (15%) patients had both APC resistance and the 1691 G to A Factor V gene mutation, compared to 6/341 (2%) controls. Seven patients had antithrombin deficiency (1.4%), 11 had protein C deficiency (2.2%), and 4 had protein S deficiency (0.8%). The relative risk of thrombosis in APC-resistant patients was 9.4. Resistance to APC was associated mainly with venous thrombosis, the most frequent being deep-vein thrombosis of the lower limbs. Fifty-eight percent of APC-resistant patients had an associated risk factor at the first thrombotic event: pregnancy and oral contraceptive intake were associated with the first thrombotic episode in 35% and 30% of women, respectively. APC resistance is the most frequent defect of blood coagulation in the general population and in the unselected thrombotic population studied by us. Am. J. Hematol. 55:59-64, 1997. © 1997 Wiley-Liss, Inc.     

Protein C, protein S and von Willebrand factor levels correlate with bleeding symptoms: a population-based study

Although natural anticoagulant deficiencies are the established causes of thrombosis, their roles in bleeding are not fully studied. The objective is to correlate haemostatic factors with haemorrhagic symptoms quantified by a standardized questionnaire. Adult subjects were recruited from Bangkok and nearby provinces as part of routine health surveys/checkups. The validated MCMDM-1VWD form was used to assess their bleeding symptoms. At the same time, von Willebrand factor (VWF) activity, free protein S levels and protein C activity were measured. There were 5196 individuals. The mean age was 44.3 years (range 15-99) and 41% were male subjects. The mean bleeding score was -0.28 and 95% of subjects had scores between -2 and +2. The scores were lower in female subjects than in male subjects (-0.35 vs. -0.16, P < 0.001). Bleeding scores correlated negatively with age, VWF and protein C activities (Spearman's ρ-0.258, -0.091 and -0.098, respectively, all P < 0.001), but did not significantly correlate with protein S levels. Using multivariate analysis, female gender, VWF below 100 IU dL(-1), protein C below 100 IU dL(-1) and protein S over 150 IU dL(-1) significantly related to high (≥3) bleeding scores (adjusted odds ratio 1.95, 1.83, 1.56 and 2.84, P = 0.001, 0.001, 0.039 and 0.017, respectively). These findings may suggest interacting roles of VWF and natural anticoagulants in modifying bleeding symptoms.     

A young adult with coronary artery and jugular vein thrombosis: a case report of combined protein S and protein C deficiency

Protein C and protein S deficiencies increase the risk of thromboembolic events. We report a case of combined protein C and S deficiency in a young woman, with resulted in acute myocardial infarction and asymptomatic jugular vein thrombosis. The patient was treated successfully with coronary artery bypass graft surgery and systemic anticoagulation. Our report emphasizes that a combined deficiency of protein C and S may be a high risk factor for arterial thromboembolic events in young adults.     

Extrahepatic portal vein thrombosis in children and adolescents: Influence of genetic thrombophilic disorders

AIM:To explore the prevalence of local and genetic thrombophilic disorders as risk factors for portal vein thrombosis (PVT) in our series,the largest ever published in pediatric literature. METHODS:We conducted a case-control study enrolling 31 children with PVT and 26 age-matched controls. All were screened for thrombophilia,including genetic disorders,protein C,protein S and homocysteine deficiencies. All coagulation parameters were studied at least 3 mo after the diagnosis of portal vein obstruction.RESULTS:In our study we showed that most pediatric patients with PVT have local prothrombotic risk factors,which are probably the most important factors leading to PVT. However,there is a clear association between the presence of prothrombotic disorders and PVT,suggesting that these increase the risk of thrombosis in patients with local factors such as perinatal umbilical vein catheterization or sepsis. CONCLUSION:Patients with PVT should be screened for inherited prothrombotic disorders regardless of a history of an obvious local risk factor.     

蛋白C、蛋白S缺乏与肺血栓栓塞症的相关性研究进展

肺血栓栓塞症临床症状不典型,使其诊断困难,漏诊率、误诊率及病死率高,掌握高危因素对提高诊断率及合理治疗具有重要意义.对于复发性、家族性肺血栓栓塞症患者,可能存在遗传性高危因素.蛋白C、蛋白S属蛋白C系统,具有抗凝作用,其缺乏是肺血栓栓塞症的重要遗传性危险因素.掌握蛋白C、蛋白S缺乏与肺血栓栓塞症的相关性对于指导合理治疗、降低复发率及病死率具有重要意义.     

静脉血栓形成患者部分抗凝物质的变化及临床意义

目的探讨静脉血栓形成患者生理性和病理性抗凝物质的变化及其临床意义。方法采用发色底物法和血浆蝰蛇毒时间法分别检测34例静脉血栓形成患者及30例正常对照人群的血浆抗凝血酶活性(AT:A)、蛋白C活性(PC:A)和狼疮样抗凝物质比值(LAC),评价静脉血栓形成组抗凝蛋白缺陷发生情况。结果静脉血栓形成患者AT:A低于对照组(P<0.01),LAC高于对照组(P<0.01),而PC:A无显著性差异;34例静脉血栓形成患者中共有17例患者存在有生理性抗凝蛋白缺陷,其中AT缺陷占44.1%,PC缺陷占2.9%,复合缺陷占2.9%。结论静脉血栓形成可导致抗凝血酶活性下降,狼疮样抗凝物质增多是导致静脉血栓形成的因素之一。     

Inherited protein C deficiency,protein S deficiency and hyperhomocysteineaemia in a patient with hereditary spherocytosis

We report a family with hereditary spherocytosis in whom there is, in addition, a cluster of genetic predispositions to thrombosis. Although inherited prothrombotic abnormalities are prevalent in the general population, the likelihood of this combination of abnormalities being found in a single family is extremely low. The management of such high risk individuals is discussed.     

The relation of protein C and protein S levels with cardiovascular risk in patients with diabetic neuropathy

BackgroundThis study was conducted to determine the clinically significance of protein C and protein S levels as a cardiovascular risk marker in patients with diabetic neuropathy.MethodsWe included 71 subjects. 50 of them were diabetics, 27 of them also had diabetic neuropathy(DN), 21 subjects were non diabetic. We evaluated these 3 group subjects’ protein C, protein S, fibrinogen, prothrombine time (PT), activated partial thromboplastine time (aPTT), total cholesterol, levels and Framingham Coronary Risk Score (FCRS).ResultsNon diabetic group’s protein C levels were higher than patients with DN (p < 0.05) and diabetic patients without DN (p < 0.05). But there were no difference in terms of protein C levels between patients with DN and diabetic patients without DN. FCRS of control group was lower than diabetic subjects(p < 0.01).ConclusionsWe found that protein C and S levels were much lower in diabetic patients than non diabetics.There was no difference between diabetic patients with DN and diabetic patients without DN in terms of protein C and protein S levels. Further, we couldn’t detect any finding that we can say protein C and Protein S levels can be used as a cardiovascular risk assessment marker in diabetic neuropathic patients.     

Mesenteric artery thrombosis: A case report of combined protein S and protein C deficiency

Individuals with more than one defect in natural coagulant/anticoagulant systems have been postulated to be at an increased risk for thrombotic events. We report a case of combined protein S and C deficiency in a young woman, which resulted in fatal arterial mesenteric thrombosis. The role of coagulation defects in arterial thrombosis is discussed. Am. J. Hematol. 58:246–247, 1998. © 1998 Wiley-Liss, Inc.     

Associated von Willebrand disease as a possible cause of lack of thrombosis in an AT III abnormality (AT III Trento)

Summary In a family with a known antithrombin III abnormality (AT III Trento) an associated von Willebrand defect (Type I) was found. The two defects seem to segregate independently. In fact four types of individuals were present, namely: subjects with isolated AT III abnormality, subjects with isolated von Willebrand defect, patients with double defect and normal subjects. Only one of the two patients with isolated AT III abnormality showed a thrombotic tendency. None of the patients with double defect showed thrombotic disease, indicating a possible protective action of the von Willebrand defect against thrombotic manifestations. Patients with isolated von Willebrand defect showed neither thrombotic nor bleeding manifestations. The study emphasizes the need for a careful evaluation of the hemostatic balance of patients with AT III abnormalities before concluding that they are symptomatic or asymptomatic.This study was supported by Grants from the CNR (Grant 84.02363.56 II 5.01677), from the M. P. I. Rome (Grant 1592–1984) and from the Veneto Region, Venice, Italy     

Resistance to activated protein C in healthy women taking oral contraceptives

Summary. Resistance to activated protein C (APC) is at present considered the most frequent laboratory abnormality in patients with deep-vein thrombosis. An increased risk for venous thrombosis is associated to the use of oral contraceptives (OC).
We studied APC sensitivity in 50 healthy women taking OC and in 50 healthy controls, matched for age, smoking habit, educational and social levels, and the main biochemical routinary parameters. Subjects with a personal or familial history of thrombosis and also with chronic or acute diseases were excluded. Protein C, protein S, antithrombin III and lupus anticoagulant activity (LAC) were also evaluated. Increased fibrinogen and protein C levels, decreased protein S, and shortened PT and APTT were also observed in women taking OC. APC sensitivity ratio (APC-SR) was significantly lower in the OC group than in a control group (2.6 ± 0.38 v 2.81 ±0.35, P <0.01). Seven of eight women with APC ratio ≤ 2 (APC resistant) were OC users: the difference of prevalence was statistically significant (chi-squared test, P <:0'05). Only two out of eight women were found heterozygous for the Leiden factor V mutation. Two APC-resistant women without the Leiden mutation subsequently discontinued OC and both then normalized their APC-SR. We conclude that acquired factors, i.e. oral contraceptives, may play an important role in determining plasma APC resistance.     

Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project

Deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) or an impaired PC anticoagulant pathway increase the risk of venous thrombosis (VT). By conducting a genome-wide association study (GWAS) on two independent samples of VT patients totalling 951 subjects typed for 472 173 single nucleotide polymorphisms (SNPs), we observed that common SNPs explain 21% and 27% of the genetic variance of plasma AT and PS levels, even though no SNP reached genome-wide significance. For PC, we showed that two PROCR SNPs, rs867186 (Ser219Gly) and rs6060278, additionally explained c. 20% (P = 1·19 × 10(-31)) of the variance of plasma PC levels. We also observed that c. 40% of the remaining genetic variance of PC levels could be due to yet unidentified common SNPs. The PROCR locus was also found to explain c. 8% (P < 10(-10)) of agkistrodon contortrix venom (ACV) (exploring the PC pathway) variability which was under the main control of the F5 and F2 loci that further explained about 40% and 10%, respectively. We presented here the first GWAS for plasma AT and free-PS levels and ACV in Caucasian samples. We identified three independent loci associated with ACV (F2, F5 and PROCR) and replicated two independent effects on plasma PC levels at the PROCR locus.     

Difference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test-based classification

Hereditary protein S (PS) deficiency type I is an established risk factor for venous thromboembolism. Contradictionary data on type III deficiency suggests a difference in risk between both types. We studied 156 first degree relatives (90% of eligible relatives) from type I deficient probands (cohort 1) and 268 (88%) from type III deficient probands (cohort 2) to determine the absolute risk of venous and arterial thromboembolism. Annual incidences of venous thromboembolism were 1.47 and 0.17 per 100 person-years in deficient and non-deficient relatives in cohort 1 [relative risk (RR) 8.9; 95% confidence interval (CI) 2.6-30.0], and 0.27 vs. 0.24 in cohort 2 (RR 0.9; 95% CI 0.4-2.2). Type III deficiency was demonstrated in 20% of non-deficient relatives in cohort 1 and the annual incidence in this subgroup was 0.70 (RR 4.3;0.95-19.0). The cut-off level of free PS to identify subjects at risk was 30%, the lower limit of its normal range (65%). PS deficiency was not a risk factor for arterial thromboembolism. In conclusion, type I deficiency was found to be a strong risk factor for venous thromboembolism, in contrast with type III deficiency. This was because of lower free PS levels in type I deficient subjects and a free PS cut-off level far below the lower limit of its normal range.