Anticoagulant Deficiency Research Articles

Diagnostic algorithm for thrombophilia screening

Thrombophilia screening is aimed at detecting the most frequent and well-defined causes of venous thrombosis, such as activated protein C resistance/factor V Leiden mutation, prothrombin G20210A gene mutation, deficiencies of natural anticoagulants, such as antithrombin, protein C and protein S, the presence of antiphospholipid antibodies, hyperhomocysteinemia and increased factor VIII activity. At this time, thrombophilia screening is not recommended for those possible congenital or acquired risk factors, whose association with increased risk of thrombosis has not been proven sufficiently. Laboratory investigations should include a step-wise approach to the diagnosis of thrombotic disorders with respect to the assays and methods of analysis that are used. The assays recommended for the first diagnostic step of screening should establish, whether the subject has one of the common causes of thrombophilia. If one or more abnormal results are obtained, the second diagnostic step includes the assays recommended for confirmation and/or characterization of the defect. When performing the investigation of thrombophilia, it is important to consider all pre-analytical and other variables that may affect the results of thrombophilia testing, including time of testing, age, gender, liver function, hormonal status, pregnancy or the acute phase response to inflammatory diseases. This is necessary, in order to avoid, any misinterpretation of the results. This review summarizes the current knowledge concerning thrombophilia investigations, with special focus on the diagnostic algorithm regarding patient selection, the assays and methods of analysis used and all the variables that should be considered when employing tests for the diagnosis of thrombophilia.

Role of Thrombophilia in Adverse Obstetric Outcomes and Their Prevention Using Antithrombotic Therapy

A series of case-control studies in the last decade have shown the role of inherited thrombophilia in the occurrence of adverse obstetric outcomes. In small series of cases, it has been proven that rare inherited causes of thrombophilia such as natural anticoagulant deficiencies can be associated with fetal losses. The confirmed presence of antiphospholipid antibodies in plasma, representing an acquired thrombophilic condition, is also an established cause of fetal losses, although other studies with a smaller sample size have found an association with other obstetric complications, namely preeclampsia, fetal growth restriction, and abruption placentae. Case-control studies have been performed regarding the potential association between unexplained fetal losses and mild hyperhomocysteinemia. Although case-control and prospective studies are also available regarding hyperhomocysteinemia and other gestational vascular complications, published data are conflicting. Intervention studies have been performed to prevent adverse obstetric outcomes in women with inherited or acquired thrombophilia and previous adverse outcomes. There is much debate in the literature regarding the need for treatment of women with thrombophilia during pregnancy. Although in most cases these are not randomized controlled trials, all studies found significantly better outcomes in treated pregnancies compared with those of untreated pregnancies.

Inherited Thrombophilia: Implications for Prevention and Treatment of Venous Thromboembolism

Inherited thrombophilia, defined as a genetically determined tendency to develop venous thromboembolism (VTE), contributes to the pathogenesis of approximately 40% of VTE episodes. About 50% of carriers of inherited thrombophilic traits develop VTE, but the impact of the different abnormalities is variable in terms of clinical penetrance. Some rare abnormalities (natural anticoagulant deficiencies, homozygous factor V Leiden, and combined defects) result in more severe thrombophilic phenotypes, characterized by early-onset events, more frequent recurrence, and positive family history, whereas the common polymorphisms (heterozygous factor V Leiden and prothrombin G20210A) are associated with lower VTE risk, often in association with triggering risk factors. Therefore, clinical implications of inherited thrombophilia should be assessed in the framework of coexisting and/or circumstantial risk factors involved in the multifactorial pathogenesis of VTE. These considerations should be taken into account when assessing the need and modalities of primary and secondary thromboprophylaxis in patients carrying inherited thrombophilic traits.

Acquired coagulation disorders: revisited using global coagulation/anticoagulation testing

Acquired coagulation defects are characterized by a decrease of both pro- and anti-coagulants. Because of this, we hypothesise that global tests, such as the prothrombin and partial thromboplastin times (PT and APTT), might be unsuitable for their investigation. Indeed, these tests are not good predictors of bleeding in acquired coagulopathies as they are in the congenital ones. This article discusses the possible reasons for this, using cirrhosis and the neonatal period as epitomes of acquired coagulation defects. Both display normal thrombin generation in the presence of thrombomodulin, in spite of prolonged PT and APTT. We surmise that, because of their design, the PT and APTT are responsive to thrombin generated as a function of pro-coagulants, but much less to thrombin inhibited by the anti-coagulants, especially protein C, which is activated to a limited extent in the absence of thrombomodulin. In conclusion, the PT and APTT can tell us whether or not a patient is deficient in one or more pro-coagulants, but not whether this deficiency is counterbalanced by a parallel deficiency of anti-coagulants. Thrombin generation assays are more suitable than PT and APTT for use in acquired coagulation defects.

Inherited Thrombophilia is Associated With Pregnancy Losses That Occur After 12th Gestational Week in Serbian Population

Recurrent fetal loss (RFL) is a significant clinical problem, occurring in 1% to 5% of reproductive females. Inherited or acquired thrombophilia has been diagnosed in 50% to 65% of women with history of unexplained fetal loss. The objective of our study was to determine the prevalence of thrombophilia in women with unexplained RFL in Serbian population and to find out whether the presence of thrombophilia is associated with pregnancy losses that occur later than 12th gestational week. We have examined 147 women with unexplained RFL or intrauterine fetal death and 128 healthy women with at least 1 uncomplicated pregnancy. The antithrombin (AT), protein C (PC), protein S (PS), activated protein C (APC) resistance, factor V (FV) G1691A, factor II (FII) G20210A, and MTHFR C677T were determined. At least 1 inherited thrombophilic defect was found in 54 (36.7%) of 147 women with repeated fetal losses and in 11 (8.59%) of 128 controls (P < .001, OR 6.17, 95% CI 3.06-12.48). The most common thrombophilic abnormalities were homozygosity for MTHFR 677TT, FV Leiden, and FII G20210A. Deficiency of natural anticoagulants occurred in 10 patients, with protein S deficiency being the most frequent one. Thrombophilia was found in 46 of 94 women with RFL that occurred later than the 12th gestational week and in only 8 of 53 with RPL earlier than 12th week (P = .001). Our study has shown the association between the hereditary thrombophilia and RFL that occurred after the 12th gestational week in Serbian population.

Low level of factor V is associated with development of deep-vein thrombosis in Japanese patients

Background Factor V, having two functions (procoagulant and anticoagulant), is a key factor in blood coagulation, and low plasma levels of factor V may be a risk factor for thrombosis. Objective The levels of plasma factor V antigen (FV:Ag), and the phospholipid binding capability of Factor V (FV:PL-bound) were evaluated in patients with deep-vein thrombosis (DVT). Methods Levels of FV:Ag, and FV:PL-bound were expressed as a percentage of the normal level found in pooled plasma from control subjects. One hundred and twenty-three Japanese patients with deep-vein thrombosis (DVT) were included, with 100 age and sex-matched healthy control subjects. Results The FV:Ag, and FV:PL-bound values were significantly lower in DVT patients than in healthy subjects (p < 0.05 and p < 0.005, respectively). Among the 123 patients, 30 for FV:Ag (24.4%), and 32 for FV:PL (26%) had less than the arbitrary cutoff point (set at the 5th percentile of the value for FV:Ag and FV:PL-bound from healthy subjects), and the odds ratios (ORs) were 6.1 (95% confidence interval [CI], 2.3-16.5) and 6.7 (95%CI, 2.5-17.9), respectively. When patients with a deficiency of natural anticoagulants (antithrombin, protein C, and protein S) were excluded from the analysis, the ORs increased for all patients (6.6 for FV:Ag (95%CI, 2.4-18.3) and 7.4 for FV:PL-bound (95%CI, 2.7-20.3). Moreover, twenty-one (17%) of the 123 DVT patients, and 1 (1%) of 100 control subjects had values below the cutoff points for both FV:Ag and FV:PL-bound, and the OR was 21.6 (95%CI, 2.85-163.1). Conclusions These results suggest that low levels of factor V are associated with development of DVT, and may be a predictor for DVT.

VTE recurrence in patients with inherited deficiencies of natural anticoagulants

Thromb Haemost 2009; 101: 5–6 Venous thromboembolism (VTE) is a serious clinical condition manifesting as deep venous thrombosis (DVT) and/or pulmonary embolism (PE). Patients with VTE have a considerable risk of recurrent VTE that persists for many years (1, 2). In a population based cohort study, Heit et al. (1) found an overall cumulative percentage of VTE recurrence at 180 days, 1 and 10 years of 10.1%, 12.9%, and 30.4%, respectively. In another recent prospective cohort study, Prandoni et al. (2) reported, in patients with a first episode of VTE followed for eight years after oral anticoagulant therapy (OAT) withdrawal, a cumulative incidence of recurrence of 17.5% after two years, 24.6% after five years, and 30.3% after eight years. OAT is effective in reducing the VTE recurrence rate. However, anticoagulant treatment is associated with an increased risk for bleeding complications (3). Thus, anticoagulation has to be discontinued when the benefit of treatment no longer outweighs its risks and this clearly depends on the estimated risk of recurrence. The optimal duration of OAT is established, either after a first episode of VTE, in patients with a transient or with a persistent risk factor for VTE with an average risk of bleeding. Patients with a persistent risk factor for VTE had a high risk of recurrence. In patients with cancer, the risk of recurrent VTE after stopping anticoagulant therapy is as high as 10% to 20% in the first year, particularly among those with metastatic disease or among those who received concurrent chemotherapy (2, 4). Thus, in view of the persistently high risk of VTE recurrence, a prolonged anticoagulant treatment is currently recommended in patients as long as the cancer remains active. Conversely, in patients with major reversible risk factor such as surgery, immobilization or trauma, the risk of recurrence is relatively low (5), and to stop anticoagulant therapy after three months of treatment appears to be a reasonable option. On the other hand, the optimal duration of OAT in patients with a first unprovoked episode of VTE is still uncertain, and recent guidelines of the American College of Chest Physician suggested to carefully assess the potential risks and benefits of long-term OAT in each patient (6). Recently, several studies have assessed the role of some individual features evaluated at the end of conventional anticoagulant treatment as risk factors for recurrence (7, 8). The main aim of this approach was to identify those patients with unprovoked VTE who could benefit from extended anticoagulant treatment. In a randomized controlled study, Palareti et al. showed that patients one month after discontinuation of anticoagulation with an abnormal D-dimer level had a significantly higher incidence of recurrent VTE compared to patients with normal D-dimer, and that resumption of anticoagulation was effective in reducing thromboembolic complications in these patients (7). In a prospective cohort study on 313 consecutive symptomatic outpatients with proximal DVT, Prandoni et al. showed that persistence of residual venous thrombosis at follow-up visits was associated with an increased risk VTE recurrence (8). Several studies and a meta-analysis have revealed that men have at higher risk of recurrence than women (9) and first manifestation of thrombosis as PE seems to be associated with an increased risk of VTE recurrence (10). During the last decade several abnormalities in the coagulation system have been shown to be associated with an increased risk of thrombosis. Their impact on the recurrence rate has been the focus of several clinical studies. Factor V Leiden and the prothrombin G20210A variation, the commonest inherited risk factors for thrombosis, are associated with an increased risk of VTE recurrence (11). However, the magnitude of the risk conferred by the presence of one of these risk factors is modest and not sufficient to warrant long-term anticoagulation. Inherited deficiencies of natural anticoagulants antithrombin, protein C, and protein S are present in less than 10% of VTE patients (12). Patients with these deficiencies are considered at higher risk for VTE (13). On the other hand, only few studies with a limited number of included patients have assessed the risk of recurrence associated with these thrombophilic abnormalities (14, 15). In these studies, the risk of recurrence in patients with first VTE and a thrombophilic defect and in patients without a thrombophilic defect was similar. However, these studies also included patients with other thrombophilic defects such as factor V Leiden, prothrombin G20210A mutation and included a relatively small number of patients with deficiencies of natural anticoagulants.

Deficiency of the natural anticoagulant proteins in women with pregnancy related venous thromboembolism

Inherited thrombophilia can be defined as a predisposition to thrombosis caused by heritable defects, such as mutations in genes encoding the natural anticoagulants or clotting factors. Pregnancy related risk of VTE is sixfold increased comparing to non pregnant age matched women. Pregnancy is an independent risk factor for the development of venous thromboembolism and this risk is further increased by the presence of thrombophilia. The aim of the study was to evaluate the association between deficiency of natural anticoagulants: antithrombin, protein C and protein S and pregnancy related thromboembolism. We have determined the activities of antithrombin, protein C and protein S in 74 women with pregnancy related thrombosis and in 45 healthy women who had at least two uncomplicated pregnancies. Among the women with the history of venous thromboembolism antithrombin deficiency was found in 4 (5.4%), protein C deficiency in 2 (2.7%) and protein S deficiency in 5 (6.76%). The total of 11 (14.6%) women was found to be deficient. Not a single woman in the control group was found to be deficient in natural anticoagulants. Deficiencies of coagulation inhibitors are associated with an increased risk of venous thrombosis during pregnancy and puerperium (p=0.006). Antithrombin, protein C and protein S deficient women are at higher risk of developing venous thromboembolism during antepartal period (p=0.0097). Prophylactic treatment with heparin should be recommended from the very beginning of the following pregnancy in women with antithrombin, protein C or protein S deficiency.

Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension

Idiopathic portal hypertension (IPH) is characterized by non-cirrhotic presinusoidal intrahepatic portal hypertension. The etiopathogenesis of the disease is poorly understood. Obliteration with microthrombosis of the small portal vein branches may lead to lesions underlying portal hypertension. We aimed to put forward a comprehensive thrombophilic mutation profile in IPH and its probable contribution to pathogenesis. Eleven patients and 12 controls were included. We used the CVD-StripAssay which is based on the reverse-hybridization principle to identify a total of 12 thrombophilic gene mutations: Factor V R506Q, Factor V H1299R, prothrombin G20210A, Factor XIII V34L, beta-Fibrinogen -455 G-A, PAI-1 4G/5G, platelet GPIIIa L33P, MTHFR C677T, MTHFR A1298C, ACE I/D, Apo B R3500Q and Apo E2/E3/E4, respectively. We also evaluated some blood parameters and protein C, protein S, AT-III levels using commercially available assays. IPH patients and controls were similar in respect to gender distribution (P = 1.000). Mean age was 31.2 in patients and 29.1 in controls (P = 0.622). Pica history was present in 54.5% of the patients. Mean protein C and AT-III levels were lower in patients than that of controls (P = 0.002 and 0.001, respectively). Factor XIII V34L, PAI-1, GPIIIa L33P, MTHFR C677T and MTHFR A1298C frequencies of genetic polymorphisms were found to be significantly higher among patients than that of controls. Apolipoprotein E2/E3/E4 analysis showed an inverse relationship with IPH when E2 plus E4 compared with E3. A higher frequency of Beta-Fibrinogen -455G-A mutation was observed in patients, but this difference did not reach a statistical significance. Our data represent the most comprehensive study to date with respect to thrombophilic gene polymorphisms in IPH. The data support a possible pathogenetic role in IPH, at least by some of the prothrombotic mutations. In order to confirm or refuse this proposal, a larger cohort of patients is needed.

Antithrombotic prophylaxis during pregnancy in women with deficiency of natural anticoagulants

Prevalence of obstetric complications in women with deficiency of natural anticoagulants is difficult, because these defects are very rare in general population. Furthermore, the available data on prophylactic intervention in such individuals to decrease the obstetric risk are also very limited. To evaluate in a setting of women with rare hereditary thrombophilias, deficiency of antithrombin, protein C or protein S whether thromboprophylaxis during pregnancy could affect foeto-maternal outcome. Retrospective cohort study in two Italian thrombosis centres: 32 women with an established hereditary deficiency of natural anticoagulants antithrombin, protein C or protein S were enrolled because of a history of unexplained foetal losses with or without venous thromboembolism. Overall, information on the management of 103 pregnancies was obtained and the outcome in the absence or in the presence of enoxaparin treatment was recorded. Live births were recorded in 18 women (56.2%). Ten women had early foetal losses, 16 intrauterine foetal death and six both. Eight pregnancies were treated with enoxaparin. Seven out of eight treated pregnancies [87.5%, 95% confidence interval (CI) 52.9-97.7] and 27 out of 95 not-treated pregnancies (28.4%, 95% CI 20.3-38.1) resulted in the delivery of a live newborn (Fisher exact test: P=0.002), with a risk of foetal loss in untreated pregnancies 3.1 times (95% CI 1.7-3.5) higher than in treated ones. In this setting of patients with rare causes of thrombophilia, antithrombotic prophylaxis during pregnancy improves foeto-maternal outcome.

Genetic Basis of Inherited Thrombophilia in Korea: A Single-Institution Experience.

Background: Inherited thrombophilia (HT) is a condition that genetically imposes a risk to develop thrombosis. It has been known that the genetic basis of IT is different between Caucasians and Asians; factor V Leiden mutation (R506Q) and the prothrombin gene mutation G20210A are major causes of HT among Caucasians, while they are extremely rare among Asians. Thus the deficiency of anticoagulant factors such as protein C (PC), protein S (PS), and antithrombin (AT) are believed to play a major role in Asians. Genetic study is important to confirm the diagnosis, since there are many acquired conditions including anticoagulant therapy that may mimic inherited form of deficiency. In this study, consecutive patients with a clinical and laboratory suspicion of IT were recruited for genetic diagnosis at a single institution, Samsung Medical Center, Seoul, Korea.Materials and Methods: From December 2004 to July 2005, a total of 15 patients had presumptive diagnosis of IT; seven were suspected to have PC deficiency (activity, 43~ 51%), four PS deficiency (free Ag; 12~38%), and four AT deficiency (activity, 63~67%). All exons and their flanking sequences of the PROC gene, PROS1, or SERPINC1 were directly sequenced and analyzed.Results: All seven patients with PC deficiency were shown to have a mutation in PROC. Of note, four of them had a common missense mutation, and the haplotype analysis using polymorphic markers showed that it is a mutation hot focus rather than a founder effect. Two other mutations were novel. Two of four patients with PS deficiency had a mutation in PROS1, each of which was novel. Three of four AT deficiency had a mutation in SERPINC1; one with a novel splice mutation and two shared a common splice mutation, which has not been reported, either. Overall, nine mutation carriers were detected through family study.Conclusion: This study revealed the genetic basis, mutation spectrum, and the mutation detection rate of IT in consecutive Korean patients. Since diverse (known or novel) mutations underlie genetic deficiency of anticoagulants in Koreans, genetic studies employing direct sequencing for the whole gene are necessary to confirm the diagnosis, and for further family studies.

Hémostase et grossesse

Normal pregnancy is an acquired hypercoagulable and inflammatory state. Hypercoagulability in normal pregnancy is due to increased levels of procoagulant coagulation factors, as well as hypofibrinolysis and decreased levels of natural anticoagulants. In addition, regulation of the maternal immune system contributes to a successful pregnancy outcome. Specific pregnancy diseases are defined by their occurrence in relation with the gravid state and their recovery when gestation ends, after delivery, most of the time in emergency conditions in case of: disseminated intravascular coagulation, thrombotic microangiopathies, such as preeclampsia, HELLP syndrome, or the rare thrombotic thrombocytopenic purpura. On the contrary, diseases that enhance bleeding risk are present before pregnancy when hereditary, or detected at the time of pregnancy when acquired: hereditary diseases include von Willebrand disease, thrombopathies, or conducting state of haemophilia, and acquired states are mainly related to autoimmune diseases, such as immune thrombocytopenic purpura. Various corrections may be performed for pregnancy-induced abnormalities and their management and follow-up are achieved accordingly. Diseases that increase the thrombotic risk involve hereditary thrombophilia (deficiencies of natural anticoagulants, factors V or II mutations), and acquired thrombophilia (antiphospholipids antibodies). Normal pregnancy and post-partum also constitute an acquired thrombotic factor and women with thrombophilic defects have been shown to be at increased risk. There is a consensus that such women with a personal history of thrombosis should receive anticoagulant prophylaxis. A good evaluation of the thrombotic risk is necessary in order to determine the most appropriate anticoagulant treatment. Warfarin crosses the placenta and has a known teratogenic effect (warfarin embryopathy). Hence, prophylaxis of gestational thrombosis mainly relies upon the use of heparin, during pregnancy and post-partum.

P0238 ANTITHROMBIN SUPPLEMENTATION AFTER LIVER TRANSPLANTATION

Introduction: After liver transplantation deficiencies of natural anticoagulants including antithrombin (AT) are associated with increased risk of hepatic artery thrombosis (HAT), a potentially fatal complication. Recently, AT supplementation was added to the routine management of children after liver transplantation in Queensland. We report the response to AT supplementation in six children so treated. Methods: All cases treated with AT after liver transplantation at Royal Children’s Hospital were retrospectively reviewed. Results: 6 children (3 male) aged 3 wks-1.5 y (median 1y) and weighing 4–10.8kg (median 8.9kg) were transplanted between June 2002 and March 2003 and received antithrombin. Transplant indications were: extrahepatic biliary atresia (n=3), cryptogenic cirrhosis (1), ornithine transcarbamylase deficiency (1) and idiopathic acute hepatic failure (1). Grafts were reduced (3), split (1) and whole (2) cadaveric organs. All received routine post-op care, including triple drug immunosuppression (tacrolimus, azathioprine and methylprednisolone). Prostaglandin E1 infusion was started intra-operatively to enhance hepatic blood flow: dose 0.02 mcg/kg/min, continued post-op for 24 hours. Pro-phylaxis with AT and low dose heparin (load of 75u/kg followed by infusion of 10 u/kg/hr, aiming for minimal / no change in APPT) was commenced immediately post-op in 5 and on day 6 post-op in the other case, after detection of reduced hepatic artery flow (no thrombus). AT and heparin were continued for 10 days postop. AT dosage was 70–10 0 IU/kg, titrated to keep trough levels (taken 18–21hours post dose) > 0.7 IU/mL (NR 0.79–1.31). Patients’ pretreatment AT levels were 0.43–0.57 IU/mL (median 0.52 IU/mL) and post-infusion were 1.19–1.83 IU/mL (median 1.5I IU/mL). AT was well tolerated. One patient bled from the cut surface of the graft, requiring transfusion. No other hemorrhagic complications occurred and there were no cases of HAT. By comparison, in a group of 23 historical controls transplanted at this center, aged 0–1.5years at transplant (median 1.15y), weight 3.8–12.5kg (median 8.9kg)(p=NS vs current series), the rate of HAT was 22%. Conclusion: Post-transplantation AT supplementation was well tolerated in this group of infants. Due to their small size, age and low initial AT levels this group was considered to be at high risk of HAT. The absence of HAT in this cohort suggests that AT supplementation is effective for the prevention of HAT after liver transplantation and that further research on this agent is warranted.

Élévation du facteur VIIIc coagulant et risque de thrombose veineuse : analyse critique des études cas–témoins

Introduction. – Deep venous thrombosis is a frequent and potentially serious disease. Its causes are multifactorial, associating facilitating circumstances and genetic or acquired coagulation abnormalities. Genetic currently well known abnormalities are quantitative deficiencies of some natural anticoagulants (proteins C and S, antithrombin), and mutations of V and II (G20210-A) genes. The Leiden group has recently shown that the elevation of some coagulation factors level could also constitute a risk factor for deep venous thrombosis. Current knowledge and key points. – Elevation of factor VIIIc is associated with a higher risk for thrombosis than in the general population but the threshold for normality of this factor is difficult to define. It is a probable constitutional abnormality whose prevalence in the general population vary from 6 to 36%. Risks of deep venous thrombosis associated to this factor elevation is more elevated in patients who have this anomaly (odds ratios vary from 2,2 to 10,3) (95% CI). Future and projects. – The frequency of this anomaly and its association with a high risk for thrombosis are reasons to assess the potential usefulness of screening for these anomalies in patients who had thrombosis or in their family. The probable genetic origin of these anomalies has to be confirmed by other studies.

Surgical restoration of portal flow corrects procoagulant and anticoagulant deficiencies associated with extrahepatic portal vien thrombosis

Extrahepatic portal vein thrombosis (EHPVT) is associated with abnormal circulating procoagulants and anticoagulants. Eleven children with EHPVT and abnormal coagulation factors underwent a mesenterico-left portal vein bypass to restore portal flow. Coagulation factors had returned to normal by one year. The data suggest that portal venous flow is essential for maintaining normal coagulation. (J Pediatr 2003;142:197-9)

Thromboendarterectomy in a Patient with Unilateral Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is considered to be an aberrant outcome of acute pulmonary thromboembolism, due to inadequate thrombus dissolution. However, the mechanism of thrombi dissolution failure remains unclear. With respect to inherited thrombophilia, the co-occurrence of natural anticoagulant deficiencies with CTEPH was found to be rare. Pulmonary thromboendarterectomy (PTE) is a potentially curative surgical procedure for CTEPH, but it is associated with considerable mortality due to postoperative complications, such as reperfusion pulmonary edema and right heart failure. The postoperative course after PTE poses a unique series of ventilatory care and hemodynamic management challenges. We present the case of a 42-year-old woman with unilateral CTEPH combined with thrombophilia (Protein S deficiency). Successful PTE was followed by independent lung ventilation with unilateral nitric oxide (NO) inhalation, which resulted in functional improvement without postoperative complications.

Coagulation factor abnormalities in patients with single-ventricle physiology immediately prior to the fontan procedure

Background. Coagulation abnormalities have been reported following the Fontan operation and have been attributed to various aspects of Fontan-associated physiology. Using age-matched controls, this study evaluated coagulation abnormalities in children who had undergone a bidirectional Glenn procedure to test the hypothesis that coagulation abnormalities are present before the Fontan operation. Methods. Coagulation factors were assayed in 38 children (mean age 34.4 ± 15 months) immediately before the Fontan operation; 37 healthy children (mean age 33 ± 17 months) were assayed as controls. Concentration of factors II, V, VII, VIII, IX, and X and of antithrombin III, plasminogen, proteins C and S, fibrinogen, serum albumin, and liver enzymes were measured. Normal reference intervals based on the control patients were determined using 95% confidence limits. Patient demographic data, hemodynamic variables, and elapsed time after the Glenn procedure were evaluated as possible predictors of coagulation abnormalities. Results. Concentrations of protein C; factors II, V, VII, and X; plasminogen; and antithrombin III were significantly lower before the Fontan operation compared with age-matched controls ( p < 0.01); no specific hemodynamic variables were predictive of a pro- or anticoagulant deficiency. There were significant positive correlations between patients who had abnormally low factor VII, protein S, and protein C levels and a longer interval between the bidirectional Glenn procedure and the Fontan operation ( p < 0.001). Conclusions. Coagulation abnormalities that could predispose patients to increased risk for clotting or bleeding are evident early in the course of staged single-ventricle repair.

Portal Vein Thrombosis in Pregnancy: Case Report and Review of the Literature

Portal vein thrombosis (PVT) is a rare occurrence in pregnancy. The most common underlying causes are abdominal trauma pancreatitis myeloproliferative disorders and hereditary deficiency of natural anticoagulants (protein C S and anti-thrombin III). We report a case of acute PVT in a seven-week pregnant woman with no past history of thrombosis or evidence of coagulation disorder or thrombophilia. (excerpt)

Coagulation abnormalities in patients with single-ventricle physiology precede the Fontan procedure

Objective: Thromboembolic events in patients who have undergone the Fontan operation have been reported to be as high as 20% to 33%. A hypercoagulable state with deficiencies in proteins C and S has been implicated. Using age-matched control subjects, we evaluated whether an altered coagulation state is present earlier in the course of staged single-ventricle repair. Methods: After informed consent had been obtained, coagulation factors were assayed in 36 infants (mean age, 7.7 ± 3.6 months) with single-ventricle cardiac defects immediately before undergoing the bidirectional Glenn procedure; 34 infants (mean age, 8.4 ± 2.6 months) without cardiac disease were assayed as control subjects. Concentration of factors II, V, VII, VIII, IX, and X; antithrombin III; plasminogen; proteins C and S; fibrinogen; serum albumin; and liver enzymes were measured. Normal reference intervals on the basis of the control subjects were determined by using 95% confidence limits. Patient demographic and hemodynamic variables were evaluated as possible predictors of coagulation abnormalities. Results: Concentrations of protein C; factors II, V, VII, IX, and X; plasminogen; fibrinogen; and antithrombin III were significantly lower in the pre-Glenn infants compared with in the age-matched control subjects (all P <.001, Student t test). On the basis of multiple logistic regression, no specific hemodynamic variables were predictive of a procoagulant or anticoagulant deficiency. Ventricular dysfunction did predict the presence of multiple coagulation abnormalities (P <.001). Conclusion: Procoagulant and anticoagulant factor abnormalities occur early in the course of single-ventricle repair and precede the cavopulmonary connection.J Thorac Cardiovasc Surg 2002;123:459-65

Genetic polymorphisms associated with venous and arterial thrombosis: an overview.

To provide an overview of genetic polymorphisms associated with thrombotic cardiovascular disease. A literature search using the National Library of Medicine database. The literature on genetic polymorphisms associated with venous and arterial thrombosis was reviewed. Based on the literature review, the clinical significance of polymorphisms in various coagulation proteins was assessed and a summary was developed. Thrombosis is a multifactorial disorder, with both congenital and acquired risk factors. It is now clear that there are many genetic abnormalities that impart an increased risk for thrombophilia, and the presence of more than 1 abnormality results in a further increased risk of thrombosis. In hemostasis, there is a balance between procoagulant factors and natural anticoagulant proteins. The first genetic thrombotic disorders described were deficiencies of the natural anticoagulants, such as antithrombin, protein C, and protein S, but these abnormalities are rare and are caused by many different mutations. More recently, single polymorphisms that are relatively common in the general population have been described in procoagulant factors, such as factor V and prothrombin, which impart an increased risk for venous thrombosis. As more scrutiny is placed on the hemostatic system, further polymorphisms have come to light. The current challenge is to elucidate the relationship between these new polymorphisms and either venous or arterial thrombotic cardiovascular disease.