Pregnancy-induced antithrombin deficiency.

OBJECTIVE: This retrospective study was performed to characterize the laboratory features and water metabolism of women with pregnancy-induced antithrombin deficiency (PIATD). METHODS: Among 1493 women who gave birth to a singleton infant at our institution, 114 women who developed PIATD and/or pregnancy-induced hypertension (PIH) were reviewed with respect to perinatal changes in laboratory variables (hematocrit value, fibrinogen, fibrinogen degradation product, D-dimer, uric acid, aspartate aminotransferase, lactate dehydrogenase) and body weight. PIATD was defined as a gradual decline in antithrombin (AT) activity to

Screening for deep venous thrombosis after idiopathic scoliosis surgery in children: a pilot study.

BACKGROUND: Venous thrombosis remains an uncommon disorder in childhood. However, the incidence appears to be increasing for a multitude of reasons. The aim of the study was to detect asymptomatic deep venous thrombosis and prothrombotic diseases in nonsyndromic children undergoing scoliosis surgery. METHODS: A prospective study including forty successive teenagers scheduled for posterior spinal fusion. Patients with scoliosis with a history of hemoglobinopathies, cardiac defects, blood clots, early onset osteoporosis, as well as patients with skeletal dysplasias and nonskeletal dysplastic syndromic entities have been excluded. The protocol was designed for active screening of deep venous thrombosis using color Doppler ultrasonography on a day before surgery and repeated on the 3rd, 7th and 15th day postoperatively. Evaluation of prothrombotic disorders included antithrombin and protein C activities, and total protein S antigen level. RESULTS: No patient has manifested clinical symptoms of venous thrombosis in our study. Preoperative Doppler and ultrasound examinations were normal in all patients. Although repeated Doppler ultrasonography demonstrated a transient small clot in two patients. Congenital antithrombin deficiency of 5% has been observed in one child only, without the development of deep venous thrombosis. CONCLUSION: Thromboembolic event seems to be rare after scoliosis surgery. Prophylaxis for venous thrombosis should not be recommended in such patient. But, larger series are required to confirm such results.

Unraveling the thrombophilia paradox: from hypercoagulability to the prothrombotic state.

The thrombophilia paradox whereby thrombophilia testing identifies defects associated with an increased risk of a first venous thrombosis but not of a particularly high risk of recurrence is likely the result of limitations imposed by a limited dichotomous testing strategy compounded by test inaccuracy and imprecision. Consequently, the observed intermediate phenotype (defined by limited laboratory test results) is not fully concordant with the heritable genotype. The next generation of thrombophilia tests, which utilize either individual genomic analysis or global measurement of the composite plasma intermediate phenotype, may more accurately quantify the thrombophilic risk. In conjunction with clinical risk assessment a more quantitative measurement of hypercoagulability and definition of the prothrombotic state should facilitate transition of clinical management from a disease-focused to a more patient-focused strategy.

Acute mesenteric and aortic thrombosis associated with antithrombin deficiency: a rare occurrence.

Antithrombin is a potent inhibitor of the coagulation cascade exerting its primary effects on activated factors X, IX and II. It is the mechanism by which heparin and low-molecular weight heparin cause anti-coagulation. Deficiency of antithrombin presents as a hypercoagulable state, and may result in unexplained deep venous thrombosis, arterial thrombosis and systemic embolization.

Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency.

Methods routinely used for investigating the molecular basis of antithrombin (AT) deficiency do not detect large SERPINC1 rearrangements. Between 2000 and 2008, 86 probands suspected of having AT-inherited type I deficiency were screened for SERPINC1 mutations in our laboratory. Mutations causally linked to the deficiency were identified by sequencing analysis in 63 probands. We present here results of multiplex ligation-dependent probe amplification (MLPA) analysis performed in 22 of the 23 remaining probands, in whom sequencing had revealed no mutation. Large deletions, present at the heterozygous state, were detected in 10 patients: whole gene deletions in 5 and partial deletions removing either exon 6 (n = 2), exons 1-2 (n = 1) or exons 5-7 (n = 2) in 5 others. Exon 6 partial deletions are a 2,769-bp deletion and a 1,892-bp deletion associated with a 10-bp insertion, both having 5' and/or 3' breakpoints located within Alu repeat elements. In addition, we identified the 5' breakpoint of a previously reported deletion of exons 1-2 within an extragenic Alu repeat. Distinct mutational mechanisms explaining these Alu sequence-related deletions are proposed. Overall, in this series, large deletions detected by MLPA explain almost half of otherwise unexplained type I AT-inherited deficiency cases.

Genetic susceptibility to VTE: a primary care approach.

Genetic thrombophilic disorders are variably common and primary care clinicians must be aware of them because of the increased risk of VTE. A physical examination will not be able to determine if a given VTE resulted from a genetic predisposition or not. In some instances, a patient's personal and family history will alert a clinician to the existence of a thrombophilic disorder, but diagnosis of the specific thrombophilia will require laboratory evaluation and referral to a specialist. The acute management of VTE is the same regardless of the presence of a genetic thrombophilia; therefore, laboratory testing or evaluation by a specialist is not cause to delay treatment of the acute thrombotic event. After the initial treatment and stabilization of the patient, ample time exists to perform a thrombophilia workup. Long-term management of thrombophilia disorders is complicated and needs to be individualized, so referral to specialists is necessary. Primary care clinicians need to keep abreast of the studies being conducted on thrombophilia because numerous families continue to be plagued by VTEs without a recognizable cause. Undoubtedly, new causes of inherited thrombophilias are yet to be unveiled.

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

UNLABELLED: 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. AIM OF THE STUDY: 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.

Impact of reduced endogenous anti-coagulation protein activity on vascular events of peripheral arterial disease.

AIM: Aim of the study is to elucidate the prevalence and the prognosis of patients with peripheral arterial disease (PAD) who have reduced endogenous anti-coagulation protein activity. METHODS: Ninety six patients with PAD were studied, including 45 patients with intermittent claudication and 51 with critical limb ischemia. Among them 65 patients underwent peripheral artery bypass grafting. Venous blood samples were obtained and plasma activity level of Protein C (PC), Protein S (PS), Plasminogen (PLG), Antithrombin (AT) were measured. Based on the patients' clinical database the prevalence and clinical relevance was studied. RESULTS: In our PAD patients PC activity is reduced in 18.8%, PS activity is reduced in 16.7%, PLG activity was reduced in 15.6% and AT activity was reduced in 24.0%. The incidence of AT activity deficiency was significantly higher in patients with critical limb ischemia than patients with claudication (P<0.01). After revascularization, arterial event free rate of patients with PC or PS activity deficiency and those with PLG deficiency were significantly lower than those without during the mean follow-up period of 26+/-31 months. The incidence of thromboembolic episodes and leg amputation rate were significantly worse in patients with PC deficiency. CONCLUSIONS: PAD patients with reduced endogenous anti-coagulation proteins show worse prognosis than those without. Surgeons must be aware of it to improve the outcome of arterial revascularization.

Higher prevalence of thrombophilia in patients with varicose veins and venous ulcers than controls.

BACKGROUND: Uncontrolled studies suggest that patients with chronic venous ulceration (CVU) have an increased prevalence of thrombophilia, similar to that observed in patients with deep vein thrombosis. This study compared the nature and prevalence of thrombophilia in patients with varicose veins (VV, CEAP clinical [C] grade C(2) to C(3)) and patients with CVU (C(5) to C(6)) with an age- and sex-matched population without clinical or duplex ultrasound evidence of venous disease. METHODS: Twenty-seven patients with VV, 27 patients with CVU, and 54 age- and sex-matched case controls with no clinical or duplex evidence of lower limb venous disease, underwent testing for factor V Leiden and prothrombin 20210A mutations, antithrombin deficiencies, and levels of antiphospholipid antibodies, homocysteine, protein C and S, and factor VIII, IX, and XI. RESULTS: The overall prevalences of single and multiple thrombophilias were significantly higher in cases than in controls. Specifically, in VV patients, the prevalences of no, single, and multiple thrombophilias were 33%, 52%, and 15%, respectively, compared with 63%, 26%, and 11% in VV controls. In CVU patients, the prevalences of no, single, and multiple thrombophilias was 26%, 30%, and 44%, respectively, compared with 66%, 22%, and 11% in CVU controls. Compared with controls, only factor XI levels were significantly higher in VV patients, and homocysteine and factor VIII, IX, and XI levels were all significantly higher in CVU patients. CONCLUSION: Patients with VV, and particularly CVU, have significantly higher prevalences of single and multiple thrombophilias than age- and sex-matched controls without clinical or duplex evidence of lower limb venous disease. These data support the hypothesis that thrombophilia predisposes to the development of superficial and deep lower limb venous reflux, and so VV and CVU, through the increased occurrence of clinical and subclinical thrombosis.

[Resistance to curative treatment by unfractionned heparin]. / Les résistances aux traitements curatifs par l'héparine non fractionnée.

Unfractionated heparin has been used as antithrombotic therapy for many years. Its main effect is attributed to the activation of antithrombin (AT), the heparin/AT complex inactivating both factor IIa (thrombin) and factor Xa. Resistance to unfractionated heparin with clinical or biological expression is uncommon. The occurrence of venous or arterial thrombosis or the extension of thrombosis in a patient receiving unfractionated heparin, should always raise suspicion of either AT deficiency or type 2 heparin-induced thrombocytopenia (HIT type 2). HIT type 2 is not a true heparin resistance but an immune complication that requires heparin discontinuation and the use of alternative anticoagulants. Biological heparin resistance is suspected in the presence of a normal or not prolonged activated partial thromboplastin time despite the administration of increasing dose of heparin. Measurement of anti-Xa activity is useful to adjust heparin treatment. Isolated biological heparin resistance is encountered in several physiological and pathological situations including inflammatory and infectious disorders, pregnancy and thrombocytosis. It also occurs in acquired antithrombin deficiency of nephrotic syndrome, l-asparaginase treatment or cardiopulmonary bypass. Biological heparin resistance is relatively common, but clinically significant resistance to heparin is rare and should always raise suspicion of either AT deficiency or type 2 heparin-induced thrombocytopenia.

Advances in understanding pathogenic mechanisms of thrombophilic disorders.

Venous thromboembolism is a major medical problem, annually affecting 1 in 1000 individuals. It is a typical multifactorial disease, involving both genetic and circumstantial risk factors that affect a delicate balance between procoagulant and anticoagulant forces. In the last 50 years, the molecular basis of blood coagulation and the anticoagulant systems that control it have been elucidated. This has laid the foundation for discoveries of both common and rare genetic traits that tip the natural balance in favor of coagulation, with a resulting lifelong increased risk of venous thrombosis. Multiple mutations in the genes for anticoagulant proteins such as antithrombin, protein C, and protein S have been identified and constitute important risk factors. Two single mutations in the genes for coagulation factor V (FV Leiden) and prothrombin (20210G>A), resulting from approximately 20,000-year-old mutations with subsequent founder effects, are common in the general population and constitute major genetic risk factors for thrombosis. In celebration of the 50-year anniversary of the American Society of Hematology, this invited review highlights discoveries that have contributed to our present understanding of the systems that control blood coagulation and the genetic factors that are involved in the pathogenesis of venous thrombosis.

[Therapeutic consequences of thrombophilic testing]. / Conséquences thérapeutiques de la mise en évidence d'une thrombophilie.

OBJECTIVE: The objectives of this article are to review the data about the consequences of thrombophilia testing and to think about its indications. CURRENT KNOWLEDGE AND KEY POINTS: The indications of congenital thrombophilic testing have extended since the discovery of prevalent abnormalities, such as mutations of factor V or II genes. However, thrombophilia does not result in a significant increase in the risk of recurrence unlike the spontaneous occurrence of thrombotic events. The factor V Leiden mutation is associated with a moderate increase in recurrence rate, while the G20210A mutation of factor II is not associated with a significant increase in recurrence. Regarding the decrease in natural anticoagulants is concerned, there is no definite conclusion, although the decrease in antithrombin is suspected of being associated with an increase in recurrence. FUTURE PROSPECTS AND PROJECTS: Finally, identification of a constitutional thrombophilia most often do not influence the therapeutic decisions unless some rare abnormalities are found, such as a decrease in antithrombin, homozygous mutations in factors V or II genes or associations of thrombophilia. One must remember that antiphospholipid antibodies must be searched because their impact on recurrences is well-known. Diagnostic work-up for thrombophilia is not useful after a distal or a superficial venous thrombosis (except for antiphospholipid antibodies in case of distal venous thrombosis).

Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations.

During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.