Inherited factor II deficiency with paradoxical hypercoagulability: a case report.

: Congenital deficiency of factor II is a very rare autosomal recessive disorder that can result in a bleeding diathesis. Genotypically, individuals are either homozygous for a defective prothrombin gene or a compound heterozygote with different mutated prothrombin genes inherited from each parent. Phenotypically, it is characterized by either a low production of normal prothrombin or a near-normal production of dysfunctional prothrombin. Treatment is aimed at restoring normally functioning factor II circulating levels to sufficient concentration for hemostasis. Paradoxical thrombosis in patients born from a nonconsanguineous marriage with factor II deficiency has not been reported. A woman with known congenital factor II deficiency confirmed by history and hemostatic laboratory analysis presented with an unprovoked spontaneous thrombosis of the common femoral vein detected on color Doppler. Venous thrombosis can occur in congenital deficiency of factor II and inferior vena cava filter can be life-saving.

Bleeding manifestations in heterozygotes with prothrombin deficiency or abnormalities vs. unaffected family members as observed during a long follow-up study.

: To investigate the prevalence of bleeding in heterozygotes for prothrombin deficiencies. Homozygotes or compound heterozygotes with Factor II (FII) levels of less than 10% of normal are always severely symptomatic.On the contrary little is known about the heterozygous population who have FII levels around 40-50% of normal.Forty-four patients heterozygous for this defect, in comparison with age and sex matched 44 unaffected family members, have been followed during a mean observational period of 22.5 years (range 4-35 years). The study was carried out in Padua between the years 1971 and 2010.The mean prothrombin activity was 0.49 IU/dl (range 0.38-0.62) and 0.91 IU/dl (range 0.81-1.10) in the heterozygotes and in the normal counterparts, respectively.In total, 14 patients showed bleeding manifestations vs. only three among the controls. Bleeding was sometimes spontaneous but more frequently occurred after tooth extractions, surgery, or delivery.Some heterozygous patients had also to be given replacement therapy to control the bleeding. No substitution therapy was ever needed for the normal counterparts.The prothrombin activity levels in the patients who were symptomatic tended to be lower than in those who remained asymptomatic.The difference in the frequency of bleeding and in the bleeding score between patients and unaffected family members was statistically significant (P = 0.007 and 0.0007).Prothrombin levels of about 40-50% of normal may not represent well tolerated hemostatic levels in case of surgical procedures, tooth extraction, or delivery. These data may have general clinical significance even for patients who have acquired defects.

Renal failure due to renal vein thrombosis in a fetus with growth restriction and thrombophilia.

We report a case of renal vein thrombosis diagnosed at 27 weeks of gestation in a dichorionic twin pregnancy. The left kidney of one fetus was hyperechoic and enlarged with echoic streaks following the direction of interlobular veins and the loss of corticomedullary differentiation. In the following weeks, left kidney became smaller and echoic, and Doppler examination showed no flow in both artery and vein. The right kidney had totally normal appearance in the beginning, but it became enlarged and hyperechoic, and progressed into a small echoic kidney with no flow in artery and vein. In the postnatal ultrasound examination, both kidneys appeared hyperechoic with no vascularization in the hilum region. There was thrombosis in arteries and veins of both kidneys, as well as in the inferior vena cava. The investigation for thrombophilia resulted with the combined presence of heterozygote mutation in factor V Leiden and prothrombin 20210 genes.

Congenital factor II deficiency: moroccan cases.

BACKGROUND: Clotting factor II, or prothrombin, is a vitamin K-dependent proenzyme that functions in the blood coagulation cascade. Inherited factor II deficiency is an extremely rare autosomal recessive disorder affecting both genders: clinical bleeding can vary widely in homozygous individuals, and heterozygotes often remain clinically asymptomatic. This study highlights the rarity of inherited factor II deficiency and the importance of coagulation testing in the diagnosis of this condition. METHODS: We report four cases of factor II deficiency at our institution. RESULTS: At diagnosis, two patients were 3 days old, whereas the other two patients were 13 and 40 years of age. Three patients were female, and one was male. Symptoms of factor II deficiency were reported at referral in three patients; the deficiency was an incidental finding in the remaining case. The parents of all four patients were consanguineous (first degree). Factor II enzymatic activity was 1% in 3 cases and 5% in the incidental case. The treatment consisted of transfusion with fresh frozen plasma in all cases. CONCLUSIONS: The congenital deficiency of factor II is a rare inherited disorder. The diagnosis is mainly based on coagulation tests. However, the prognosis of this disease and access to medication are associated with the risk of occurrence of severe bleeding.

Prophylactic administration of prothrombin complex concentrates for congenital prothrombin deficiency with a novel frameshift mutation, prothrombin saitama.

Prothrombin (Factor II, FII) deficiency is an extremely rare autosomal recessive condition with an estimated incidence of 1:2 million. As severe and life-threatening bleeding is rare in FII deficiency, on demand therapy with administration of prothrombin complex concentrates (PCCs) or fresh frozen plasma is generally performed, and prophylactic therapy for FII deficiency has been reported in only three cases. Thus, its optimal dosage and schedule has remained uncertain. Here we report a case of severe prothrombin deficiency with a novel frameshift mutation of the F2 gene, who was started on prophylactic administration.

Prevalence of coagulation factor II G20210A and factor V G1691A Leiden polymorphisms in Chechans, a genetically isolated population in Jordan.

BACKGROUND: Coagulation factor II G20210A and coagulation factor V (Leiden) G1691A single nucleotide polymorphisms (SNPs) are major inherited risk factors of venous thromboembolism. In view of the heterogeneity in their world distribution and lack of sufficient information about their distribution among Chechans, we addressed the prevalence of these SNPs in the Chechan population in Jordan, a genetically isolated population. METHODS AND RESULTS: Factor II G20210A and factor V Leiden SNPs were analysed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method and Amplification refractory mutation detection system (ARMS) respectively in 120 random unrelated subjects from the Chechan population in Jordan. Among the subjects studied for factor II G20210A mutation there were three individuals carrying this mutation as heterozygous (one female and two male), giving a prevalence of 2.5 % and an allele frequency of 1.25 %. No homozygous factor II allele was found. Factor V Leiden G1691A mutation was detected as heterozygous in 22 of 120 of individuals (17 female and five male) indicating a prevalence of 18.3 % and allele frequency of 9.2 %. No homozygous allele was found. CONCLUSION: Our results indicated that prevalence of factor II G20210A mutation in the Chechan population is similar to prevalence in Jordan and Caucasian populations (1-6 %) while the prevalence of factor V Leiden was higher in the Chechan population compared to Jordan and Caucasian populations (2-15 %).

A severe neonatal presentation of factor II deficiency.

Prothrombin deficiency is an autosomal recessive disorder associated with moderate or severe bleeding tendency. In this study, a three-month-old boy with non-consanguineous parents was referred for convulsions because of intracerebral hemorrhage. Standard coagulation tests revealed that the patient's plasma prothrombin activity was 12%, while his father's and mother's levels were 55% and 70%, respectively. Analysis of the prothrombin gene revealed that this patient is a compound heterozygote for two missense mutations: one maternally inherited point mutation in the propeptide (p.Arg4Gln) and one paternally inherited mutation in the kringle-2 (p.Arg220Pro) domain. Structural analysis was performed and confirmed that the resulting mutations were inferred to respectively affect the cleavage of the propeptide from the Gla domain, and the stability of the kringle-2 domain, both resulting in a severe hypoprothrombinemia. In unusually bleeding newborn of non-consanguineous parents, rare severe homozygous bleeding disorders need to be considered to facilitate early diagnosis and treatment.

¿Influyen los factores de riesgo de trombosis venosa cerebral en el desarrollo de infarto venoso asociado? / Do cerebral venous thrombosis risk factors influence the development of an associated venous infarction?

Introducción: La trombosis venosa cerebral (TVC) es un proceso multifactorial con amplio espectro clínico y de factores de riesgo (FR), que puede presentar o no infarto venoso. Estudiamos los FR que influyen en el desarrollo del infarto venoso en pacientes con diagnóstico de TVC.Pacientes y métodos: Estudio observacional con inclusión de pacientes consecutivos con diagnóstico de TVC atendidos por la Unidad de Ictus del servicio de Neurología entre los años 1995 y 2007. Se identifican los FR y se analiza su distribución en función de la presencia del infarto venoso.Resultados: Se incluyeron 52 pacientes (37 mujeres; 71,15%) con edad media de 46,73 años (18-78 años). Los factores de riesgo de TVC más frecuentes fueron los estados de hipercoagulabilidad hereditarios (26,92%) y el uso de anticonceptivos orales (ACO) (25% del total muestral y 35,13% de las mujeres). Entre los FR identificados en pacientes con infarto venoso predominan los trastornos de hipercoagulabilidad hereditarios (40,9%) mientras que en los casos sin infarto venoso, el factor más frecuente es el uso de ACO (26,7%; 38% de las mujeres), estando presentes los estados de hipercoagulabilidad sólo en el 16,5%. No observamos ningún caso de infarto venoso con tratamiento ACO y sin estado de hipercoagulabilidad asociado. Conclusiones: En los pacientes con infarto venoso asociado a TVC parece existir un diferente perfil de factores de riesgo asociado, predominando la presencia de estados protrombóticos hereditarios (AU)

Introduction: Cerebral venous thrombosis (CVT) is a multifactorial process with a wide clinical spectrum and many associated risk factors (RF) that could be complicated with venous infarction (VI). We study the influence of RF in the developing of venous infarction in patients with CVT.Patients and methods: An observational study with consecutive inclusion of patients with CVT diagnosis admitted to the Stroke Unit of a Neurology Department between 1995 and 2007. RF were identified and their distribution according to the presence of VI was analysed. Results: A total of 52 patients were included (37 female; 71.15%) with mean age of 46.73 years (range 18-78 years). The most frequent RF associated with CVT were thrombophilia (26.92%) and oral contraceptives (OC) (25% of all the patients and in 35.13% of females). The most frequent RF in patients with venous infarction was thrombophilia (40.9%), whilst in the CVT group without venous infarction the use of oral contraceptives predominated (26.7% of the total sample; 38% of females), with thrombophilic states only being detected in 16.5%. No cases of venous infarction were found in the group of patients with oral contraceptives but without an associated thrombophilic state. Conclusion: There appears to be a different profile of associated RF in patients with venous infarction associated to CVT, with the presence of thrombophilia prevailing (AU)

[Specificities of neonatal hemostasis and implications in pathologic situations]. / Particularités de l'hémostase chez le nouveau-né et implications en pathologie.

The haemostasis of healthy newborn differs from those of normal adult but remains well balanced without bleeding or thrombosis. However, this equilibrium is unstable, and the neonate is exposed to acquired or inherited haemostasis disorders that necessitate to be early diagnosed in order to be appropriately treated. Several studies provided reference ranges for haemostatic components in the foetus, the newborn and throughout childhood. The particularities of neonatal haemostasis are therefore better defined and contribute to further understand the pathophysiology and characteristics of hemorrhagic and thrombotic disorders that occur in newborns. Some examples of the impact of age on haemostasis are: the risk of neonatal alloimmune thrombocytopenia is high in the first newborn of a woman at risk since the involved antigens are fully expressed by foetal platelets; the newborn is at risk for vitamin K deficiency with bleeding due to poor transport of vitamin K across the placenta and low levels of coagulation factors II, VII, IX, X; the diagnosis of some inherited coagulation deficiencies can be difficult in the newborn due to physiologically low levels of coagulation factors; thrombotic events are rare in the healthy neonate, despite physiologically very low levels of several coagulation inhibitors; the pharmacokinetic and effects of antithrombotic agents are influenced by the specificities of haemostasis in neonates. This review will discuss about the foetal development of haemostasis until birth, and some implications regarding the pathophysiology, the diagnosis and the treatment of bleeding disorders in the human neonate.

The clinical significance of the lack of arterial or venous thrombosis in patients with congenital prothrombin or FX deficiency.

Several reports have dealt with the occurrence of both arterial and venous thrombosis in patients with haemophilia A, haemophilia B, and von Willebrand disease. Similar thrombotic events have been occasionally reported also in rare congenital coagulation disorders, particularly in fibrinogen or FVII deficiencies. On the contrary no sure venous or arterial thrombotic event has ever been reported in congenital prothrombin or Factor X deficiency. The significance of this observation is discussed. This discrepancy cannot be explained on the basis of the rarity of the two conditions, since in similarly rare congenital bleeding disorders such as FV or FXIII deficiency a few patients with thrombosis have been described. It appears that only these two defects are able to allow a sure protection from thrombosis. These observations may indirectly support the rationale for the use of direct thrombin or Factor X inhibitors in the prophylaxis and/or therapy of thrombotic manifestations.

The laboratory approach to inherited and acquired coagulation factor deficiencies.

Besides the long-recognized hemophilias, there are many other factor deficiencies. Some also are inherited, but others are acquired because of both immune and nonimmune etiologies. Understanding the optimal laboratory approach to evaluating factor deficiency will aid physicians and laboratory scientists in obtaining a prompt diagnosis and in avoiding pitfalls in coagulation testing.

Congenital prothrombin deficiency.

Prothrombin deficiency is among the rarest inherited coagulation disorders, with a prevalence of approximately 1:2,000,000. Two main phenotypes can be distinguished: (1) hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen; and (2) dysprothrombinemia (type II deficiency), characterized by the normal or near-normal synthesis of a dysfunctional protein. In some cases, hypoprothrombinemia associated with dysprothrombinemia was also described in compound heterozygous defects. No living patient with undetectable plasma prothrombin has been reported to date. Prothrombin is encoded by a gene of approximately 21 kb located on chromosome 11 and containing 14 exons. Forty different mutations have been identified and characterized in prothrombin deficiency. Many of them surround the catalytic site, whereas another "hot spot" is localized in the recognition domain called anion binding exosite I, also called fibrinogen recognition site. Recently, mutations were identified also in the Na (+)-binding loop and in the light A-chain of thrombin. Most hypoprothrombinemia-associated mutations are missense, but there are also nonsense mutations leading to stop codons and one single nucleotide deletion. Finally, the main aspects of clinical manifestations and therapy of congenital prothrombin deficiency are presented and discussed.

The risk of symptomatic pulmonary embolism due to proximal deep venous thrombosis differs in patients with different types of inherited thrombophilia.

It is uncertain whether the presence of inherited thrombophilia influences the risk of developing symptomatic pulmonary embolism (PE) and whether different thrombophilic alterations are associated with different risks of symptomatic PE. To investigate such issue, we retrospectively studied 920 patients with proximal deep vein thrombosis (DVT) of the legs with or without symptomatic PE referred for thrombophilia screening; patients with overt cancer or antiphospholipid antibodies had been excluded. Three hundred fifty-four patients (38.5%) had deficiency of antithrombin (AT, n = 16), protein C (PC, n = 26), protein S (PS, n = 22), factor V Leiden (FVL, n = 168), prothrombin G20210A (PT-GA, n = 87), or multiple abnormalities (n = 35), and 566 had none of the studied thrombophilic abnormalities. Symptomatic PE complicated the first DVT in 242 patients (26%); the risk of PE was increased in patients with AT deficiency (relative risk [RR] 2.4, 95% confidence interval [CI] 1.6-3.6) or with PT-GA (RR 1.5, 95%CI 1.1-2.0) and decreased in those with FVL (RR 0.7, 95%CI 0.5-1.0) in comparison with those with unknown inherited defect. These data suggest that patients with proximal DVT have different risks of symptomatic PE according to the type of inherited thrombophilia.

Congenital bleeding disorders of the vitamin K-dependent clotting factors.

Congenital bleeding disorders of the vitamin K-dependent coagulation factors represent only about 15-20% of all congenital bleeding disorders. However, they played an important role of the history of blood coagulation. Prothrombin was the first entity dealt with. Subsequently, in the late 1940s or early 1950s, the discovery of factor IX allowed the separation of hemophilia into two groups, A and B. In the 1950s, the discovery of factors VII and X allowed the formulation of a logic and plausible explanation for the clotting mechanism. The subsequent discovery of vitamin K-dependent proteins with an inhibitory effect on blood coagulation has further enhanced the importance of the vitamin K-dependent clotting factors. Recently, the study of families with multiple defects of the prothrombin complex has spurred the interest in vitamin K metabolism and the gamma-carboxylation system. The relevance of these studies had also an important role in the understanding the mechanism of action of other noncoagulation-related proteins. The vitamin K-dependent clotting factors represent a homeostatic mechanism at the basis of the hypercoagulability (thrombosis)-hypocoagulability (hemorrhagic) system, namely, to a mechanism that is vital for survival. The different bleeding condition will be dealt with separately, namely, prothrombin or Factor II, Factor VII, Factor IX (hemophilia B), and Factor X deficiencies. An additional heading deals with the combined defect of the prothrombin complex, namely, combined deficiency of Factor II, Factor VII, Factor IX, and Factor X. Since, sometimes, a hemorrhagic role has been attributed to Protein Z deficiency, another vitamin K-dependent protein, this defect will also be dealt with, even though briefly. Each deficiency has been approached in a global manner, namely, with adequate reference to history, background, prevalence, classification, hereditary pattern, biochemistry and function, molecular biology, clinical picture, updated laboratory diagnosis, prognosis, and therapy. Particular emphasis has been placed on the significance of cases with "true" deficiency [cross-reacting material (CRM negative)] and cases with abnormalities (CRM positive). The genetic, clinical, and laboratory implications of these two forms have been extensively discussed in every instance. The importance of a multiple, combined diagnostic approach that has to include whenever possible clotting, chromogenic, immunological, and molecular biology studies has been underlined. Clotting tests have to be carried out using different activating agents since results may vary, thereby indicating a different reactivity of the abnormal protein. Molecular biology techniques, alone, are unable to supply plausible diagnostic conclusions. In fact the genotype-phenotype relation has not been clarified so far for most of these bleeding conditions. Recent progress in management such as the use of recombinant factor concentrates, results of liver transplantation, and attempts at genetic therapy has been discussed. Potential complications of therapeutic measures have also been discussed. A section dealing with future putative aims of research in this field will close the chapter.