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.

Hereditary prothrombin deficiency.

Hereditary prothrombin deficiency is one of the rare congenital coagulation defects. We report a case of 4 months old child who initially presented at 11/2 month of age with high-grade fever, generalized convulsions and brownish aspirate through nasogastric tube, diagnosed and managed as meningitis and sepsis. He was readmitted at 4 months of age with bruises over legs. Coagulation profile was suggestive of common pathway defect. Further evaluation revealed absent prothrombin level while other factors were within normal limits.

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.

Congenital deficiencies and abnormalities of prothrombin.

Prothrombin (factor II) deficiency was first described in 1947 by Quick et al., although the first prothrombin abnormality was reported in 1969 by Shapiro et al. The condition is still considered very rare. In spite of its rarity, the defect has allowed important improvements in our understanding of both congenital and acquired prothrombin deficiencies. The diagnosis of prothrombin deficiency or abnormality can be made using a combination of clotting, chromogenic and immunological assays. In cases of true deficiency, a parallel decrease in all these assays is observed, regardless of the activating agent. If discrepancies among the clotting assays are noted, particularly using viper venoms, a dysprothrombinemia should be suspected. Usually, activity levels less than 10% of normal are found in homozygotes, and between 40 and 60% in heterozygotes. Factor II levels in congenital dysprothrombinemias are more variable since one may encounter homozygotes, heterozygotes and compound heterozygotes between a heterozygous abnormality and heterozygous 'true' deficiency or between two distinct abnormalities. Usually the levels of factor II vary between 1 and 50% of normal. Antigen levels in congenital dysprothrombinemias will be normal, near normal or slightly decreased but always higher than the clotting counterpart. Cases with a parallel decrease in prothrombin activity and antigen should not be considered as examples of hypoprothrombinemia. The gene involved in the synthesis of prothrombin is located in chromosome 11. It is composed of 10 exons and 8 introns. Molecular biology studies have discovered several point mutations in some of the dysprothrombinemias. Bleeding manifestations may be severe in homozygous 'true' deficiency and may be more variable in dysprothrombinemias. Heterozygotes are usually asymptomatic. Prognosis is variable and generally in agreement with the prothrombin activity level. In homozygous true deficiency, hemarthroses and intracranial bleeding have been described. Substitution therapy is based on the administration of prothrombin complex concentrates or of plasma. The long half-life of prothrombin injected, about 70 h, allows the achievement of hemostatically effective levels (about 50% of normal) without difficulty.

Pregnancies in a patient with congenital absence of prothrombin activity: case report.

Congenital hypoprothrombinemias are very rare, inherited disorders in which factor II (prothrombin) levels and/or activity are extremely low or absent. We report eight pregnancies in a patient with this disorder. Obstetric complications attributed to the coagulation disturbance included first-trimester bleeding in each pregnancy, miscarriage in four of the pregnancies, spontaneous maternal subarachnoid hemorrhage in one, and postpartum hemorrhage in one of four term pregnancies despite administration of clotting factor concentrate. The management of pregnancy in congenital hypoprothrombinemia, and issues of coagulation factor replacement, are discussed.

[Intracranial hemorrhage in congenital factor II deficiency]. / Emorragia endocranica nel deficit congenito del fattore II.

A case of congenital defect of factor II is reported. It concerns a newborn with a not traumatic haematoma due to congenital hypoprothrombinaemia, which is rarely described in scientific literature.

Risk factors of bleeding diathesis secondary to low prothrombin complex level in infants: a preliminary report.

Twenty infants aged 2 weeks to 3 months with the diagnosis of bleeding disorder secondary to low prothrombin complex level were studied. Sixty children of the control group were matched to the cases by age +/- 2 weeks, sex and race. The ratio of boys to girls was 2.3:1. The median, mean, and range of age of the cases and controls were 43.5 days, 43.7 days, 21-73 days and 43.5 days, 46.8 days, 26-28 days respectively. Most of them were pale with a mean hematocrit of 23.55%. The partial thromboplastin time and prothrombin time were markedly prolonged. The means of vitamin K dependent coagulation factors II, VII, IX and X were 1.10%, 5.87%, 2.86%, and 4.47% of adult activity, respectively. The clinical manifestations related to the bleeding of the cases were drowsiness and convulsion (95%), pallor (85%), and apparent bleeding (10%). The sites of the bleeding were demonstrated in the cranial cavity (95%), gastrointestinal tract and oral cavity (15%), and skin (5%). Nineteen patients with intracranial hemorrhage had bleeding in the subdural space (79%), intracerebral (42%), intraventricular (32%), and subarachnoid space (5.2%). The mortality rate and permanent brain damage occurred in 10% and 45%, respectively. Only 45% of the cases recovered normally. The permanent neurological sequelaes were hemiparesis (44.4%), microcephaly (33.3%), convulsive disorder (33.3%), mental retardation (33.3%), spasticity (22.2%), and hydrocephalus (11.1%). Breast feeding alone up to the day of study (OR = 7.0, p < 0.005) was found to be a significant risk factor for bleeding in these infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Dicumarol content in alcoholic herb elixirs: one of the factors at risk induced IVKD-I.

Nine medicinal plants known to be the ingredients of the traditional herbal medicinal elixir, and seven popular commercial alcoholic herb elixirs were investigated for the content of dicumarol by using high pressure liquid chromatography (HPLC) and thin layer chromatography (TLC) methods. Umbelliferae (Conioselinum Univittatum) were the only medicinal plants found to contain dicumarol 0.04 mg/dl. Dicumarol content was also found in three out of seven brands of commercial alcoholic herb elixirs with the concentration of 0.58, 1.86 and 6.00 mg/dl. These findings indicated that the traditional herbal medicinal elixirs containing dicumarol in varying amount may play a role in inducing bleeding diathesis in breast-fed infants of mothers known to consume the elixir.

Antenatally diagnosed subdural haemorrhage in congenital factor X deficiency.

The presence of a subdural haemorrhage was observed in a fetus during antenatal ultrasound examination. The infant was found to be a homozygote for factor X deficiency. Prompt recognition permitted replacement treatment from an early stage. Inherited coagulation disorders should be suspected when intracranial haemorrhage is detected antenatally.

Prothrombin Segovia: a new congenital abnormality of prothrombin.

A family with a new congenital dysprothrombinemia is presented. The propositus is a 21-yr-old man who presented simultaneously with hemartrosis of the left knee and an extensive hematoma following a minor trauma. Prothrombin time and activated partial thromboplastin time were prolonged. Prothrombin activity was very low when measured by biological assay using physiological activators (7% by one-stage method and 20% by two-stage method) or a Russel's viper venom-cephalin mixture (23%), Notechis scutatus scutatus venom (15%) and Echis carinatus venom (17%); in contrast, the level was found to be borderline to normal using Taipan viper venom (64%) and normal by both staphylocoagulase and immunologic methods. Family studies revealed consanguinity between the propositus' mother and father and both presented a 50% reduced prothrombin level when physiological activators or Echis carinatus viper venom were used. A line of identity between normal and abnormal prothrombin was observed on immunodiffusion. The migration of the abnormal prothrombin was less anodic and was not changed by the addition of calcium. The patient's serum showed 3 bands in the bidimensional immunoelectrophoresis system, whereas normal serum showed only 2 bands. The term prothrombin Segovia is proposed to define this new prothrombin abnormality.

Severe congenital factor X deficiency with intracranial haemorrhage.

A Saudi Arabian infant with severe factor X deficiency who had had two intracranial haemorrhages is described. Attempts to raise his factor X level and improve his prothrombin time (PT) and partial thromboplastin time (PTT) by using vitamin K, oestradiol and danazol have failed. New therapeutic trials are necessary for patients with severe forms of this rare disorder.

Prothrombin Habana: a new dysfunctional molecule of human prothrombin associated with a true prothrombin deficiency.

A Cuban family with a new congenital dysprothrombinaemia is described. The propositus was a 5-year-old female who presented with umbilical bleeding after birth followed by easy bruising and bleeding tendency throughout her life. The main laboratory features of the defect included prolongation of prothrombin time and partial thromboplastin time. Prothrombin activity was less than 10% in several one- and two-stage systems. However, the staphylocoagulase-complexed prothrombin level and immunologic methods yielded levels of about 50%. The migration of the abnormal prothrombin was more anodic in single and bidimensional immunoelectrophoresis system and did not change by the addition of calcium. Family studies revealed that the father had approximately 50% prothrombin activity and antigen, whereas the mother had 45% prothrombin activity but about 100% prothrombin antigen. We suggest that the propositus is heterozygous for an abnormal prothrombin and heterozygous for true prothrombin deficiency.

Prothrombin antigen evaluation by means of laser nephelometry in health and disease.

Prothrombin antigen concentration was evaluated by means of laser nephelometry in 10 patients on coumarin therapy, in 17 patients with cirrhosis of the liver, and in four patients with congenital hypo- or dysprothrombinemias. The average values obtained were 46.4, 37.7, and 35.6%, respectively, for anticoagulated, cirrhotic, and congenitally abnormal patients. These values correlated well with those obtained by means of electroimmunoassay (Laurell) and immunodiffusion (Mancini) methods. Similarly, satisfactory results were obtained in eight normal subjects. Multiple evaluations at different incubation times, also allowed the authors to construct kinetic curves of the interaction between antigen and antibody. However, an abnormal kinetic curve was demonstrated only for coumarin-treated patients.

Prothrombin Gainesville. A dysprothrombinemia in a pair of identical twins.

A pair of identical twins was evaluated for menometrorrhagia and mild post-operative bleeding. Each had a slightly prolonged partial thromboplastin time and prothrombin time. Full hemostatic evaluation was normal, except that plasma prothrombin activity was 23% and 25% of normal with a Russell's viper venom assay. Each twin had 70% of normal plasma prothrombin antigen. Prothrombin kinetic data were obtained before and during hysterectomy. In these twins, infused prothrombin (Konyne) was found to have a volume of distribution of approximately one and one-half times the plasma volume and a half-life of 34 hours. The previously reported dysprothrombins are briefly reviewed. Prothrombin Gainesville is the twelfth such disorder reported.