Pediatric systemic lupus erythematosus with lupus anticoagulant hypoprothrombinemia syndrome-A case series with review of literature.

INTRODUCTION: Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) is a rare phenomenon that leads to concomitant thrombosis and hemorrhage in children with SLE. LAHPS in pediatric SLE (pSLE) has a protracted course requiring long-term immunosuppressive therapy. Due to the rarity of this syndrome and paucity of reported cases, there is lack of standardized management. We herewith report 5 children with pSLE with LAHPS.Methodology: We retrospectively reviewed clinical features, laboratory features, treatment and outcome for 5 children with lupus anticoagulant hypoprothrombinemia syndrome with SLE and a review of literature of similar cases published. RESULTS: Mean age of presentation was 10.2 ± 2.38 years (mean ± SD) and female to male ratio was 4:1. All children presented with mild to severe bleeding manifestations like gum bleed, epistaxis, hematuria, menorrhagia and subarachnoid bleed. Coagulation profile revealed prolonged PT and aPTT, with low prothrombin levels and positive Lupus anticoagulant in all children. Mixing studies were characteristic in these children. On comparing laboratory parameters majority had low C3, C4 levels, ANA and anti-DsDNA antibody positivity and three children had anticardiolipin positivity. One child had lupus nephritis along with LAHPS at presentation. All responded well to steroids and supportive measures. CONCLUSION: High index of suspicion is needed when child with lupus presents with bleeding manifestations for early diagnosis and treatment.

Hypoprothrombinemia and severe perioperative haemorrhagic complications in cardiac surgery patients treated with high-dose cefazolin for infective endocarditis.

Endocarditis is a serious and common disease that requires prolonged antimicrobial therapy. The recent shortage of oxacillin has led to the use of other antimicrobial agents such as cefazolin to treat endocarditis due to methicillin-sensitive Staphylococcus aureus. We describe four cases of life-threatening haemorrhagic complications (fatal in two cases) in patients treated with high-dose cefazolin. All of these patients with major bleeding presented with hypoprothrombinemia secondary to hypovitaminosis K. This adverse event may be due to inhibition of vitamin K epoxide reductase and/or gamma-glutamyl-carboxylase by the 2-methyl-1,2,3-thiadiazol-5-thiol group of cefazolin. This inhibition may result in hypoprothrombinemia by altering the synthesis of vitamin K-dependent coagulation factors. The increasing use of cefazolin, especially at a high dose and for a prolonged period of time, should be accompanied by regular monitoring of coagulation, including prothrombin index, and vitamin K supplementation.

Lupus anticoagulant hypoprothrombinemia syndrome associated with severe thrombocytopenia in a child.

Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) comprises lupus anticoagulant, acquired hypoprothrombinemia, and often mild thrombocytopenia or normal platelets. It is usually associated with autoimmunity or postviral illness. We describe a case of a 10-year-old boy with oral bleeding and severe thrombocytopenia initially suggestive of immune thrombocytopenia. Secondary to bleeding, evaluation demonstrated prolonged coagulation tests and subsequently revealed the presence of lupus anticoagulant and hypoprothrombinemia, along with marked autoimmunity, suggestive of LAHPS. He was treated with intravenous immunoglobulin and hydroxychloroquine. This case report and discussion highlight the diagnostic and therapeutic challenges associated with LAHPS and coincident severe thrombocytopenia.

Lupus anticoagulant acquired hypoprothrombinemia syndrome in childhood: two distinct patterns and review of the literature.

INTRODUCTION: Lupus anticoagulant associated with acquired prothrombin deficiency also known as 'lupus anticoagulant hypoprothrombinemia syndrome' (LAHS) is an entity that is well described in adults and is usually associated with autoimmune conditions (LAHS-AI). However, in children, LAHS has unique features that are distinct from the adult type. AIMS: We report two paediatric cases of LAHS, describe their distinct patterns and review the paediatric literature on LAHS. METHODS: Case studies on two patients with LAHS were reviewed, details on their presentation, work up and management were extracted. A Medline search was conducted on LAHS in children between 1960 and 2014; Articles in languages other than English were excluded. RESULTS: The case studies highlight the differences in the two patterns of childhood LAHS. Additionally the review of the literature reveals that there are 15 case reports and 5 case series that report 25 children with LAHS-AI, 9 case reports and 6 case series report 26 children of LAHS associated with viral infections (LAHS-VI). At presentation, all patients with LAHS-AI had positive laboratory tests for autoimmune diseases, most commonly for systemic lupus erythematosus while these tests were negative in LAHS-VI. All patients with LAHS-AI had a protracted course and needed prolonged treatment with immune-suppressive therapy while patients with LAHS-VI resolved spontaneously or needed short-term immune-modulating therapy. CONCLUSION: In childhood, two distinct patterns of LAHS are observed, either associated with infection or autoimmune disease. Initial diagnostic investigations are critical to differentiating these two patterns as the prognosis and outcome for each is distinct.

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.

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 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.

Control of ovulation-induced hemoperitoneum by oral contraceptives in a patient with congenital hypoprothrombinemia and in another with congenital factor V deficiency.

Hemoperitoneum is a serious and often life-threatening bleeding manifestation. This is particularly true for women who carry congenital bleeding disorders. We describe here a hemoperitoneum occurring in 1 patient with congenital prothrombin deficiency and another with congenital factor V deficiency. Both patients have been followed by us for many years. The patient with prothrombin deficiency underwent laparoscopy but was treated consecutively with whole blood, plasma transfusions and 1,000 units of prothrombin complex concentrates. Response was good and she was then placed on oral contraceptives (OC) which prevented any recurrence. The patient with factor V deficiency presented several episodes of ovulation-related bleeding which required hospitalization and fresh frozen plasma transfusions. On the fifth occasion, the patient had to undergo surgery, and a left oophorectomy was carried out. After this last episode, she was also placed on OC which were very effective in preventing further recurrences. Both patients tolerated the medications very well which, in addition, were able to control menometrorrhagia with a consequent decrease over time in transfusional needs. OC are the treatment of choice in congenital bleeding disorders to control both the menorrhagia and, more importantly, ovulation-related hemoperitoneum.

The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation.

The rare coagulation disorders are heritable abnormalities of haemostasis that may present significant difficulties in diagnosis and management. This review summarizes the current literature for disorders of fibrinogen, and deficiencies of prothrombin, factor V, FV + VIII, FVII, FX, the combined vitamin K-dependent factors, FXI and FXIII. Based on both collective clinical experience and the literature, guidelines for management of bleeding complications are suggested with specific advice for surgery, spontaneous bleeding, management of pregnancy and the neonate. We have chosen to include a section on Ehlers-Danlos Syndrome because haematologists may be consulted about bleeding manifestations in such patients.

Rescue of prothrombin-deficiency by transgene expression in mice.

Prothrombin has diverse biological functions in addition to its well established role in blood coagulation. In order to study these functions in more detail mouse model systems are needed. Since deficiency of prothrombin in mice results in partial embryonic lethality and neonatal death, alternative approaches are required to study the biology of prothrombin in the adult mouse. The liver is the major site of synthesis of prothrombin and therefore liver-specific promoters were used to express prothrombin in transgenic mice. Mice generated from crosses with these transgenic mice and mice hemizygous for the knock-out allele were used to test whether liver-specific expression is sufficient to correct the phenotype of null mice and whether liver-specific expression is sufficient for the development and survival of mice to adulthood. The mouse albumin promoter/enhancer was used initially for transgene expression without success in obtaining transgene positive, endogenous prothrombin null mice. Two lines of transgene positive, endogenous prothrombin deficient mice were obtained using the mouse transthyretin (TTR) promoter/enhancer driving expression of a human prothrombin cDNA. One line was able to rescue both the embryonic and the neonatal lethality while the other line was only able to correct the embryonic lethality. Expression of prothrombin was restricted to the liver and stomach in one line and to the liver, pancreas, stomach and kidney in the other line of mice. Thrombin activity for one line was determined to be at 5-10% of wildtype levels. These mice developed normally and did not have spontaneous bleeding events unless traumatized. Therefore, transgenic expression of human prothrombin is sufficient for the rescue of the lethality found for prothrombin deficiency in mice.

Combined deficiency of factors II, VII, IX, and X (Borgschulte-Grigsby deficiency) in pregnancy.

BACKGROUND: Combined deficiency of vitamin K-dependent coagulation factors (II, VII, IX, X) is an uncommon challenge for the expectant gravida. CASE: A 34-year-old primigravida had congenital combined deficiency of factors II, VII, IX, and X that were incompletely sensitive to vitamin K. She had an altered form of vitamin K-dependent factors that retained immunologic activity but lacked coagulant activity and the normal complement of gamma-carboxyglutamic acid residues. She required vitamin K supplementation throughout her life. After an uneventful pregnancy she had postpartum hemorrhage resulting from an episiotomy. Fresh frozen plasma was administered to achieve hemostasis. The remainder of her postpartum course was normal. CONCLUSION: Combined congenital deficiency of factors II, VII, IX, and X can be managed in pregnancy with the use of vitamin K and fresh frozen plasma.

Severe bleeding due to acquired hypoprothrombinemia-lupus anticoagulant syndrome. Case report and review of literature.

A 17-year-old girl was admitted to our department with a hemorrhagic syndrome due to a serious coagulopathy; prothrombin time (PT) INR was 2.46 and the activated partial thromboplastin time (aPTT) ratio 3.46. Coagulation tests with pooled normal fresh plasma did not correct aPTT because of a coagulation inhibitor, and only partially corrected PT. Factor II activity reached only 5%. Diluted Russell viper venom tests (dRVVT) and kaolin clotting time (KCT) of patient plasma (PP) and of a mixture of PP/normal plasma (NP) detected the lupus anticoagulant (LA). The level of factor II antigen was 10%. We diagnosed systemic lupus erythematosus (SLE) with a rare acquired hypoprothrombinemia-LA syndrome (HLAS). The patient was treated with corticosteroids and high-dose Ig and a normal PT value was re-established.

[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.

Replacement therapy for congenital Factor X deficiency.

We studied a young woman with severe (less than 1%) congenital factor X deficiency during a 2-year period in order to document the levels of factor X required to provide hemostasis for vaginal bleeding, epistaxis, and hemarthroses, as well as during surgery. Factor X levels of 9 to 17 percent, achieved with fresh-frozen plasma (FFP) were satisfactory for minor bleeding. Hemostasis was achieved during emergency surgery for hemoperitoneum by increasing the factor X level to 35 percent with a Factor IX concentrate, followed with infusions of FFP to maintain levels between 10 and 20 percent for 6 days postoperatively. These data suggest that factor X levels of 10 to 20 percent are sufficient for hemostasis in factor X-deficient patients even in the immediate postoperative period.

Resolution of factor X deficiency in primary amyloidosis following splenectomy.

A 57-year-old man with primary amyloidosis was initially seen with hematuria, cutaneous bleeding, and hepatosplenomegaly. Factor X was determined to be 10% to 16% of normal plasma values. Administration of vitamin K-dependent factor concentrate transiently improved in vitro clotting tests but did not alter the clinical course. Following a splenectomy, bleeding ceased and factor X levels returned to normal, remaining so despite discontinuation of factor concentrate infusion. Amyloid fibrils extracted from the patient's spleen were determined to be derived from lambda V1 light chains. The importance of splenectomy as an effective therapeutic modality is discussed.