1/114. Prothrombin carora: hypoprothrombinaemia caused by substitution of Tyr-44 by Cys. Two members of a family from Carora, venezuela, were found to have prothrombin activity levels at 4% of normal and undetectable antigen levels. All exons of the prothrombin gene from the proband were sequenced and a mutation at nucleotide 1305 was identified that would result in the substitution of Cys for Tyr at residue 44. Residue 44 is present in the aromatic stack region of the protein. Substitution of a Cys in this region would result in an abnormal folding of the protein which could be the cause for the observed lack of secretion of the abnormal prothrombin. ( info) |
2/114. Lupus anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus: report of 2 cases and review of literature. We describe two patients whose initial presentation of systemic lupus erythematosus (SLE) was accompanied by haemorrhagic episodes and significant coagulopathy. Further investigation demonstrated positive lupus anticoagulant and decreased Factor II (prothrombin) activity. Both patients were diagnosed with lupus anticoagulant-hypoprothrombinemia syndrome (LAC-HPS) as a result of non-neutralizing antibodies directed against Factor II. LAC-HPS is a rare clinical entity that can occur in association with SLE, transient viral infections, drug reactions or even in healthy individuals. Mixing studies, which can be affected by other coagulation factor inhibitors, play an important role in the diagnosis of LAC-HPS. Factor VII level was decreased in the second patient, a finding that has not previously been reported in association with SLE. In both patients, bleeding stopped promptly and coagulation studies improved significantly with high dose corticosteroids. We discuss the pathogenesis, diagnosis and management of LAC-HPS in patients with SLE. ( info) |
| ciprofloxacin, when given to patients previously anticoagulated with warfarin, can occasionally cause an exaggerated hypoprothombinemic response and bleeding diatheses. Two such cases encountered at our institution are presented and data is combined with 64 cases reported to the food and Drug Administration's (FDA) Spontaneous Reporting System (SRS) database, which included all cases reported from 1987 through 1997. Of 66 total cases the median age was 72 (range 36-94). The mean time to detection of the coagulopathy following the ciprofloxacin challenge was 5.5 days (n = 50). hospitalization was reported in 15 cases, bleeding in 25 cases, and death in one case. The median prothrombin time (PT) and international normalized ratio (INR) was 38.0 (n = 13) and 10.0 (n = 23), respectively. The mean number of medications taken was 6.5 (n = 45). The mean time to correction was significantly shorter between the treated (2.5 days) and the untreated (4.0 days) groups (P < 0. 008). The ciprofloxacin-warfarin coagulopathy occurred most commonly in patients in their seventh decade and in those who require polypharmacy. Active treatment of the coagulopathy results in more rapid resolution than observation alone. Clinicians should be aware of the potential bleeding complications that can occur with the ciprofloxacin-warfarin drug-drug interaction. ( info) |
4/114. Prothrombin San Antonio: a single amino acid substitution at a factor xa activation site (Arg320 to His) results in dysprothrombinemia. Three members of a San Antonio, texas, family were identified with prothrombin activity levels half the normal level but to have normal levels of antigen. All exons of the prothrombin gene from the proband were sequenced. A G-to-A mutation at nucleotide 7543 was found that resulted in the substitution of His for Arg at residue 320. The Arg320-Ile321 bond is 1 of 2 sites in prothrombin cleaved by factor xa in the prothrombinase complex to form thrombin. Substitution of His for Arg at this site resulted in the blockage of factor xa cleavage, forming a dysfunctional molecule. The proband, her mother, and her maternal aunt were found to be heterozygous for this mutation. This is the first known observation of an amino acid substitution at this site that resulted in dysprothrombinemia. (Blood. 2000;95:711-714) ( info) |
5/114. Hereditary prothrombin deficiency presenting as intracranial haematoma in infancy. Hereditary deficiency of prothrombin is a rare autosomal recessive bleeding disorder, with severe bleeding diathesis in homozygotes, but rarely resulting in intracranial haematoma. We describe two infants of consanguineous parents, presenting with acute subdural haematoma. Because such haematomas in infancy are highly indicative of trauma caused by child battering and because the socio-economic status of the family was unstable, there was a suspicion of child battering. However, further investigations revealed a bleeding diathesis due to a prothrombin deficiency. dna analysis of the prothrombin gene showed homozygosity for a novel mutation, substituting Lys for Glu at codon 7 and resulting in decreased specific clotting activity. We discuss the probability of bleeding diathesis versus child battering in the aetiology of intracranial haematoma. ( info) |
6/114. Cyclooxygenase-2 inhibitor celecoxib: a possible cause of gastropathy and hypoprothrombinemia. Gastrointestinal side effects from nonsteroidal anti-inflammatory drugs (NSAIDs) result mainly from inhibition of the enzyme cyclooxygenase (COX)-1; it is responsible for the synthesis of prostaglandin E2, which leads to increased mucosal blood flow, increased bicarbonate secretion, and mucus production, thus protecting the gastrointestinal mucosa. In inflammation, COX-2 is induced, causing synthesis of the prostaglandins in conditions such as osteoarthritis and rheumatoid arthritis. Two NSAIDs (celecoxib and rofecoxib) with very high specificity for COX-2 and virtually no activity against COX-1 at therapeutic doses have been approved for clinical use. In trials of celecoxib and rofecoxib, only 0.02% of patients had clinically significant gastrointestinal bleeding, compared to a 1% to 2% yearly incidence of severe gastrointestinal side effects with NSAIDs. Our patient had arthritis of the hips and chronic atrial fibrillation and was on warfarin therapy for stroke prevention; less than a week after starting celecoxib therapy, gastrointestinal bleeding and hypoprothrombinemia occurred. ( info) |
7/114. Gingival bleeding, epistaxis and haematoma three days after gastroenteritis: the haemorrhagic lupus anticoagulant syndrome. A 3 year and 9 month-old girl presented with gingival bleeding, epistaxis, and multiple haematomas 3 days after an acute episode of gastroenteritis. prothrombin time and activated partial thromboplastin time were prolonged with reduced clotting activity of factor II (< 10%), VIII (<1%), IX (3%), XII (10%) and evidence of a high titre inhibitor. Prothrombin (factor II) level was below the detection limit, both in a functional and immunological assay. It did not increase after administration of vitamin k or fresh frozen plasma. Further studies revealed presence of a strong lupus anticoagulant and a specific IgG antibody against prothrombin. factor viii antigen levels also were reduced (31%), but to a lesser extent than functionally determined factor viii (<1%). blood coagulation normalised following clinical recovery 6 weeks after admission. The pathophysiology of this acquired inhibitor phenomenon (accelerated clearance of complexes of clotting factors and phospholipids) is discussed. CONCLUSION: The haemorrhagic lupus anticoagulant syndrome (acquired hypoprothrombinaemia lupus anticoagulant syndrome) is a rare presentation of acquired bleeding diathesis in childhood. Since most cases in post-infectious children are asymptomatic, it might be underdiagnosed. In children with newly appearing bleeding symptoms or unclear prolonged prothrombin time or activated partial thromboplastin time, one has to consider this syndrome which could lead to relevant bleeding. ( info) |
8/114. Acquired bleeding disorder in a patient with malignant lymphoma: antibody-mediated prothrombin deficiency. BACKGROUND: Bleeding manifestations secondary to acquired hemostatic abnormalities in cancer patients have been well described. Bleeding due to the development of hemostatic inhibitors is observed less frequently. In this report, the authors describe a patient with a low grade lymphoma who presented with an acquired bleeding disorder and abnormal hemostatic screening tests. methods: Patient plasma samples were collected initially and during the course of treatment. Mixing studies and specific coagulation factor assays were performed to detect and confirm any deficiencies. Patient immunoglobulin g was isolated from plasma, and binding to prothrombin was demonstrated by immunoblot method and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: Initial prolongations in the prothombin time and the activated partial thromboplastin time suggested a factor deficiency in the common pathway of coagulation. Factor assays confirmed that the coagulation abnormality in this patient was the result of an acquired prothrombin (factor II) deficiency. This was confirmed by an immunoassay for prothrombin antigen. Further studies demonstrated the presence of a noninhibitory antibody to prothrombin that interacted with a calcium dependent epitope. CONCLUSIONS: Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of all hemostatic abnormalities and manifestations. An acquired prothrombin deficiency has not been reported previously in association with a malignancy, and this patient represents the first such documented case. ( info) |
9/114. 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. ( info) |
10/114. diagnosis of lupus anticoagulant in the lupus anticoagulant-hypoprothrombinemia syndrome: report of two cases and review of the literature. We report a severe hemorrhagic disorder in two pediatric patients with lupus anticoagulant (LA) associated to acquired factor II (prothrombin) deficiency. In both patients, hemorrhagic symptoms resolved after corticosteroid therapy. Serial coagulation studies showed that Staclot LA assay was more sensitive than DVVconfirm and Staclot PNP tests to confirm the presence of LA when associated with severe factor II deficiency. Both patients had non-neutralizing anti-prothrombin antibodies and their titers inversely correlated with factor II activity (r = -1.0, P < 0.0001). Associated findings in these patients included positive immunologic tests for systemic lupus erythematosus, a positive anti-cardiolipin antibody, and anti-beta(2) GPI antibodies in one case. Our findings point out the difficulty in diagnosing LA associated with acquired factor II deficiency and suggest that, in confirmation of its phospholipid dependency, the inclusion of a source of normal human plasma in the test sequence to correct for any factor deficiency and a confirmatory step utilizing hexagonal (II) phase phospholipids may be crucial to the diagnosis of LA in some patients with LA-hypoprothrombinemia syndrome. ( info) |