Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiency

Factor XI (FXI) inhibitors are a rare complication of inherited FXI deficiency. We report the successful use of recombinant factor VIIa (FVIIa) in a patient with a high-responding inhibitor undergoing cataract extraction. At the time of surgery there were limited available data on the optimal management of patients with FXI deficiency. A 62-year-old Ashkenazi Jewish woman had a lifelong history of excessive bleeding secondary to severe FXI deficiency (2 U dL-1), and received FXI concentrate (FXI:C) when she underwent a colposuspension procedure. She was subsequently diagnosed with a FXI inhibitor of 16 Bethesda units (BU) when she developed a poor response to FXI:C at the time of total hip replacement. Two months later she was admitted for cataract extraction. The FXI level was < 1 U dL-1 with an inhibitor titre of 48 BU. She received 90 microg kg-1 of FVIIa immediately preoperatively followed by continuous infusion at a rate of 20 microg kg-1 h-1 for 24 h. The cataract extraction was successful and there was no excess bleeding during surgery or in the postoperative period. Mutation analysis of the FXI gene showed that the patient was homozygous for the type II genotype [exon 5, Glu117-->Ter]. The reason for the low prevalence of inhibitor formation in patients with FXI deficiency is unclear but may reflect a number of factors including reporting bias, the rarity of absent circulating FXI:C activity, and the infrequent use of FXI replacement therapy.     

Successful childbirth by a patient with congenital factor XI deficiency and an acquired inhibitor

Summary. Acquired inhibitors in factor XI deficiency (FXI) are rare. The presence of an inhibitor during pregnancy poses a potential haemorrhagic risk to the fetus. We report an uncomplicated pregnancy and successful childbirth by a woman with congenital FXI deficiency and an acquired inhibitor, and discuss the persistence of residual FXI activity in the presence of an inhibitor.     

Clinical experience of factor XI deficiency: the role of fresh frozen plasma and factor XI concentrate

Summary. Factor XI deficiency is a rare autosomally transmitted coagulopathy that is associated with a variable bleeding tendency. Recently there have been reports of thrombotic events following the administration of a virally inactivated factor XI concentrate (BPL) to factor XI deficient patients. We have therefore reviewed a single centre's experience of the use of factor XI concentrate over a 6-year period and compared this to our previous experience of either no treatment or treatment with fresh frozen plasma (FFP) in 103 patients.
There were 156 procedures performed without haemo- static cover. The incidence of bleeding was greatest following tonsillectomy (71%) and dental extraction (Sl'h). There was a trend for bleeding complications to be associated with lower levels of factor XI but patients with all levels of factor XI suffered bleeding complica- tions. There were 38 procedures carried out under FFP cover, with only one patient suffering excessive bleeding and no serious complications.
Factor XI concentrate was given to 25 patients to cover 45 episodes. There were no bleeding complications. Three patients suffered serious complications. One patient, with a previous history of cardiovascular disease, died of a myocardial infarction and a second had an ischaemic episode resulting in a %day hospital admission. These episodes both occurred on the same day as the factor XI infusion. A third patient suffered bilateral pulmonary emboli 7 weeks after a prolonged course of factor XI concentrate.
These finding suggest that factor XI concentrate should be contraindicated in patients with a history of cardiovascular disease, when FFP should be used. Guide- lines for the use of factor XI concentrates should be revised, and work performed to establish the mechanism of these thrombotic events.     

Successful hip arthroplasty in an adult male with severe factor XI deficiency using Hemoleven®, a factor XI concentrate

Summary. Severe factor XI (sFXI) deficiency is a rare bleeding disorder (RBD). FXI replacement is most often required for surgical hemostasis. Plasma, the sole US treatment option, is often complicated by life‐threatening allergic reactions. In such circumstances, the FDA offers a mechanism for institution‐industry collaboration to facilitate limited use of replacement products licensed abroad. A 58 years old man with sFXI deficiency, required hip replacement. In the past, he received prophylactic plasma for thyroidectomy and experienced a severe allergic reaction. A single use institutional IND FDA application was initiated in collaboration with LFB (Les Ulis, France) to access Hemoleven^®, a plasma‐derived FXI concentrate. The application required an investigator‐initiated IRB‐approved protocol for treatment and safety/efficacy monitoring that included: preoperative thrombophilia, FXI inhibitor and pharmacokinetic (PK) evaluations; peri‐ postoperative administration of ≤ 4 doses of 10‐15 U/kg Hemoleven^®; DIC monitoring; postoperative thromboprophylaxis; observation for product efficacy and potential complications. PK study demonstrated the expected 1.8% FXI recovery per U/kg with half‐life of 62 hours. Mild D‐Dimer elevation was noted 6‐9 hours post‐infusion. The initial dose (15U/kg) was administered 15 hours before surgery; subsequently, 3 doses (10U/kg) were infused every 72 hours. Hemostasis was excellent. No complications were observed. Collaboration allowed for successful patient access to Hemoleven^® with excellent PK, safety, and efficacy. This case underscores the need for additional efforts to ensure safe and effective licensed replacement therapies for RBD patients.     

Successful emergency operation for subdural hematoma and acute epidural hematoma in a patient with acute promyelocytic leukemia]

A 22-year-old woman was admitted with purpura. Acute promyelocytic leukemia (APL) with disseminated intravascular coagulation (DIC) was diagnosed. On the 17th day after treatment with all-trans retinoic acid (ATRA), left subdural hematoma developed. Although coagulation abnormalities were still observed, emergency surgery was performed. Acute epidural hematoma was confirmed by computed tomographic scan after the operation. A second operation for drainage was successful. Post-operative intracranial hematoma may be caused by rapid decompression induced by surgery, but DIC could also be involved. This case underscored the need for careful consideration of the indications for surgical treatment of such DIC patients, with close follow-up monitoring for the postoperative development of neurological symptoms.     

Occurrence of subdural hematoma closely associated with danazol administration in a patient with refractory ITP

We reported a 34-year-old female patient with refractory idiopathic thrombocytopenic purpura (ITP) in whom a subacute subdural hematoma occurred without any preceding trauma during danazol administration which resulted in a marked decrease of plasma fibrinogen level. It is strongly suggested that danazol should be very carefully administered in ITP patients with serious bleeding tendency.     

Use of fresh‐frozen plasma at Royal Darwin Hospital: a retrospective audit

Background: The aim of the study was to assess the appropriateness of use of fresh‐frozen plasma (FFP) at Royal Darwin Hospital against the National Health and Medical Research Council and Australian and New Zealand Society for Blood Transfusion guidelines. Methods: A retrospective review of blood product request forms, online pathology storage system data, pathology records and clinical notes between 1 January 2006 and 31 December 2006 was carried out. The appropriateness of requests was assessed against existing guidelines. The percentage of appropriate and inappropriate FFP transfusions was obtained. Results: Six hundred and forty‐eight of 950 units (68%) of FFP were used with an appropriate indication as per National Health and Medical Research Council/Australian and New Zealand Society for Blood Transfusion guidelines. Of the remaining units, 14% (137 units) was given without a clear indication and a decision of appropriateness could not be established for 17% (165 units) because of inadequate clinical or pathology information (e.g. coagulation results). Multiple issues around prescribing practice were identified. Conclusion: There is significant use of FFP at Royal Darwin Hospital without clear clinical indication. The employment of a transfusion nurse to monitor use of FFP (and other blood products) and provide education is aimed at improving transfusion efficiency and patient safety.     

A novel factor XI gene mutation associated with mild factor XI deficiency in a symptomatic patient.

Congenital factor XI deficiency is a rare condition, in which plasma factor XI levels correlate poorly with the severity of haemorrhage. The condition is typically characterized by post-traumatic bleeding. The factor XI gene is located on chromosome 4 and contains 15 exons. More than 80 mutations have so far been described. We describe a novel mutation in the factor XI gene associated with mild factor XI deficiency. The patient, who is of Irish descent, has a history of post-traumatic bleeding and was found to have a borderline factor XI deficiency. DNA sequence analysis of the factor XI gene revealed a novel T to A mutation at nucleotide 168 resulting in the substitution of the cysteine residue at codon 38 with a stop codon (Cys38STOP). The mutation predicts the premature termination of translation of factor XI mRNA resulting in a truncated, and probably unstable, factor XI protein. The presence of the mutation is consistent with the patient's borderline factor XI deficiency.     

The management of factor XI deficiency

Summary. Factor XI deficiency leads to a more variable bleeding tendency than haemophilia A or B. Although severely deficient individuals are likely to bleed excessively especially after surgery in areas of the body with increased fibrinolysis, there is evidence that some partially deficient individuals are at risk of excessive bleeding. This will entail careful planning for surgery. Several therapeutic modalities are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs and desmopressin. The advantages and risks of these are considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used, it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.     

Myocardial infarction in a patient with factor XI deficiency and a lupus anticoagulant

A 64-year-old man with both Factor XI deficiency and a lupus anticoagulant who suffered two myocardial infarctions within a 3-month period is described. Although thromboembolic disorders, including myocardial infarction, have been associated with the antiphospholipid syndrome, myocardial infarction in patients with Factor XI deficiency is rare. The potential role of Factor XIa in fibrinolysis is discussed.     

The characterization and impact of microparticles on haemostasis within fresh‐frozen plasma

Background We have previously demonstrated that clot formation in fresh‐frozen plasma (FFP) is influenced by the presence of microparticles (MP). In this study, the cellular source(s), properties and influence of MPs on clot formation within FFP were further characterized. Methods Fresh‐frozen plasma was prepared after an overnight hold of whole blood at 4°C. We examined the effect of a 0·2 µm filtration device designed to remove cellular MPs on thrombin generation test (TGT) and Thrombelastography (TEG®) as well as clotting factors and physiological inhibitors: prothrombin time (PT); activated partial thromboplastin time (APTT), fibrinogen (Fg), factor VIII (FVIII), von Willebrand factor antigen (VWF:Ag), antithrombin III (AT‐III) and protein C (PC). MPs were measured using a functional assay and also by flow cytometry. Results Microparticle levels by functional assay were reduced by filtration (pre‐ 5·11 vs. post‐ 4·43 nmol/l phosphatidylserine equivalent, P < 0·0001). Flow cytometry showed that the most numerous MPs were derived from red blood cells, with ~87% binding annexin V, most of which (94%) were removed by filtration. MP removal had minimal effect on the PT, APTT, Fg, VWF:Ag, AT‐III or PC or FVIII, but a major effect on TGT (endogenous thrombin potential: pre‐ 1722 vs. post‐ 990 nM thrombin, P < 0·0001; peak thrombin: pre‐ 91 vs. post‐ 44 nM thrombin, P < 0·0001), which in turn reflected the changes seen in TEG®, where post‐filtration clots started forming more slowly and the rate of clot formation was reduced. Conclusion These data suggest that MPs contribute towards clot formation in FFP.     

Two factor XI mutations in a Chinese family with factor XI deficiency

We describe a Chinese family with factor XI deficiency, the first reported to date. The proband had factor XI activity of 1% and was heterozygous for two nonsense mutations, an exon-8 C713-->T mutation resulting in Gln263-->Term, and an exon-10 C979-->A mutation resulting in Tyr351-->Term. Two daughters were heterozygous for the Gln263-->Term mutation and two for the Try351-->Term mutation. All showed a reduction of factor XI activity to about 50%. The Gln263-->Term mutation has been described in two Japanese families, and it remains to be determined whether a common founder exists between the three kindreds. The Try351-->Term mutation is novel.     

Pulmonary embolism in a patient with severe congenital deficiency for factor V during treatment with fresh frozen plasma

Thrombosis is a rare complication in patients with congenital clotting factor deficiencies. In most cases, it is related to inherited procoagulant factors, use of central venous catheters or administration of coagulation factor concentrates. There are only a few case reports about thrombotic events during treatment with fresh frozen plasma (FFP). We report the case of a patient with homozygous inherited factor V deficiency, who developed a pulmonary embolism at a time of treatment with methylene blue treated FFP (MBFFP). The patient had only two other factors predisposing to thrombosis and both were acquired: obesity and bed rest. He started anticoagulant treatment with low molecular weight heparin (LMWH) while the deficient factors were replaced with MBFFP. After 8 days of treatment the patient developed a severe respiratory insufficiency. Pulmonary haemorrhage was considered among the differential diagnosis and LMWH was stopped. An inferior vena cava filter was placed without any further thrombotic complications. To our knowledge, there are no reports about patients with clotting factor deficiencies who developed a thrombotic event during treatment with MBFFP.