Fernando Hernandez-Navarro

Nutritional recommendations in hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation is a procedure necessitating the administration of high-dose chemoradiotherapy. This therapy may induce aggressive disruptions that can lead to special nutritional and metabolic conditions. These patients are at an increased risk for malnutrition in the phase before transplantation and afterward. Artificial nutrition, total parenteral nutrition in particular, is provided to patients undergoing hematopoietic stem cell transplantation to help minimize adverse nutritional consequences.

Prophylaxis in 10 patients with severe haemophilia A and inhibitor: different approaches for different clinical situations.

Summary.  The effect of bypassing agents is not as predictable as replacement therapy with the deficient factor in inhibitor patients. Consequently, these patients have more levels of arthropathy than patients without inhibitors. Prophylaxis for inhibitor patients has gained attention over the last decade and some papers have reported that bypassing agents could work in the prevention of arthropathy. However, there is a lack data to support any specific agent or regimen or even to recommend their use in different clinical conditions. We report ten patients with haemophilia A and inhibitors treated prophylacticaly with bypassing agents (5 with FEIBA and 5 with NovoSeven). The variable conditioning the choice of one agent or the other was the intention to initiate of immune tolerance induction therapy (ITI) in the future. In 8/10 patients (4 in FEIBA group and 4 in rFVIIa group) there was a decrease of bleeding episodes while 9/10 maintained or increased their joint range of motion (ROM). In the rFVIIa prophylaxis group, prophylaxis can be considered primary since all of them had had less than one joint bleed before prophylaxis. Economic analysis showed that prophylaxis is an expensive treatment. In our experience both agents seem to be safe and effective in reducing the number of bleeds in patients with inhibitors. The anamnestic response provoked by FEIBA could be an issue while awaiting a decline in titres before ITI can be initiated and so rFVIIa may be the best option for prophylaxis in patients with inhibitors who have not yet begun ITI.

Orthopaedic surgery for inhibitor patients: a series of 27 procedures (25 patients)

Summary.  We report on a series of 27 orthopaedic surgical procedures. It includes 20 radiosynoviortheses and seven major orthopaedic procedures, performed on 26 patients. The average age of patients was 36 years (range: 8–53) and the average follow‐up time was 2.5 years (range:1–5). There were 23 good results and four fair. In the synoviorthesis group (20 patients, 20 synoviortheses) the average age was 13.5 years (range: 9–26) and the average follow‐up was 4.5 years (range: 1–7). There were 19 good results and one fair. All synoviortheses were done with activated prothrombin complex concentrates (FEIBA), all the responses being good except in one case (which had the final fair result). The total dose of FEIBA used was 600 IU kg−1, except in a patient that had a haemorrhagic complication. In fact, he required a prolongation of treatment up to a total dose of 2000 IU kg−1. In the group of major orthopaedic procedures, the average age of the six patients was 30.5 years (range: 11–53) and the average follow‐up was 2.5 years (range: 1–5). There were six good results and one fair. Postoperative bleeding complications occurred in one of the seven major orthopaedic procedures performed (arterial pseudoaneurym after a total knee arthroplasty). Despite such complication, which had the final fair result, our study has shown that haemophilic patients with high inhibitor titres requiring orthopaedic surgery can undergo such procedures with a high expectation of success. In other words, orthopaedic surgery is now possible in haemophilia patients with high‐titre inhibitors, leading to an improved quality of life for these patients.

The use of haemostatic drugs in haemophilia: desmopressin and antifibrinolytic agents

Summary.  Over the last 4 decades, there have been very significant advances in the treatment of haemophilia. Plasma products first became available in the 1960s, beginning with cryoprecipitate and then intermediate‐purity plasma concentrates, for the treatment of haemophilia A and B. The disasters of viral infections amongst people with haemophilia in the 1980s served to stimulate both the development of techniques of viral inactivation of concentrates and the manufacture of purer products. We therefore now have safe plasma products that are also pure in that they are concentrates of only the deficient protein responsible for the congenital coagulopathy. Preparations of specific coagulation proteins obtained using recombinant biotechnology techniques have been available since 1995.

Controversies and Challenges in Elective Orthopedic Surgery in Patients With Hemophilia and Inhibitors

Until recently, orthopedic surgery was strongly contraindicated in patients with hemophilia and inhibitors. However, recent advances in our knowledge of bypassing agents (particularly recombinant activated factor VII [rFVIIa]) that provide effective surgical hemostasis have allowed us to successfully perform major orthopedic procedures in these patients. Adequate hemostasis during surgery and postoperative rehabilitation is crucial, as development of a wound hematoma may jeopardize long-term outcomes. It also should be noted that success depends not only on appropriate drug therapy but also on preoperative preparations and adequate perioperative surveillance. Preoperative assessment of vascular status is very important, and strong motivation--on the part of the patient, the surgeon, and the hematologist--is needed to ensure a satisfactory result. Although inhibitor patients undergoing surgery face a higher risk of bleeding and other complications than their non-inhibitor counterparts, outcomes are generally good if a multidisciplinary team approach is applied.

Clinical efficacy in bleeding and surgery in von Willebrand patients treated with Fanhdi® a highly purified, doubly inactivated FVIII/VWF concentrate

Summary.  Therapy with factor VIII/von Willebrand factor (FVIII/VWF) concentrate is the mainstay therapy in patients with von Willebrand disease (VWD) unresponsive to desmopressin. There are several commercially available FVIII/VWF concentrates that have been tested in VWD patients. We retrospectively analized the clinical efficacy in bleeding episodes and surgery of a highly purified FVIII/VWF complex with two inactivation steps (Fanhdi®) in VWD patients. Sixty patients were included in the study. Treatment schedule consisted of one or more doses (standard dose 40 IU/kg body weight of FVIII) of Fanhdi®. One hundred and fifty bleeding episodes were treated. These were: 28 serious bleedings; 92 moderate and 30 mild. An excellent clinical efficacy in almost 95% of cases was observed. Fanhdi® was administered during 66 surgical procedures (38 major and 28 minor) with an overall efficacy of 98%. Fanhdi® a highly purified, doubly virus‐inactivated FVIII/VWF concentrate, with a high content of active VWF and an excellent record of clinical safety, is a valid choice in treating VWD.

Experiences in the prevention of arthropathy in haemophila patients with inhibitors.

Summary.  Haemophilia patients with inhibitor have a higher level of arthropathy and more severe joint morbidity than patients without inhibitors. In recent years, interest has grown in the possibility that bypassing agent regimens could prevent bleeding and, consequently, arthropathy in inhibitor patients. Nevertheless, doubts about efficacy, complications and cost exist, questioning the justification of an uncertain prophylaxis in patients with inhibitors. Activated prothrombin complex concentrate (aPCC) has been used in more than 70 haemophilia patients with inhibitors in different clinical situations. aPCC prophylaxis seems to be safe and effective for the reduction of bleeding episodes in some patients. Recombinant activated factor VII (rFVIIa) has been employed prophylactically in over 44 haemophilia patients with inhibitors; 22 patients were included in the only randomized, prospective clinical trial of bypassing agents in prophylaxis. Bleeding frequency was reduced and this reduction was maintained during the postprophylaxis period. No thromboembolic events were reported during prophylaxis with rFVIIa. Although the effect of aPCC can last longer than that of rFVIIa, their efficacy rates are similar, suggesting that the biological effect of rFVIIa is actually much longer than indicated by its short plasma half‐life. aPCC contains residual factor VIII antigen and may cause an anamnestic response in the inhibitor titre. This is crucial when immune tolerance induction is postponed to allow the inhibitor titre to decline to <10 Bethesda Units. In this setting, aPCC is not recommended as a first‐line prophylaxis because of its potential to protract anamnesis, and rFVIIa is the preferred agent.

Review: Factor XI deficiency: review and management in pregnant women.

Factor XI deficiency is a rare disease found predominantly in Ashkenazi Jews. There is a poor correlation between factor XI level and bleeding in patients with factor XI deficiency. Individuals with severe factor XI deficiency are usually at risk of excessive bleeding after surgery and injury, particularly when trauma involves tissues rich in fibrinolytic activity. Women with partial or severe deficiency are at risk of excessive uterine bleeding during labor. The unpredictable nature of factor XI deficiency complicates management during pregnancy and delivery. This review gives an overview of the management of pregnant women with factor XI deficiency.

Acquired von Willebrand syndrome

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder. In spite of there have been reported around 300 cases of AVWS to an international registry, there are no accurate estimates of its prevalence [1]. Acquired von Willebrand syndrome is distinguished from the congenital form by several factors such as age at presentation, absence of personal and family history of bleeding disorders and the frequent association with underlying diseases, most commonly lymphoproliferative (48%) and myeloproliferative disorders (15%), neoplasia (5%), immunological (2%), cardiovascular (21%) and miscellaneous disorders (9%) [1,2]. The onset is usually late in life and the severity of bleeding varies considerably among the patients [3]. The pathophysiology of AVWS is complex and for many cases no clear pathogenetic mechanism has been recognized. In most cases, von Willebrand factor (VWF) is rapidly removed from plasma because of the action of one of the following pathogenetic mechanisms: increased proteolytic degradation of VWF (myeloproliferative syndromes are the main cause for proteolysis), because of substances like hyaluronic acid in Wilm s tumour or drugs (ciprofloxacin, valproic acid) and, infrequently, antibodies to VWF or inmunoadsorption of VWF–factor VIII (FVIII) onto a malignant clone of cells. The least frequent pathogenetic mechanism is decreased VWF synthesis, which only occurs in patients with hypothyroidism [1,2,4]. Diagnosis of AVWS is still difficult. Laboratory features are the same as in congenital von Willebrand s disease (VWD). Only the measurement of VWF propeptide (also known as VWF Ag II) has been suggested as helpful to discriminate between congenital and acquired VWD. In AVWS, the propeptide levels remain normal because VWF synthesis is normal or higher [2,3]. Treatment is necessary in order to control bleeding and to prevent bleeding when an invasive procedure is indicated. The options include desmopressin (DDAVP), FVIII/VWF concentrates and high dose i.v. immunoglobulins. It is also very important to treat the underlying disease if possible [3]. We report six patients diagnosed with AVWS. The clinical and laboratory features of our six patients are summarized in Table 1. The median age of patients at the time of diagnosis was 67 years (range 50–88 years). Five were male and one was female. Interestingly, none of them had a previous personal or family history of coagulation disorders. Two patients had not suffered any bleeding episodes. The other four showed mucosal bleeding resembling those of congenital VWD: epistaxis (patients 1, 3, 6), gingivorrhagia (patient 1), gum bleeding (patient 3), easy bruising (patients 2, 6), gastrointestinal bleeding (patients 1, 6), postdental surgery bleeding and thoracic haematoma after sternal bone marrow aspiration (patient 3). Five patients showed monoclonal gammopathy, three multiple myeloma and two monoclonal gammopathy of undetermined significance. These disorders are commonly associated with AVWS [1]. All patients showed a haemostatic profile consistent with the diagnosis of VWD. Prolonged bleeding time, and decreased FVIII:C, VWF antigen and VWF activity. Even though the multimeric pattern most commonly seen is a selective decrease in the highmolecular-weight multimers (type 2), our cases showed a multimeric type 1 pattern [1]. In five patients, FVIII/VWF concentrates were administered; in three cases in response to different bleeding episodes and in two cases to avoid bleeding (cranial trauma in one patient and prior to a bone marrow aspiration and a lymph node biopsy in the other one). All of the patients were successfully managed and presented a good recovery with no further complications. In only one of them, it was necessary to associate high-dose i.v. immunoglobulin Correspondence: Maria Teresa Alvarez, Haematology, Hospital Universitario La Paz, P Castellana, n 261, Madrid 28046, Spain. Tel.: +34 659916474; fax: 91-7277226; e-mail: talvarezroman@gmail.com

Haemoperitoneum in a female patient with haemophilia A caused by a ruptured ovarian follicle.

Haemophilia A is an X-linked disorder caused by mutations in the coagulation factor VIII (FVIII) gene leading to deficient or dysfunctional FVIII. Deficient FVIII clotting activity is found in type 2 N von Willebrand disease, with a phenotype that mimics haemophilia A, or in patients with inhibitory antifactor VIII antibodies. The incidence of the disease is approximately 1 in 5000 males, and haemophilia A is classified as mild, moderate or severe, depending on the amount of residual FVIII. Severe manifestation of X-linked recessive disorders, including haemophilia A, is rare in females. However, such disorders have been observed in females with numerical or structural abnormalities in an X chromosome. The very few cases reported in the literature, were because of one of the following mechanisms: (i) compound heterozygous mutations affecting both F8 alleles, (ii) homozygosity for the mutation, (iii) extreme lyonization in a heterozygous female leading to the inactivation of the normal X-chromosome, (iv) abnormalities of the X chromosome structure or number, as occurs in Turner syndrome and (v) coincidence of a Swyer syndrome and a FVIII gene missense mutation [1– 4]. We report an unusual case of haemorrhagic shock following haemoperitoneum complicating ovulation in an 18-year-old patient affected by mild haemophilia A. The patient is an 18-year-old female with mild haemophilia A (7% endogenous FVIII activity). She was diagnosed at 8 years old because of the formation of a post-traumatic haematoma in the gluteus region. The activated partial thromboplastin time was 43.7 s. Her disease was caused by a compound heterozygous condition as the family s medical history revealed that the father had haemophilia A and the mother was a carrier of haemophilia A. The patient had a normal female karyotype. She was hospitalized on three occasions for spontaneous haematomas in the gluteus region. These bleeding episodes responded well to the infusion of FVIII concentrate. There had never been any evidence of the development of a FVIII-specific inhibitor. Her gynaecological history was unremarkable with normal menstrual cycles. She had delivered one time by spontaneous vaginal delivery without any excessive vaginal bleeding. She presented in our centre, three months after the delivery, with severe acute pain in the hypogastrium and both the iliac fossae. On general examination, she appeared sweaty, pale and tachycardic but showed no signs of heart or respiratory failure; abdomen was distended with tenderness in the hypogastric area and both iliac fossae; bowel sounds were present and normal. Blood pressure was 90/ 50 mmHg. No evidence of external bleeding was reported. Vaginal gynaecological examination revealed no bleeding from vulva, vagina and cervix. On admission, haemoglobin level was 7.4 g dL, haematocrit 20.4%, WBC 8.37 · 10 L and platelet count was within the normal range (237 · 10 L). An ultrasonographic examination showed multiple bilateral ovarian cysts and free intraperitoneal fluid, probably blood. The haemorrhage was controlled with intravenous bolus infusions of FVIII concentrate in a dosage sufficient to provide a 100% correction in the FVIII level (50 U kg) for 10 days. Transfusion of two red cell concentrates was also required. Twenty-four hours after starting factor replacement therapy, abdominal tenderness on palpation and distension had disappeared. Oral contraceptive treatment was started with the aim of preventing any further heavy periods. Correspondence: V. Jimenez-Yuste, Servicio de Hematologı́a, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain. Tel.: +34 91727726; fax: +34 917277225; e-mail: vjimenez.hulp@salud.madrid.org