Effectiveness of the scheduled transfusion strategy for factor V deficiency with platelet dysfunction during coronary artery surgery.

BACKGROUND: Factor V deficiency is a rare disease, with an incidence of one in a million. Symptoms are mostly scant, and it is often diagnosed by the presence of an abnormality on PT-INR or APTT. In addition, no established therapy exists and platelet dysfunction is seldom found to be concomitant with this disease CASE PRESENTATION: A 64-year-old man who had both factor V deficiency and platelet dysfunction had angina in the past year. Coronary surgery was required, and we successfully performed coronary artery bypass grafting under strategic planned platelet transfusion with additional adequate cryoprecipitates transfusion. No perioperative problems nor any postoperative major bleeding issues were observed. The postoperative course was also uneventful. CONCLUSION: Strategic planned platelet transfusion with the additional transfusion of an adequate amount of cryoprecipitates is thus considered to be feasible for cases presenting with factor V deficiency and platelet dysfunction.

High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies.

Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder.

Cell therapy for factor V deficiency: An approach based on human decidua mesenchymal stem cells.

Deficiency of factor V is a congenital autosomal recessive coagulopathy associated with mutations in the F5 gene that results in mild-to-severe bleeding episodes. Factor V is a component of the prothrombinase complex responsible for accelerating conversion of prothrombin to thrombin. At the present time there are no therapeutic factor V concentrates available. This study was designed to lay the preliminary foundations for future cell-based therapy for patients with severe factor V deficiency. The study showed that hepatospheres, which produce coagulation factors VIII, IX, and V, synthetize and store intracellular glycogen and express albumin levels up to 8 times higher than those of undifferentiated cells. Factor IX and factor V gene expression increased significantly in hepatospheres as compared to undifferentiated cells, whereas factor VIII gene expression remained constant. The factor V protein was detected in the hepatospheres´ secretome. Considering the enormous potential of mesenchymal stem cells as therapeutic agents, this study proposes a highly reproducible method to induce differentiation of mesenchymal stem cells from human placenta to factor V-producing hepatospheres. This strategy constitutes a preliminary step towards a curative treatment of factor V deficiency through advanced therapies such as cell therapy.

Factor V activity in apheresis platelets: Implications for management of FV deficiency.

BACKGROUND: Allogeneic platelet (PLT) infusion is a strategy to raise Factor V (FV) levels in patients with congenital FV deficiency. However, since FV is labile in vitro, we hypothesized that FV activity could be low in PLT units. STUDY DESIGN AND METHODS: FV activity was tested using a prothrombin time-based platform in the supernatant and platelet lysate (PL) of apheresis PLT units (16 units stored in PLT additive solution with acetate and phosphate [PAS-C] and 10 units stored in plasma only), on post-collection days 3-6. Statistical analysis was performed using Student's t test (P < .05). RESULTS: FV activity was severely diminished in PAS-C PLTs (N = 16) supernatant (3.70% ± 1.02%) and PL (3.26% ± 1.02%). FV activity in plasma-only PLTs (N = 10) was lower in both supernatant (44.55% ± 6.46%) and lysate (39.67% ± 6.33%) relative to normal plasma levels, but both were significantly higher (P < .0001) compared to PAS-C PLTs. In a separate set of experiments, FV activity in PAS-C PLTs examined serially over storage time (N = 3 for these experiments) showed that FV levels were reduced by day 3 and not significantly different by day 5 of storage (Day 3 supernatant 5.03% ± 1.41%; Day 5 supernatant: 3.10% ± 0.57%; P = .2; Day 3 lysate: 3.89% ± 1.03%; Day 5 lysate: 2.61% ± 0.41%; P = .4). CONCLUSION: Plasma should be considered over PLTs as first-line therapy for non-complex FV deficiency-associated hemorrhage. If PLTs are considered for transfusion, plasma-only PLT units should be preferentially utilized, as PAS-C PLT have near-absent FV activity.

Platelet transfusion as treatment for factor V deficiency in the parturient: a case report.

BACKGROUND: Congenital factor V deficiency, also called parahemophilia, is a rare hematological disorder that can be treated with platelet transfusion. CASE PRESENTATION: A 27-year-old G2P0100 with factor V deficiency was admitted for induction of labor and requested labor epidural analgesia. Throughout her hospital course, factor V levels were managed per recommendation from her hematologist, which included transfusing fresh frozen plasma (FFP) to maintain a factor V level of 50% before any neuraxial technique and 40% for postpartum hemostasis. The parturient required multiple transfusions of FFP to stay at this level, which eventually resulted in pulmonary edema. Given the request to maintain high levels of factor V, the parturient was transfused with platelets as an alternative source of factor V. The parturient eventually delivered a healthy neonate without signs of postpartum hemorrhage or epidural hematoma. CONCLUSION: A major learning point from this case is that platelet transfusion is an effective alternative in the management of factor V deficiency. Factor V released by platelets has enhanced procoagulant function, resulting in local factor V concentrations 100 times more than that of plasma, and has a significantly extended half-life. Platelet transfusion should be considered as a therapy in treating parturients with factor V deficiency.

Déficit de factor V grave / Severe factor V deficiency

Se presenta un caso de factor V severo, deficiencia (<1%) asociada con múltiples episodios de sangrado en diferentes zonas del cuerpo. El curso clínico ha sido complicado aún más por el desarrollo de reacciones transfusionales, tras tratamiento con plasma fresco congelado. Sería interesante realizar investigaciones para poder disponer de factor V purificado (AU)

We present a case of severe factor V, deficiency (<1%) associated with multiple episodes of bleeding in different areas of the body. The clinical course has been further complicated by the development of transfusion reactions following treatment with Fresh Frozen Plasma. It would be interesting to carry out investigations in order to have purified factor V (AU)

Phenotype Report on Patients with Congenital Factor V Deficiency in Southern Iran: Recent Ten Years' Experience.

This study aimed to investigate clinical symptoms in patients with congenital factor V (FV) deficiency and the relationship between phenotype and factor activity level. Thirteen patients with congenital FV deficiency were investigated and the factor activity level and first clinical presentations were studied for each patient. The most common first signs and symptoms were post-surgery, post-partum, post-circumcision, and post-traumatic bleeding (30.76%), followed by easy bruising in 23.10% of the patients. The median age at the onset of clinical signs was 18 (range: 1-53) years. Patients were categorized into two groups of major and minor bleeding based on their first clinical bleeding symptoms. There was not a significant difference between the two groups with regard to factor activity level, age at diagnosis, prothrombin time, partial thromboplastin time, and international normalized ratio (p>0.05). There is a discrepancy between plasma FV activity level and the severity of clinical presentations.

Factor V and VIII deficiency treated with therapeutic plasma exchange prior to redo mitral valve replacement.

A 33-year-old male was admitted to the hospital for a repeat mitral valve replacement. The original surgery, performed in India in 2008 due to rheumatic heart disease, required massive amounts of plasma replacement during and after the surgery. The patient was admitted to our hospital with extremely low Factor V and Factor VIII activities due to a rare combined Factor V and Factor VIII deficiency. His clinical condition on admission was grave due to severe pulmonary hypertension. It was decided to replace the patient's Factor V using therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) just prior to surgery, and his Factor VIII with Factor VIII concentrate. The patient tolerated the valve replacement surgery very well, without excessive bleeding, and received several more TPE procedures postoperatively. He was successfully made replete with both coagulation factors with little to no bleeding during the procedure and postoperatively. TPE is a promising modality for the treatment of patients with similar factor deficiencies for which a specific factor concentrate is not available, especially those at risk of fluid overload from plasma transfusion. J. Clin. Apheresis 32:196-199, 2017. © 2016 Wiley Periodicals, Inc.

Pregnancies with factor V deficiency: a case report and review of the literature.

CASE REPORT: A 30-year-old Japanese nulliparous woman visited for pregnancy at 33 weeks with a massive ovarian tumor located in the pouch of Douglas. By preoperative screening, her prothrombin time (PT) and activated partial thromboplastin time (APTT) were prolonged, and her FV activity was significantly decreased to 4.8%. After prophylactic FFP 20 ml/kg was administered and her FV factor was 19.3%, cesarean delivery was performed, and her perioperative course was uneventful. One year later, she underwent a dilatation and evacuation because of a missed abortion, although prophylactic FFP was not administered. During a third pregnancy, after prophylactic FFP 20 ml/kg was administered and FV activity increased to 21.1%, elective cesarean delivery was performed, and her postoperative course was uneventful. CONCLUSION: For surgical therapy or delivery, the goal of therapy is to maintain FV activity above 20%. It is particularly useful to administer prophylactic FFP.

Acquired Factor V Inhibitor.

Inhibitors directed against factor V rarely occur, and the clinical symptoms vary. We herein report the case of a patient who presented with a decreased factor V activity that had decreased to <3 %. We administered vitamin K and 6 units of fresh frozen plasma, but she thereafter developed an intracerebral hemorrhage. It is unclear whether surgery >10 years earlier might have caused the development of a factor V inhibitor. The treatment of acquired factor V inhibitors is mainly the transfusion of platelet concentrates and corticosteroids. Both early detection and the early initiation of the treatment of factor V inhibitor are thus considered to be important.

Transfusion management of factor V deficiency: three case reports and review of the literature.

BACKGROUND: Factor V (FV) deficiency may be inherited as an autosomal recessive disease or acquired as a result of autoantibody formation, either spontaneously or secondary to exposure to bovine thrombin or medications. Congenital FV deficiency has traditionally been treated with plasma transfusions. However, recent evidence has suggested that platelet (PLT) transfusions may be a better alternative as FV stored within PLT alpha granules has greater procoagulant potential and is released locally at sites of vascular injury. We report three cases of FV deficiency, one congenital and two acquired, and emphasize the different management approaches. CASE REPORTS: Patient 1 was a 30-year-old man with congenital FV deficiency who presented with a trauma-induced hematoma of his lower extremity. He was treated with 5 PLT units over 48 hours. Patient 2 was a 64-year-old woman who presented with an upper-extremity thrombus and was discovered to have a FV inhibitor, likely secondary to antibiotics. Patient 3 was a 75-year-old woman with hepatitis C virus (HCV) who presented with minor ecchymosis and was found to have a FV inhibitor secondary to either HCV or antibiotic exposure. Corticosteroids alone were able to eradicate the inhibitors in both patients with acquired inhibitors. CONCLUSIONS: FV deficiency can present with a diverse range of symptoms. For bleeding patients, PLT transfusions should be the initial therapy. In patients with thrombosis, the risks and benefits of anticoagulation must be carefully assessed before treatment. For patients with minor bleeds, transfusions may be withheld, and elimination of the inhibitor should be the primary objective.

The use of fresh frozen plasma for reproduction in severe factor V deficiency.

OBJECTIVE: Severe factor V (FV) deficiency is rare. There are case reports describing pregnancy outcomes in women with FV deficiency and one case report of successful pregnancy following the use of fresh frozen plasma (FFP) in several cycles of ovulation induction and intrauterine insemination and at delivery. The authors report another case to support the use of FFP for reproduction. CASE: A 27-year-old woman with severe FV deficiency was given FFP at the time of ovulation induced with clomiphene citrate, human menopausal gonadotropin (hMG), and human chorionic gonadotropin. Intrauterine insemination (IUI) was done 35 hours later. She became pregnant with twins and delivered vaginally at 36 weeks of gestation with the prophylactic use of FFP. CONCLUSION: Fresh frozen plasma can be offered for reproduction to women with severe FV deficiency.

Platelet-delivered therapeutics.

We have proposed that modified platelets could potentially be used to correct intrinsic platelet defects as well as for targeted delivery of therapeutic molecules to sights of vascular injury. Ectopic expression of proteins within α-granules prior to platelet activation has been achieved for several proteins, including urokinase, factor (F) VIII, and partially for FIX. Potential uses of platelet-directed therapeutics will be discussed, focusing on targeted delivery of urokinase as a thromboprophylactic agent and FVIII for the treatment of hemophilia A patients with intractable inhibitors. This presentation will discuss new strategies that may be useful in the care of patients with vascular injury as well as remaining challenges and limitations of these approaches.

Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency.

Whole genome sequencing of an individual completely devoid of plasma- and platelet-derived factor V (FV) identified 167 variants in his F5 gene including previously identified and damaging missense mutations at rs6027 and Leu90Ser. Because the administration of fresh frozen plasma (FFP) prevents gastrointestinal bleeding in this individual, its effects on his plasma- and platelet-derived FV concentrations were assessed. The patient's plasma FV levels peaked by 2 hours following FFP administration and were undetectable 96 hours later. In contrast, increased platelet-derived FV/Va concentrations were observed within 6 hours, peaked at 24 hours, decreased slowly over 7 days, and originated from megakaryocyte endocytosis and intracellular processing of plasma FV. Ten days after transfusion, no thrombin was generated in a tissue factor-initiated whole blood clotting assay unless exogenous FV was added, consistent with the complete absence of plasma FV. In marked contrast, release of the patient's platelet-derived FV/Va (7% of normal) following platelet activation resulted in robust thrombin generation, similar to that in an individual with normal plasma- and platelet-derived FV concentrations. Thus, total FV deficiency can be corrected by plasma administration, which partially repletes and sustains the platelet cofactor pool, thereby highlighting the critical role of platelet-derived FV/Va in ensuring hemostatic competence.

Factor V and VIII combined deficiency: clinical perioperative management for tonsillectomy in a child.

Combined factors V (FV) and VIII (FVIII) deficiency is a rarely seen hereditary coagulation disease. Experience of its management in surgery with a high-risk of bleeding is rare. The interest of this case report is to propose a strategy of perioperative management for such a deficit, but also to recall that a careful preoperative anesthetic evaluation with questioning and physical examination permits to detect unsuspected coagulation disorders and to schedule the preventive treatment. The protocol for the perioperative period consisted of the administration of desmopressin and fresh frozen plasma one hour before surgery. The administration of desmopressin was continued for 48hours. Fresh frozen plasma and tranexamic acid were administered during the first 9 postoperative days. A local bleeding occurred at 8 days (scab coming off) and required systematically a surgical hemostasis and an intensification of the therapeutic protocol. Recombinant plasmatic factor VIII was administered for 7 days together with a daily perfusion of fresh frozen plasma for a total treatment period of 14 days.