hello everyone thank you for joining this uh webinar on the basics of factor seven deficiency i hope everyone is staying safe and healthy during this pandemic i'm suchitra acharya at the kohen children's medical center of new york and i would like to thank nhf for this opportunity and chelsea and jasmine for organizing this session in the next 30 minutes or so i will discuss the role of factor 7 in the clotting process the clinical presentation of factor 7 deficiency diagnostic testing and treatment options for an individual with factor seven deficiency and finally uh focus a little bit on girls and women with factor seven deficiency these are my disclosures none of which are relevant to the presentation today i would like to start off with a vignette because this is like a real world case which actually demonstrates uh some of the bleeding symptoms that can occur in a patient with factor seven deficiency so we were referred the seven-year-old female after she was oozing for about two days after she had a tooth pulled and the oozing would not stop despite pressure with gauze and ice going back into a history the parents reported that she had a history off and on of bilateral ankle pain and swelling for which they had seen an orthopedist who had done x-rays on her and notified them that he saw some bony changes in her right ankle also her ten-year-old brother who's an avid soccer player reported an episode of severe joint pain and swelling while playing soccer and he had an episode of a severe nosebleed which lasted 30 minutes for which they had to go to the emergency room to get his nostril packed both parents are first cousins from ecuador just keep this background in mind because eventually we will get to the diagnostic testing and how we manage this young girl so in order to understand the role of factor seven in the clotting process i would like to share this visual uh representation of how a blood clots which has been developed by doctors usha reddy and roshni kulkarni sorry just give me a minute to pull this up okay so this visual represents a blood vessel uh which is a tube lined by endothelial cells that you can see here and there are two components in the blood cells red cells white cells and platelets and the liquid component which we refer to as plasma which contains clotting proteins proteins that help in clot formation proteins that prevent clot formation and proteins that are involved in clot breakdown so with any kind of injury whether it's due to trauma or a surgical procedure there's breach in the continuity of the vessel wall and platelets are the first cells to go to this site of injury and what platelets do is they bind to the lining of the vessel as they are activated and as more and more platelets get activated they recruit more platelets to the site and these platelets then stick to each other in a process referred to as pellet aggregation in order to form a platelet plug simultaneously when platelets are being recruited to the site to form a platelet plug clotting proteins in the blood also become activated so tissue injury releases tissue factor which then activates factor seven to form activated factor seven uh and subsequently other components of the extrinsic pathway uh the intrinsic pathway as well as the common pathway all grouped together to form a fibrin clot and factor 13 eventually is required for cross-linking of the fibrin network in order to form a tensile fibrin clot this is a very important process because unless and until you form a tensile fibrin clot you cannot begin the healing process and soon after a tensile clot is formed the healing begins healing is completed and the vessel returns to normal and so factor seven is classified as a rare bleeding disorder because it occurs in one and a half million uh individuals and rare bleeding disorders comprise three to five percent of inherited bleeding disorders after von willebrand's disease and uh the hemophilias uh there are two reports the report that was published by the world federation of hemophilia and a report by the european network of rare eating disorders spearheaded by dr flora paivandi in milan italy that have reported that factor seven is the most common of the rare bleeding disorders occurring at a prevalence of around 37 percent um the prevalence of rare bleeding disorders has been noted due to registries that have been established in uh the uk italy and iran and as a result of these registries we have fast vastly improved our knowledge of these rare bleeding disorders in the slide you will find a table showing you the prevalences of the hemophilias factor eight and factor nine deficiency which is similar in the uk the italy and iranian registries however when you look at the prevalence of factor seven deficiency you see that it is three to fivefold higher in the registry reported from iran as compared to the registries in italy and the uk and why is that the reason for this is a high rate of consanguinity which is first cousin marriages uncle nice marriages that are common in countries like iran and other countries in the middle east and southeast asia and the rate of consanguinity reported is anywhere from 40 to 85 percent which translates into a three to seven fold higher uh prevalence of rare bleeding disorders in the middle east and southeast asia as compared to the western world factor seven deficiency is autosomal recessive inheritance which means that both parents have to carry the mutation in order for a child to manifest the disorder as you can see in this pedigree there is an affected boy there's an affected girl and there's a cat boy who's a carrier and both parents are carriers and therefore in an autosomal recessive disorder with every pregnancy there is a 25 chance of a child being affected uh the world federation of hemophilia reported that factor seven deficiencies equally distributed amongst males and females males represented in red females in blue which is unlike the hemophilias which are predominantly represented in males because of the x-linked recessive inheritance now one of the interesting things with factor seven deficiency uh is that factor seven levels do not correlate with bleeding symptoms and uh dr paivandi's work from the european network of rare bleeding disorders reported that a little over half the patients with factor seven deficiency actually do not have any bleeding symptoms about 17 percent can bleed with trauma and 22 percent actually have minor bleeding symptoms such as mild spontaneous bleeds in areas such as the mouth the nose skin and sometimes heavy menses in females only seven percent of individuals with factor seven deficiency tend to have major bleeding symptoms such as bleeding into the joints and muscles bleeding into the gastrointestinal tract umbilical cord bleeding and intracranial bleeding dr mariani from italy established the stir registry way back in 2007 and reported that bleeding into the skin and lining areas occurs in about 30 percent of individuals with factor 7 deficiency while other sites such as the brain the muscle intestines kidneys umbilical cord joints tend to be less common in under 15 percent so clinical symptoms predominantly involve skin and lining areas uh in the form of petechiae nose bleeds gum bleeds heavy menses prolonged bleeding at labor and delivery and rarely excessive bleeding at procedures including circumcision uh the more frequent symptoms reported in severe factor seven deficiencies include intracranial bleeding joint bleeding soft tissue hematomas and umbilical cord bleeding whenever an individual presents with severe bleeding symptoms we do screening tests such as the complete blood count to estimate if the individual has developed any form of anemia which needs to be treated as well as coagulation tests such as the prothrombin time which screens for factors 2 5 7 and 10 and the partial thromboplastin time which screens for factors eight nine eleven and twelve and so in an individual with uh factor seven deficiency the prothrombin time tends to be prolonged um after noticing a prolonged prothrombin time the next step is to actually measure individual factor levels that is screened for by the prothrombin time and most laboratories um the factor seven level less than seventy percent is diagnostic of factor seven deficiency however patients unless and until they have levels less than thirty percent do not tend to have bleeding symptoms uh so the factor seven level that we talk about is the factor seven activity assay we also need to do a factor seven antigen which quantitates the amount of factor seven protein that is produced and once a diagnosis is established it would be important also to look for genetic mutations in the factor 7 gene in order to identify other individuals at risk and for future progeny as mentioned earlier there's a weak association between factor seven level and bleeding symptoms and based on data again from the european network of rare bleeding disorders there are individuals with levels less than 20 percent who may have significant bleeding symptoms whereas there are patients with less than uh one percent levels who do not bleed and therefore the european network recommended classifying factor 7 deficiency as severe deficiency when levels are less than 10 percent moderate deficiencies for levels between 10 and 20 percent and mild deficiencies levels be more than 20 but less than 70 percent treatment options for factor 7 deficiency are very effective and the most preferred treatment is a recombinant factor 7 product which is made in the laboratory it's effective but needs to be given more frequently in order to maintain factor 7 levels above 20 percent to reduce the risk of severe bleeding there is a small risk for inhibitor development that is an antibody to factor seven which occurs in about two percent of severe factor seven deficiency and there may be a risk also of uh thrombosis or developing a blood clot which is an interesting observation which is not very well understood if for some reason recombinant factor 7a is not available other options include fresh frozen plasma the disadvantages of fresh frozen plasma is that it's not virally inactivated and also a large volume needs to be infused because of the low concentration of factor seven in plasma and it also carries the additional disadvantage of potential transmission of blood-borne pathogens prothrombin complex concentrates contain factors 2 7 9 and 10 and can also be used uh to treat a bleed or prior to a procedure in a patient with factor seven deficiency the advantages being it is purified as well as the volume of infusion is low there may be a risk of thrombosis with repeated dosing in the perioperative setting apart from these replacement products anti-fibrinolytic agents or clot strengthening agents such as amino coproic acid and tranexamic acid also play a major role in the therapeutic armamentarium of factor seven deficiency and the reason for this is lining areas produce an abundance of clot breakdown enzymes and so these anti-fibrinolytic agents by strengthening the clot along with replacement products help control uh bleeding treatment strategy in an individual with factor seven deficiency uh can be based on age and the type of bleeding at presentation as mentioned earlier skin and lining areas of mucocutaneous bleeding can occur at any age and are is generally mild so most times they may not require treatment or can be used uh can i'm sorry and can be treated on demand with the use of anti-fibrinolytics such as amino coproic acid and tranexamic acid with or without recombinant factor 7a heavy menses in teenaged and older women could be mild or severe and prophylaxis could be used only during the menses with anti-fibrinolytics and recombinant 7a or it may be used only on demand joint bleeds which tend to occur in toddlers and older children tend to be severe in somebody with severe factor 7 deficiency and these individuals are the ones which who go on prophylaxis uh intracranial bleeds and gastrointestinal beads which can present in the newborn period tend to be very severe and in these individuals long-term prophylaxis with recombinant factor 7a is highly recommended so is there a role for prophylaxis in uh factor 7 deficiency this is usually determined by bleeding frequency the severity of the bleed as well as the risk for long-term sequelae two types of prophylaxis can be envisioned primary prophylaxis is before any major bleeding occurs in order to prevent intracranial hemorrhage and secondary prophylaxis is implemented after a bleeding event in order to prevent a life-threatening bleed or recurrent joint bleeds however data in factor seven deficiency and the benefits of prophylaxis is sparse but we know that it is feasible uh despite the short half-life of factor seven which uh lasts um about an hour to three hours and therefore prophylaxis is usually indicated in infants with severe deficiency who may be prone to severe and frequent bleeding it's all it is also indicated in severe disease when a child develops an intracranial bleed or a severe gastrointestinal bleed or repeated joint bleeds and a female with heavy menses with extremely low factor seven levels and prophylaxis is doable either two to three times a week or on an every other day schedule and sometimes may be required on a daily basis with recombinant factor 7a depending upon the response of the patient to factor 7a and the bleeding frequency and how well the bleeding is controlled with prophylaxis um the stir registry has reported that bleeding symptoms at diagnosis actually can predict subsequent bleeding events in an individual with factor 7 deficiency so let's say for example a patient is identified with low factor 7 levels because of pre-op screening of and a prolonged pt is identified leading to a diagnosis of factor 7 deficiency and this individual is completely asymptomatic has not suffered from any bleeding events this individual's risk for subsequent bleeding events is much lower than an individual who presented with a minor or a major bleeding event and then was diagnosed with factor 7 deficiency as a cause of that bleeding event girls and women with factor 7 deficiency have a life time risk of bleeding especially those with severe factor 7 deficiency during menses pregnancy and around the time of delivery or postpartum a heavy menstrual bleeding has been reported in about half of the girls and women with severe factor 7 deficiency and apart from heavy menstrual bleeding girls and women can also develop bleeding mid-cycle during ovulation and develop a condition called hemoperitoneum which is bleeding into the lining of the abdomen and this could be a life-threatening event and is an emergency which needs to be addressed immediately to prevent serious bleeding very high rates of postpartum bleeding have also been reported in women with severe factor 7 deficiency heavy menstrual bleeding really needs to be addressed in a teenager who presents um with with the bleeding phenotype in factor 7 deficiency because this teenager can go on to develop severe iron deficiency and iron is required for higher functions such as focus concentration and so her ability to do well in school is really adversely affected apart from that there's limitation in daily activities with a reduced quality of life time loss from work and school causing adverse psychosocial events and women with heavy menstrual bleeding tend to undergo repeated hospitalizations which can increase maternal mortality uh management of heavy menstrual bleeding depends upon whether a woman is considering pregnancy soon or not if a woman is considering pregnancy soon um treatment options would be the use of recombinant factor 7a during her menstrual cycle along with tranexamic acid or amino coproic acid clot strengthening agents if pregnancy is not being considered soon hormonal control in the form of a levonorgestrel iud a combined oral contraceptive pill or a progesterone only pill are good options if reproduction is completed endometrial ablation and hysterectomy are other treatment options to be considered pregnancy in a woman with severe factor 7 deficiency should really be managed at a bleeding disorder center or a hemophilia treatment center and replacement therapy should be based on the woman's past bleeding history and sometimes may need to start as early as the first trimester all women should be carefully monitored through a multi-disciplinary team approach involving not only the obstetrician but the hematologist along with the anesthesiologist primary care physician with access to a lab 24 7 for monitoring of levels epidural anesthesia can be used but make sure that levels are more than 50 at the time of catheter placement and 24 hours after removal of the catheter uh the the route of delivery vaginal versus c-section should be based uh on what is safe for mother and child and postpartum hemorrhage which can occur in women with severe factor seven deficiency should be strongly considered and discussed with the patient as well as the risk for a late postpartum hemorrhage which can occur up to two weeks after delivery should also be addressed all uh women with uh severe factor seven deficiencies should have a cbc check before discharged and counseled about excessive uh bleeding and follow-ups for the suspected newborn vaginal delivery can be conducted in a woman with severe factor seven deficiency but if the second stage of labor is prolonged avoid use using forceps vacuum or fetal scalp monitoring in order to prevent an intracranial hemorrhage and if the second stage of labor is prolonged uh go right away to a c-section without the use of these other interventions once the baby is born cord blood can be sent for factor seven levels and a screening head ultrasound uh should be done to rule out an intracranial bleed uh the mother should be educated to report symptoms of vomiting lethargy and seizures which can be presentations of a delayed intracranial hemorrhage which can occur up to seven days after delivery all babies need to receive vitamin k but in general any vaccines should be administered subcutaneously rather than intramuscular injections in order to avoid muscle bleeds there is a risk for inhibitor development although this risk in the newborn is not very well known and therefore avoid elective procedures as much as possible in the newborn period and all newborns who are diagnosed with severe factor 7 deficiency should be referred to a hemophilia treatment center or a bleeding disorder center for ongoing management and comprehensive care so going back to our patient who presented with the oozing after dental extraction and who has a history of multiple joined leads along with her brother who has a history of joint bleeds and nosebleeds we investigated this girl further and found that she had a prolonged pt prothrombin time at 22.5 seconds with a normal partial thromboplastin time and her factor seven level was two percent the activity and the antigen was five percent diagnosing her with severe factor seven deficiency so she was treated with recombinant factor seven a for a day along with uh amino coproic acid for seven days with prompt bleed resolution in her mouth and subsequently she was started on secondary prophylaxis with recombinant factor 7 every other day in order to prevent her recurrent joint blades thank you so much for your attention and it would be very helpful if you could fill out the session evaluation in order for us to understand how to improve these sessions for the future thank you so much