My purpose for blogging about hemophilia stems from my deep desire to share my history and experiences with you, my reader, my guide and my mentor. There is a lack of understanding, frequently a misunderstanding of this chronic, lifelong, potentially debilitating, sometimes fatal, bleeding disorder. I hope I can help with clarifying some of this. My writings on hemophilia are by no means exhaustive. However, they are the outcome of my readings and experiences. This the main blog which provides links to blogs on other topics I have written.
There are a few things I would like to get out of this blog in addition to knowledge transfer (both ways). I would like to read your comments and questions. I would like to learn about the myths out there. I would like to improve my blogs based on your critical review. Please feel free to share this knowldege in your community in your own way.
My experiences are from 50 years of living with hemophilia, in two different countries- India and the USA. I have experienced the worst of care (no care, often incorrect diagnosis and treatment) to the best care available. Most days for a hemophiliac starts out like for normal people. Typically, hemophilia interferes with an activity in case of a bleed. A bleed is more frequently (not always, as you will learn) caused by trauma of some kind. So that's where I start my story.
The TRAUMA
"Oh no, I'm falling. Not again!!"
I was walking towards the elevator. I had two bags- in one hand, an office bag and on the other my lunch bag. It was just another day in summer. My shoe caught the tiled floor for an extra sub second and I plunged to the floor, face forward. My glasses flew off my face. The bags left my hand and scattered and my body twisted and turned sideways as I went down. All this was happening within the same second- I was trying to hit the ground in a more comfortable position than face first.
Well, people trip and stumble often. Some even fall and pick themselves up and move along. Not a big deal. Not me. When I start to go down, I make sure I fall- safely. The maneuver above was by design. I try to control the way I fall so as to not injure myself. That's the best I can hope for. Injuries are bad, in my case.
Once I am on the ground I cannot get up on my own strength. I waited for the next person to come by and literally pick me up, lift me from behind. I stood up and made sure I was stable, collected my belongings and my bifocals (thankfully they did not break). I returned to my car and headed back home. I was shaken and a bit nervous. While I drove, I called Sridevi, my wife, to ask her to setup supplies on the table for an infusion. I also asked her to take out a "3000+ U dose" from the refrigerator. Once I reached home, I infused. I then started to asses the damage from the fall.
I had a small swelling on each arm below the elbow. My lower back was hurting. So was my right shoulder, which had barely just recovered when I fell. The muscle on the posterior side my left arm was hurting. I sent an email to my nurse about the fall and the infusion and asked for an plan of action for the next 3-4 days. I placed an ice pack behind my lower back, turned on my laptop and worked from home.
My name is Murali Pazhayannur and I have hemophilia A. I was
diagnosed in India when I was 4 and half years old.
What is Hemophilia? Hemophilia is a type of bleeding disorder. My blood takes more time to form a clot and hence uncontrolled bleeding occurs in the body. A lot more bleeds tend to occur in the joints- especially in the weight bearing ones such as in the lower extremities (knees and ankles), but can affect any joint, even the ones on my finger. Bleeds can also occur in any muscle but is largely noticed in large muscle groups such as in the thigh, the hips. Intracranial bleeds are particularly dangerous as the symptoms are non-specific.
To understand what causes hemophilia we need to understand, first, how blood clots.
This is a diagrammatic representation of the coagulation pathway. An animated version of this pathway is shown
here. This clotting mechanism has two pathways: intrinsic and extrinsic. There are 13 proteins working in conjunction to finally form a blood clot. These clotting proteins, commonly known as "Factors" are circulating in blood in their primary (inactive) form and are activated in a sequence to eventually form the clot. In hemophilia, either Factor VIII (FVIII) or Factor IX (FIX) is diminished or missing.
Hemophilia is classified into three broad categories based on the plasma Factor level: Severe (Factor levels < 1% of normal), moderate (1-5%) and mild disease (5-40%). Patients within these range of Factor VIII have Hemophilia A and with levels of Factor IX have Hemophilia B. Hemophilia B is also called
Christmas disease, named after the first patient. According to CDC hemophilia A occurs in
1 in 5000 live male births. Hemophilia B is even rarer. Hemophilia A is four times more common than hemophilia B. The US has an estimated 20,000 cases of hemophilia. There are other less common bleeding disorders caused by lack of Factors I, V, XIII and vonWillebrand Factor (vWF). Then there is
acquired hemophilia, which is caused by alloantibodies (inhibitors) against coagulation factors, frequently against FVIII.
The genes for FVIII and FIX are located in the long arm of the chromosome X, within the Xq28 (FVIII) or Xq27 region. FVIII is a large molecule, representing 186 kb of the X chromosome and contains 2332 amino acids. The mature FIX protein contains 415 amino acids and has a size of 34 kb. The sizes of the gene have a relevance in the development of future treatments for each condition. Hemophilia is decribed originally as an inherited, X-linked, recessive disorder affecting maies. More recently, there is plenty of evidence that Hemophilia affects females also. Further, a third of the cases, occur due to spontaneous mutation in the genes.
I was born in a small town in Tamil Nadu, India, with no prior family history of hemophilia. Couple of points to be noted are- lack of family history might also have been due to un-recorded births or deaths in a previous generation. I emphasize this because I have maternal cousins (living and dead) who have hemophilia. I was diagnosed at the age of 4 in Vellore, India. I have hemophilia A, severe, with < 1% FVIII levels. With no family history and no doctor knoweldagable to treat I had a number of uncontrolled internal bleeds from bumping onto objects.
Diagnosis
The initial diagnosis of hemophilia is done if it is suspected due to family history. However, since there is a propensity of cases without a previous record, the following measures are used o diagnose hemophilia:
Genetic carrier and fetal testing
Complete blood count: Normal or low hemoglobin/hematocrit values
Coagulation studies: Normal or prolonged Activated partial thromboplastin time (aPTT)
Factor assays: Lower levels of FVIII, FIX, vWF
Signs and Symptoms
Hemorrhage present in the form of easy bruising, insufficient clotting after trauma or spontaneous (without apparent injury) are normally noticed early in life. In neonates execssive bleeding at the time of circumcision is an indication. Some of the other signs of internal hemorrhage are:
Joints: warmth, tingling, swelling,pain, stiffness, favoring or supporting of limb
Soft-tissue: bleeding dueing teething
Muscular: visible bruises, swelling
Intra-organ or system bleeds may present as: hematemesis, abdominal pain, hematuria, epistaxis, vomiting, lathery, irritability.
Management
Primary care for hemophilia varies in different parts of the world. Treatment takes one of two forms- symptomatic or on-demand, following a bleeding episode, or prophylactic, which is preventive. Treatment for bleeds take different courses based on its intensity. For severe hemophiliacs bleeds are controlled by Factor replacement therapy. FVIII or FIX is available on a powder (lyophilized) form and is mixed with appropriate diluent and injected intravenously- an infusion.
Ideally, continued care for patients is provided at the regional hemophilia treatment center (HTC). Home administration of i.v. drug is common both while on-demand on prophylactically. Hospitalization is advised for severe or life-threatening bleeds
In the developing world, access to Factor is a chronic problem. Either there is a scarcity or limited supply, or the HTC is not within reach or drugs are unaffordable. For these and more reasons patients are inadequately treated. They frquently take recourse to no care or attempt a combination of rest, icing the joint, compression with crepe bandage, elevation- specially of the weight beraing joints. This is commonly known as RICE therapy. This is followied by the rehabilitation of the joint (more in Physcial Therapy section)
In my early days- in the 60s and until late 70s my care was various forms of RICE and occasional whole matched fresh blood in case of unstoppable external bleeds given intravenously. Whole blood provides the necessary Factor to stem the bleed. In the late 70s I had access to limited supply of cryoprecipitate (detailed in Accident section). Cryoprecipitate (Cryo) is a frozen plasma concentrate product discovered by Judith Graham Pool. Cryo was more effective and administered i.v. in a much smaller volume.
Accident
Though I have had multiples bleeds before I was 18 I stayed somewhat active in sports, playing cricket and soccer in school. This kept me active enough and my joints continued to rehab naturally. This changed with a major accident, at 18, which set of an internal muscle bleed in the right hip. The time and source of the injury is not very certain. I would have bled at least for a week when it was noticeable due to the pain and change in gait. At hospitalization I was severely anemic and given several units of fresh blood. This was the first time I received cryo. The pain was intense to the extent that I was on pain-killers for months after the bleed was controlled and got addicted to pains medicines. The damage caused by this pelvic hemorrhage had a lasting effect. I had to miss a year at school. The clot that eventually formed, also compressed on multiple nerves on my right leg leading to partial paralysis along with inability to walk.
Education
After the year of rest and physical therapy with Indian traditional medicines I went back to complete high school. I continued and obtained a B.S and M.S. (Microbiology) and a PhD in Immunology. While doing my PhD I also came across the first
publication on the cloning of the FVIII gene. Ever since I have followed the development of FVIII and therapy for hemophilia, in general, and hemophilia A, in particular. I came to the US to do a post-doctoral fellowship in August, 1989.
US
For the first time in my life I was covered by health insurance. The group plan had a
pre-existing condition clause. I was under the care of a hematologist at the Medical College of Wisconsin (MCW). I started treating on-demand. The process was that I would have to go to out-patient section in the hematology dept. The nurse would order Factor. This was a monoclonal antibody purified product. The product had to be stored refrigerated. The i.v. injected volume was 50-60 ml. Compared to whole blood or cryo there was significant reduction in volume. Furthermore this was the standard treatment available. In addition, I was diagnosed with high blood-pressure and was prescribed an ACE inhibitor (enalapril). I also met with a nephrologist as I had significant proteinurea. I had early signs of kidney disease. This remained stable for 20 years.
After a couple of years under the care of Dr. Pisciotta for hemophilia, I moved to be under the care Dr. Joan Gill who specialized in hemophilia care. In 1992 there was a FDA press release on the approval of the first recombinant FVIII. I have covered it in some detail in another
blog. I am not sure exactly when I switched to recombinant, perhaps it was in the mid-to-late 90s. I started infusing Recombinate on-demand. I would have the vials in my fridge at home and the lab technician or the research Fellows would infuse me as needed. Life became much better for me, for the very first time. I had access to care under my own control.
In 1997, I went back to school. I enrolled to get a MS in Computer Science at the Univ. of Chicago. Since I was no longer employed, I continued treatment at the MCW and was on COBRA for insurance. My premium had more than tripled. For the first time I also had to self-infuse as I did not have any assistance. During this time I was hospitalized at MCW in early 1998 for two days with severe anemia. An educated guess would be that I was bleeding internally. Since there was no visible injury or joint pain I'll assume that the old clot on my hip was bleeding. This was controlled with Factor.
Once employed, at Sears, in 1999, I registered to be treated at RUSH and was in the care of Dr. Leonard Valentino. I continued to use Recombinate, on demand. I also started on the Board of the Hemophilia Foundation of Illinois (HFI). I worked with a college student to build their first website. This was also my first exposure to other members of the hemophilia community. I was 31 and had never met another hemophiliac in the US!! I would attend the few HFI events.
In Nov 2001 I attended NHF's annual meeting in Orlando. There was a talk on pseudotumors. I had one. It was the clot on my hip and it was growing. I could feel it on my right side specially when I lay on my back. I was starting to feel hard also. One of the diagnostics was to do an MRI. The MRI showed a large mass. The clot had grown in size. Dr. V suggested that it be removed surgically. A successful surgery was performed in Oct 2003. I have been pseudotumor-free until today.
Advate
Around the time when I was preparing for surgery, in the summer of 2003, Baxter announced a new Factor VIII product. It was called Advate. Dr. V had been on the study that had tested Advate and he suggested that I try it out. I started on Advate about a month before my surgery and Advate was used to cover my FVIII needs during the surgery also. A case report of my surgery was published in Hemophilia in 2006. As I recovered from the surgery Dr. V also recommended that I strengthen my joints and muscles with aquatic therapy. I joined the pool in a water aerobics class in the summer of 2006. This has helped with preserving the range of motion I had remaining. Around 2010 I transitioned to the care of Dr. Boggio who was caring for adult hemophiliacs while Dr. V treated pediatric cases.
Community involvement
My first exposure to a hemophilia community was when I became a board member of HFI. I would attend HFI events and went to one NHF annual meeting. I met a number of other hemophiliacs at these meetings. I also had opportunities to speak to the community at events supported by HFI and Baxter. The next big step forward came when I went o my first HFA meeting. HFA is a community based organization. I also became part of the Blood Brotherhood group who had their own special events and forum for adult men. I am also a contracted speaker for Baxter's branded program - "True Identity". I have spoken at HFA. I have also been on patient advisory boards for several product manufacturers. I have evaluated infusion devices; completed tens of market research surveys; been on photo-shoots and done a video for manufactures.
Kidney disease
I cannot tell exactly when I started to notice proteinuria but this has been with me since my teens. A kidney biopsy was risky with the hemophilia and was avoided. I was on BP meds and around 2004-5 my BP started to rise again. Dr. Rodby, the nephrologist, tried additional drugs which did not control the BP. After some trial and error the BP settled down after starting on 3 different drugs and has remained stable. Around 2010 my kidney disease started to get worse. The serum creatinine which was stable for decades started to rise. In 2013 after a lot testing detailed
here, I was listed on a Transplant list at RUSH in Chicago. I follow up annually and continue to be listed and am awaiting the call for a kidney. The hope is that I would not need dialysis and could get a matched kidney.
Prophylaxis
In 2012, in summer, I had a right knee bleed that did not resolve for over a month despite treating with Factor, on-demand. After ruling out inhibitors via blood test I chose to try a round of physical therapy for the knee. At the end of the PT series I also acquired the walking stick. The stick took the load off my knee and my knee bleed has reduced significantly and occurs only in case of trauma. Another major change was introduced to my infusion regimen- I went from on-demand to prophylaxis with ADVATE. This was also prompted by the publication that helped FDA approve ADVATE for prophy. Prophy'ing has reduced the number of bleeds I have per month.
Hot Treatment Topics
In 2014, Biogen-Idec got approval from the FDA to market two extended half-life Factor products- Eloctate (FVIII) and Alprolix (FIX). Baxter has a porcine FVIII (Obizur) to treat Acquired Hemophilia. Novo Nordisk entered the FVIII market with NOVOEight in 2015. There are a number of
new products to treat hemophilia A, B and vWF in various phases of clinical trials or awaiting FDA approval for clinical use. Studies are also being conducted to identify alternate (non-i.v.) routes of Factor treatment. The care philosophy has transitioned from 'by the book' standards to 'personalized' comprehensive care.
Today
As of now, I am still waiting a new kidney, have hemophilia, doing prophylaxis with Advate, lots of PT, full-time job, attend conferences and chapter events, participate in Blood Brotherhood forum and travel a fair amount.
See also
