SIPPET Study: Relevance to the Developing World

As the Annual Congress of the World Federation of Hemophilia concluded in Orlando, Florida I want to shift your attention to and comment on the significance of the SIPPET study to the developing world.

It is fair to say that a majority of the persons with a bleeding disorder live in the developing world and a majority in this group is yet to be diagnosed.  This is a very powerful statement and it is true.  The findings of the SIPPET study (SIPPET) have a whole different meaning to the developing world.  Let us revisit some of the premise of the SIPPET first, focusing on keywords used. Subjects in SIPPET were 'PUPs' (previously untreated patients) who were 'Toddlers' (<6 years old).

In the developing world PUPs and Toddlers are not mutually exclusive. I mean PUPs are not always Toddlers.

What was the definition of PUPs in SIPPET?  PUPs were defined as: "no previous treatment with any factor VIII concentrate, no treatment or minimal treatment (<5 times) with blood components (whole blood, fresh-frozen plasma, packed red cells, platelets, or cryoprecipitate), no treatment with investigational drugs, and a negative test for factor VIII inhibitors at the central laboratory."

By this definition a majority of the diagnosed bleeders in the developing world are PUPs.  This is due to the cost and chronic scarcity of purified (plasma or recombinant) factor in the developing world.  For example, I was a PUP until 29 years of age (in India) until I received my first dose of monoclonal antibody affinity-purified Factor VIII which I received in the US.  There are many PUPs in the developing world.  Some younger, some older.  These PUPs are not 'toddlers'.  Once again this is among the diagnosed bleeders.  In the undiagnosed population, ALL ARE PUPS irrespective of age!!
It is important to follow the adult PUP population in the developing world and chart their genetics and inhibitor development- a 'SIPPET' in adult PUPs.  Are the findings in this population are similar to those on toddlers?


Personal stories
I have previously written about my life in India with hemophilia.  After studying the SIPPET paper and knowing that by definition I was a PUP and on recombinant Factor why I did not develop an inhibitor (thankfully!)?  Here are my thoughts.  Yes, as a PUP, I started on purified plasma-derived Factor VIII.  Recombinant FVIII was not available in the early '90s.  After 4-5 years on this I switched to recombinant Factor in the mid-90s.  I do not have an inhibitor to FVIII as of today.


In the case of another Indian I know; he was diagnosed at the age of 25 and had received minimal treatment for hemophilia until he came to the US at 27.  By SIPPET definition he is a PUP. He started on Recombinant FVIII.  A Factor VIII recovery study showed the recovery was poor. Inhibitor analysis led to him being diagnosed with an inhibitor.


I am by no means suggesting any pattern of inhibitor development depending on treatment with plasma-derived or recombinant FVIII.  These anecdotes goes to validate that inhibitors can develop in PUPs of any age. The cost of treating and the consequences of not diagnosing and therefore not treating an inhibitor in bleeding disorders is too high to leave SIPPET to toddlers alone. A SIPPET-like study in PUP adults is warranted.

SIPPET Study: Relevance to the Developing World

As the Annual Congress of the World Federation of Hemophilia concluded in Orlando, Florida I want to shift your attention to and comment on the significance of the SIPPET study to the developing world.

It is fair to say that a majority of the persons with a bleeding disorder live in the developing world and a majority in this group is yet to be diagnosed.  This is a very powerful statement and it is true.  The findings of the SIPPET study (SIPPET) have a whole different meaning to the developing world.  Let us revisit some of the premise of the SIPPET first, focusing on keywords used. Subjects in SIPPET were 'PUPs' (previously untreated patients) who were 'Toddlers' (<6 years old).

In the developing world PUPs and Toddlers are not mutually exclusive. I mean PUPs are not always Toddlers.

What was the definition of PUPs in SIPPET?  PUPs were defined as: "no previous treatment with any factor VIII concentrate, no treatment or minimal treatment (<5 times) with blood components (whole blood, fresh-frozen plasma, packed red cells, platelets, or cryoprecipitate), no treatment with investigational drugs, and a negative test for factor VIII inhibitors at the central laboratory."

By this definition a majority of the diagnosed bleeders in the developing world are PUPs.  This is due to the cost and chronic scarcity of purified (plasma or recombinant) factor in the developing world.  For example, I was a PUP until 29 years of age (in India) until I received my first dose of monoclonal antibody affinity-purified Factor VIII which I received in the US.  There are many PUPs in the developing world.  Some younger, some older.  These PUPs are not 'toddlers'.  Once again this is among the diagnosed bleeders.  In the undiagnosed population, ALL ARE PUPS irrespective of age!!
It is important to follow the adult PUP population in the developing world and chart their genetics and inhibitor development- a 'SIPPET' in adult PUPs.  Are the findings in this population are similar to those on toddlers?


Personal stories
I have previously written about my life in India with hemophilia.  After studying the SIPPET paper and knowing that by definition I was a PUP and on recombinant Factor why I did not develop an inhibitor (thankfully!)?  Here are my thoughts.  Yes, as a PUP, I started on purified plasma-derived Factor VIII.  Recombinant FVIII was not available in the early '90s.  After 4-5 years on this I switched to recombinant Factor in the mid-90s.  I do not have an inhibitor to FVIII as of today.


In the case of another Indian I know; he was diagnosed at the age of 25 and had received minimal treatment for hemophilia until he came to the US at 27.  By SIPPET definition he is a PUP. He started on Recombinant FVIII.  A Factor VIII recovery study showed the recovery was poor. Inhibitor analysis led to him being diagnosed with an inhibitor.


I am by no means suggesting any pattern of inhibitor development depending on treatment with plasma-derived or recombinant FVIII.  These anecdotes goes to validate that inhibitors can develop in PUPs of any age. The cost of treating and the consequences of not diagnosing and therefore not treating an inhibitor in bleeding disorders is too high to leave SIPPET to toddlers alone. A SIPPET-like study in PUP adults is warranted.

SIPPET Study: The European response

It appears that Europeans are interested in further investigating the development of inhibitors in response to different classes of Factor concentrates  (Recombinant vs Plasma -derived).


The Pharmacovigilance Risk Assessment Committee (PRAC) is the committee at the European Medicines Agency that is responsible for assessing and monitoring safety issues for human medicines. According to the EMA website the responsibility of PRAC is


"to prepare recommendations on any questions relating to pharmacovigilance activities related to a medicine for human use and on risk-management systems, including the monitoring of the effectiveness of those risk-management systems."


I think of PRAC in the EU as an equivalent of MASAC in the US. PRAC met in early July, 2016 and has provided the meeting highlights.  Here they provide a timeline of their procedure and also and opportunity for public hearings to hear the EU citizen's voice.


There is also a response from the United Kingdom Haemophilia Center Doctors' Organization (UKHCDO).  Their jurisdiction is England, Scotland, Northern Ireland and Wales.  UKHCDO released a statement on the SIPPET study.  The statement concludes:


"Pragmatically, UK clinicians should counsel parents about the implications of known inhibitor studies if the presenting clinical scenario allows. Recombinant FVIII concentrates remain an acceptable standard of care for PUPs, with plasma-derived concentrates considered on an individualized basis."