thrombotic thrombocytopenic purpura ( ttp ) is a rare acquired or congenital disorder with an annual incidence of six cases per million ( 1 ) .
its pathogenesis involves an imbalance between von willebrand factor ( vwf ) multimers and adamts13 .
if there is a gene mutation existing congenitally leading to absent or severely deficient adamts13 activity , it is called upshaw - shulman syndrome . autoantibodies against adamts13 leading to its decreased activity
pex is the first - line treatment and is effective in most of the cases .
however , in secondary ttp with normal or moderately reduced adamts13 activity and no evidence of adamts13 inhibitor , pex is not effective in many cases ( 3 ) .
atypical hemolytic uremic syndrome ( ahus ) is a disorder characterized by complement gene mutations or anti - factor h autoantibodies ( cfh ) autoantibodies causing dysregulation of the alternative complement pathway .
some other mutations identified in ahus are as follows : inactivating mutations of cfh ( factor h ) , cfi ( factor i ) , mcp ( membrane cofactor protein ) , or thrombomodulingain - of - function mutations of factor b and c3 , and anti - cfh autoantibodies 
  inactivating mutations of cfh ( factor h ) , cfi ( factor i ) , mcp ( membrane cofactor protein ) , or thrombomodulin gain - of - function mutations of factor b and c3 , and anti - cfh autoantibodies but only 70% of patients will be found to have these mutations and more mutational analyses need to be done including the recent finding of mutations of diacylglycerol kinase  in patients with suspected ahus .
the first - line treatment for ahus is still pex because there is no test available that can initially differentiate between ttp and ahus .
( 4 ) demonstrated that in patients with anti - cfh antibody - mediated ahus , the instantaneous use of pex and immune - suppressive therapy can improve outcomes .
eculizumab ( soliris ) was approved by food and drug administration ( fda ) in september 2011 for patients refractory to pex .
mortality rate before that was 67% and has gone down a lot where four out of five patients are able to come off dialysis . to note , end - stage renal disease was the major cause of death in people surviving initial hospitalization with ahus ( 5 ) .
it has always been a dilemma to differentiate ahus from ttp . in the past ,
traditionally , ttp is the diagnosis when there is an involvement of central nervous system ( cns ) , and ahus is the diagnosis when renal impairment is predominant .
now it is known that both these entities are in fact different disorders with distinct characteristics .
therefore , clinically , patients with ttp may have renal dysfunction and those with ahus may develop cns manifestations .
even though , it is now possible to differentiate these two disorders , we still do not have the capability to differentiate them at presentation . hence
, initial treatment for both these disorders is same , that is , pex therapy .
although a severe deficiency of the adamts13 protease ( < 510% ) and documented mutations of complement proteins are not required for the diagnosis of acquired ttp and ahus , respectively , both findings in the appropriate clinical context serve to confirm the clinical diagnosis .
, the two conditions were found to be secondary to completely different mechanisms as explained above .
eculizumab was approved by fda in 2011 for ahus and has become the gold standard therapy for this .
but it still remains a challenge to differentiate them and the decision has to be made on clinical judgment .
adamts13 can differentiate in most of the conditions but takes days to weeks to come back depending on the location .
meanwhile , starting therapy as soon as possible is really necessary to improve survival outcomes .
c3 , c4 , and ch50 can not be used because they are very non - specific and can be abnormal in a lot of situations .
ttp seems to cause more severe thrombocytopenia , and ahus is associated with more severe renal failure and is a leading cause of death in these patients .
diagnosis is likely to be ttp if platelet count is less than 30,000/l and creatinine is less than 2.25 mg / dl . on contrary
, ahus is the likely diagnosis if platelet count is greater than 30,000/l and creatinine is more than 2.25 mg / dl . on suspicion of ttp or ahus , emergent treatment with pex
should be instituted but should be rethought in 35 days in non - responders and focus should be shifted to eculizumab .
pex should be avoided when giving eculizumab because it gets washed out ( algorithm 1 ) .
approach to thrombotic thrombocytopenic purpura pancreatitis is one of the most common and severe complications after ercp .
, we need to understand the mechanism behind pep which is thought to be due to sphincter of oddi spasms or papillary edema leading to pancreatic drainage blockage .
pd stenting can itself increase post - ecrp complications if there are any manipulation accidents during placement . therefore , safety remains an important concern during prophylactic pd stent placement ( 6 , 7 ) .
nsaids have been proposed to reduce the incidence of pep by their anti - inflammatory action , but pd stent was the only major prevention method .
recently , a study showed that placebo had four times more pep compared to rectal indomethacin .
the incidence of the complication was 4.87% ( 4/82 ) in the study group and 20.23% ( 17/84 ) in the placebo group ; this difference was significant ( p=0.01 ) .
rectal indomethacin reduced the incidence of pep among patients at high risk of developing this complication ( 8) . a study done comparing pd stenting with placebo showed that placebo had three times more pep incidence than patients getting pd stenting .
pancreatitis is a well - known complication of ttp , but ttp - ahus secondary to acute pancreatitis is a rare occurrence .
hosler et al . ( 9 ) found that 30 out of 51 patients diagnosed with ttp had pancreatic involvement .
there was a major study done in japan in 2008 that looked at 919 patients with thrombotic microangiopathy ( tma ) and none of them were triggered by acute pancreatitis ( 10 ) .
the median time from pancreatitis to the development of ttp - ahus is 3 days which is true in our patient .
( 11 ) reported 5 patients and reviewed 16 cases from the literature , in which acute pancreatitis preceded clinically and laboratory signs of ttp by a median of 3 days ( 12 ) . in the great majority of cases , ttp develops in healthy individuals .
it has been associated with pregnancy , vascular disease , malignancy , and certain drugs , and the newest associations are hiv and pancreatitis ( 1 ) .
case reports have shown ttp - ahus secondary to autoimmune pancreatitis , alcohol abuse , gallstones , and granulomatous pancreatic inflammation due to sarcoid .
the mechanism in ttp - induced pancreatitis is not well understood but is proposed to be pancreatic tissue damage occurring as a result of intracellular activation of enzymes leading to a secondary inflammatory response and release of cytokines ( 1 ) . in case of ttp occurring after pancreatitis , it is plausible that the widespread immunological response as a result of pancreatitis may be involved .
further , as a result of vascular insult , there is a deficiency of adamts13 .
no data has shown any direct correlation between pancreatitis and ahus because most people can respond to pex and are considered to have ttp . looking at our case , there could be a real possibility of ahus having an association with pancreatitis and should be kept in mind in future . to conclude , the association of pancreatitis is more appropriate to make with tma and not just ttp or ahus
. in any case presenting with tma , the first step should be pex . on the failure of therapy for 35 days , eculizumab should be considered without any further delay because mortality in an ahus increases with delay in its treatment .
the authors have not received any funding or benefits from the organization or elsewhere to conduct and publish this study .
 thrombotic thrombocytopenic purpura ( ttp ) is a rare multisystem microvascular disorder , which is characterized by pentad of thrombocytopenia , microangiopathic hemolytic anemia , and organ dysfunction due to occlusive thrombi . 
 the proposed pathophysiology involves an imbalance between unusually large von willebrand factor multimers and the cleaving protease adamts13 . 
 acute pancreatitis is a well - described consequence of ttp , but ttp secondary to acute pancreatitis is a rare phenomenon . 
 we present a patient who developed ttp due to post - ercp pancreatitis with hematologic , cardiovascular , pulmonary , and renal complications and is the first case of this kind . despite early initiation of therapy 
 , the patient did not recover making it among the 10% of cases of ttp that prove fatal despite appropriate therapy . 
Discussion
Conclusion
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