What Causes Thrombotic Thrombocytopenic Purpura?Crystal Koralis Colón-OrtizAbstractThrombotic Thrombocytopenic Purpura (TTP) is a severe and rare blood disorder thataffects the coagulation of diverse organs of the body, precisely their minor veins. A specificcause for the disease has not yet been found, but there are three establish possibilitiesnamely; a hereditary deficiency of ADAMTS-13 (Upshaw- Schulman Syndrome), a resultof a previous disease or condition (Secondary Thrombotic Thrombocytopenic Purpura), orno previous condition (Idiopathic Thrombotic Thrombocytopenic Purpura). Thepredominant causes for this disorder are a deficiency of ADAMTS-13, and the differentfamily medical history backgrounds. These variables will determine the type of TTP.IntroductionThrombotic ThrombocytopenicPurpura (TTP) is a type of thromboticmicroangiopathy (Matsumuto et al.2012), arare blood disorder that leads to unusual bloodclotting in the small blood vessels(Reichstetter, 2010) and affects diverse organsof the body. Since it is a rare disorder, it hasnot been studied extensively.It affectsprincipally adult women, and it is estimatedthat 4-7 million people are diagnosed with iteach year in the United States (Steady health,2010). Half of the diagnosed patients do notknow the principal cause for this life-threathening disease that requires an earlydiagnosis. Treatments have not yet beendeveloped for it.Scientists have established variousdisease categories. These are Immune TTP,Secondary TTP, and Upshaw- SchulmanSyndrome.Idiopathic TTP (ITP) is anautoimmune disorder characterized by a lowplatelet count and mucocutaneous bleeding(Cines and Blanchette, 2002). It is notdeveloped as a result of a previous disease.Secondary TTP (STP) occurs as acomplication of a primary disease orconditions such as certain cancers, pregnancy,and HIV. Upshaw- Schulman syndrome(HUS) shows a hereditary mutation of theADAMTS-13 gene.These are all related to the deficientactivity of the von Willebrand factor (VWF)cleaving protease ADAMTS-13. VWF is amultimeric glycoprotein which has animportant function for high-shearstressassociated platelet adhesion andaggregation (Loirat C. et al. 2009). When apatient suffers from ADAMTS-13 deficiency,VWF displays multimers that bind to plateletsinfluencing them to aggregate in plasma andplatelet thrombi in the micro veins of theorgans (Loirat et al.2009).The objective of this review is topresent knowledge about these three causes ofTTP and determine which one is the mostcommon.
Symptoms and TreatmentsMost of the symptoms of TTP are triggeredby infections due to the low platelet in thebody or due to vaccinations. The generalsymptoms for TTP are fever, distress, acuterenal insufficiency, anemia, and weakness, andchronic fatigue, confusion, bleeding, andbrushing. The presence of microangiopathichemolytic anemia due to the mechanicaldamage of erythrocytes (Loirat et al. 2009) is asymptom as well.There is no specific treatment for thedisease, other than plasma exchange. If thepatient is an adult, he or she will be treatedwith plasma exchange containing FFP orplasmapheresis, cryosupernatant plasma, andgradually more immunosuppressive therapies(Wyrick-Glatzel et al. 2004). If the patient is achild, he or she will be treated with plasmaexchange associated with steroids, and the useof rituximab (Bredlau, 2011).CausesSince the discovery and initial recognitionof Thrombotic Thrombocytopenic Purpura in1924, Dr Eli Moschcowitz, knew he wasfacing a serious disorder. (Lämmle, Kreme,Alberio, 2005). By 1998 scientists proposedthat it was related to a familiar absence oracquired inhibition of plasma VWF-cleavingmetalloprotease. Time passed, and they finallydiscovered three different types of TTP (ITP,STP, and HUS) categorized by different typesof causes, but with one main characteristic forall of them; the deficient activity of the VWFcleaving protease ADAMTS-13, as suspectedin 1998.Immune Thrombotic ThrombocytopeniaPurpuraImmune thrombotic thrombocytopenicpurpura is an autoimmune disordercharacterized by a low platelet count andmucocutaneous bleeding. The incidence is of100 cases per 1 million persons per year(Cines and Blanchette, 2002). Children areaffected as well by this disorder. Thisincidence depends mainly on the environment.The major problem of this type of TTP is thatthere is not a main cause established, and it isnot developed as an effect of a previousdisease making it difficult to treat anddiagnose. Several studies have been done inattempts to decipher this rare disease for itsdiagnose and treatment. One of them wasmade by a group of Japanese scientists whostudied the history of 919 patients registeredin their database. Of these 919, only 186 werediagnosed with first onset of acquiredidiopathic and a deficiency of ADAMTS-13.They used this data to compare severalcharacteristics with other similar studies indifferent countries like United States, Korea,and Europe. Some of the results were that themedian age of this group of patients was 54comparing to the other groups that were fromthe ages of 39 to 34. Fifty-seven percent(57%) of them were females versus 60% in theother groups. They concluded thatdemographic characteristics differ in Japanesepatients (Matsumuto et al. 2012). Studies likethis one are important in order to look forcommon characteristic and to find an easierway to target the disease.
Secondary Thrombotic ThrombocytopeniaPurpuraSecondary ThromboticThrombocytopenic Purpura occurs as acomplication of a primary disease like; certaincancers, pregnancy, and HIV. Having thisdisorder as a secondary cause will dependmainly in the immune system of the patient.Chang & Naquvi (2003) aftercompleting the study entitled “ThromboticThrombocytopenic Purpura Associated withBone Narrow Metastasis and SecondaryMylefibrosis in Cancer” concluded that TTPcan be associated with cancer, but in a verysmall fraction of cancer patients. Compared tothe incidence of pregnancies associated withTTP, which is: 5% of normal pregnancies arefound with a reduction in platelets counts, areonly one in 25,000 pregnancies (Gerth et al.2009)? Also, 0.3% out of 6,022 patients withHIV tested positive for TTP. (Becker S. et al.2004).Of these three diseases, pregnancy isthe most common cause for STP. A group ofscientists emphasized the importance ofmeasuring ADAMTS-13 activity andADAMTS-13 inhibitor in childhood andduring pregnancy, in order to reduce thecipher. They concluded that pregnancyconstantly induces Thrombocytopenia duringthe second-third trimester, and it eventuallypresents TTP. In order to arrive at theseconclusions, they identified 37 patients withUSS, focusing only on 9 women from 6different families diagnosed during their firstpregnancy. The measurement of ADAMTS-13activity, ADAMTS-13 inhibitor, ADAMTS-13antigen, and ADAMTS-13 gene analysis wasprimordial to understanding the role ofADAMTS-13 in USS and its relationship withpregnancy (Fujimura et al.2008).Upshaw-Schulman SyndromeWhen TTP is inherited, it isdenominated as Upshaw-Schulman Syndrome(HUS) and shows an ADAMTS-13 genemutation. It is a disorder of “complementactivation regulation on cell (endothelial)surfaces, due to mutations in the genesencoding complement factor H, factor I, factorB or membrane co factor protein”(Loirat et al.2009). The age rate when this disease isexpressed is between 40-49 years old (Terrelet al, 2005). Of the three other types of TTP,HUS has more established protocols fordiagnostic and treatment. After all, there is stilla lot to know about how TTP gets complicatedwith other diseases like acute renal failure.Seven scientists curious about a case ofa 31 year old patient with thromboticmicroangiopathy and acute renal failure.Suspected that he had Upshaw SchulmanSyndrome because of his performance assaysof ADAMTS-13. In order to find the cause, itwas necessary to do several analyses like theassay of ADAMTS-13 activity and itsinhibitor, and ADAMTS-13 gene analysis.The investigation showed that the patient hadan exceedingly low ADAMTS-13 activity andno inhibitors of ADAMTS-13. Also theyfound two novel mutations on two exons. Onemutation was from his mother and the otherfrom his father. Studies like this emphasizethe significance of assays of ADAMTS-13activity and its inhibitors in patients who haveepisodes of renal insufficiency associated withUpshaw Schulman Syndrome as a way to findan easier diagnostic and select an appropriatetreatment (Shigaki et al. 2006).
ConclusionAfter reviewing studies of the threetypes of TTP, we can conclude that the mostcommon one is STP because of the prevalenceof cancer, HIV, and pregnancy cases. Of thethree common diseases or conditions,pregnancy was the one that led to the mostdevelopment of the disorder. In general, theneed for more investigation in this area isevident. During the time the study was made,statistics concerning this topic were not found.In order to obtain reliable result, statistics areessential. The development of an earlydiagnostic and an efficient treatment is needed.An early diagnostic can save a lot of lives.There is a lot to do, and to learn about thisrare, but existing disorder, that has beenforgotten.All of the three types of TTP showedits common cause to be a deficient activity ofVWF cleaving protease ADAMTS-13. Thecomplication or genetic information willdetermine which one of the three types will bedeveloped. Immune ThromboticThrombocytopenia Purpura is the one thatneeds more investigations, in order to establishwhat in the environment that can lead to thedevelopment of the disorder.The aims of this review werecompleted after finding the main cause forTTP, and which one of them had higherincidences. We expect to repeat this review in5 years, to obtain more information andeventually, compare it with this study.References1. Becker S., Fusco J., Balu R., GangjeeS., Brennan C., Feinberg J.2004.HIV-Associated ThromboticMicroangiopathy in the Era of HighlyActive Antiretroviral Therapy: AnObservational Study.39(5):267-275.2. Bredlau A. , Semple J., SegelG.2011.Management of ImmuneThrombocytopenic Purpura inChildren Potential Role off NovelAgents.Pediatr Drugs.13(4):213-223.3. Chang J., Naquvi T.2003.ThromboticThrombocytopenic PurpuraAssociated with Bone NarrowMetastasis and SecondaryMyelofibrosis in Cancer.TheOncologist.8(4):375-380.4. Cines D., Blanchette V. 2002. ImmuneThrombocytopenic Purpura. N Engle JMed. 346:995-1008.5. Matsumoto M, Matsumoto M, Kokame K,Isonishi A, Soejima K, Akiyama N,Tomiyama J, Natori K, Kuranishi Y,Imamura Y et al. 2008. Pregnancy-induced thrombocytopenia and TTP, andthe risk of fetal death, in Upshaw–Schulman syndrome: a series of 15pregnancies in 9 genotyped patients.BritishJ Haematology 144:742–754.6. Gerth J., Schleussner E., KentoucheK., Busch M., Seifert M., WolfG.2009.Pregnancy-associatedThrombotic Thrombocytopenicpurpura.Thrombosis-online.[Internet];[revised 2007 December 14; citated2012 November 1]doi:10.1160/TH07-12-0739.7. Lammle B., Kremer JA., AlberioL.2005.ThromboticThrombocyropenicpurpura.PubMed[Internet];[revised2005 August ;citated 2012 November1].3(8):1663-75.
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