View source for Medicine:Thrombotic thrombocytopenic purpura

{{Infobox medical condition (new)
| name            =  Thrombotic thrombocytopenic purpura
| synonyms        = Moschcowitz syndrome,<ref name=Kre2017/> idiopathic thrombotic thrombocytopenic purpura<ref name=GARD2018/>
| image           = Echymosis.jpg
| width           =
| alt             =
| caption         = Spontaneous bruising in a woman with critically low platelets
| pronounce       =
| field           = [[Medicine:Hematology|Hematology]]
| symptoms        = [[Medicine:Ecchymosis|Large bruises]], [[Medicine:Fever|fever]], weakness, shortness of breath, confusion, [[Medicine:Headache|headache]]<ref name=Jol2017/><ref name=GARD2018/>
| complications   =
| onset           = Adulthood<ref name=Jol2017/>
| duration        =
| types           =
| causes          = Unknown, bacterial infections, certain medications, [[Medicine:Autoimmune disease|autoimmune disease]]s, [[Medicine:Pregnancy|pregnancy]]<ref name=Jol2017/>
| risks           =
| diagnosis       = Based on symptoms and blood tests<ref name=GARD2018/>
| differential    = [[Medicine:Hemolytic-uremic syndrome|Hemolytic-uremic syndrome]] (HUS), [[Medicine:Atypical hemolytic uremic syndrome|atypical hemolytic uremic syndrome]] (aHUS)<ref name=Geo2010/>
| prevention      =
| treatment       = Plasma exchange, [[Chemistry:Immunosuppressant|immunosuppressant]]s<ref name=Kre2017/>
| medication      =
| prognosis       = < 20% risk of death<ref name=Kre2017/>
| frequency       = 1 in 100,000 people<ref name=Jol2017/>
| deaths          =
}}

'''Thrombotic thrombocytopenic purpura''' ('''TTP''') is a blood disorder that results in blood clots forming in small blood vessels throughout the body.<ref name="GARD2018">{{Cite web |title=Immune-mediated thrombotic thrombocytopenic purpura |url=https://rarediseases.info.nih.gov/diseases/4607/thrombotic-thrombocytopenic-purpura-acquired |website=Genetic and Rare Diseases Information Center |publisher=U.S. Department of Health & Human Services |access-date=2018-10-10 |archive-date=2018-10-20 |archive-url=https://web.archive.org/web/20181020052040/https://rarediseases.info.nih.gov/diseases/4607/thrombotic-thrombocytopenic-purpura-acquired |url-status=dead }}</ref> This results in a [[Medicine:Thrombocytopenia|low platelet count]], low red blood cells due to their breakdown, and often kidney, [[Biology:Heart|heart]], and [[Biology:Brain|brain]] dysfunction.<ref name=Kre2017/> Symptoms may include [[Medicine:Ecchymosis|large bruises]], [[Medicine:Fever|fever]], [[Medicine:Weakness|weakness]], shortness of breath, [[Medicine:Confusion|confusion]], and [[Medicine:Headache|headache]].<ref name=GARD2018/><ref name="Jol2017">{{Cite journal |last1=Joly |first1=Bérangère S. |last2=Coppo |first2=Paul |last3=Veyradier |first3=Agnès |name-list-style=vanc |date=May 2017 |title=Thrombotic thrombocytopenic purpura |journal=Blood |volume=129 |issue=21 |pages=2836–2846 |doi=10.1182/blood-2016-10-709857 |issn=0006-4971 |pmid=28416507|s2cid=2543348 |doi-access=free }}</ref> Repeated episodes may occur.<ref name=Jol2017/>

In about half of cases a trigger is identified, while in the remainder the cause remains unknown.<ref name=Jol2017/> Known triggers include bacterial infections, certain medications, [[Medicine:Autoimmune disease|autoimmune disease]]s such as [[Medicine:Systemic lupus erythematosus|lupus]], and [[Medicine:Pregnancy|pregnancy]].<ref name=Jol2017/> The underlying mechanism typically involves [[Biology:Antibody|antibodies]] inhibiting the [[Biology:Enzyme|enzyme]] [[Biology:ADAMTS13|ADAMTS13]].<ref name=Kre2017/> This results in decreased break down of large multimers of [[Biology:Von Willebrand factor|von Willebrand factor]] (vWF) into smaller units.<ref name=Kre2017/> Less commonly TTP is [[Biology:Heredity|inherited]], known as [[Medicine:Upshaw–Schulman syndrome|Upshaw–Schulman syndrome]], such that ADAMTS13 dysfunction is present from birth.<ref name="Moake2004">{{Cite journal |last=Moake |first=Joel L |name-list-style=vanc |date=January 2004 |title=Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura |url=https://www.sciencedirect.com/science/article/pii/S0037196303002683 |journal=Seminars in Hematology |volume=41 |issue=1 |pages=4–14 |doi=10.1053/j.seminhematol.2003.10.003 |issn=0037-1963 |pmid=14727254}}</ref> Diagnosis is typically based on symptoms and blood tests.<ref name=GARD2018/> It may be supported by measuring activity of or antibodies against ADAMTS13.<ref name=GARD2018/>

With plasma exchange the risk of death has decreased from more than 90% to less than 20%.<ref name="Kre2017">{{Cite journal |last1=Kremer Hovinga |first1=Johanna A. |last2=Coppo |first2=Paul |last3=Lämmle |first3=Bernhard |last4=Moake |first4=Joel L. |last5=Miyata |first5=Toshiyuki |last6=Vanhoorelbeke |first6=Karen |name-list-style=vanc |date=April 2017 |title=Thrombotic thrombocytopenic purpura |url=https://www.nature.com/articles/nrdp201720 |journal=Nature Reviews Disease Primers |language=en |volume=3 |page=17020 |doi=10.1038/nrdp.2017.20 |issn=2056-676X |pmid=28382967 |s2cid=11960153 |article-number=17020}}{{Cbignore}}</ref> [[Chemistry:Immunosuppressant|Immunosuppressant]]s, such as glucocorticoids, and [[Chemistry:Rituximab|rituximab]] may also be used.<ref name=Jol2017/> [[Medicine:Platelet transfusion|Platelet transfusion]]s are generally not recommended.<ref>{{Cite book |last1=Wood |first1=Marie E. |url=https://books.google.com/books?id=KNP1b_VTcwQC |title=Hematology/Oncology Secrets |last2=Philips |first2=George K. |publisher=Elsevier |year=2003 |isbn=978-1-56053-516-4 |edition=3rd |pages=68}}</ref>

About 1 per 100,000 people are affected.<ref name=Jol2017/> Onset is typically in adulthood and women are more often affected.<ref name=Jol2017/> About 10% of cases begin in childhood.<ref name=Jol2017/> The condition was first described by Eli Moschcowitz in 1924.<ref name=Jol2017/> The underlying mechanism was determined in the 1980s and 1990s.<ref name=Jol2017/>

==Signs and symptoms==
The signs and symptoms of TTP may at first be subtle and nonspecific. Many people experience an [[Biology:Influenza-like illness|influenza-like]] or diarrheal illness before developing TTP.<ref name="Shatzel2017">{{Cite journal |last1=Shatzel |first1=Joseph J. |last2=Taylor |first2=Jason A. |name-list-style=vanc |date=March 2017 |title=Syndromes of Thrombotic Microangiopathy |url=https://www.sciencedirect.com/science/article/pii/S0025712516373618 |journal=Medical Clinics of North America |volume=101 |issue=2 |pages=395–415 |doi=10.1016/j.mcna.2016.09.010 |issn=0025-7125 |pmid=28189178 |s2cid=24123004}}</ref> Neurological symptoms are very common and vary greatly in severity. Frequently reported symptoms include [[Medicine:Fatigue|feeling very tired]], [[Medicine:Delirium|confusion]], and [[Medicine:Headache|headache]]s.<ref name="Shatzel2017"/> [[Medicine:Seizure|Seizure]]s and symptoms similar to those of a [[Medicine:Stroke|stroke]] can also be seen.<ref name="Shatzel2017"/> Other symptoms include, but are not limited to [[Medicine:Jaundice|jaundice]] or paleness of the skin, a fast heart rate or shortness of breath,<ref>{{Cite web |title=Thrombotic thrombocytopenic purpura |url=https://medlineplus.gov/genetics/condition/thrombotic-thrombocytopenic-purpura/ |website=MedlinePlus Genetics |publisher=National Library of Medicine |language=en}}</ref> or dots on the skin known as petechiae.<ref name=":1">{{Cite web |orig-date=Updated March 24, 2022 |title=Platelet Disorders - Thrombotic Thrombocytopenic Purpura (TTP) |url=https://www.nhlbi.nih.gov/health/thrombotic-thrombocytopenic-purpura |website=[[Organization:National Heart, Lung, and Blood Institute|National Heart, Lung, and Blood Institute]] |date=24 March 2022 |language=en}}</ref> High blood pressure has also been observed as a symptom.<ref>{{Cite journal |last1=Shibagaki |first1=Yugo |last2=Fujita |first2=Toshiro |name-list-style=vanc |date=January 2005 |title=Thrombotic Microangiopathy in Malignant Hypertension and Hemolytic Uremic Syndrome (HUS)/Thrombotic Thrombocytopenic Purpura (TTP): Can We Differentiate One from the Other? |journal=Hypertension Research |language=en |volume=28 |issue=1 |pages=89–95 |doi=10.1291/hypres.28.89 |pmid=15969259 |s2cid=139098502 |issn=1348-4214|doi-access=free }}</ref>

As TTP progresses, blood clots form within small blood vessels (microvasculature), and platelets (clotting cells) are consumed. As a result, bruising, and rarely bleeding can occur. The bruising often takes the form of purpura, while the most common site of bleeding, if it occurs, is from the nose or gums. Larger bruises (ecchymoses) may also develop.<ref>{{Cite journal |last1=Chiasakul |first1=Thita |last2=Cuker |first2=Adam |name-list-style=vanc |date=November 2018 |title=Clinical and laboratory diagnosis of TTP: an integrated approach |url=https://doi.org/10.1182/asheducation-2018.1.530 |journal=Hematology |volume=2018 |issue=1 |pages=530–538 |doi=10.1182/asheducation-2018.1.530 |issn=1520-4391 |pmc=6246034 |pmid=30504354 |s2cid=54564230}}</ref> The classic presentation of TTP, which occurs in less than 10% of people, includes five medical signs. These are:<ref name="Jol2017" />
* [[Medicine:Fever|Fever]]
* Changes in mental status
* [[Medicine:Thrombocytopenia|Thrombocytopenia]]
* Reduced kidney function
* Hemolytic anemia (microangiopathic hemolytic anemia).<ref name="Shatzel2017"/>

==Causes==
TTP, as with other microangiopathic hemolytic anemias (MAHAs), is caused by spontaneous [[Biology:Platelet#Adhesion and aggregation|aggregation]] of platelets and activation of coagulation in the small blood vessels. Platelets are consumed in the aggregation process and bind [[Biology:Von Willebrand factor|vWF]]. These platelet-vWF complexes form small blood clots which circulate in the blood vessels and cause shearing of red blood cells, resulting in their [[Medicine:Hemolysis|rupture]] and formation of schistocytes.<ref name="Moake2002">{{Cite journal |last=Moake |first=Joel L. |name-list-style=vanc |date=August 2022 |title=Thrombotic Microangiopathies |url=http://www.nejm.org/doi/abs/10.1056/NEJMra020528 |journal=New England Journal of Medicine |language=en |volume=347 |issue=8 |pages=589–600 |doi=10.1056/NEJMra020528 |issn=0028-4793 |pmid=12192020 |s2cid=40055198}}</ref> The two best understood causes of TTP are due to [[Medicine:Autoimmunity|autoimmunity]] ([[Biology:Acquired characteristic|acquired]] TTP), caused by autoantibodies targeting [[Biology:ADAMTS13|ADAMTS13]],<ref name=":2">{{Cite book |last1=Stanley |first1=Michael |title=StatPearls |last2=Killeen |first2=Robert B. |last3=Michalski |first3=Joel M. |date=January 2023 |publisher=StatPearls Publishing |chapter=Thrombotic Thrombocytopenic Purpura |pmid=28613472 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK430721/ |name-list-style=vanc}}</ref> or congenital TTP: an inherited deficiency of ADAMTS13 (known as the [[Medicine:Upshaw–Schulman syndrome|Upshaw–Schulman syndrome]]).<ref name=Moake2002/>

===Autoimmune===
In 1998, the majority of cases were shown to be caused by the inhibition of the enzyme [[Biology:ADAMTS13|ADAMTS13]] by [[Biology:Antibody|antibodies]]. Knowledge of this relationship between reduced ADAMTS13 and the [[Medicine:Pathogenesis|pathogenesis]] of TTP is credited to two independent groups of researchers (Furlan and Tsai) who published their research in the same issue of the ''New England Journal of Medicine''.<ref>{{Cite journal |last=Moake |first=Joel L. |name-list-style=vanc |date=November 1998 |title=Moschcowitz, Multimers, and Metalloprotease |url=http://www.nejm.org/doi/abs/10.1056/NEJM199811263392210 |journal=New England Journal of Medicine |language=en |volume=339 |issue=22 |pages=1629–1631 |doi=10.1056/NEJM199811263392210 |issn=0028-4793 |pmid=9828253}}</ref>

ADAMTS13 is a [[Biology:Metalloproteinase|metalloproteinase]] responsible for the breakdown of [[Biology:Von Willebrand factor|von Willebrand factor]] (vWF), a protein that links [[Biology:Platelet|platelets]], blood clots, and the blood vessel wall in the process of blood coagulation. Very large vWF multimers are more prone to lead to coagulation. Hence, without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the microvasculature, part of the blood vessel system where vWF is most active due to high [[Physics:Shear stress|shear stress]].<ref name=Moake2004/>

===Genetic===
[[Image:Autosomal recessive - en.svg|thumb|Thrombotic thrombocytopenic purpura is inherited in an autosomal recessive manner.<ref>{{cite web |title=THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY; TTP |url=https://www.omim.org/entry/274150 |website=OMIM |language=en-us}}</ref><ref>{{cite web |title=Thrombotic thrombocytopenic purpura |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=54057 |website=Orphanet |language=en}}</ref>]]
TTP may also be congenital. Such cases may be caused by mutations in the [[Biology:ADAMTS13|ADAMTS13]] gene.<ref>{{Cite journal |last1=Conboy |first1=Erin |last2=Partain |first2=Paige I. |last3=Warad |first3=Deepti |last4=Kluge |first4=Michelle L. |last5=Arndt |first5=Carola |last6=Chen |first6=Dong |last7=Rodriguez |first7=Vilmarie |name-list-style=vanc |date=January 2018 |title=A Severe Case of Congenital Thrombotic Thrombocytopenia Purpura Resulting From Compound Heterozygosity Involving a Novel ADAMTS13 Pathogenic Variant |url=https://journals.lww.com/jpho-online/abstract/2018/01000/a_severe_case_of_congenital_thrombotic.12.aspx |journal=Journal of Pediatric Hematology/Oncology |language=en-US |volume=40 |issue=1 |pages=60–62 |doi=10.1097/MPH.0000000000000895 |issn=1077-4114 |pmid=28678087 |s2cid=3470460}}</ref><ref>{{Cite journal |last1=Lämmle |first1=Bernhard |last2=Hovinga |first2=Johanna A. Kremer |last3=George |first3=James N. |name-list-style=vanc |date=February 2008 |title=Acquired thrombotic thrombocytopenic purpura: ADAMTS13 activity, anti-ADAMTS13 autoantibodies and risk of recurrent disease |url=https://haematologica.org/article/view/4736 |journal=Haematologica |language=en |volume=93 |issue=2 |pages=172–177 |doi=10.3324/haematol.12701 |issn=1592-8721 |pmid=18245649|s2cid=17777111 |doi-access=free }}</ref> This hereditary form of TTP is called the [[Medicine:Upshaw–Schulman syndrome|Upshaw–Schulman syndrome]] (also spelled Upshaw–Schülman).<ref>{{Cite journal |last1=Kremer Hovinga |first1=Johanna A. |last2=George |first2=James N. |name-list-style=vanc |date=October 2019 |editor-last=Longo |editor-first=Dan L. |title=Hereditary Thrombotic Thrombocytopenic Purpura |url=http://www.nejm.org/doi/10.1056/NEJMra1813013 |journal=New England Journal of Medicine |language=en |volume=381 |issue=17 |pages=1653–1662 |doi=10.1056/NEJMra1813013 |pmid=31644845 |s2cid=204864996 |issn=0028-4793}}</ref><ref>{{Cite journal |last1=Chapman |first1=Kent |last2=Seldon |first2=Michael |last3=Richards |first3=Ross |name-list-style=vanc |date=February 2012 |title=Thrombotic Microangiopathies, Thrombotic Thrombocytopenic Purpura, and ADAMTS-13 |journal=Seminars in Thrombosis and Hemostasis |language=en |volume=38 |issue=1 |pages=47–54 |doi=10.1055/s-0031-1300951 |issn=0094-6176 |pmid=22314603|s2cid=13963783 |doi-access=free }}</ref> People with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased von Willebrand factor levels, e.g. infection. Reportedly, less than 5% of all TTP cases are due to Upshaw–Schulman syndrome.<ref>{{Cite book |last=Tsai |first=Han-Mou |title=Wintrobe's Clinical Hematology |publisher=Wolters Kluwer |year=2023 |isbn=978-1-975184-69-8 |editor-last=Means |editor-first=Robert T. Jr. |edition=15th |volume=2 |chapter=Thrombotic Thrombocytopenic Purpura, Hemolytic-Uremic Syndrome, and Related Disorders |editor-last2=Arber |editor-first2=Daniel A. |editor-last3=Glader |editor-first3=Bertil E. |editor-last4=Appelbaum |editor-first4=Frederick R. |editor-last5=Rodgers |editor-first5=George M. |editor-last6=Dispenzieri |editor-first6=Angela |editor-last7=Fehniger |editor-first7=Todd A. |editor-last8=Michaelis |editor-first8=Laura C. |editor-last9=Leonard |editor-first9=John P. |name-list-style=vanc}}</ref> People with this syndrome generally have 5–10% of normal ADAMTS-13 activity.<ref name=":0">{{Cite journal |last1=Levy |first1=Gallia G. |last2=Nichols |first2=William C. |last3=Lian |first3=Eric C. |last4=Foroud |first4=Tatiana |last5=McClintick |first5=Jeanette N. |last6=McGee |first6=Beth M. |last7=Yang |first7=Angela Y. |last8=Siemieniak |first8=David R. |last9=Stark |first9=Kenneth R. |last10=Gruppo |first10=Ralph |last11=Sarode |first11=Ravindra |last12=Shurin |first12=Susan B. |last13=Chandrasekaran |first13=Visalam |last14=Stabler |first14=Sally P. |last15=Sabio |first15=Hernan |name-list-style=vanc |date=October 2001 |title=Mutations in a member of the ''ADAMTS'' gene family cause thrombotic thrombocytopenic purpura |journal=Nature |language=en |volume=413 |issue=6855 |pages=488–494 |bibcode=2001Natur.413..488L |doi=10.1038/35097008 |issn=1476-4687 |pmid=11586351 |s2cid=4380010 |hdl-access=free |hdl=2027.42/62592}}</ref><ref>{{Cite journal |last1=Kokame |first1=Koichi |last2=Matsumoto |first2=Masanori |last3=Soejima |first3=Kenji |last4=Yagi |first4=Hideo |last5=Ishizashi |first5=Hiromichi |last6=Funato |first6=Masahisa |last7=Tamai |first7=Hiroshi |last8=Konno |first8=Mutsuko |last9=Kamide |first9=Kei |last10=Kawano |first10=Yuhei |last11=Miyata |first11=Toshiyuki |last12=Fujimura |first12=Yoshihiro |name-list-style=vanc |date=September 2002 |title=Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity |journal=Proceedings of the National Academy of Sciences |language=en |volume=99 |issue=18 |pages=11902–11907 |bibcode=2002PNAS...9911902K |doi=10.1073/pnas.172277399 |issn=0027-8424 |pmc=129366 |pmid=12181489 |s2cid=20496927 |doi-access=free }}</ref>

===Secondary===

Secondary TTP is diagnosed when the person's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:<ref name=Moake2002/>
* [[Medicine:Cancer|Cancer]]
* Bone marrow transplantation
* [[Medicine:Pregnancy|Pregnancy]]
* [[Chemistry:Medication|Medication]] use:
** Antiviral drugs (acyclovir)
** Certain [[Medicine:Chemotherapy|chemotherapy]] medications such as [[Chemistry:Gemcitabine|gemcitabine]] and [[Biology:Mitomycin C|mitomycin C]]
** [[Chemistry:Quinine|Quinine]]
** [[Chemistry:Oxymorphone|Oxymorphone]]
** [[Chemistry:Quetiapine|Quetiapine]]
** [[Chemistry:Bevacizumab|Bevacizumab]]
** [[Chemistry:Sunitinib|Sunitinib]]
** Platelet aggregation inhibitors ([[Chemistry:Ticlopidine|ticlopidine]], [[Chemistry:Clopidogrel|clopidogrel]], and [[Chemistry:Prasugrel|prasugrel]])
** Immunosuppressants ([[Chemistry:Ciclosporin|ciclosporin]], [[Biology:Mitomycin|mitomycin]], [[Chemistry:Tacrolimus|tacrolimus]]/FK506, [[Biology:Interferon|interferon-α]])
** Hormone altering drugs (estrogens, contraceptives, [[Chemistry:Hormone replacement therapy|hormone replacement therapy]])<ref>{{cite book| last1= Menkes| first1= John H.| first2= Harvey B. | last2= Sarnat| first3= Bernard L. | last3= Maria| chapter= Thrombotic Thrombocytopenic Purpura and Hemolytic-Uremic Syndrome| title= Child Neurology| edition= 7th | location= Philadelphia| publisher= Lippincott Williams & Wilkins| year= 2006 |page= 525 |isbn= 9780781751049}}</ref>
* HIV-1 infection

The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage,<ref>{{Cite journal |last1=van Mourik |first1=Jan A. |last2=Boertjes |first2=Ria |last3=Huisveld |first3=Inge A. |last4=Fijnvandraat |first4=Karin |last5=Pajkrt |first5=Dasja |last6=van Genderen |first6=Perry J.J. |last7=Fijnheer |first7=Rob |name-list-style=vanc |date=1999-07-01 |title=von Willebrand Factor Propeptide in Vascular Disorders: A Tool to Distinguish Between Acute and Chronic Endothelial Cell Perturbation |url=https://www.sciencedirect.com/science/article/pii/S000649712067495X |journal=Blood |language=en |volume=94 |issue=1 |pages=179–185 |doi=10.1182/blood.V94.1.179.413k18_179_185 |issn=1528-0020 |pmid=10381511}}</ref> although the formation of thrombi resulting in vessel occlusion may not be essential in the pathogenesis of secondary TTP.<ref name=Iwata2001>{{cite journal |vauthors=Iwata H, Kami M, Hori A, Hamaki T, Takeuchi K, Mutou Y |title=An autopsy-based retrospective study of secondary thrombotic thrombocytopenic purpura |journal= Haematologica |volume=86 |issue=6 |pages=669–70 |date=June 2001 |pmid= 11418383 |url=http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=11418383}}</ref> These factors may also be considered a form of secondary aHUS; people presenting with these features are, therefore, potential candidates for anticomplement therapy.

==Pathophysiology==
The underlying mechanism typically involves autoantibody-mediated inhibition of the enzyme [[Biology:ADAMTS13|ADAMTS13]], a metalloprotease responsible for cleaving large multimers of [[Biology:Von Willebrand factor|von Willebrand factor]] (vWF) into smaller units. The increase in circulating multimers of vWF increases platelet adhesion to areas of [[Biology:Endothelium|endothelial]] injury, particularly where [[Biology:Arteriole|arteriole]]s and [[Biology:Capillary|capillaries]] meet, which in turn results in the formation of small platelet clots called [[Medicine:Thrombus|thrombi]].<ref name=":3">{{Cite journal |last=Tsai |first=Han-Mou |name-list-style=vanc |date=January 2010 |title=Pathophysiology of thrombotic thrombocytopenic purpura |url=https://doi.org/10.1007/s12185-009-0476-1 |journal=International Journal of Hematology |language=en |volume=91 |issue=1 |pages=1–19 |doi=10.1007/s12185-009-0476-1 |issn=1865-3774 |pmc=3159000 |pmid=20058209}}</ref> As platelets are used up in the formation of thrombi, this then leads to a decrease in the number of overall circulating platelets, which may then cause life-threatening bleeds. Red blood cells passing the microscopic clots are subjected to [[Physics:Shear stress|shear stress]], which damages their membranes, leading to [[Medicine:Hemolysis|rupture of red blood cells]] within blood vessels,<ref name=":1" /> which in turn leads to microangiopathic hemolytic anemia and schistocyte formation. The presence of the thrombi reduces blood flow to organs resulting in cellular injury and [[Medicine:End organ damage|end organ damage]].<ref name=":2" />

=== Recovery ===
[[Medicine:Depression (mood)|Depression]] is common in those recovering from TTP; 59% of recovered TTP patients screened positive for depression within 11 years after recovery.<ref>{{Cite journal |last1=Han |first1=Bowie |last2=Page |first2=Evaren E. |last3=Stewart |first3=Lauren M. |last4=Deford |first4=Cassandra C. |last5=Scott |first5=James G. |last6=Schwartz |first6=Lauren H. |last7=Perdue |first7=Jedidiah J. |last8=Terrell |first8=Deirdra R. |last9=Vesely |first9=Sara K. |last10=George |first10=James N. |name-list-style=vanc |date=August 2018 |title=Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura: Depression and Cognitive Impairment Following TTP |journal=American Journal of Hematology |language=en |volume=90 |issue=8 |pages=709–714 |doi=10.1002/ajh.24060 |pmc=4509840 |pmid=25975932}}</ref>

==Diagnosis==
===Differential diagnosis===
TTP is a form of [[Medicine:Thrombotic microangiopathy|thrombotic microangiopathy]] (TMA),<ref name=":4">{{Cite journal |last1=Arnold |first1=Donald M. |last2=Patriquin |first2=Christopher J. |last3=Nazy |first3=Ishac |name-list-style=vanc |date=January 2017 |title=Thrombotic microangiopathies: a general approach to diagnosis and management |url=https://www.cmaj.ca/content/189/4/e153 |journal=CMAJ |language=en |volume=189 |issue=4 |pages=E153–E159 |doi=10.1503/cmaj.160142 |issn=0820-3946 |pmc=5266569 |pmid=27754896}}</ref> the formation of blood clots in small blood vessels throughout the body, which can lead to microangiopathic hemolytic anemia and [[Medicine:Thrombocytopenia|thrombocytopenia]].<ref name=":4" /> This characteristic is shared by two related syndromes, [[Medicine:Hemolytic-uremic syndrome|hemolytic-uremic syndrome]] (HUS) and [[Medicine:Atypical hemolytic uremic syndrome|atypical hemolytic uremic syndrome]] (aHUS).<ref name=Geo2010>{{Cite journal |last=George |first=James N. |name-list-style=vanc |date=November 2010 |title=How I treat patients with thrombotic thrombocytopenic purpura: 2010 |journal=Blood |language=en |volume=116 |issue=20 |pages=4060–4069 |doi=10.1182/blood-2010-07-271445 |issn=0006-4971 |pmid=20686117 |s2cid=26844964|doi-access=free }}</ref> Consequently, differential diagnosis of these TMA diseases is essential. Both TTP and HUS are characterized by [[Medicine:Fever|fever]], [[Medicine:Anemia|anemia]], [[Medicine:Thrombocytopenia|thrombocytopenia]], renal failure, and neurological symptoms. Generally, TTP has higher rates of neurological symptoms (≤80%) and lower rates of renal symptoms (9%) than HUS (10–20% and 90%, respectively).<ref>{{Cite web |date=2023-04-26 |title=MAHA, TTP, HUS, DIC... Oh My! Understanding Microangiopathic Hemolytic Anemias |url=https://www.tampaemergencymedicine.org/blog/maha-ttp-hus-dic-oh-my-understanding-microangiopathic-hemolytic-anemias |access-date=2023-08-23 |website=Tampa Emergency Medicine Blog |publisher=[[Organization:University of South Florida|University of South Florida]] |language=en-US}}</ref>

Unlike HUS and aHUS,<ref>{{Cite book |last=Abrams |first=Charles S. |title=Goldman's Cecil Medicine |publisher=Elsevier |year=2012 |isbn=978-1437716047 |editor-last=Goldman |editor-first=Lee |edition=24th |volume=1 |chapter=Thrombocytopenia |pages=1124–1131 |doi=10.1016/B978-1-4377-1604-7.00175-5 |quote=In contrast to TTP, HUS is not caused by a deficiency of ADAMTS13. |editor-last2=Schafer |editor-first2=Andrew I. |chapter-url=https://www.sciencedirect.com/science/article/abs/pii/B9781437716047001755 |name-list-style=vanc}}</ref><ref>{{Cite journal |last1=Feng |first1=Shuju |last2=Eyler |first2=Stephen J. |last3=Zhang |first3=Yuzhou |last4=Maga |first4=Tara |last5=Nester |first5=Carla M. |last6=Kroll |first6=Michael H. |last7=Smith |first7=Richard J. |last8=Afshar-Kharghan |first8=Vahid |name-list-style=vanc |date=August 2013 |title=Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome |journal=Blood |volume=122 |issue=8 |pages=1487–1493 |doi=10.1182/blood-2013-03-492421 |issn=1528-0020 |pmc=3750341 |pmid=23847193 |quote=Complement dysregulation leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura.}}</ref> TTP is known to be caused by a defect in the ADAMTS13 protein,<ref>{{Cite journal |last1=Cataland |first1=Spero R. |last2=Wu |first2=Haifeng M. |date=April 2014 |title=How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome |url=https://ashpublications.org/blood/article/123/16/2478/32643/How-I-treat-the-clinical-differentiation-and |journal=Blood |language=en |volume=123 |issue=16 |pages=2478–2484 |doi=10.1182/blood-2013-11-516237 |pmid=24599547 |issn=0006-4971|doi-access=free }}</ref> so a lab test showing ≤5% of normal ADAMTS13 levels is indicative of TTP.<ref name=":3" /> ADAMTS13 levels above 5%, coupled with a positive test for [[Biology:Shiga toxin|shiga-toxin]]/enterohemorrhagic ''E. coli'' (EHEC), are more likely indicative of HUS,<ref>{{Cite journal |last1=Bitzan |first1=Martin |last2=Schaefer |first2=Franz |last3=Reymond |first3=Didier |name-list-style=vanc |date=September 2010 |title=Treatment of typical (enteropathic) hemolytic uremic syndrome |url=https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0030-1262881 |journal=Seminars in Thrombosis and Hemostasis |volume=36 |issue=6 |pages=594–610 |doi=10.1055/s-0030-1262881 |issn=1098-9064 |pmid=20865636 |s2cid=6129618}}</ref> whereas absence of shiga-toxin/EHEC can confirm a diagnosis of aHUS.<ref name=":3" />

==Treatment==
Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only microangiopathic hemolytic anemia and [[Medicine:Thrombocytopenia|thrombocytopenia]] are seen, and therapy is started. Transfusion is contraindicated in thrombotic TTP, as it fuels the coagulopathy. Since the early 1990s, [[Medicine:Plasmapheresis|plasmapheresis]] has become the treatment of choice for TTP.<ref name="Cochrane2009">{{cite journal |last1=Michael |first1=M |last2=Elliott |first2=EJ |last3=Ridley |first3=GF |last4=Hodson |first4=EM |last5=Craig |first5=JC |date=January 2009 |title=Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. |journal=The Cochrane Database of Systematic Reviews |volume=1 |issue=1 |pages=CD003595–CD003595–63 |doi=10.1002/14651858.CD003595.pub2 |pmc=7154575 |pmid=19160220 |hdl=10072/61440}}</ref><ref name="Blood2015">{{cite journal |vauthors=Lim W, Vesely SK, George JN |date=March 2015 |title=The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura |journal=Blood |volume=125 |issue=10 |pages=1526–31 |doi=10.1182/blood-2014-10-559211 |pmc=4351502 |pmid=25573992}}</ref> This is an [[Medicine:Exchange transfusion|exchange transfusion]] involving removal of the person's [[Biology:Blood plasma|blood plasma]] through [[Medicine:Apheresis|apheresis]] and replacement with donor plasma ([[Medicine:Fresh frozen plasma|fresh frozen plasma]] or [[Medicine:Cryosupernatant|cryosupernatant]]); the procedure must be repeated daily to eliminate the inhibitor and abate the symptoms. If apheresis is not available, fresh frozen plasma can be infused, but the volume that can be given safely is limited due to the danger of fluid overload.<ref name=ALLFORD2003>{{cite journal |vauthors=Allford SL, Hunt BJ, Rose P, Machin SJ |s2cid=38774829 |title=Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias |journal=British Journal of Haematology |volume=120 |issue=4 |pages=556–73 |date=February 2003 |pmid=12588343 |doi=10.1046/j.1365-2141.2003.04049.x |doi-access=free }}</ref> Plasma infusion alone is not as beneficial as plasma exchange.<ref name=Cochrane2009/> [[Chemistry:Glucocorticoid|Corticosteroids]] ([[Chemistry:Prednisone|prednisone]] or [[Chemistry:Prednisolone|prednisolone]]) are usually given.<ref name=Blood2015/> [[Chemistry:Rituximab|Rituximab]], a [[Biology:Monoclonal antibody|monoclonal antibody]] aimed at the [[Biology:CD20|CD20]] molecule on [[Biology:B cell|B lymphocytes]], may be used on diagnosis; this is thought to kill the B cells and thereby reduce the production of the inhibitor.<ref name=Blood2015/> A stronger recommendation for rituximab exists where TTP does not respond to corticosteroids and plasmapheresis.<ref name=Blood2015/>

[[Chemistry:Caplacizumab|Caplacizumab]] is an alternative option in treating TTP as it has been shown that it induces a faster disease resolution compared with those people who were on [[Placebo-controlled study|placebo]].<ref>{{Cite journal |last1=Peyvandi |first1=Flora |last2=Scully |first2=Marie |last3=Kremer Hovinga |first3=Johanna A. |last4=Cataland |first4=Spero |last5=Knöbl |first5=Paul |last6=Wu |first6=Haifeng |last7=Artoni |first7=Andrea |last8=Westwood |first8=John-Paul |last9=Mansouri Taleghani |first9=Magnus |name-list-style=vanc |date=February 2016 |title=Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura |url=https://air.unimi.it/handle/2434/829303 |journal=New England Journal of Medicine |volume=374 |issue=6 |pages=511–522 |doi=10.1056/NEJMoa1505533 |issn=0028-4793 |pmid=26863353 |s2cid=19482364 |doi-access=free |hdl=2434/829303|hdl-access=free }}</ref> However, the use of caplacizumab was associated with increase bleeding tendencies in some studied subjects.<ref>{{Cite journal |last1=Goshua |first1=George |last2=Bendapudi |first2=Pavan K. |name-list-style=vanc |date=December 2022 |title=Evidence-Based Minireview: Should caplacizumab be used routinely in unselected patients with immune thrombotic thrombocytopenic purpura? |url=https://doi.org/10.1182/hematology.2022000412 |journal=Hematology |volume=2022 |issue=1 |pages=491–494 |doi=10.1182/hematology.2022000412 |issn=1520-4391 |pmc=9820987 |pmid=36485149}}</ref>

People with refractory or relapsing TTP may receive additional immunosuppressive therapy, e.g. [[Chemistry:Vincristine|vincristine]], [[Chemistry:Cyclophosphamide|cyclophosphamide]], cyclosporine A, or [[Medicine:Splenectomy|splenectomy]].<ref name=Jol2017/><ref name="ALLFORD2003" />

Children with [[Medicine:Upshaw–Schulman syndrome|Upshaw-Schulman syndrome]] receive prophylactic plasma every two to three weeks; this maintains adequate levels of functioning ADAMTS13. Some tolerate longer intervals between plasma infusions. Additional plasma infusions may be necessary for triggering events, such as surgery; alternatively, the platelet count may be monitored closely around these events with plasma being administered if the count drops.<ref>{{Cite journal |last1=Loirat |first1=Chantal |last2=Girma |first2=Jean-Pierre |last3=Desconclois |first3=Céline |last4=Coppo |first4=Paul |last5=Veyradier |first5=Agnès |name-list-style=vanc |date=January 2009 |title=Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children |url=https://doi.org/10.1007/s00467-008-0863-5 |journal=Pediatric Nephrology |language=en |volume=24 |issue=1 |pages=19–29 |doi=10.1007/s00467-008-0863-5 |issn=1432-198X |pmid=18574602 |s2cid=22209831}}</ref>

Measurements of blood levels of [[Biology:Lactate dehydrogenase|lactate dehydrogenase]], [[Biology:Platelet|platelets]], and schistocytes are used to monitor disease progression or remission.<ref name=":2" /><ref name=":5">{{Cite journal |last1=Saha |first1=M. |last2=McDaniel |first2=J.K. |last3=Zheng |first3=X.L. |name-list-style=vanc |date=October 2010 |title=Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics |url=https://doi.org/10.1111/jth.13764 |journal=Journal of Thrombosis and Haemostasis |volume=15 |issue=10 |pages=1889–1900 |doi=10.1111/jth.13764 |issn=1538-7836 |pmc=5630501 |pmid=28662310 |s2cid=40493167}}</ref> ADAMTS13 activity and inhibitor levels may be measured during follow-up, but in those without symptoms the use of rituximab is not recommended.<ref name=Blood2015/>

[[Biology:Apadamtase alfa|Apadamtase alfa]] (Adzynma) was approved for medical use in the United States in November 2023.<ref name="FDA PR">{{cite press release | title=FDA Approves First Treatment for Patients with Rare Inherited Blood Clotting Disorder | website=U.S. Food and Drug Administration | date=9 November 2023 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-rare-inherited-blood-clotting-disorder | access-date=30 November 2023}}</ref><ref>{{cite press release | title=Takeda's Adzynma (ADAMTS13, recombinant-krhn) Approved by U.S. FDA as the First and Only Recombinant ADAMTS13 Enzyme Replacement Therapy for the Treatment of Congenital Thrombotic Thrombocytopenic Purpura (cTTP) | publisher=Takeda Pharmaceuticals | via=Business Wire | date=9 November 2023 | url=https://www.businesswire.com/news/home/20231106845467/en/ | access-date=30 November 2023}}</ref>

==Prognosis==
The mortality rate is around 95% for untreated cases, but the prognosis is reasonably favorable (80–90% survival) for people with idiopathic TTP diagnosed and treated early with [[Medicine:Plasmapheresis|plasmapheresis]].<ref>{{cite journal |last=Tsai |first=Han-Mou |name-list-style=vanc |date=February 2006 |title=Current Concepts in Thrombotic Thrombocytopenic Purpura |journal=Annual Review of Medicine |volume=57 |pages=419–436 |doi=10.1146/annurev.med.57.061804.084505 |pmc=2426955 |pmid=16409158}}</ref>

==Epidemiology==
The incidence of TTP is about 4–5 cases per million people per year.<ref name="Terrell2005">{{cite journal |vauthors=Terrell DR, Williams LA, Vesely SK, Lämmle B, Hovinga JA, George JN |date=July 2005 |title=The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency |url=https://www.jthjournal.org/article/S1538-7836(22)16225-2/fulltext |journal=Journal of Thrombosis and Haemostasis |volume=3 |issue=7 |pages=1432–6 |doi=10.1111/j.1538-7836.2005.01436.x |pmid=15978100 |s2cid=24914279|doi-access=free }}</ref> Idiopathic TTP occurs more often in women as well as people of African descent, and TTP secondary to autoimmune disorders such as [[Medicine:Systemic lupus erythematosus|systemic lupus erythematosus]] occurs more frequently in people of African descent, although other secondary forms do not show this distribution.<ref name="Terrell2010">{{cite journal |vauthors=Terrell DR, Vesely SK, Kremer Hovinga JA, Lämmle B, George JN |date=November 2010 |title=Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes |journal=American Journal of Hematology |volume=85 |issue=11 |pages=844–7 |doi=10.1002/ajh.21833 |pmc=3420337 |pmid=20799358 |s2cid=23118040}}</ref> Although [[Biography:Black people|Black people]] are at an increased risk for TTP, its presentation in Black people does not have any distinguishable features compared to those of other races.<ref>{{Cite journal |last1=Martino |first1=Suella |last2=Jamme |first2=Mathieu |last3=Deligny |first3=Christophe |last4=Busson |first4=Marc |last5=Loiseau |first5=Pascale |last6=Azoulay |first6=Elie |last7=Galicier |first7=Lionel |last8=Pène |first8=Frédéric |last9=Provôt |first9=François |last10=Dossier |first10=Antoine |last11=Saheb |first11=Samir |last12=Veyradier |first12=Agnès |last13=Coppo |first13=Paul |last14=Microangiopathies |first14=French Reference Center for Thrombotic |date=2016-07-06 |title=Thrombotic Thrombocytopenic Purpura in Black People: Impact of Ethnicity on Survival and Genetic Risk Factors |journal=PLOS ONE |language=en |volume=11 |issue=7 |pages=e0156679 |doi=10.1371/journal.pone.0156679 |issn=1932-6203 |pmc=4934773 |pmid=27383202 |bibcode=2016PLoSO..1156679M |doi-access=free }}</ref> Pregnant women and women in the ''[[Medicine:Postpartum period|post partum]]'' period accounted for a notable portion (12–31%) of the cases in some studies; TTP affects about one in 25,000 pregnancies.<ref>{{cite journal |author=Zheng |first1=X. Long |last2=Sadler |first2=J. Evan |name-list-style=vanc |year=2008 |title=Pathogenesis of Thrombotic Microangiopathies |journal=Annual Review of Pathology |volume=3 |pages=249–277 |doi=10.1146/annurev.pathmechdis.3.121806.154311 |pmc=2582586 |pmid=18215115}}</ref>

==History==
TTP was initially described by Eli Moschcowitz at the Beth Israel Hospital in {{wipe|New York City}} in 1924.<ref name=":5" /><ref>{{Cite journal |last1=Sukumar |first1=Senthil |last2=Lämmle |first2=Bernhard |last3=Cataland |first3=Spero R. |name-list-style=vanc |date=January 2021 |title=Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management |journal=Journal of Clinical Medicine |language=en |volume=10 |issue=3 |pages=536 |doi=10.3390/jcm10030536 |issn=2077-0383 |pmc=7867179 |pmid=33540569 |doi-access=free }}</ref> Moschcowitz ascribed the disease (incorrectly, as now known) to a toxic cause. Moschcowitz noted his patient, a 16-year-old girl, had anemia, small and large bruises, microscopic [[Medicine:Hematuria|hematuria]], and, at autopsy, [[Medicine:Disseminated disease|disseminated]] microvascular thrombi.<ref>{{cite journal |author=Moschcowitz |first=Eli |name-list-style=vanc |year=1924 |title=Hyaline Thrombosis of the Terminal Arterioles and Capillaries: A Hitherto Undescribed Disease |url=https://archive.org/details/proceedings22newy/page/20/mode/2up |journal=Proceedings of the New York Pathological Society |volume=24 |pages=21–24}}

* {{Cite journal |last=Moschcowitz |first=Eli |author-mask=2 |name-list-style=vanc |date=1925 |title=An Acute Febrile Pleiochromic Anemia with Hyaline Thrombosis of the Terminal Arterioles and Capillaries: An Undescribed Disease |url=https://doi.org/10.1001/archinte.1925.00120130092009 |journal=Archives of Internal Medicine |volume=36 |issue=1 |pages=89–93 |doi=10.1001/archinte.1925.00120130092009 |issn=0730-188X |postscript=:}}</ref> In 1966, a review of 16 new cases and 255 previously reported cases led to the formulation of the classical pentad of symptoms and findings (i.e., thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, kidney failure, fever); in this series, mortality rates were found to be very high (90%).<ref>{{Cite journal |last1=Amorosi |first1=Edward L. |last2=Ultmann |first2=John E. |name-list-style=vanc |date=March 1966 |title=Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature |url=https://journals.lww.com/md-journal/citation/1966/03000/thrombotic_thrombocytopenic_purpura__report_of_16.3.aspx |journal=Medicine |language=en-US |volume=45 |issue=2 |pages=139 |doi=10.1097/00005792-196603000-00003 |s2cid=71943329|doi-access=free }}</ref>

While a response to blood transfusion had been noted before, a 1978 report and subsequent studies showed blood plasma was highly effective in improving the disease process.<ref name=Sadler2008 /> In 1991, plasma exchange was reported to provide better response rates compared to plasma infusion.<ref>{{cite journal |doi=10.1056/NEJM199108083250604 |author=Rock GA |title=Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group |journal=New England Journal of Medicine |volume=325 |issue=6 |pages=393–7 |date=August 1991 |pmid=2062330 |name-list-style=vanc|author2=Shumak KH |author3=Buskard NA |display-authors=3 |last4=Blanchette |first4=Victor S. |last5=Kelton |first5=John G. |last6=Nair |first6=Rama C. |last7=Spasoff |first7=Robert A.|doi-access=free }}</ref> In 1982, the disease had been linked with abnormally large von Willebrand factor multimers. The identification of a deficient [[Biology:Protease|protease]] in people with TTP was made in 1998. The location of ADAMTS13 within the human genome was identified in 2001.<ref name=Sadler2008>{{cite journal|last=Sadler|first=JE|title=Von Willerbrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura|journal=Blood|year=2008|volume=112|issue=1|pages=11–18|doi=10.1182/blood-2008-02-078170|pmid=18574040|pmc=2435681}}</ref>
==References==
{{reflist}}

==External links==
{{Medical resources
 | DiseasesDB     = 13052
 | ICD10          = {{ICD10|M|31|1|m|30}} (ILDS M31.110)
 | ICD9           = {{ICD9|446.6}}
 | OMIM           = 274150
 | MedlinePlus    = 000552
 | eMedicineSubj  = emerg
 | eMedicineTopic = 579
 | eMedicine_mult = {{eMedicine2|neuro|499}} {{eMedicine2|med|2265}}
 | MeshID         = D011697
}}

{{Diseases of megakaryocytes|us=y}}

{{DEFAULTSORT:Thrombotic Thrombocytopenic Purpura}}
[[Category:Autoimmune diseases]]
[[Category:Rare diseases]]
[[Category:Syndromes affecting blood]]
[[Category:Wikipedia medicine articles ready to translate]]

{{Sourceattribution|Thrombotic thrombocytopenic purpura}}