CC BY
7of RHEUMATOLOGY
EAAHNIKH PEYMATQAOriA
26 2
2015
ANAXKOnHXH REViEW
GpoMßuTiKn öpoMßoneviKn nopQüpa-Mia öxi ouxvn eKönAwon tuv peupaTiKuv na9noeuv.
AaZapoq I. iqkkoq, MD, DM, PhD(UK), FRCP(UK), EuaYYeAia rewpyiou, MD
Peu|jaToAoYiKn KAiviKr], navenioTHMiaKÖ reviKÖ NoooKopeio Aapioaq Kai laipiKr] ^xoAr], navenioirpo OeooaAiaq
nEPIAH^H
H 9po|ßwTiKn 9poMßoneviKn nop^üpa (00n) avnKei pe pia opäSa ouvSpopuv, pe to ovopa 9po|ßwTiKn MiKpoaYYeiona9eia (0MA). H 0MA npoKaAeiTai anö eKTeTapevn 9pö|ßwön Kai evöo9r|AiaKn ßAäßn MiKpüv aYYeiwv (|iKpoaYYeiona9eia) nou oönYei oe MiKpoaYYeiona9nTiKn ai|oAuTiKn avapa (MAAA), 9po|ßonevia eK KaTaväAwonQ, Kai ioxapKn ßAaßn opYävuv. H 00n o0eiAeTai oe eAAei^n tou ADAMTS13, pia npuTeaon nou Siaona noAupepn tou napäYovia von Willebrand. H eAAei^n tou ADAMTS13 pnopei va eivai KAnpovopiKq n eniKTnTn. H KAnpovopiKn 00n o0eiAeTai oe peTäAAa^n tou Yoviöiou ADAMTS13. H eniKTnTn 00n o^eiAeTai oe avTi-ADAMTS13 avaoTaATiKa auToavTioüpaTa. H TeAeuTaia eivai iöiona9nQ n öeuTepona9nQ oe ouoTmaTiKÖ epu-9maTw6n Aüko. H MAAA eivai aipoAuTiKn avapa (aü^non LDH, aü^non ¿MMeonQ xoAepu9pi-vnQ) nou eivai pn auToävoon (äpeon Coombs avTiöpaon, apvnTiKn), Kai evöoaYYeiaKn (gxigto-
KüTTapa oto nAaKäKi aipaToq, xapnAn anToo0aipivn opoü). H 9popßonevia oTn 00n eivai ßapeiä pe api9MÖ aiponeTa-Aiwv <30.000/uL. To öpYavo nou npooßäAAeTai nio ouxvä eivai to KevTpiKÖ veupiKÖ oüoTnpa, evü n ve0piKq npooßoAn Sev eivai noAü ouxvn Kai ouvh9wq nma. H Küpia 9epaneia eivai n nAaopa0aipeon nou eivai noAü anoTeAeopaTiKn aAAä npenei va apxioei öoo to SuvaTÖ nio ¿YKaipa Yia va exei KaAn anoTeAeopaTiKOTnTa. Eninpöo9eTn avoooKaTaoToAn pe GTepoeiön, rituximab, cyclophosphamide Kai äAAa xpeiäZoviai Yia Tnv npöAn^n unoTponüv.
YnEü8uvoq aAAr|Aoypa0iaq;
Ka8nvnTnQ AäZapoQ I. ZaKKäq PeupaxoAoyiKn KAIVIKH, laTpiKÖ TMHMa, ZxoAq EniCTTHM^v YyeiaQ, naveniCTTHMio QeaaaAiaq BiönoAiQ 41110, AäpiCTa Tr|A +241350 2813, Fax: +2413501016, E-mail: [email protected] Corresponding author; Professor Lazaros I. Sakkas Department of Rheumatology Faculty of Medicine, School of Health Sciences, University of Thessaly and University General Hospital of Larissa Biopolis 41110, Larissa Tel:+241350 2813, Fax:+241350 1016, E-mail: [email protected]
Mediterr J Rheumatol 2015; 26(2): 12-17
Ae^eiQ-KAeiöiä: 9po!ßonevia, 9po^wTiKn 9po!ßoneviKn nopQüpa, 9po^wTiKn MiKpoaYYeionä9eia, ouGTnMQTiKÖQ epu9nMQTÜönQ AÜKOQ
of RHEUMATOLOGY
EAAHNIKH PEYMATQAOriA
26 2
2015
Thrombotic thrombopenic purpura-an unusual manifestation of rheumatic diseases.
Lazaros I. Sakkas, MD, DM, PhD(UK), FRCP(UK) , Eva Georgiou, MD
Department of Rheumatology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
ABSTRACT
Thrombotic thrombopenic purpura (TTP) belongs to a group of syndromes, known as thrombotic microangiopathy (TMA). Thrombotic microangiopathy is caused by thrombosis and injury of endothelial cells in small vessels (microangiopathy) that results in microangiopathic haemolytic anaemia (MAHA), consumptive thrombocytopenia, and organ injury. Thrombotic thrombopenic purpura is caused by deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with Thrombospondin Type 1 motif, member 13) that cleaves von Willebrand factor polymers. ADAMTS13 deficiency may be hereditary or acquired. Hereditary ADAMTS13 deficiency is caused by mutation of the relevant gene. Acquired ADAMTS13 deficiency is caused by anti-ADAMTS13 inhibitory autoantibodies. The latter is idiopathic or secondary to systemic lupus erythematosus. Microangiopathic haemolytic anaemia is haemolytic anaemia (elevated serum LDH and indirect bilirubin) which is not autoimmune (direct Coombs test negative) and intravascular (schistocytes in peripheral blood smear, low-to-absent haptoglobin). Thrombocytopenia in TTP is severe with very low <30,000/uL) platelet count. The organ most frequently affected is central nervous system whereas renal injury is not frequent. The mainstay of treatment is plasma exchange which is very effective but must start as soon as possible for optimal effectiveness. Additional immunosuppressants to prevent relapses include steroids, rituximab, cyclophosphamide and others.
Mediterr J Rheumatol 2015; 26(2): 12-17
Keywords: Systemic lupus erythematosus, thrombocytopenia, thrombotic thrombopenic purpura, thrombotic microangiopathy
of RHEUMATOLOGY 2
EAAHNIKH PEYMATOAOriA 2015
INTRODUCTION
Rheumatic diseases can affect other organs/systems besides connective tissues. Some manifestations due to hematologic involvement of central nervous system involvement can be the presenting manifestation of rheumatic diseases, and require early recognition and prompt treatment to achieve a successful outcome. In this report, we review thrombotic thrombopenic purpura (TTP).
THROMBOTIC THROMBOPENIC PURPURA
Thrombotic thrombopenic purpura (TTP) belongs to a group of syndromes, known as thrombotic microangiopathy (TMA). Thrombotic microangiopathy is characterized by thrombosis and endothelial damage in small vessels (arterioles and capillaries) that results in thrombocytopenia (due to platelet consumption), mi-croangiopathic haemolytic anaemia (MAHA), and organ injury (due to ischemia). The most important clue for diagnosis of TMA is the diagnosis of MAHA. Microangiopathic haemolytic anaemia is haemolytic anaemia (elevated serum LDH and indirect bilirubin) which is non-immune (direct Coombs test negative) and intravascular (schistocytes in peripheral blood smear, and low-absent haptoglobin). The diagnostic algorithm in a patient with anaemia plus thrombocytopenia is shown in Table 1. Thrombotic microangiopathy encompasses several entities of different aetiologies (Table 2). Thrombotic thrombopenic purpura is caused by deficiency of ADAMTS13 (A Disintegrin And Metallopro-teinase with Thrombopondin type 1 motif, member 13); a proteinase that is secreted from vascular endothelial cells and cleaves von Willebrand factor poly-
mers. Deficiency of ADAMTS13 results in very long von Willebrand factor polymers that clot small vessels. ADAMTS13 is hereditary or acquired. Hereditary TTP is caused by homozygous or compound heterozygous mutations of ADAMTS13 gene. It is occurs in children but also in pregnant women; as pregnancy is a trigger factor for TTP. Acquired TTP is caused by anti-ADAMTS13 inhibitory autoantibodies, usually in patients with systemic lupus erythematosus. Acquired TTP can also be idiopathic. Acquired TTP is most frequent in adults but an infrequent entity with an incidence ranging from of 0.2-1 cases/105/year to 2.9 cases/million/year.1,2 It manifests with MAHA and thrombocytopenia. Platelet count frequently is very low (< 30,000/uL), hence purpura as a clinical sign. The central nervous system (CNS) is the most frequent organ affected usually with transient focal neurological manifestations, whereas kidneys are infrequently affected.
Diagnosis and differential diagnosis of TTP
Diagnosis of TTP is based on MAHA with very low platelet count, normal or mildly elevated serum creatinine, ADAMTS13 activity < 5-10%, or anti-ADAMTS13 antibodies (even in the presence of normal ADAMTS13 activity).3 Thrombotic thrombopenic purpura should be differentially diagnosed form other TMA syndromes (Table 2). Some of these syndromes are detailed below.
Shiga toxin-mediated TMA (Haemolytic uraemic syndrome)
Haemolytic uraemic syndrome (HUS) is caused by Shi-
Table 1. Algorithm of anaemia plus thrombocytopenia
Table 2. Thrombotic microangiopathy syndromes
Thrombotic thrombopenic purpura (TTP)
ADAMTS13 deficiency
Hereditary (mutations of ADAMTS13 gene) Acquired (anti-ADAMTS13 inhibitory antibodies) Shiga toxin-mediated TMA (Haemolytic uraemic syndrome,HUS)
Shiga toxin-producing E.Coli (STEC) Complement-mediated TMA (atypical HUS).
Mutation of complement factor H (CFH), CFI, membrane co-factor protein (MCP), C3 leading to uncontrolled activation of alternative pathway of complement Malignancy-mediated TMA Transplantation-mediated TMA Pregnancy-associated TMA TTP acquired or hereditary HELLP
Pre-eclampsia Drug-mediated TMA
Quinine, clopidogrel, cyclosporine, sirolimus, interferon, gemcitabine Malignant hypertension-mediated TMA Catastrophic antiphospholipid (CAPS)-mediated TMA Infection (except STEC)-mediated TMA
0ROMBQTIKH QPOMBOnENIKH nOPOYPA-MIA 0X1 IYXNH EKAHAQXH TON REYMATIKQN nAQHIEQN THROMBOTiC THROMBOPENiC RURRURA-AN UNUSUAL MANiFESTATiON OF RHEUMATiC DiSEASES
ga toxin-producing Escherichia Coli. The most important E. Coli serotypes are O157:H7 and 0104:H4.4 In these cases, mostly from uncooked burger, most often occur in children but also in women and the elderly. Haemolytic uraemic syndrome is preceded by bloody diarrhoea that can progress to bowel gangrene and perforation. The most frequently affected organ are the kidneys, followed by bowel, lung, pancreas and CNS. Diagnosis in a patient with MAHA, elevated serum creatinine and preceding diarrhoea is confirmed by the detection of Shiga toxin in stools and/or polymerase chain reaction (PCR) for Shiga toxin or Shiga toxin-producing E.Coli (STEC) in stools. Treatment is supportive with fluid repletion.
Complement-mediated TMA (Atypical HUS) Complement-mediated TMA (atypical HUS) is caused by uncontrolled activation of the alternative pathway of complement. It is hereditary, caused by loss-of-func-tion mutation of inhibitory complement factors (complement factor H [CFH], complement factor I [CFI], membrane cofactor protein [MCP] which inhibits C3 convertase), or gain-of-function mutation of C3.5 It can
also be acquired, caused by anti-complement factor H inhibitory antibodies.
Atypical HUS is suspected in a patient with MAHA, thrombocytopenia plus elevated serum creatinine, without preceding diarrhoea. Shiga toxin in stools is negative and ADAMTS13 activity is normal. Diagnosis is confirmed by analysis of gene mutations of CFH, CFI, MCP, and C3. Serum levels of C3, CFH, and CFI are usually decreased but they may be normal.
Drug-mediated TMA
Drugs can cause TMA either due to immune-mediated process or to toxicity. Immune-mediated TMA manifests with acute onset of symptoms within 21 days, following the exposure to a medication. In this category, quinine is most frequently reported. Toxic drug-mediated TMA is due to toxic dose or manifests with gradual onset, often presenting as renal failure. In this category, cyclosporine, tacrolimus, sirolimus, interferon, gemcitabine, and bevacizumab are included.6
Scleroderma renal crisis
Scleroderma renal crisis (SRC) occurs in 4-6% of pa-
of RHEUMATOLOGY 2
EAAHNIKH PEYMATQAOriA 2015
tients with systemic sclerosis (SSc), predominantly in the diffuse cutaneous SSc during the first 4 years of the disease. It manifests with hypertension, elevated serum creatinine, and TMA, with moderate decrease in platelet count.7
HELLP syndrome
Features of Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP) syndrome include severe hypertension, heavy proteinuria, ADAMTS13 activity normal, diffuse intravascular coagulation, and no fever. Other causes of TMA, mentioned in Table 2, such as malignancy and malignant hypertension, should be searched for. Other unusual causes to be considered follow.
Vitamin B12 metabolism abnormality Abnormalities of cobalamin C (vitamin B12) can cause TMA. These abnormalities are caused by homozygous or compound heterozygous mutation of a gene for methylmalonic aciduria and homocystinuria type C protein that results in hyperhomocysteinemia, decreased plasma methionine and methylmalonic aciduria. It occurs in infants and very rarely in adults with MAHA, thrombocytopenia, and elevated serum creatinine.8 Distinguished features for vitamin B12 deficiency include leukopenia with hypersegmented neutrophils in peripheral blood, and megaloblasts and giant myeloid precursors in bone marrow aspirate.9 Diagnosis is confirmed by hyperhomocysteinemia, decreased plasma methionine, and methylmalonic aciduria.
Paroxysmal nocturnal hemoglobinuria (PNH) Paroxysmal nocturnal hemoglobinuria carries an increased risk of thrombosis and can manifest with MAHA and thrombocytopenia. Paroxysmal nocturnal hemoglobinuria is a clonal disorder affecting multiple haematopoietic lineages and is caused by a deficiency of complement regulatory proteins CD55 and CD59. Paroxysmal nocturnal hemoglobinuria, as causing chronic intravascular haemolysis, leads to iron deficiency and iron repletion can exacerbate haemolysis. Diagnosis is confirmed by cytometric-based test for CD55 and CD59 in peripheral blood.9 Thrombotic microangiopathy should also be differentiated from diffuse intravascular coagulation (DIC). In DIC, tissue factor released from injured endothelia and monocytes activates factor VII to initiate thrombosis, thus leading to depletion of FV, FX, and fibrinogen. As a consumptive syndrome, DIC manifests with low platelet count, prolonged PT, prolonged APTT, low fi-brinogen, elevated D-dimers. There is also decreased protein C, and decreased antithrombin III.10
Treatment of TTP
In acquired TTP, plasma exchange (PE) plus cortico-steroids are the standard treatment and should start as soon as possible. PE (40-60 mL/Kg) daily for 5 days or until platelet count>150,000/uL and serum LDH normal for two consecutive days, and stable or improved neurological status, according to 2012 American Association of Apheresis Consensus statement.11 About 40% of primary TTP relapse or are refractory to PE and require additional immunosuppression.12 Additional medications to prevent relapses include rituximab, cy-clophosphamide or other immunosuppressants. In a new patient with MAHA and thrombocytopenia, we start with PE. If ADAMTS13 activity is not low (<10%), and there is elevated creatinine, we start with Eculizum-ab until complement genetic studies are available.13
0ROMBQTIKH QPOMBOnENIKH nOPOYPA-MIA OXI IYXNH EKAHAQXH TON REYMATIKQN nAQHIEQN THROMBOTiC THROMBOPENiC PURPURA-AN UNUSUAL MANiFESTATiON OF RHEUMATiC DiSEASES
REFERENCES
1. Rosove MH. Thrombotic microangiopathies, Semin Arthritis Rheum 2014; 43: 797-805.
2. Reese JA, Muthurajah DS, Kremer Horinga JA, Vesely SK, Terrell DR, George JN. Children and adults with thrombotic thrombopenic purpura associated with severe ,acquired Adamts13 deficiency: comparison of incidence, demographic and clinical factors. Pediatr Blood Cancer 2013; 60: 1676-82.
3. George JN. Measuring ADAMTS13 activity in patients with suspected thrombotic thrombocytopenic purpura: when, how, and why? Transfusion 2015; 55: 11-3.
4. Jandhyala DM, Vanguri V, Boll EJ, Lai Y, McCormick BA, Leong JM. Shiga toxin-producing Escherichia coli O104:H4: an emerging pathogen with enhanced virulence. Infect Dis Clin North Am 2013; 27: 631-49.
5. Davin J-C, van de Kar NC. Advances and challenges in the management of complement-mediated thrombotic microangiopathies. Ther Adv Hematol 2015; 6: 171-85.
6. Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood 2015; 25: 616-8.
7. Mouthon L, Bussone G, Berezné A, Noël LH, Guillevin L.
Scleroderma renal crisis. J Rheumatol 2014; 41: 1040-8.
8. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371: 654-66.
9. Green R. Anemias beyond B12 and iron deficiency: the buzz about other B's, elementary, and nonelementary problems. Hematology Am Soc Hematol Educ Program 2012; 2012: 492-8.
10. Nguyen TC, Carcillo JA. Bench-to-bedside review: thrombo-cytopenia-associated multiple organ failure-- a newly appreciated syndrome in the critically ill. Crit Care 2006; 0: 235-43.
11. Sarode R, Bandarenko N, Brecher ME, Kiss JE, Marques MB, Szczepiorkowski ZM, et al. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher 2014; 29: 148-67.
12. Clark WF. Thrombotic microangiopathy: current knowledge and outcomes with plasma exchange. Semin Dial 2012; 25: 214-9.
13. Scully M, Goodship T. How I treat thrombotic thrombocytope-nic purpura and atypical haemolytic uraemic syndrome. Br J Haematol 2014; 164: 759-66.
