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Mediterr J Rheumatol 2015; 26(2): 12-17
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Thrombotic thrombopenic purpura-an unusual manifestation of rheumatic diseases
Lazaros I. Sakkas, Eva Georgiou
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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.
Keywords: Systemic lupus erythematosus, thrombocytopenia, thrombotic thrombopenic purpura, thrombotic microangiopathy
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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), microangiopathic 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 Metalloproteinase with Thrombopondin type 1 motif, member 13); a proteinase that is secreted from vascular endothelial cells and cleaves von Willebrand factor polymers.  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 το 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.

Table 1. Algorithm of anaemia plus thrombocytopenia
 

Shiga toxin-mediated TMA (Haemolytic uraemic syndrome) 

Haemolytic uraemic syndrome (HUS) is caused by Shiga toxin-producing Escherichia Coli. The most important E. Coli serotypes are O157:H7 and O104: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.

Table 2. Thrombotic microangiopathy syndromes
 

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-function 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 patients 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 fibrinogen, elevated D-dimers. There is also decreased protein C, and decreased antithrombin III.10   

Treatment of TTP

In acquired TTP, plasma exchange (PE) plus corticosteroids 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, cyclophosphamide 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 Eculizumab until complement genetic studies are available.13
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