What Is Thrombotic Thrombocytopenic Purpura?

Thrombotic Thrombocytopenic Purpura (TTP) is a severe diffuse thrombotic microangiopathy with microangiopathy hemolytic anemia, reduced platelet aggregation and depletion, and organ damage (such as kidney, Central nervous system, etc.). Previously, the prognosis of TTP was poor, the course of disease was short, and the mortality rate was 80-90% if not treated in time. With the clinical application of plasma exchange, the prognosis was greatly improved, and the mortality rate was reduced to 10-20%.

Zhang Yuanyuan	(Attending physician)	Institute of Hematology, Peking University People's Hospital
Lu Jin	(Chief physician)	Institute of Hematology, Peking University People's Hospital
Huang Xiaojun	(Chief physician)	Institute of Hematology, Peking University People's Hospital

Western Medicine Name: Thrombotic thrombocytopenic purpura

English name: Thrombotic Thrombocytopenic Purpura, TTP
Affiliated Department: Internal Medicine-Hematology

Introduction to thrombotic thrombocytopenic purpura disease

Thrombotic Thrombocytopenic Purpura (TTP) is a severe disseminated thrombotic microangiopathy with microangiopathy hemolytic anemia, reduced platelet aggregation and depletion, and organ damage (such as kidney, Central nervous system, etc.). The disease was first described by Moschowitz in 1924. In 1958, Amorosi and Vltman summarized the five clinical features of the disease, namely thrombocytopenic purpura, microangiopathic hemolysis, central nervous system symptoms, fever, and kidney damage. The triad is called. Most patients with TTP have a rapid onset of illness and a dangerous condition, with a mortality rate of up to 90% if left untreated.

Thrombotic thrombocytopenic purpura epidemiology

The incidence rate reported abroad is 1/100 million. There is no such data in China. In recent years, with the further understanding of the disease, the diagnosis rate has increased, and the number of patients secondary to other diseases and drugs has increased. The incidence rate is on the rise. Between 2 and 8/1 million. The incidence is usually not related to racial differences, there are slightly more women, and they are more common in childbearing age.

The pathogenesis of thrombotic thrombocytopenic purpura

The vast majority of patients are due to abnormalities in vWF proteolytic enzyme (vWFCP). vWFCP is an interaction between endothelial cell performance, platelet surface receptors, and vWF multimers during high-shear blood flow during normal hemostasis, resulting in platelet and endothelial cell adhesion. Excessive levels of vWF can cause chronic endothelial cell damage and can lead to thrombotic diseases. In 1982, Joel Moake and others first discovered and confirmed the existence of an ultralarge multimers of von Willebrand factor (UL-vWF) from the serum of TTP patients. In 1996, Furlan and other scholars isolated a metalloprotease that can cleave vWF from serum. It was also found in clinical studies that TTP patients lack this protease. In 2001, Geririseten et al. Applied different methods to purify the enzyme, and determined that the protease belongs to the ADAMTS (A Disintegrin And Metalloprotease with ThromboSpondin 1 repeats) metal protease family and named it vascular hemophilia factor lyase (ADAMTS13 ), And its gene was mapped at 9q34. Through this series of studies, it has been revealed that the pathogenesis of TTP is closely related to ADAMTS13, and the understanding of the pathogenesis of TTP has been further clarified. vWFCP (ADAMTSl3) plays an etiological role in the onset of TTP, and its reduced activity is only a manifestation. The essential factor is its quality, quantity or the presence of antibodies. ADAMTSl3 is deficient, its activity is reduced, and excessively large vWF multimers are formed, which can trigger pathological platelet aggregation and lead to TTP.

TTP can be divided into hereditary TTP and acquired TTP according to the cause, and the latter can be divided into idiopathic TTP and secondary TTP according to whether the cause is clear. The basic cause of hereditary TTP is the ADAMTSl3 mutation.

Most patients with hereditary TTP are complex heterozygotes, there are also reports of individual homozygotes, and some blood-related family cases. ADAMTS13 gene mutations occur in about 10% of cases, causing hereditary protease deficiency and resulting in familial recessive TTP.

Clinically, 70% -80% of TTP patients have acquired ADAMTS13 deficiency, which is inhibited by a circulating autoantibody that disappears with the remission of the disease, and 97% -100% of patients can detect ADAMTS13 autoantibodies. The inhibitory anti-ADAMTS13 autoantibodies are mainly IgG, part of which are IgG1 and IgG4 subtypes, and may also be IgM and IgA types. Recent studies have shown that the main site of action of inhibitory autoantibodies for acquired TTP is in the cysteine-rich region and spacer of ADAMTS13, but there are also those that directly attack the epitope, mainly the leader peptide and thrombin sensitivity. Region and complement binding region, these findings suggest that the deletion of acquired ADAMTS13 is a polyclonal autoantibody response.

In acquired TTP, it is divided into idiopathic and secondary, such as can be secondary to infection, drugs, autoimmune diseases, tumors, bone marrow transplantation and pregnancy and other diseases and pathophysiology. The molecular mechanism of idiopathic TTP is basically elucidated.

Causes and classification of thrombotic thrombocytopenic purpura

1. Hereditary TTP is a disease that is extremely rare in newborns and children (its incidence is about one in a million), but is not only related to autosomal recessive inheritance. It is a metal encoded by chromosome 9 q34. Defects (mutations or deletions) of the protease ADAMTSl3 gene cause abnormal synthesis or secretion, resulting in a serious lack of activity, generally lower than 5% to 10% of the normal activity, unable to degrade the high-adhesion ultra-large molecular weight vWF, thereby causing platelet microvascular The onset of thrombosis.

2. Acquired TTP can be divided into primary (idiopathic) TTP and secondary TTP according to whether the predisposing factors are clearly defined. A large proportion of patients with acquired TTP, especially idiopathic TTP, can detect the presence of anti-ADAMTSl3 autoantibodies. This autoantibody neutralizes or inhibits the activity of AMADTSl3, and similarly reduces the activity of ADAMTSl3, leading to disease.

1) Primary (idiopathic) TTP: The incidence of primary TTP is 33 to 57%, and 90% of patients with primary TTP can detect anti-ADAMTSl3 autoantibodies when they develop disease

2) Secondary TTP: The incidence of secondary TTP is about 43 to 66%, which can be secondary to infections, drugs, autoimmune diseases, tumors, bone marrow transplantation and pregnancy, and other diseases and pathophysiological processes. It has been reported abroad that ADAMTSl3 autoantibodies can also be detected in some patients with secondary TTP, such as some drugs (Ticlopidine, Clopidogrel, etc.)-Related TTP, pregnancy-related TTP, pancreatitis-induced TTP, and SLE-related Autoantibodies were found in patients with sexual TTP and transplant-related TTP, but some secondary TTP patients did not detect anti-ADAMTSl3 autoantibodies.

Clinical manifestations of thrombotic thrombocytopenic purpura

The disease can occur at any age, and it can occur in newborns and elderly people over 90 years of age, but the peak age is 20 to 60 years and the median age is 35 years. The onset of this disease is rapid, and a few are slow onset. It is common in acute outbreaks, and 10% -20% are chronic recurrent. According to the patient's performance, it is clinically divided into: a triad with thrombocytopenia, microangiopathic hemolytic anemia, central nervous system symptoms, and a triad with renal damage and fever.

1. Fever: More than 90% of patients have fever, and they can have fever in different stages, mostly moderate. The reasons are unknown and may be related to the following factors: secondary infection but negative blood culture results; hypothalamic temperature regulation dysfunction; tissue necrosis; release of hemolysates; antigen-antibody reaction causes macrophages and granulocytes Damaged and releases endogenous pyrogens.

2. Nervous system changes: including headaches, mental changes, local movement or sensory deficits, blurred vision, and even coma. It is characterized by variable symptoms, transient in the initial stage, and can be improved in some patients and can be recurrent. The variability of nervous system performance is one of the characteristics of thrombotic thrombocytopenic purpura, and its severity often determines the prognosis of thrombotic thrombocytopenic purpura.

3. Bleeding caused by thrombocytopenia: mainly skin and mucous membranes, which are manifested as stasis spots, bruises or purpura, nosebleeds, retinal hemorrhage, genitourinary tract and gastrointestinal bleeding. In severe cases, intracranial bleeding depends on the degree of thrombocytopenia Different.

4, microangiopathic hemolytic anemia: varying degrees of anemia. About one-half of the cases have jaundice, 20% have hepatosplenomegaly, and in some cases have Raynaud phenomenon.

5, kidney damage: gross hematuria is uncommon. In severe cases, renal failure eventually results in acute renal failure ^[1] .

The diagnosis of thrombotic thrombocytopenic purpura

The diagnostic criteria for this disease are as follows.

Main diagnosis basis

(1) Thrombocytopenia

1) The platelet count is significantly reduced, and giant platelets can be seen in the film

2) Bleeding to the skin and / or other parts.

3) The number of megakaryocytes in the bone marrow is normal or increased, which may be accompanied by a disorder of maturity.

4) Platelet life is shortened.

(2) Microangiopathic hemolytic anemia:

1) Orthocytic positive pigmented moderate to severe anemia.

2) There are more abnormal red blood cells (> 2%) and red blood cell fragments in the blood film.

3) Reticulocyte count increased.

4) Compensatory hyperplasia of bone marrow, which is mainly red, and the grain / red ratio decreases.

5) Jaundice and elevated blood bilirubin, mainly indirect bilirubin.

6) Plasma free hemoglobin may increase, globin and heme binding protein may decrease, and lactate dehydrogenase may increase.

7) Hemoglobinuria is occasionally seen with dark urine.

The above two items (1) and (2) are collectively referred to as the TTP dual sign.

(3) There is no obvious reason to explain the above-mentioned dual sign.

TTP can be preliminarily diagnosed by having the above three items (1) to (3).

2. Other diagnostic basis

(1) Neuropsychiatric disorders: Psychiatric disorders, thrombocytopenia, and MAHA coexist as a triad of TTP (Triad)

(2) Kidney damage: proteinuria, microscopic hematuria.

(3) Fever: mostly low to moderate fever, often with chills and high fever, does not support the diagnosis of idiopathic TTP-HUS

Renal damage, fever, and triad are called the TTP pentagram.

(4) Gastrointestinal symptoms: 25% -50% of patients have enlarged liver and spleen due to abdominal pain due to microthrombus in the pancreas and gastrointestinal tract.

(5) Weakness

(6) Auxiliary inspection:

1) Determination of ADAMTS13: those with severe reduction have diagnostic value ^[2] .

2) Histopathological examination: can be used as a diagnostic auxiliary condition, without specificity. Typical pathological manifestations are homogeneous "clear-like" platelet thrombosis in small arteries and capillaries, PAS staining is positive, and contains vWF factors, with extremely low fibrin / fibrinogen content. In addition, there are vascular endothelial hyperplasia, "clear-like" substance deposition under the endothelium, concentric fibrosis around the arterioles, etc. There may be necrosis locally in the embolism, and generally there is no inflammatory reaction. It is rarely used at present, except to find a primary disease.

3) Examination of blood coagulation: examination should be sought to assist diagnosis if possible. PT and fibrinogen were basically normal in this disease, D-dimer, fibrin degradation products, thrombin-antithrombin complex, plasminogen activating factor inhibitor (PAI-1), thrombomodulin (Thrombomodulin) can be slightly increased.

4) Direct Coombs test: The majority of cases should be negative in this disease.

5) Others: The increase of vWF factor in plasma can be found in anti-platelet antibodies, anti-CD36 antibodies, UL-vWF, etc., liver transaminase can also be increased. If HUS is suspected, a bacteriological examination of E. coli should be performed.

Differential diagnosis of thrombotic thrombocytopenic purpura

1. Diffuse intravascular coagulation (DIC): The first disease that TTP needs to identify is DIC. Identification points are shown in the table below

1. Hemolytic Uremia Syndrome (HUS)

The relationship between HUS and TTP is currently considered to be a separate but not independent syndrome. TTP and HUS can be distinguished by ADAMTSl3 activity detection, that is, ADTPS3 activity in TTP patients is mostly lacking, while HUS patients have only mild or moderate reduction in activity. However, some scholars argue that it is not necessary to subdivide the two because these two diseases are currently treated with plasma exchange therapy, so they are often referred to as TTP-HUS syndrome ^[3] .

Table 1. Identification of TTP from other diseases

	TTP	HUS	HELLP	DIC
Neuropsychiatric symptoms	+++	+/-	+/-	+/-
Kidney damage	+/-	+++	+	+/-
heat	+/-	-/ +	-	+/-
Liver damage	+/-	+/-	+++	+/-
hypertension	-/ +	+/-	+/-	-
Hemolysis	+++	++	++	+
Thrombocytopenia	+++	++	++	+++
Coagulopathy	-	-	+/-	+++

3. Evans syndrome autoimmune hemolytic anemia with immune thrombocytopenic purpura. There may be manifestations of impaired renal function, positive Coombs test, no deformities and broken red blood cells, no neurological symptoms.

4. HELLP (Hemolysis, Elevated / Liver function, Low Platelets) syndrome: It is a serious complication related to hypertension during pregnancy. The pathological manifestations are thrombotic microvascular changes, and the clinical manifestations are hemolysis, abnormal liver function and Thrombocytopenia is not associated with ADAMTS13 deficiency and may be related to autoimmune mechanisms. However, in women with hereditary or acquired ADAMTS13 deficiency, pregnancy itself can induce acute TTP.

Thrombotic Thrombocytopenic Purpura Treatment

1. Plasma exchange: Since the introduction of plasma exchange therapy, the mortality rate of primary TTP has decreased from 90% to about 10%. The mechanism of plasma exchange is to correct the lack of enzymes and remove the adverse factors and autoantibodies that cause endothelial cell damage and platelet aggregation. The principle of plasma exchange is: early, sufficient, high quality, combined, as long as the patient has significant thrombocytopenia and microangiopathic hemolytic anemia, can not be explained by other diseases, it is started to use. Foreign literature recommends that the amount of plasma exchange is 40-80ml / (kg / d) once a day until thrombocytopenia and neurological symptoms are relieved, hemoglobin is stable, serum lactate dehydrogenase levels are normal, and then gradually within 1 to 2 weeks Reduce the amount of replacement until it stops. Plasma substitutes are mostly cold supernatants or fresh frozen plasma. Although patients have severe thrombocytopenia, avoiding platelet transfusion is still critical. Plasma exchange is not effective in patients with chronic recurrent familial TTP.

2. Plasma infusion: For patients with hereditary TTP, plasma infusion is the preferred treatment. It is also used as an alternative treatment when plasma exchange is performed unconditionally, but it is not as effective as plasma exchange. Mostly used in combination with glucocorticoids, intravenous immunoglobulins, cyclosporin A, etc.

3. Glucocorticoids can stabilize platelets and endothelial cell membranes and inhibit IgG production. It is usually applied at the same time as plasma exchange, and continues until the disease is relieved, and then gradually decreases. Prednisone 1-2mg / (kg ·· d) or dexamethasone 20mg / d, can also be a large dose of methylprednisolone 1000mg / d, intravenous drip.

4. Immunosuppressants have been reported that azathioprine and cyclophosphamide can be used to treat refractory TTP by inhibiting the production of autoantibodies. Anti-CD20 mAb-Rituximab can clear ADADTS13 inhibitory antibodies produced by B cell clones, leading to disease remission. The specific usage is 375mg / m² / week, with an average of about 4 courses. Cyclosporin A can inhibit the function of helper T cells by inhibiting calcineurin-mediated dephosphorylation, thereby inhibiting the differentiation of B cells and producing beneficial antibodies, and is usually used in combination with plasma exchange. High-dose immunoglobulins can have a certain effect on patients with partial plasma exchange failure by inhibiting platelet aggregation and spleen damage to platelets and red blood cells. .

5, splenectomy

The exact role of the spleen in the pathogenesis of TTP is unclear. As the reticuloendothelial system, the spleen is the main site for autoantibody production and antigen-antibody complex clearance. Therefore, the site of antibody production can be removed by splenectomy. Because the curative effect is not very certain, it is rarely used at present, and it is mostly used for those who have failed other treatments or have relapsed repeatedly.

6, supplement ADAMTS13 protein

Plasma purified ADAMTS13 protein. Cloning the ADAMTS13 gene to obtain functional ADAMTS13 recombinant protein is still in the experimental research stage, and it is the most promising TTP treatment method at present. In theory, using rh-ADAMTSl3 to replace patients with hereditary TTP will be a promising treatment. .

Prognosis and outcome of thrombotic thrombocytopenic purpura

Previously, the prognosis of TTP was poor, the course of disease was short, and the mortality rate was 80-90% if not treated in time. With the clinical application of plasma exchange, the prognosis was greatly improved, and the mortality rate was reduced to 10-20%. Studies have shown that the ADAMTS13 activity of TTP patients is an ideal prognostic indicator. Patients with severely deficient ADAMTS13 had a higher recurrence rate than those with less severe deficiencies, 60% and 19%, respectively.