Guidelines Overview Chinese Guidelines for the Diagnosis and Treatment of Thrombotic Thrombocytopenic Purpura (2022 Edition) (2)

Thrombotic thrombocytopenic purpura (TTP) is a rare and severe thrombotic microangiopathy whose main clinical features include microangiopathic hemolytic anemia (MAHA), thrombocytopenia, neuropsychiatric symptoms, fever, and renal failure.
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The Thrombosis and Hemostasis Group of the Chinese Society of Hematology has formulated the "Chinese Guidelines for the Diagnosis and Treatment of Thrombotic Thrombocytopenic Purpura (2022 Edition)"
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In the previous article, the editor organized and shared the clinical manifestations, laboratory tests and clinical diagnosis of TTP (for details, please refer to: "Guideline Overview | Chinese Guidelines for the Diagnosis and Treatment of Thrombotic Thrombocytopenic Purpura (2022 Edition) (1)) ")
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In this article, the editor brings you the relevant content of TTP treatment and prognosis
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01 Principles of treatment and treatment The disease is often acute, and if it is not treated in time, the mortality rate is high
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Clinically, relevant treatment should be started as soon as possible when the disease is moderately or highly suspected
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Plasma exchange therapy is the first choice for iTTP, and glucocorticoids are used in combination as appropriate
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cTTP is mainly based on replacement therapy, which is divided into on-demand therapy and preventive therapy
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Platelet transfusions should be used with extreme caution in highly suspected and confirmed cases and should only be considered in the event of severe, life-threatening bleeding after plasma exchange
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Therapeutic plasmapheresis is indicated for the treatment of iTTP and for the initial emergency treatment of moderate/high clinical suspicion of TTP
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Plasma exchange uses fresh (frozen) plasma.
The recommended amount of plasma exchange is 2000-3000 ml or 40-60 ml/kg body weight each time, 1-2 times a day, until symptoms are relieved and platelet counts return to normal for 2 consecutive days.
Prolong plasma exchange intervals until discontinued
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When renal failure, it can be combined with hemodialysis
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Plasma exchange works by removing ADAMTS13 inhibitors or IgG antibodies and other pathogenic factors from the blood and replenishing the lack of ADAMTS13
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The response of patients to plasma exchange varies greatly.
For patients who have not achieved clinical response after 5 consecutive plasma exchange treatments, it is not recommended to stop plasma exchange prematurely.
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For those who do not have plasma exchange conditions, fresh (frozen) plasma can be temporarily infused at 20-40 ml/kg per day
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Pay attention to fluid balance
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Glucocorticoids Glucocorticoids can reduce inflammation, protect organ function, and inhibit the production of autoantibodies, and are mainly suitable for iTTP therapy
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Methylprednisolone (80-120 mg/d) or dexamethasone (15-20 mg/d) can be used for intravenous infusion, and can be transitioned to prednisone (1-2 mg·kg-1·d- 1) and gradually reduce to stop
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Adverse reactions of endocrine, cardiovascular and neuropsychiatric systems should be considered when using glucocorticoids.
Special attention should be paid to the adverse reactions of drugs in patients with hypertension, diabetes, mental illness and the elderly
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Rituximab Rituximab reduces ADAMTS13 inhibitor or IgG antibody titers by selectively depleting B lymphocytes, effectively restoring plasma ADAMTS13 activity
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Clinical studies have confirmed that the use of rituximab in the acute exacerbation of iTTP can improve the treatment efficiency, reduce early mortality, reduce the recurrence rate, and prolong the remission period
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The recommended dose of rituximab is 375 mg/m2 once a week for 4 weeks
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The effect of low-dose rituximab therapy (100 mg once a week for 4 weeks) is under investigation
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It is recommended that rituximab be started after plasma exchange, with an interval of 20-24 hours from the next plasma exchange
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Caplacizumab Caplacizumab can block the binding of VWF A1 region to platelet glycoprotein GP Ib, prevent platelet-VWF interaction and prevent microthrombosis in arterioles and capillaries, reduce terminal Organ damage
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Caprolizumab is most beneficial when used early in the onset of TTP
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However, caprolizumab did not correct ADAMTS13 deficiency, nor did it clear ADAMTS13 autoantibodies
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The first 10 mg of caprolizumab was intravenously infused, and 10 mg was subcutaneously injected daily from the next day, and continued use for 30 days after plasma exchange was stopped
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High-dose intravenous immunoglobulin is less effective than plasma exchange in the treatment of iTPP, and is only suitable for patients with refractory TTP or cases with multiple recurrences
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Other immunosuppressive agents (bortezomib, cyclosporine A, etc.
) can be used for iTTP patients who are ineffective against rituximab or relapse
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Bortezomib exerts a therapeutic effect by preventing ADAMTS13 autoantibody production.
The usual dose is 1.
3 mg/m2 subcutaneous injection, 4 times per course (1st, 4th, 8th, 11th days), 1~2 courses
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The usual dose of cyclosporine A is 3-5 mg·kg-1·d-1, and the dose is adjusted according to the plasma concentration
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Acetylcysteine ​​is the precursor of reduced glutathione, which can reduce the disulfide bond between polypeptide chains, reduce the degree of VWF multimerization, and reduce tissue oxidative damage
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It has a certain role in adjuvant therapy after plasma exchange
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The usual dose is 8 g/d by slow intravenous infusion
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In principle, platelet transfusion should not be performed in patients with high suspicion of TTP who have not undergone plasmapheresis, as it may increase microthrombosis and organ damage
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However, platelet transfusions may be considered after plasma exchange if there is life-threatening bleeding in vital organs
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Prophylactic plasma infusion is suitable for the prophylactic treatment of cTTP patients.
Fresh frozen plasma is usually used at 10-15 ml/kg each time.
The infusion interval is determined according to the changes of the patient's platelet count, once every 1-3 weeks
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Repeated transfusions require attention to the risk of transmission of transfusion-related diseases
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Recombinant human ADAMTS13 has entered phase III clinical research, especially suitable for the preventive treatment of cTTP patients
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Antiplatelet drug iTTP patients can choose dipyridamole or aspirin after their condition is stable, which has a certain effect on reducing recurrence
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Supportive treatment This disease involves multiple organs, and it is necessary to dynamically assess the function of each organ in a timely manner, and give corresponding supportive treatment to protect organ function
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Treatment plan and adjustment For patients with clinically moderate or highly suspected or confirmed TTP (especially iTTP), therapeutic plasma exchange combined with glucocorticoid therapy should be started immediately, and combination therapy with caprecizumab may be considered
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Adjust treatment according to ADAMTS13 activity and inhibitor or IgG antibody results: if the measured plasma ADAMTS13 activity of the patient is <10% and the inhibitor or IgG antibody is positive, if iTTP is met, the above treatment will continue and rituximab will be given in time; if If the inhibitor is negative, cTTP is considered, glucocorticoids can be discontinued, and plasma exchange can be changed to plasma infusion; if the patient's plasma ADAMTS13 activity is >20%, other diagnoses should be considered and the corresponding treatment should be used; if the plasma ADAMTS13 activity is 10%-20% Patients should continue or discontinue current therapy based on clinical judgment
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For relapsed iTTP patients, in addition to therapeutic plasma exchange combined with glucocorticoid therapy, if rituximab has not been used before or if rituximab is effective but relapsed after 1 year, add rituximab resistance to treatment
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For patients with relapse within 1 year after rituximab, other immunosuppressants (such as bortezomib and cyclosporine A) can be used to remove ADAMTS13 inhibitors and restore ADAMTS13 activity
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For patients with cTTP in remission, preventive strategies such as plasma transfusion or close observation are recommended, and treatment options are determined according to the patient's condition, wishes, and possible adverse reactions
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Prophylaxis is recommended for patients with cTTP with neonatal onset and organ damage
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Plasma-derived factor VIII concentrates are not recommended due to their very low levels of ADAMTS13
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Recombinant ADAMTS13 will be a more convenient and efficient treatment method
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Women with iTTP have a higher risk of disease recurrence during pregnancy, especially those with persistently decreased plasma ADAMTS13 activity are often a precursor to recurrence, which has adverse effects on both mother and fetus
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Prophylactic treatment may help reduce maternal and infant mortality.
For example, if the activity of plasma ADAMTS13 in pregnant women with iTTP is less than 10%, plasma exchange can be performed once or twice a week; if clinical manifestations of TTP appear, plasma exchange is required once a day; combined use of glucose corticosteroid therapy
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Anti-CD20 mAbs are not recommended during pregnancy
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Early termination of pregnancy is required when the above treatments are ineffective or accompanied by other pathological obstetric conditions (such as pregnancy-induced hypertension)
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For pregnant women with cTTP, it is recommended to perform plasma infusion from the beginning of pregnancy, and the infusion interval gradually shortens with the pregnancy period, ranging from once every 2 weeks to once every other day; if clinical manifestations of TTP occur, the infusion volume should be increased or changed.
For plasma exchange; plasma transfusion therapy should be maintained until 3 weeks postpartum
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Recombinant ADAMTS13 is more suitable for the preventive treatment of cTTP pregnant women
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02 The Prognosis International TTP Working Group recently revised the definition of iTTP treatment outcome again
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①Clinical response: After plasma exchange and other treatments, the platelet count was ≥100×109/L and LDH was less than 1.
5 times the upper limit of normal, and there was no ischemic injury to new organs or aggravation of ischemic injury to existing organs
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Those who have not achieved clinical response after 5 plasma exchange treatments are called refractory TTP
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②Clinical deterioration: within 30 days after stopping plasmapheresis or anti-VWF treatment after obtaining clinical response, platelet count <100×109/L appeared again, with or without clinical evidence of recurrence of organ ischemia injury
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③Clinical remission: those who can continue to maintain clinical response after stopping plasma exchange or anti-VWF therapy for 30 days, or those who achieve ADAMTS13 remission (ADAMTS13 partial remission: ADAMTS13 activity ≥20% and < lower limit of normal value; ADAMTS13 complete remission: ADAMTS13 activity> lower limit of normal)
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④Clinical recurrence: after achieving clinical remission, platelet count <100×109/L and ADAMTS13 activity <10%, with or without clinical evidence of organ ischemia injury
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⑤ ADAMTS13 recurrence: After ADAMTS13 remission, ADAMTS13 activity <20% occurred again
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ADAMTS13 relapses often progress to clinical relapses
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Patients with iTTP have a risk of recurrence after clinical remission from the initial attack.
Infection, surgery, and pregnancy are all predisposing factors.
Plasma ADAMTS13 activity <10%, ADAMTS13 inhibitor or IgG antibody persistently positive are high risk factors for clinical recurrence
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In addition to routine blood tests, all iTTP patients in remission should regularly review ADAMTS13 activity and its inhibitors or IgG antibodies, at least once a month within the first 6 months of the first month, and every 3 months within the next 6 months.
Once a month, once every 6 months in the second year
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With the early use of immunosuppressive therapy, the relapse rate of iTTP has a tendency to decrease significantly
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Patients with cTTP often have a long-term fluctuating condition after the first attack, requiring preventive treatment; cTTP patients with neonatal onset are often severely ill and have a high possibility of long-term organ damage, and preventive treatment is required as soon as possible
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Because the pathogenesis of TTP involves multiple organs, ischemia and hypoxia injury occurs
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The common sequelae of the nervous system after clinical remission of TTP include cognitive impairment, fatigue, abnormal attention and memory, etc.
, but do not affect normal work and activities.
Some TTP patients are prone to depression and depression after recovery
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It can also cause kidney disease, myocardial damage, hypertension, etc.
, and is related to organ damage
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The cooperation of multidisciplinary medical team can better evaluate the patient's disease status and implement corresponding treatment
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This article is excerpted from the Thrombosis and Hemostasis Group of the Chinese Society of Hematology.
Chinese Guidelines for the Diagnosis and Treatment of Thrombotic Thrombocytopenic Purpura (2022 Edition) [J] .
Chinese Journal of Hematology, 2022, 43(1) : 7-12.
DOI : 10.
3760/cma.
j.
issn.
0253-2727.
2022.
01.
002.
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