In-hospital management of patients with thrombocytopenia caused by hematological diseases (1) - immune thrombocytopenia

Author: Liu Jiajun, Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen
University
Immune thrombocytopenia (ITP) is an acquired immune-mediated thrombocytopenia disease defined as peripheral platelets below 100x109/L, excluding other triggers or underlying diseases that cause thrombocytopenia
.

Its pathogenesis is immune intolerance to platelet self-antigens, leading to abnormal activation of humoral and cellular immunity, which together mediate excessive platelet destruction and insufficient platelet production by megakaryocytes
.

ITP is a common bleeding disorder and the most common bleeding disorder in the department of hematology.
The incidence of ITP in adults is about 2-10/100,000, accounting for about 30% of the total number of bleeding disorders
.

The elderly over the age of 60 is a high-risk group, and the incidence rate of women of childbearing age is slightly higher than that of men of the same age group
.

Evaluation and process of ITP The diagnosis of ITP is an exclusive diagnosis, and ITP can be established only after excluding thrombocytopenia caused by other secondary factors through medical history, physical examination, blood cell count, and peripheral blood smear microscopy
.

From the medical history, the onset of ITP is usually insidious, the course of the disease is persistent or repeated, and it rarely resolves spontaneously.
A detailed medical history inquiry is helpful to investigate the cause of thrombocytopenia, and special attention is paid to exclude other secondary factors that cause thrombocytopenia, such as infection , bleeding, thrombosis, abnormal liver function, drugs, surgery,
etc.

In terms of clinical manifestations, fatigue is the most common clinical manifestation, and more than half of the patients have symptoms of fatigue, sometimes combined with inattention and memory loss
.

Bleeding is the main clinical manifestation of ITP, ranging from mild to asymptomatic thrombocytopenia or skin and mucous membrane bleeding, severe to severe visceral hemorrhage, and even fatal intracranial hemorrhage.
Generally, the symptoms of bleeding are related to the number of platelets.
Bleeding; when platelets are between 30x109/L~50x109/L, a small number of patients will have skin purpura, petechiae, ecchymosis; when platelets are between 10x109/L~30x109/L, patients may suffer from minor trauma Bleeding is difficult to stop; there is a risk of spontaneous, severe and even life-threatening bleeding when platelets are <10x109/L (Table 1)
.

In addition, advanced age, hypertension, use of antiplatelet and anticoagulant drugs, coagulation disorders, history of trauma or surgery, platelet function defects, heavy physical activity, and history of previous bleeding can also increase the risk of bleeding in patients
.

There are also more than 30% of patients without any clinical manifestations, and thrombocytopenia was found through physical examination
.

From the physical examination, patients often have different degrees of bleeding according to the condition, such as ecchymosis, petechiae, hematoma, etc.
, according to the different bleeding sites, the positive signs of physical examination are different
.

In addition, it should be noted that the spleen in patients with ITP is generally not large
.

After admission, patients need to undergo relevant examinations to confirm the diagnosis.
According to the Chinese Guidelines for the Diagnosis and Treatment of Primary Immune Thrombocytopenia in Adults (2020 Edition), it can be divided into general examinations and special examinations
.

General examinations include (1) blood routine: at least 2 consecutive blood routines are required to indicate a decrease in platelet count
.

(2) Blood smear examination: the peripheral blood smear microscopic examination requires no obvious abnormality in blood cell morphology; (3) Bone marrow examination: The morphology of bone marrow cells in ITP patients is often characterized by increased or normal megakaryocytes, accompanied by maturation disorders
.

Special tests for diagnosing ITP are: (1) Platelet glycoprotein-specific autoantibodies: have high specificity for antibody-mediated immune thrombocytopenia, and can differentiate immune and non-immune thrombocytopenia; (2) Serum Determination of thrombopoietin (TPO) levels: Helps to differentiate between ITP and bone marrow failure disorders (elevated TPO levels)
.

See Table 2
.

Other secondary thrombocytopenia diseases to be excluded include: autoimmune disease, thyroid disease, lymphoproliferative disease, myelodysplastic syndrome, aplastic anemia, various hematological malignancies, tumor infiltration, chronic liver disease, spleen function Hyperactivity, common variant immunodeficiency disease, infection, and vaccination-induced secondary thrombocytopenia, decreased platelet consumption, drug-induced thrombocytopenia, alloimmune thrombocytopenia, gestational thrombocytopenia, congenital thrombocytopenia, and Pseudo-thrombocytopenia
.

After the diagnosis is confirmed, the disease should be staging and grading.
Generally, ITP can be divided into three stages according to the length of the disease: (1) newly diagnosed ITP is the patient within 3 months of diagnosis; (2) persistent ITP: 3 to 12 months after diagnosis Patients with persistent thrombocytopenia, including those who did not spontaneously remission or could not maintain complete remission after stopping treatment; (3) Chronic ITP: patients with persistent thrombocytopenia for more than 12 months
.

In addition, the severity of the patient's disease can be assessed according to the number of platelets.
Severe platelets are defined as the number of platelets <10x109/L, or the bleeding score ≥5
.

Refractory ITP was defined as patients who failed to respond to first-line drugs, thrombopoietin-promoting drugs and rituximab in second-line therapy, or failed splenectomy or recurred after surgery, and were still diagnosed with ITP after re-evaluation
.

Treatment of ITP ITP treatment emphasizes the principle of individualization and encourages patients to participate in treatment decision-making
.

The treatment goal of ITP is to increase platelet counts to safe levels and reduce bleeding events on the basis of minimizing adverse effects of treatment measures, rather than requiring normal platelet counts, and also to optimize the patient's health-related quality of life.

.

The timing of ITP treatment: when platelets ≥ 30x109/L, no bleeding symptoms, and no factors that increase the risk of bleeding, follow-up can be observed; if the patient has active bleeding symptoms (bleeding symptom score ≥ 2 points), regardless of the degree of thrombocytopenia, the Treatment should be initiated; maintenance of higher platelet counts is required in patients >60 years of age, with other comorbidities, and in patients receiving anticoagulation
.

First-line glucocorticoids are still the standard initial treatment for newly diagnosed ITP patients, and compared with conventional-dose prednisone (PDN) regimens, high-dose dexamethasone (HD-DXM) has a faster onset and higher safety.
Can be used as first-line treatment of choice
.

(1) High-dose dexamethasone (HD-DXM) 40 mg/d×4d, administered orally or intravenously, can be repeated for 1 cycle for ineffective or relapsed patients
.

(2) Prednisone 1mg·kg-1·d-1 (maximum dose 80mg/d, divided or taken in a single dose), reduce the dose as soon as possible after the onset of effect, stop within 6-8 weeks, and the effect cannot be maintained after the reduction Consider second-line therapy, and the safe dose of prednisone for maintenance therapy should not exceed 5 mg/d
.

If prednisone treatment fails within 2 weeks, it should be stopped as soon as possible
.

The response rate within 7 days of HD-DXM treatment was significantly higher than that of prednisone, but there was no significant difference in the sustained response rate and the improvement of severe bleeding (level Ib evidence)
.

(3) IVIg: It is mainly used for emergency treatment, patients with glucocorticoid intolerance or contraindications, and before pregnancy or childbirth
.

The recommended dose is 400mg·kg-1·d-1×5d or 1g·kg-1·d-1×1~2d
.

If conditions permit, platelet glycoprotein-specific autoantibodies can be detected, and it should be used with caution in patients with IgA deficiency and renal insufficiency
.

Second-line treatment For patients who have failed first-line treatment or are hormone-dependent, the following treatments should be considered: (1) Platelet survival drugs: including rhTPO, thrombopoietin receptor agonist drugs (TPO-RA), such as eltrombopag, Avatrombopag, Romistine,
etc.

This type of drug promotes megakaryocyte differentiation, development and platelet production by binding to TPO receptors.
It is characterized by fast onset and high efficiency, about 1 to 2 weeks, and the second-line treatment effect can reach 80%.
influence
.

When TPO-RA is used continuously, the curative effect can be maintained for 6 to 8 years, but the curative effect cannot be maintained after drug withdrawal, and individualized maintenance treatment is required
.

If the efficacy of TPO-RA is not good or the efficacy is lost during the application, it can be combined with low-dose prednisone (5-15 mg) or switched to other second-line therapy
.

①The usage of rhTPO is 300U/(kg·d), continuous administration for 14d, subcutaneous injection
.

2 weeks of ineffectiveness should be discontinued, and individualized maintenance therapy should be performed for those who are effective
.

② Eltrombopag should be taken at an initial dose of 25 mg/d on an empty stomach, and if it is ineffective within 2 weeks, the dose should be increased by 25 mg/d, and the maximum dose should be 75 mg/d.
If the maximum dose is ineffective for 2 to 4 weeks, the drug should be discontinued (level A recommendation, Level Ia evidence), individualized maintenance therapy should be performed for those who are effective
.

③ Avatrombopag is a second-generation thrombopoietin (TPO) receptor agonist, approved by the U.
S.
Food and Drug Administration (FDA) for adults with chronic liver disease (CLD) undergoing elective invasive testing or surgery.
)-related thrombocytopenia and ITP, was safe, effective in increasing platelet counts, and was well tolerated
.

Some studies have shown that avatrombopag increases platelet count without lowering the threshold of platelet activation.
In addition, pharmacodynamic experiments in some studies suggest that the pharmacological effect of avatrombopag may be stronger than that of eltrombopag.
Absorption was significantly reduced when popapa was administered with a high-fat diet or a regular meal, but not when avatrombopag was administered in the fed state
.

In terms of safety, the results of phase II/III clinical studies in ITP patients showed that the incidence of adverse reactions of avatrombopag was comparable to that of other TPO receptor agonists, and the most common (≥10%) AE was fatigue.
, headache, contusions, and nosebleeds
.

When the platelet count is less than 40×109/L, the recommended dose of avatrombopag is 60mg×5d.
When the platelet count is between 40 and 50×109/L, the recommended dose is 40mg×5d.
Take it for the day, with meals
.

For patients who are ineffective or intolerable to one thrombopoietic drug, switching to other thrombopoietic drugs or continuous therapy may benefit the patient (level III evidence)
.

(2) Rituximab: the overall effective rate of anti-CD20 monoclonal antibody in the treatment of ITP is about 50%, the 1-year response rate is 38%, and the 5-year response rate is 21% (class IIa evidence, level B recommendation).
Intravenous infusion of m2, once a week for 4 weeks, or 100 mg intravenous infusion, once a week for 4 weeks, effective 4 to 8 weeks after the first administration
.

It should be noted that HBV should be detected before treatment, and patients with active hepatitis B are disabled
.

(3) Splenectomy: Splenectomy is mainly for patients who are ineffective in regular glucocorticoid treatment, hormone-dependent or have contraindications to the use of glucocorticoids
.

The effective rate of treatment is more than 70%, and the sustained remission rate can reach 45% to 60%
.

However, the current status of spleenectomy in the treatment of ITP has been impacted by new drugs
.

Because some patients may have the possibility of spontaneous remission or stable disease, splenectomy should be extended to at least 1 year after the diagnosis of ITP (Class C recommendation)
.

Before surgery, it is necessary to confirm the diagnosis of ITP again.
It is recommended to perform monoclonal antibody-captured platelet antigen technique (MAIPA) and TPO level detection.
If conditions permit, it is recommended to carry out vaccine injection of Haemophilus influenzae, meningococcus, and Streptococcus pneumoniae; Check for the presence of the accessory spleen during the operation, and if found, it should be removed together; the platelets should be monitored after the operation to be alert to the risk of thrombosis caused by the rapid and high platelet rise, and prophylactic antithrombotic therapy can be given to patients with a moderate or high risk of thrombosis.
(Class C recommended)
.

(4) Combination regimen: rhTPO combined with rituximab can be used in patients with ineffective or recurrent glucocorticoid therapy.
The total effective rate of this regimen is 79.
2%, the median onset time is 7 days, and the half-year sustained response rate is 67.
2 % (level A recommendation, level Ib evidence)
.

Medication method: rhTPO 300U/(kg·d), rituximab 100mg intravenous drip, once a week for 4 weeks
.

In addition, there is no priority in the selection of specific second-line regimens, and the principle of individualization should be followed, and patients' wishes should be respected
.

Third-line treatment For patients who have failed first- and second-line treatment, some prospective multi-center clinical trials can be selected, including: (1) all-trans retinoic acid (ATRA) combined with danazol, ATRA 20mg/d combined with danazol 400mg/d (2 oral doses) for 16 weeks, the 1-year continuous effective rate of this regimen for glucocorticoid ineffective or relapsed patients is about 62%, the median onset time is 5 weeks, and the patients are well tolerated (Grade B recommendation, level Ib evidence)
.

(2) Decitabine: 3.
5mg·m-2·d-1×3d intravenous infusion, re-administered at 3-week intervals for a total of 3-6 cycles, if 3 cycles are ineffective, discontinue use.
The efficiency is 50%, the 6-month sustained response rate is about 40%, and the adverse reactions are mild (level B recommendation, level III evidence)
.

In addition, danazol, cyclosporine A, mycophenolate mofetil, azathioprine, vinblastine, etc.
are also optional treatment options, but there is still a lack of sufficient evidence-based medical evidence, and should be based on physician experience and patient conditions.
Make individual choices
.

The diagnosis and treatment process is shown in Figure 1
.

Efficacy evaluation (1) Complete remission (CR): platelets ≥100×109/L and no bleeding after treatment
.

(2) Effective (R): platelets ≥30×109/L after treatment, 2 times or more higher than the baseline, and no bleeding
.

(3) Invalid (NR): platelets <30×109/L after treatment, or the increase rate is lower than 2 times of the baseline, or there is bleeding
.

(4) Relapse: After the treatment is effective, the platelets decrease again and are less than 30×109/L, or less than 2 times of the baseline, or bleeding occurs again
.

When defining CR and R, platelet counts should be detected at least 2 times with an interval of ≥7d; when defining recurrence, platelet counts should be detected at least 2 times with an interval of ≥1d
.

In special cases, the platelet level to be maintained should be maintained (1) Dental operations, such as supragingival scaling and deep cleaning, require a platelet level of ≥20×109/L~30×109/L; (2) Tooth extraction or For tooth filling, the platelet level should be ≥30×109/L~50×109/L; (3) The platelet level should be ≥50×109/L during minor surgery; (4) The platelet level should be ≥80×109 during major surgery.
(5) For major neurosurgery surgery, platelet level ≥100×109/L; (6) For antiplatelet or anticoagulation monotherapy, platelet level ≥30×109/L~50×109/L ; (7) When antiplatelet combined with anticoagulation therapy, the platelet level should be ≥50×109/L~70×109/L; (8) During natural delivery, the platelet level should be ≥50×109/L; (9) During cesarean section , requires platelet level ≥ 80 × 109/L
.

Precautions for glucocorticoid treatment During the treatment of ITP with glucocorticoids, blood pressure and blood sugar should be monitored, and attention should be paid to the prevention of infection and peptic ulcer
.

Glucocorticoid dependence refers to the need for more than 5 mg/d of prednisone or frequent intermittent use of glucocorticoids to maintain PLT ≥ 30 × 109/L or to avoid bleeding
.

Long-term use of glucocorticoids can cause adverse reactions such as hypertension, hyperglycemia, acute gastric mucosal lesions, osteoporosis, necrosis of the femoral head, etc.
In addition, glucocorticoids also have an impact on mental health, so the HRQoL of patients should be regularly evaluated during use ( depression, fatigue, mental state, etc.
)
.

Antiviral drugs, prevention of herpes virus, and hepatitis B virus reactivation are recommended at the same time as HD-DXM is used (level C recommendation, level IV evidence)
.

Glucocorticoids should be used with caution in patients with high levels of HBV-DNA replication
.

Emergency treatment of ITP When ITP patients have life-threatening bleeding or emergency surgery, etc.
that need to quickly raise the platelet count to a safe level, emergency treatment is given
.

The alternatives are as follows: human immunoglobulin IVIg for intravenous injection 1g/(kg·d)×1~2d (grade C recommendation), high-dose glucocorticoid methylprednisolone for intravenous injection: 1g/d×3d or recombinant human Thrombopoietin (rhTPO: 300U/kg/d, subcutaneous injection)
.

The above regimens can be monotherapy or combination therapy with platelet transfusion (level III/IV evidence)
.

If the above regimen is not effective, TPO receptor agonists or rituximab can also be added as soon as possible.
Other emergency treatment measures include vinblastine drugs, emergency splenectomy, etc.
, but they are rarely used
.

At the same time, it is necessary to strengthen support and adjuvant therapy, such as controlling hypertension, controlling menorrhagia, adding antifibrinolytic drugs, and stopping antiplatelet and anticoagulant drugs
.

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