In-hospital management of patients with thrombocytopenia caused by hematological diseases (3) - hematopoietic stem cell transplantation

Author: Liu Jiajun, Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen
University
Hematopoietic stem cell transplantation (HSCT) is an important treatment for hematological malignancies, and thrombocytopenia during transplantation is a common complication, with an incidence of 5% to 37%
.

Thrombocytopenia during HSCT significantly increases the bleeding risk of patients and affects their long-term survival
.

Therefore, aggressive treatment of thrombocytopenia during transplantation is particularly important to reduce the risk of bleeding in patients and improve their prognosis
.

Evaluation and procedure of HSCT-induced thrombocytopenia HSCT-induced thrombocytopenia predilection period Thrombocytopenia in patients with hematological malignancies receiving HSCT usually occurs in 2 periods: pre-transplantation (myelosuppression after pre-transplantation) and post-transplantation (post-transplantation) 30～90d)
.

The chemotherapeutic drugs used in the pre-transplantation conditioning regimen have inhibitory effects on both bone marrow and megakaryocytes, making the platelet count in peripheral blood lower than the normal reference range
.

The post-transplant period is also a prevalent period for patients with thrombocytopenia
.

Megakaryocyte reconstitution within 1 month after transplantation (platelet count greater than 20 × 109/L and 7 consecutive days from platelet transfusion)
.

60 days after transplantation, the platelet count is lower than 50×109/L and the granulocyte and erythroid reconstitution is good, which is defined as poor platelet reconstitution; due to infection, GVHD, thrombotic microangiopathy and other factors, the platelet count after platelet reconstitution drops again to 50×109 /L or less for 7 days or more, it is called secondary thrombocytopenia
.

A small number of patients have refractory thrombocytopenia, manifested as platelet count below 30 × 109/L 60 days after transplantation, recombinant human thrombopoietin (rhTPO), TPO receptor agonists and other conventional measures (glucocorticoids, gamma globulin, etc.
) was ineffective after 1 month of treatment
.

Bleeding severity graded thrombocytopenia after hematopoietic stem cell transplantation and bleeding-related complications are one of the main causes of death in patients undergoing HSCT
.

The clinical manifestations of hemorrhage in different organs after hematopoietic stem cell transplantation are different, and the overall classification is based on the severity and duration of hemorrhage (Table 1)
.

Diagnostic points of important bleeding sites 1 Digestive tract bleeding is often closely related to complications such as intestinal GVHD, infection, and severe thrombocytopenia
.

The clinical manifestations vary according to the location, speed and amount of bleeding.
Hematemesis and melena suggest upper gastrointestinal bleeding.
Bloody stools are usually caused by lower gastrointestinal bleeding, often accompanied by abdominal pain
.

When the amount of bleeding is large, the performance of peripheral circulatory failure such as blood pressure drop and rapid pulse may occur
.

Laboratory tests include abnormalities such as hemoglobin level, hematocrit, platelet count, coagulation index, blood urea nitrogen, and fecal occult blood
.

Endoscopy helps to detect gastrointestinal lesions, determine their location and nature
.

For patients with hemodynamic instability, active fluid resuscitation should be considered before endoscopy
.

2 Intracranial hemorrhage Risk factors for intracranial hemorrhage after transplantation include systemic infection, thrombocytopenia and hypofibrinemia
.

Symptoms are related to the bleeding site, bleeding volume, bleeding speed, hematoma size, and the general condition of the patient.
There may be sudden headaches, nausea and vomiting, slurred speech, limb movement disorders, and disturbances of consciousness of varying degrees.
Some patients have epileptic seizures.

.

Imaging examinations include brain CT and magnetic resonance imaging; EEG is helpful for the diagnosis of epilepsy
.

The Glasgow Coma Scale and the National Institutes of Health Stroke Scale can be used to assess the location and severity of cerebral hemorrhage, determine prognosis and guide treatment
.

In addition, it needs to be differentiated from intracranial infection, intracranial tumor infiltration, cerebral infarction, drug toxicity, demyelinating disease and thrombotic microangiopathy
.

3 Diffuse alveolar hemorrhage is mostly sudden onset and progresses rapidly
.

The clinical manifestations are rapidly progressive dyspnea, cough, hemoptysis and hypoxemia, and even respiratory failure
.

Pathological manifestations were diffuse alveolar damage and alveolar hemorrhage
.

Laboratory tests include blood routine, coagulation indexes, liver and kidney function electrolytes, blood gas monitoring, and chest CT
.

Diagnosis basis: ① Hypoxemia, multilobular lung infiltrates shown by imaging, increased alveolar-arterial oxygen partial pressure difference, restrictive ventilation disorder; ② Exclude other causes of pulmonary ventilation dysfunction; ③ Bronchoalveolar lavage suggest bloody Lavage fluid or macrophages containing hemosiderin at 20% and above
.

In addition, it is necessary to make a differential diagnosis based on clinical manifestations and laboratory tests, heart failure, and hemoptysis caused by local lesions
.

4.
Hemorrhagic cystitis Early hemorrhagic cystitis often occurs within 3 days after preconditioning, and is mostly related to preconditioning with high-dose radiotherapy and chemotherapy.
Cyclophosphamide, ifosfamide and their metabolites can damage urothelial epithelial cells.
Radiation therapy can cause diffuse mucosal edema and inflammation, telangiectasia, submucosal hemorrhage, and interstitial fibrosis
.

Delayed hemorrhagic cystitis is more common after hematopoietic stem cell transplantation, which is often related to viral infection and GVHD.
The specific immune response of the virus can lead to bladder mucosal damage, and urinary polyoma virus, cytomegalovirus or adenovirus infection are more common
.

The bladder is also one of the important target organs of GVHD
.

Hematuria, frequent urination, urgency, and dysuria are typical clinical manifestations
.

Laboratory examinations: ①Urine examination: microscopic hematuria or gross hematuria can be seen, and bacterial infection can be excluded by urine bacteriological examination; ②Virological examination, including blood, urine cytomegalovirus, urinary polyoma virus, adenovirus, etc.
; ③ Cystoscopy and bladder mucosa biopsy are the most reliable diagnostic methods, but they are invasive and should be selected carefully; ④ Bladder ultrasound and MRI can show signs of bladder wall thickening and bleeding
.

The diagnosis of hemorrhagic cystitis should be comprehensively considered in combination with clinical manifestations, onset time, comorbidities, laboratory tests and other factors, and at the same time, urinary tract stones, urinary tract tumors, urinary tract bacterial and fungal infections, pure thrombocytopenia and coagulation abnormalities should be excluded.
etc.
caused hematuria
.

Hemorrhagic cystitis can be further graded according to the degree of bleeding (Droller criteria): first degree: microscopic hematuria; second degree: gross hematuria; third degree: gross hematuria with small blood clots; fourth degree: gross gross hematuria with blood clots obstructing the urethra , Obstructive nephropathy causes renal failure
.

Treatment of HSCT-induced thrombocytopenia Increase platelet therapy (1) Return sufficient CD34+ cells (CD34+ cell count > 4×106 helps to reduce the risk of thrombocytopenia), and it is recommended to remove the antibody before transplantation if the donor-specific antibody is positive
.

(2) Actively fight infection, control GVHD and other related complications, and use with caution or discontinue related anticoagulation, bone marrow suppression and drugs that affect platelet production and function
.

(3) In patients with thrombocytopenia after transplantation, it is necessary to actively control the inducing factors
.

Transfusion of apheresis platelets to ensure that the platelet count is above 20 × 109/L, and patients with active bleeding need to maintain the platelet count > 50 × 109/L
.

Recombinant human thrombopoietin (rhTPO, 300 U·kg-1·d-1 subcutaneous injection) can promote megakaryocyte production, differentiation and platelet release, and TPO receptor agonists (eltrombopag: 50mg/d for adults) can also be tried.
Take it on an empty stomach, increase the dose to 75 mg/d for those who are ineffective after 1 week of treatment; avatrombopag: start at 20 mg/d for adults, increase the dose to 40 mg/d for those who are ineffective after 1 week of treatment), maintain platelet count > 50×109/ L.

_
If the above treatment plan is not effective, low-dose decitabine (15mg·m-2·d-1×3 d) can be given intravenously
.

Treatment of bleeding 1.
Gastrointestinal bleeding inhibits the secretion of gastric acid, digestive enzymes and pancreatic peptide hormones
.

Acid suppressants can increase gastric pH, promote platelet aggregation and fibrin clot formation, help stop bleeding and prevent rebleeding
.

Somatostatin and octreotide can reduce intestinal arterial blood flow, inhibit gastric acid and pepsin secretion, reduce pancreatic juice and bile secretion, and inhibit gastrointestinal motility
.

Most gastrointestinal bleeding is secondary to GVHD, and it is necessary to actively control GVHD in the treatment of bleeding
.

Active bleeding requires fasting and intravenous nutritional support
.

Endoscopic hemostasis and selective vascular embolization should be considered when major bleeding or conservative medical treatment fails
.

2 Intracranial hemorrhage Once intracranial hemorrhage occurs after transplantation, the mortality rate is high, and risk factors should be actively controlled, anti-infection, correction of abnormal coagulation, and improvement of platelet levels
.

Treatment focuses on hemostasis, reduction of cerebral edema and control of intracranial hypertension
.

Aggressive blood pressure lowering can prevent or prevent hematoma expansion and reduce the risk of rebleeding, but it must be weighed against the risk of decreased cerebral perfusion in patients with increased intracranial pressure
.

Surgical intervention may be considered if necessary
.

Be alert to the occurrence of epilepsy after bleeding, and prevent the occurrence of deep vein thrombosis and pulmonary embolism in bedridden patients
.

3 Diffuse alveolar hemorrhage progresses rapidly and the mortality rate is extremely high.
It is necessary to assess the severity of hypoxia as soon as possible.
In the case of hypoxia, mechanical ventilation should be administered as soon as possible.
At the same time, it is necessary to maintain water and electrolyte balance, protect renal function, and maintain effective cardiac output.

.

Early intravenous high-dose methylprednisolone pulse therapy can reduce the inflammatory response
.

Post-transplant pulmonary hemorrhage is often combined with GVHD and infection.
Active anti-GVHD treatment is required, and appropriate antibiotics should be selected as soon as possible according to the etiology or imaging examination
.

4 Hemorrhagic cystitis Hemorrhagic cystitis focuses on prevention
.

When the conditioning regimen includes drugs such as cyclophosphamide or ifosfamide, mesna should be given in combination with high-dose hydration, alkalization, and diuretic prophylaxis
.

When high-dose cyclophosphamide is used, mesna requires concurrent intravenous infusion, and the dose given is 20% of the dose of oxazafos- cine chemotherapy drugs at time points 0 hours, 4 hours and 8 hours, if continued For ifosfamide infusion, it is recommended to add mesna after an IV bolus (20%) at time 0 (start infusion, "0" hour)
.

The maximum dose is 100% of the continuous infusion dose of ifosfamide
.

In addition, after completion of ifosfamide infusion, use of mesna at 50% of the ifosfamide dose continued to maintain the uroprotective effect for 6-12 hours
.

The duration of mesna dosing depends on the duration of treatment with the oxazapine chemotherapy drug
.

Routine supportive treatment for hemorrhagic cystitis includes hydration, alkalization, diuresis, hemostasis, spasmolysis, and opioid analgesia if necessary
.

For viral infection-associated hemorrhagic cystitis, antiviral therapy can shorten the course of the disease
.

Ganciclovir (5 mg/kg, once every 12 hours) can be selected if the blood picture can tolerate it, and the dose should be adjusted according to the creatinine clearance rate in patients with renal insufficiency
.

Cidofovir can inhibit the replication of polyoma virus, cytomegalovirus and adenovirus
.

Appropriate amount of intravenous gamma globulin can be used to enhance the patient's immunity
.

Mild hemorrhagic cystitis can be improved by high-dose hydration (more than 3000ml/m2 per day), alkalization of urine and other treatments; if bleeding symptoms are not improved, indwelling three-lumen catheter can be considered for continuous bladder irrigation to reduce urine output.
Kinase levels, reduce bleeding symptoms
.

Bladder irrigation can help clear the clot when the blood clot is heavy or when the urethra is blocked
.

Intravesical drug perfusion is performed if necessary.
Recombinant human epidermal growth factor can stimulate cell production and promote mucosal repair; aminocaproic acid is a plasminogen activator inhibitor that reduces bleeding by dissolving urokinase
.

When the bleeding symptoms are difficult to control, it is recommended to apply rhFVIIa in time
.

When conservative medical treatment is ineffective, interventional embolization, hyperbaric oxygen, and surgical intervention are used as appropriate
.

5.
For bleeding from other parts of the mouth and nasal cavity, compression can be used to stop bleeding.
If necessary, vasoconstrictor drugs (norepinephrine, etc.
) can be used to gargle.
Atrophy treatment
.

Finally, post-transplant hemorrhage involves multiple systems and multiple organs, and relevant departments should be invited to assist in diagnosis and treatment
.

In special circumstances, some patients with thrombocytopenia combined with ineffective platelet transfusion should be handled separately according to the different reasons for the ineffective transfusion
.

Common ineffective transfusions after transplantation are related to immune factors, including human leukocyte antigen (HLA) and platelet-specific antigen (HPA), drug-related immune thrombocytopenia, etc.

.

After transplantation, irradiated platelets are recommended to be transfused.
HLA and HPA antibody screening can be performed before transfusion, and HLA and HPA-matched platelets can be selected for transfusion, or platelet cross-matching to increase platelet compatibility
.

In addition, intravenous gamma globulin (400mg/kg) blocking antibody can also be tried.
Rituximab and plasma exchange also have certain curative effect on some patients
.

Appropriate clinical trials may be considered for patients with refractory thrombocytopenia or ineffective transfusions who have failed to respond to known regimens
.

Reference consensus: Chinese expert consensus on the management of bleeding complications after hematopoietic stem cell transplantation (2021 edition) RECOMMEND recommended reading 1.
In-hospital management of patients with thrombocytopenia caused by blood system diseases (1) - immune thrombocytopenia 2.
Blood system diseases In-hospital management of patients with induced thrombocytopenia (2) - aplastic anemia click "read the original text", we will make progress together