Morning presentation

BY-

Dr.Papri Nasrin

Resident,Phase-B

Dept.of Haematology

BSMMU

CASE-1

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A-18yrs-old-male diagnosed case of T-ALL with unilateral leg swelling

Particulars of patient

• Name-Mr.Saiful Islam
• Age-18 years
• Gender-Male
• Occupation-Student
• Hailing from Cumilla

• Is a diagnosed case of T-Acute lymphoblastic leukemia with standard risk cytogenetics.
• on the basis of history, clinical examination, bone marrow examination, immunophenotyping and cytogenetic study.
• He was started on Standard BFM induction chemotherapy, which completed on 7^th November without any significant events.

Presenting complaints

Just after 4 days of completion of his chemotherapy patient developed-

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Left lower limb swelling and pain

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Progressively worsening

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Character of the swelling

> Acute onset

> Gradually increasing

> Associated with pain and

> tenderness

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Pain is

> Acute onset

> Severe

> Persistent

> Aggravated by walking and limb movement

> Not relieved after taking any medications

No concomitant complaints of-

> Fever

>Trauma/surgery of abdomen or lower limb

>Respiratory distress

>chest pain

>palpitation

On examination of the lower limb of the patient reveals-

• Left lower limb is swollen
• Reddish
• Shiny skin
• No visible engorged vein
• Temperature is locally raised
• Tenderness present
• Pulse normally present
• No inguinal or popliteal lymphadenopathy present

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• Opposite(right) lower limb is normal.

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On general physical examination

> Conscious

> Co-operative

> Average body built

> Decubitus on choice

> Mildly anemic

> Not-icteric

> No lymphadenopathy

> Temperature normal

> Pulse- 80b/min,regular

> BP- 120/70 mmhg

Systemic examination including Respiratory system & Cardiovascular system reveals-

No abnormality

INVESTIGATIONS

1. CBC-

Hb%- 12.2 gm/dl

ESR- 15mm in 1^st hour

Platelet- 250 ₓ 10⁹ /L

TC- 2 ₓ 10⁹ /L

ANC- 1.36 ₓ 10⁹ /L

2. Prothrombin Time(PT) – 12.40 seconds

3. Activated Partial Thromboplastin Time(APTT) – 30 seconds

4. S.Fibrinogen – 130.00 mg/L (normal range- 200.00 to 400.00 mg/L)

5. D-dimer – 1.72 microG/ml (normal range- 0.00 to 0.50 mig/ml)

INVESTIGATIONS

• Droppler ultrasound of both lower limb vessel reveals –

Deep vein thrombosis involves left common femoral vein, superficial femoral vein and popliteal veins.

DIAGNOSIS

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T-ACUTE LYMPHOBLASTIC LEUKEMIA ON CHEMOTHERAPY WITH DEEP VEIN THROMBOSIS (Left)

• 1. Which Anticoagulant therapy would best fit him as 1^st line ?
• How long should we continue the anticoagulation therapy?
• What can we do with the anticoagulation therapy if we need to start consolidation phase of BFM ?

CASE- 2

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A-36yrs-old-male diagnosed case of T-ALL with sudden Respiratory distress and Coughing out of blood

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Particulars of the patient

• Name- Saidur Rahman
• Age- 36 yrs
• Gender-Male
• Occupation- Service holder
• Hailing from khulna

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History

• Is a diagnosed case of T-Acute lymphoblastic leukemia with standard risk cytogenetics.
• on the basis of history, clinical examination, bone marrow examination, immunophenotyping and cytogenetic study.
• He is on treatment with Standard BFM induction chemotherapy.

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History

• After 12 hours of getting 3^rd week chemotherapy (Day 15), patient suddenly developed-

Severe respiratory distress and coughing out of blood

Respiratory distress was-

>Acute onset

>Gradually increasing

>Severe

>Associated with central chest pain and sweating

>Not associated with fever

• Coughing out of blood was-

>acute onset

>Moderate amount

>Fresh blood

>Associated with chest pain and respiratory distress

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On general physical examination of the patient-

Patient was dyspnic, cold-calmy peripherals.

pulse – 120 beats/min

BP – 90/60 mmhg

SpO2 – Dropped.

was enable to maintain upto 88% with 10L oxygen by GCS – 13/15

On systemic examination of the patient including Respiratory & Cardiovascular system reveals –

Emergency management

We have given –

oxygen inhalation

inj.Noradrenaline

Referrel to ICU

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To exclude Myocardial infarction we have done emergency ECG and it revealed Sinus arrythmia.

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Before further approach and management unfortunately patient died.

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With all these clinical scenario, our probable diagnosis was –

T-Acute lymphoblastic leukemia on chemotherapy with pulmonary embolism(?)

• What is the probable cause of Venous thromboembolism is this two patient?

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• Is there any common cause for both of them?

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• Should we take any preventive measure before chemotherapy?

INTRODUCTION

• Venous thromboembolism is a common complication of Asparaginase-based chemotherapy regimens for treatment of Acute lymphoblastic leukemia.

L-ASPARAGINASE

• Is an enzyme.
• Used as anti-cancer agent
• Also has antimicrobial properties.

L-ASPARAGINASE

Mechanism of action:

• L-asparaginase catalyzes the conversion of asparagine to aspartic acid and ammonia.
• Reversal of L-asparagine synthetase activity.
• Deaminates glutamine to glutamic acid.
• In the absence of asparagine and glutamine,leukemic cells undergo cell-cycle arrest and apoptosis.

L-ASPARAGINASE

• Four asparaginase preparations approved by food and drug administration.
• Three are derived from Escherichia coli (native or pegylated).
• One is derived from Erwinia chrysanthemia.
• Half life of native asparaginase is approximately 12hours
• Pegylated asparaginase ranges from 5 to 13 days.

L-ASPARAGINASE AND VTE

• Contribute to a hypercoagulable state through disruption of the hemostatic balance.

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• Decreased production or secretion of native anticoagulant protein such as Antithrombin, Protien C, Protein S

L-ASPARAGINASE AND VTE

RISK FACTORS:

In addition to asparaginase, the basis for VTE in ALL is multifactorial and higher in-

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• Adult than children
• Male than female
• Obesity
• Central venous catheter use
• Steroid administration

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• Pegylated formulation than non-pegylated

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• High risk ALL/ T-cell type
• Prior history of thromboembolism

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DIAGNOSIS OF VENOUS THROMBO�EMBOLISM

MANAGEMENT OF VTE DURING ASPARAGINASE THERAPY

• LMWH is recommended for the acute management of VTE related to asparaginase.
• Therapeutic dose of LMWH is recommended and monitoring of anti-Xa level.
• If severe thrombocytopenia ( < 50 ₓ 10⁹ /L ), anticoagulant should be stopped.
• Following resolution of severe thrombocytopenia, DOAC may be considered.

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MANAGEMENT OF VTE DURING ASPARAGINASE THERAPY

For life threatening VTE such as cerebral venous thrombosis or central pulmonary embolism-

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• Short term concurrent administration of antithrombin concentrate can be used
• Untill therapeutic anticoagulation and clinical stability is established.
• In an attempt to rapidly address the underlying thrombophilic defect.

MANAGEMENT OF VTE DURING ASPARAGINASE THERAPY

High risk thrombotic events such as cerebral venous or sinus thrombosis,central PE,proximal DVT or arterial thrombosis-

• Hold asparaginase therapy temporarily
• Resume following successful stabilization of acute thrombotic event,approx 4 weeks
• resumption should be considered on a case by case basis only under the cover of anticoagulation.

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Duration of anticoagulation

• At least 6 months
• Shorter duration may be considered on a case by case basis
• with minimum duration extending 4 to 6 weeks following completion of asparaginase therapy
• For high risk pt & not otherwise considered for increase risk of hge -continuation untill completion of chemotherapy and achievement of complete remission.

ANTITHROMBIN MONITORING AND REPLETION

• Kinetics of antithrombin changes influenced by type,dose and schedule of asparaginase.
• Nadir antithrombin level occurs 10 days following initial dose
• Level normalize in approximately 3 weeks.
• Nadir antithrombin level same among who develop VTE and who do not
• Whether routine antithrombin administration reduce the risk of thrombosis is unclear.

ANTITHROMBIN MONITORING AND REPLETION

Measurement of Antithrombin level may be done-

• weekly basis for the duration of asparaginase therapy
• Level below 50% to 60% - consider antithrombin concentration infusion.
• Repletion target in the 80% to 120% range

PREVENTION OF VTE

Can be done by thromboprophylaxis with-

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• LMWH throughout the asparaginase phase especially high risk patient.

or

• Unfractionated heparin

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or

• NOAC

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PREVENTION OF VTE

• Withhold LMWH thromboprophylaxis in case of severe thrombocytopenia ( platelet count <30 ₓ 10⁹ /L )

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• Fresh frozen plasma 10-15ml/kg on days of scheduled asparaginase if fibrinogen below 1.0g/L or Antithrombin level below 60% during induction.

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• Routine FFP infusion could moderate the antineoplastic activity of asparaginase.

TAKE HOME MESSAGE

• Before administration of L-asparaginase all patient should be monitored with conventional coagulation profile along with Anti-thrombin-III level to prevent Thromboembolism.
• All high risk group patient on asparaginase therapy should be treated with thromboprophylaxis
• LMWH, FFP, Antithrombin concentrate can be given.
• If patient developed venous thromboembolism,should be treated with therapeutic dose of LMWH or DOAC
• Treatment should be continued for atleast 6 months or until patient is getting therapy and is in remission.