A 20-year-old male presented to the emergency department  complaining of gingival bleeding of one day duration. After being  admitted to the hospital and on further questioning, the patient  informed the physician that he had been experiencing easy  fatiguability, headaches and few episodes of nose bleed. He has  had no significant past medical or surgical history. He neither  smokes nor drinks alcohol and is not taking any regular medication.  No history of allergy to drugs reported. Family and social history  were unremarkable.

fatiguability-condition where person tired or exhausted with minimal phy or mental exertion

2. gingival bleeding of one day duration episodes of nose bleed- continuous indicated insufficient amount of platelet (thrombocytopenia), potential anaemia:

aplastic anemia ,MDS

cause of bleeding: (can be spontaneous or not)

• trauma

• bone marrow disorder

• nutrient deficiency

• genetic disorder

• infections

• gum hygiene(inflammation)

• dengue (haemorrhagic fever)

  mechanism of bleeding

• MAHA

• AML-DIC

  homeostasis of coagulant defect,rupture of blood vessel (over sneezing)

• platelet defect,the quality

• coagulation defect

 3. fatiguability, headaches

• anaemia

• hypoxia

• bone marrow suppresant

• dehydration

• heat stroke

4. no significant past medical or surgical history

• no comorbidities

• no organ transplant

• immunocompetent

5. neither  smokes nor drinks alcohol

• no oral cancer (less possible)

• healthy person

• ruled out thrombocytopenia-abuse alcohol

• no exposed to chemicals,carcinogens,no tobacco

6. not taking any regular medication

• bleeding not associated with drugs

7.No history of allergy to drugs reported

• not related to allergy reaction

8. Family and social history  were unremarkable

• coagulation cascade

pathological of bleeding (hemorrhage)

• abnormal vascular permebility

• could be trauma

• clotting fac deficiency

• ruled out medication

• thrombocytopenia

• iron deficiency-impairement collagen formation

• G6PD

• vitamin C /K deficiency

• anticoagulant

possible diagnosis

• MDS

• aplastic anaemia

• acute leukimia

• scurvy

• viral infection (haemorrhage)

• MM,MULTIPLE MYELOMA

• AML-APML-DIC

• trauma

• coagulopathy

further investigation

• vital sign

• phy exam

• fbc

• fbp

• bone marrow aspiration

• immunophenotyping

• cytogenetic

• molecular studies

• blood coagulation test

• viral serology

• D-dimer (detect DIC)

On physical examination, the patient looked pale with multiple  ecchymotic skin lesion measuring from 2 to 3 cm in diameter on  lower extremities. His lungs were clear and no organomegaly  found on abdominal examination. There was no evidence of  regional lymphadenopathy. Other systemic examination was  unremarkable. 

Vital signs |Patient result |Reference value

Temperature (°C) 37.4| 36.4 – 37.6

Pulse rate (Beat per minute) 115,sinus rhythm|  60 – 100

Blood pressure (mm Hg) 110/70 |120/80

The morphology examination and cytochemistry study of the  stained smears of the peripheral blood and bone marrow aspirate  revealed the presence of abnormal mononuclear showing Auer  rods in the cytoplasm with few typical Faggot cells. These findings 

were consistent with the diagnosis of acute myeloid leukaemia  (AML). 

With the finding of bleeding manifestations associated with  abnormal blood coagulation tests accompanied by progressive  thrombocytopenia, decreasing fibrinogen, and elevated D-Dimer  levels, the patient was diagnosed as having laboratory evidence  of disseminated intravascular coagulation (DIC). 

Laboratory results:

Parameters |Patient result |Reference value

Hemoglobin (g/L) 79 | 135-175

Hematocrit (l/l) 0.33 | 0.40-0.52

MCV (fl) 90 | 80-95

MCH (pg) 30 | 27-34

MCHC (g/L) 239 | 200-350

RDW (%) 14 | 11.5 – 16.0

Total White Cell Count (TWBC) (x 10⁹/L) 10 | 4-10

Differential WBCs count Percentage  (%)

Neutrophil 10| 40-80

Lymphocytes 5| 20-40

Monocytes 3 |2-10

Eosinophils 2 | 1-6

Basophils 0 | 0-1

abnormal mononuclear cells 80 | 00

Absolute  count (x 10⁹/L)

Neutrophil 1  | 2.5-7.5

Lymphocytes 0.5 | 1.5-3.5

Monocytes 0.3  | 0.2-0.8

Eosinophils 0.2 |  0.1-2.0

Basophils 0.0 |  0-1.0

Platelet count (x 10⁹/L)  15  | 150-400

Parameters | Patient result |Reference value

C-Reactive Protein (mg /L) 15 | < 10

Prothrombin time (seconds)  25 |  12.4 (10.8– 13.9)

International normalized ratio (INR) 1.7|  0.89 (0.64– 1.17)

Activated partial thromboplastic time (seconds)  60 | 33.5 (26.6– 40.3)

Plasma fibrinogen (g/L)  1.3|  2.78 (1.56– 4.00)

D-Dimer assay (mcg/mL)  1.8|  < 0.4

Blood urea serum electrolytes (BUSE),  creatinine, and liver function tests : Normal

1. pale

2. multiple  ecchymotic skin lesion measuring from 2 to 3 cm in diameter on  lower extremities.

3. Pulse rate, high, sinus rhythm

4. presence of abnormal mononuclear showing Auer  rods in the cytoplasm with few typical Faggot cells.

5. diagnosis of acute myeloid leukaemia  (AML). 

With the finding of bleeding manifestations associated with 

6. abnormal blood coagulation tests accompanied by progressive  thrombocytopenia, decreasing fibrinogen, and elevated D-Dimer  levels, the patient was diagnosed as having laboratory

7. evidence  of disseminated intravascular coagulation (DIC). 

8. Hemoglobin (g/L) 79 | 135-175

9. Hematocrit (l/l) 0.33 | 0.40-0.52

10. MCV, MCH, MCHC, RDW normal

11. Neutrophil low

12. Lymphocytes low

13. Abnormal mononuclear cells high

14. Platelet count low

15. C-Reactive Protein high

16. D-Dimer assay high

• cytochemistry study- lab technique to detect chemical composition of cell

• Auer  rods- large, crystalline inclusion in cells that are a hallmark of APML

• Faggot cell-blast with multiple Auer rods, indicates APML

• abnormal mononuclear- mononuclear cells which are lymphocytes, monocytes that appear abnormal

• DIC- a condition where blood clots forms through out the body leading to bleeding and organ damage

• D-Dimer- protein fragments indicates blood clotting problem, fibrin degradation

• International normalized ratio (INR)- blood test measure how long the blood to clot

• Activated partial thromboplastic time- blood test that measure the time for blood clot

• vessel injuries, rupture

• bleeding disorders

1. Pulse rate, high, sinus rhythm

• tachycardia

• body mechanism due to low hb

1. presence of abnormal mononuclear showing Auer  rods in the cytoplasm with few typical Faggot cells.

   • hallmark for APML

5. diagnosis of acute myeloid leukaemia  (AML). 

   • APML

   • Correlates w DIC

   • genetic disorder- t(15;17)

   • PML-RARa- function as transcription reppressor

   • arrest differentiation of abnormal promyelocytes

6. abnormal blood coagulation tests accompanied by progressive  thrombocytopenia, decreasing fibrinogen, and elevated D-Dimer  levels, the patient was diagnosed as having laboratory

   • disturbance of coagulation

   • by granules of leukemic promyelocytes

   • causes bleeding

   • blood clotting problems due to platelet consumed in ongoing clotting process

7. evidence  of disseminated intravascular coagulation (DIC). 

   • 
     

   • substance release from the granules of the leukemic promyelocytes

   • disturbance of coagulation

   • cause bleeding

   • also due to defect in homeostatis (anti and pro coagulant)

   • hypercoagulation and bleeding tendency

   • coagulation cascades:

     • nak create fibrin mesh

     • convert protrombin to trombin

     • trombin convert fibrinogen to fibrin (monomers)

     • bila fibrin banyak, dia bind (polymerised) ke fibrinogens- become fibrin-fibrinogen complex

     • 
       

   • causes:

     • platelet depletion

     • clotting factor low

     • fibrinolysis high

     • overconsumption of platelet

   • normal cascade coagulation:

     • thrombin

     • plasmin

     • fibrinogen

     • fibrin

     • plasminogen- activated to plasmin, digest fibrin, dissolve clotting

     • fibrinolysis- dissolve the clotting

8. Hemoglobin extremely low

   • severe anaemia

   • supress bone marrow activity

   • less oxygen transport

9. Hematocrit low

   • anaemia

   • sama atas

10. MCV, MCH, MCHC, RDW normal

    • normochromic normocytic anaemia

11. Neutrophil low

    • neutropenia

    • bone marrow suppression

    • transcriptional repressor by PML-RARa

    • cause abnormal retinoic metabolism

    • treatment w retinoic acid

    • increase risk of infection

    • impaired diffrentiation of myeloid cells

12. Lymphocytes low

    • lymphocytopenia

    • sama atas

13. Abnormal mononuclear cells high

    • due to Auer rods

    • immature red cells (myeloblast)

14. Platelet count low

    • thrombocytopenia

    • bone marrow suppression

    • DIC

    • bleeding

15. C-Reactive Protein high

    • indicates infection and inflammation

    • associated w tissue injuries and malignancy during APML

    • body response to cancer

    • cytokine release

    • monitor severity of inflammation

16. D-Dimer assay high

    • DIC

    • marker of fibrin degradation

    • signal blood clots be broken down

FURTHER INVESTIGATION

• immunophenotyping

• cytogenetic study

• molecular studies

DIAGNOSIS

• APML

The patient was transferred to the haematology-oncology unit where  prompt treatment of the DIC-related bleeding with blood component  therapy was initiated and led to normalisation of the blood  coagulation tests. Treatment with specific combination  chemotherapy (all trans-retinoic acid (ATRA), idarubicin, and  arsenic trioxide) along with supportive care were started. He  achieved complete remission and had a favorable response.

2) Prompt treatment of the DIC-related bleeding with blood component  therapy was initiated and led to normalisation of the blood  coagulation tests.

3) Treatment with specific combination  chemotherapy (all trans-retinoic acid (ATRA), idarubicin, and  arsenic trioxide) along with

4) Supportive care were started.

5)achieved complete remission and had a favorable response.

• FAB AML M3

• immunophenotyping- helps identify specific type of leukemia by examining the types of markers present

• karyotyping- identify specific mutation influence the choice of therapy. diagnostic and prognostic value.

• t(15;17) 15- PML, 17-RARa - sensitive ATRA. Transcription repressor (blocks differentiate)

• FISH- Confirm the chromosomal translocation by fluorescent labelled genetic probes

2) Prompt treatment of the DIC-related bleeding with blood component  therapy was initiated and led to normalisation of the blood coagulation tests.

• FFP(4 unit), platlet(4 unit), cryoprecipitates(6 unit)

• 
  

3) Treatment with specific combination  chemotherapy (all trans-retinoic acid (ATRA), idarubicin, and arsenic trioxide)

• induction- chemotherapy(CAR-T) and ATRA , MYELOID GROWTH FACTORS

• consolidation- chemotherapy and supportive drug

• ATRA- no BM supression, bind to RARA-PML fusion protein(disrupt co-repressors- allows myeloid cell differentiate). Can also improved coagulopathy(DIC)

• idarubicin- a chemotherapy that interferes with the DNA replication and repair inside the cancer cells which prevents growth

• arsenic trioxide(ATO)- induce apoptosis by degrade PML-RARA FUISON . Free radical

• Typically combine with ATRA as treatment

• The power of drugs combination

4) Supportive care were started.

• PALLIATIVE care- provide relieve from pain and other symptoms.

• Psychosocial support- relieve spiritually and emotionally- Kaunseling

5)achieved complete remission and had a favorable response.

• PT HAS NO EVIDENCE OF SYMPTOMS AND NORMAL LEVELS OF BLOOD CELLS(MOLECULAR REMISSION)

• BUT HAS A CHANCE TO RELAPSE

CONCLUSION

• APL with DIC <3

1. Describe the normal coagulation and fibrinolytic  systems (CHOPPA)

2. Describe the types of bleeding manifestations based on  the type of haemostasis defects. (FARZ)

3. Describe the mechanism of acute leukaemia. (CARMILLA)

4. Describe clinical features of acute leukaemia. (NABILAH)

5. Outline the WHO classification of acute leukaemia, APL  variant, and describe the role of chromosomal  translocation in the development of APL. (WAFI)

6. Describe the mechanism, clinical features, and  investigations for the diagnosis of disseminated  intravascular coagulation (DIC) in APL. (SOMES)

7. Describe the peripheral blood and bone marrow findings  in APL. (HAIKAL)

8. Describe the types and role of the cytochemistry study  in the diagnosis of AML. (AIDIL)

9. Describe the principles and outline the clinical  usefulness of karyotyping, fluorescence in situ  hybridization (FISH) and immunophenotyping in the  diagnosis of APL.  (SHAZ)

10.Describe the blood component therapy and outline the  combination chemotherapy (All trans-retinoic acid  (ATRA)) in APL. (SYAKIRA)

11. Describe the pathogenesis, mechanism and diagnosis of DIC (SINEESH)