Immunhematology- seminar Vth year Internal Medicine
Transcript of Immunhematology- seminar Vth year Internal Medicine
Immunhematology- seminarVth year Internal Medicine
Dr. Ildikó Istenes
Semmelweis University Budapest
Ist Dept. of Internal Medicine
Immunhematological disorders
AIHA• Autoimmune hemolytic
anaemia
• Approach to the patient with anaemia
ITP• Immunthrombocytopenia
• Approach to the patient with thrombocytopenia
BUT: we meet the patient first, not the disease
Anaemia
• Not a disease, it is a SYMPTOM
• It is not enough to normalize hemoglobin levels, the cause of anaemia has to be found.
Hemoglobin, hematocrit or RBC count falls below normal level
Hgb <13,5 g/dl (male) Htk <40% (male)
<12 g/dl (female) <37% (female)
RBC destruction
-reticulo-endothelial system (RES)
-monocyta-macrophag system of the spleen
Red blood cellproduction needs:
Elements:
• Iron, Vitamin B12, Folicacid
Factors:
• Erythropoetin
- produced in the kidney
- to hypoxia
- binds to the receptor of the pluripotent stem cellwhich then differentiatesinto red blood cell
A patient with anaemia
• Complaints?
– Weakness, fatigue, dizziness, decreased ability to
exercise, effort dyspnoe, chest pain, ankle oedema
• Physical examination- findings?
– Paleness, icterus, ankle oedema, tachyardia,
systolic murmur
• Laboratory findings
Hemoglobin, hematocrit
MCV, MCH, MCHC, RDW
reticulocyte
Type of
anaemia?
iron parameters: ferritin↓, transferrin↑, transferrin
saturation ↓, total iron bindig capacity ↑
((Stages of iron deficiency))
Prelatent latent manifest(iron storage is deficient) (hemopoesis is iron deficient) (iron deficiency anaemia)
Serum ferritin and bone marrow iron is low
Iron absorption is increased
Serum iron ↓, transferrin↑ , transzferrin
saturation↓, total iron binding capacity↑
Number of bone marrow sideroblasts ↓
Hb, Ht, RBC ↓
As time goes by….
((Iron deficiency anaemia))• 80% of anaemias (80% female: menses, pregnancy...)
• Iron:
– Absorbed in the proximal small intestine, transported by transferrin and stored as ferritin
– Needed for the synthesis of hem
– Iron deficiency causes: hypochrom, microcytaer, hyporegenerative (reticulocyte count is low) anaemia
• Etiology of iron deficiency
– Decreased intake (children vegetarians)
– Decreased absorption (after gastric resection, bowel diseases)
– Increased need (growth, pregnancy)
– Iron loss due to bleeding (GI bleeding, surgery, blood donation, too often blood sampling, haemophilia)
• Symptoms
– Fragile hair, hair loss, dry skin, itching
– Pale skin and mucosa, weakness, effor dyspnoe, systolic murmur
• Therapy: – Treat the cause
– Iron supplementation (oral, iv. if needed): effect: 3-4 weeks: hb rise of 20g/l, normal ferritin 3-6 months
Hyperchrom macrocytic anaemia
What symptoms would you expect?
((Megaloblastic anaemias))Vitamin B12 and/or folic acid deficiency
→DNA- synthesis, maturation of the nucleus is impaired
Vitamin B12 storage of the liver is enough for 3 years
Absorption of Folic acid: Jejunum: as a monoglutamate, after deconjugation
from polyglutamate.
Drugs (oral contraceptives) may inhibit deconjugation,
thus causing folic acid deficiency)
Folic acid storage of the liver is enough for 3 months.
((Megaloblastic anaemias))Symptoms of B12 and/or folic acid deficiency: • Symptoms of chronic anaemia
very pale (elderly) patient with very low hb, which is tolerated relatively well(mouth: atrophic glossitis (burning tongue), angular cheilosis)
• Neurological complaints due to neuropathy: (in case of B12 deficiency)– Tingling, weakness, pain…
• Gastrointestinal symptoms
Diagnose: macrocytic anaemia (RBC↓, MCV↑, MCH↑), haemolysis: LDH, Indirect bi↑,
B12, folic acid measurement (Schilling test is no longer available- confirmsintrinsic factor deficiency in anaemia perniciosa)
Therapy:treat the cause, if possiblevitamin supplementation (usually both):
B12 (oral, parenteral)folic acid (oral)
Cause B12 deficiency Folic acid deficiency
1. Decreased intake Vegetarian/vegan dietB12 source: meat, fish, egg, milk etc.Elderly: decreased intake and absorption
undernutrition (alkoholism, „tea and toast” diet of theelderly)Source: liver, yeast, spinach, green leaf vegetables, nuts
2. Increased need - Hemolysis- pregnancy
3. Decreasedabsorption
Intrisic factor is missing: - anaemia perniciosa- After gastrectomy
Drugs interfering withdeconjugation (someantiepileptics, oralanticoncipients, metformin)
Severe malabsorption Malabsorption
Intestinal helminthiasis (helmints use it)
CoeliakiaIleitis terminalis
Ileum resesctionGastrointestinal bypass surgery
Lymphoma infiltrating the intestine
4. Egyéb Long term antacid and PPI treatment,Metformin
Folic antagonist therapy
74-year-old female• Examination because of recurrent gastrointestinal complaints for
years (cramps), – virtual colonoscopy negative in 2011,
– Maldigestion
– H. pylori eradication
2014
• Macrocytic anaemia- B12 deficiency, - B12 supplementation-Anaemia is not improved
• ???
• Bone marrow problem? – Peripheral flow cytometry: lymphoproliferative disease, mantle cell
lymphoma?
• Repeated colonoscopy (not virtual):– colon polyp histology: mantle cell lymphoma
• Bone marrow biopsy: lymphoma infiltrates bone marrow.
HCSÁ, female b.1952.• No relevant illnesses
2011. april: Screening labWBC: 2,9 G/l
• Ne %: 59,6, Ly %: 32,9,
RBC: 2,74T/l
– Hemoglobin: 103g/l
– Hematocrit: 0,29
– MCV 107 fl
– MCH 37,6 pg
– MCHC 351 g/l
Thrombocyte: 431G/l
Reticulocyte: 15/1000vvt (Norm: (5-15)
Diagnose: Myelodysplastic syndrome,
With 3 lineage dysplasia (bone marrow)
Message: Have a look at the other parameters as well
Hyperchrom, macrocytic,
hyporegenerative anaemia
KA. Male, b. 1953.• Hypertension
• 2007 a. iliaca stent impl. ld.
• 2007. tumor at the basis of the tongue-operation- no recidiva
• Chronic alcohol consumption
• Fvs 2,13
• Hb 81g/l, ht 0,25
• MCV 112, MCH 36,7
• Thr 78
• Pseudocholinesterase: 1534
• Cause of macrocyter anaemia?
• B12, folic acid: normal
Blood count abnormalities in chronic alcholosm: leukopenia, anaemia,
thrombopenia
Alcohol direct toxic effect-
bone marrow suppression- (leukopenia as well)
platelet function, lifetime changers
RBC macrocytosis
Bleeding
Malabsorption
Hypersplenism
Anaemia of chronic disease
• Anaemia of inflammation:
– cancer, infections, autoimmune and inflammatory diseases: rheumatoid arthritis or lupus
• Mild, micro/normocytic, hypo/normochrom anaemia, iron ↓,
• which does not improve to oral iron supplementation….
ACD: anaemia of chronic disease
1. Increased RBC destruction: due to mild extracorpuscular hemolysis
2. Decreased bone marrow RBC production
a) Iron is scarcely available to hemopoesis:
Hepcidin (produced by the liver, increased levels in inflammation)
- inhibits iron absorption from the gastrointestinum → decreased ironabsorption in inflammation (oral iron suppl is less effective)
- inhibits mobilisation from hemosiderin (iron from RBC-s is stored in the
RES and in the macrophages of the inflammated tissue as hemosiderin) → iron storageincreases, reuse of iron decreases
- transferrin is not increased in proportion to the need A → irontransport does not increse paralelly to the need
b) Erythropoetin production is not increased despite tissue hypoxy, and theeffect of EPO decreases as well.
c) Direct inhibition of bone marrow RBC production : due to elevated IL- 1 and TNF alfa
Differential diagnose of ACD and iron deficiency anaemia
Iron deficiency ACD
Serum iron Very low Normal or low
Serum transferrin elevated low
Serum iron bindingcapacity
elevated low
Serum ferritin low elevated
Solubile transferrinreceptor
elevated Normal or low
Transferrinreceptor/ferritin ratio
Highly increased >4 low ˂1
Bone marrow ironstorage
missing increased
Ferritin should be evaluated with CRP!
CRP and ferritin are acute phase proteins
Anaemia of chronic disease
• Oral iron supplement is not helping.
• The chronic disease has to be treated, and the anaemia will improve.
• Vica-versa:
– We have to think of it and search for chronic disease if we have a patient with anaemia
Hemolitic anaemia
(hyper/normochrom
Normocytic
Hyperregenerative
anaemia
Laboratory alterations in hemolytic anaemia!
Laboratory parameter reason
Hb↓, Ht ↓ Anaemia
LDH ↑, serum iron↑ cell destruction
Indirect bilirubin ↑ (icterus), urobilinogenuria
Hem destruction is increased → non-conjugated, albumin-bound (indirect) bilirubin is elevated
Haptoglobin ↓ Hgb coming out of intravascularly destroyed RBC binds to haptoglobin
Hemoglobinuria (brownishurine)
In case of massive intravascular hemolysis, whenthe tubular reabsorption capacity of the kidney is overrun
Reddish serum Free haptoglobin in the serum in case of intravascular hemolysis
Retikulocyte number↑ In case of intact bone marrow function: erythropoesis is increased, ratio of prematureRBC forms is increased
Where are RBCs broken down?
Normally: ExtravascularRBC destruction extravascularly in theRES (reticuloendothelial system) of thespleen
In case of hemolysis: in the liver, bonemarrow as well, and if their capacity is fulfilled
Intravascular hemolysis:RBCs are destroyed within the blood vessel
↓free hgb binds to haptoglobin
↓free haptoglobin↓ (measurable value)
↓free hgb will be present in the plasma, which
transforms to haematin, which is transferred to RES by haemopexin → finally haemopexin level↓
↓Free hgb is filtrated and reabsorbed in the kidney
If reabsorption capacity is overrun↓
hemoglobinuria (red urine)
Sz.E. b.1979• 1998- mild bilirubin elevation (Tbi32, dibi 10), no anaemia
• 2018 spleen is enlarged (50mmx130mm)
• Lab: Wbc 7,56, hb111, ht 0,31, MCV 86, MCH 31,2, Thr 265, ret: 102/1000vvt (norm 5-20), tbi 77, di bi 8,9, LDH 187, haptoglobin 0,01
• Coombs test is negative
• Family history: – Father: sphaerocytosis- he was splenectomized at the age of 14 after 2
severe hemolytic shubs
• Peripheral blood smear: sphaerocytes.
• treatment? : – no treatment is needed if it is a mild hemolysis
– Splenectomy is an option in case of severe hemolysis
Corpuscular haemolytic anaemia
Mentzner index: MCV (fl)
RBC (million/l)
Thalassaemia: < 13Iron deficiency anaemia: > 13
Spaerocytosis- membrane defect
Gothic palate
G6PD deficiency
Heinz body: dense bodies composed
of precipitated hb
Hemolytic shubs to oxidative stress
Bite cells:
Heinz bodies removed by the spleen
Sickle cell anaemia
Sickle cells obstruct vessels,
causing organ infarctions-
hepatoplenomagly
Acantocytes in
piruvate kinase deficiency
Etiology- hemolytic anaemia example
RBC defect=corpuscularHemolyticanémia
-membrane defect inherited: Spherocytosis, elliptocytosisacquired: paroxysmal nocturnal hemoglobinuria
-enzyme defect Glucose- 6-phosphate dehydgrogenase defectPiruvate kinase defect
-hemoglobinopathy Qualitiative problem: sickle cell anaemiaQuantitative problem: Thalassaemia (alfa, beta)
Eytra-Erythrocytercauses=Extra-CorpuscularHaemolyticanaemia
-alloantibodies hemolytic transfusion reactionMorbus hemolyticus neonatorum
-autoantibodies Autoimmune hemolytic anaemia- cold-warm- Idiopathic- secondary
-drugs Immune-mediated: Penicillin, kinidin, metildopanon immun-mediated= oxidative stress: salazopyrin
-infections Malaria, clostr. Perfringens sepsis
-mechanic: RBC fragmentationsyndrome
Cardiac origin: artificial valve, graftMicroangiopathic: TTP, HUS, DIC, HELLP, vasculitisArteriovenosus malformations
-physical- chemicaleffects
Metabolic disorder: Wilson disease (elevated copper)drugschemicals: lead, arsene, chlorineSevere burning
TTP. Trombotic trombocytopeniic purpura, HUS: hemolytic uraemic syndrome, DIC: disseminated intravascular coagulation)
B.L. male, b. 1943.• Hypertension, diabetes mellitus Type 2, inguinal hernia
operation, TEP implantation both sides, AMI- stent implantation, spine surgery
• 2018 sept: weakness- hemolytic anaemia– Warm and cold antibodies
– Serology (mycoplasma, EBV negative)
– Bone marrow biopsy: no lymphoproliferative disease infiltration
• Treatment: – Steroid- mild improvement (!hyperglycaemia)
– RBC transfusion- when anaemia was very symptomatic (hb 80, ht 0,20)
– Cyclosporin-
– Rituximab
• Now: acceptable, stable hb (100)
Zs.D, female, b. 1940.
• 1989. cold autoantibodies (no AIHA: Hb124, Ht 0,41, seBi, LDH norm)
• 2010. february: weakness-– AIHA: Hb 88 g/l, Ht 0,17, LDH681, Tbi 82, ret 48, haptoblobin: 0,08
– Serology: same as before (cold AIHA: anti-I, anti-E alloantitest, DC positive, comp coverage)
– IgM: 1366mg/dl, IgA, IgG suppressed
– crista ilei biopsy: Waldenström macroglobulinaemia with 30-40% bone marrow infiltration (CD20, CD19, CD38 positive, cytogenetics negative)
• Treatment: WM and AIHA– Immunetherapy (rituximab) and chemotherapy
• Outcome: – IgM decreased, hb/ht increased
– 2018. she is still feeling well, no hemolysis, no recidiva
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2E vvt:
100mg rituximab:
CVP
darbepoetin500 150 150 150500
150
IgM (mg/dl):
1514 826 626 511 594
20
11.0
1.2
5
20
10
.12.3
0
…….
Hemoglobin and hematocrit values
during and after treatment
Hb g/l
Ht (%)
messages• AIHA- look for underlying disease (and later as well)
• AIHA- treatment
– steroid (CAVE: side effects, hypertension, hyperglycaemia, it cannot be stopped immediately: Addison sy)
– other immunsuppressive drugs
– Rituximab: anti CD20
– Splenectomy
– Treat the underlying disease
• AIHA and transfusion?
– Principle: no, only in case of vital indication
– Vital indication:
• Chest pain, cardiopulmonal instability, shortness of breath, hypotension
Hemolysis caused by allo-antibodies:
- incompatibile transfusion: e.g. ABO incompatibile transfusion
- morbus hemolyticus neonatorum…
Hemolysis caused by auto-antibodies= autoimmune hemolytic anaemia
50%-primary (idiopathic)
50% secondary (disease: NHL, Hodgkin, drug, virus)
Warm AIHA: caused by incomplete IgG autoantibodies (90% adults, 75% children)
-IgG binds at body temperature to RBCs, that are destroyed in the liver and in thespleen → erythropoesis compensates for a while, then→ symptoms
Cold AIHA: caused by complete IgM autoantibodies
- Cold temperature causes acrocyanosis, hemolysis
- Antibodies activate complements (DAT test: complement coverage)
- acut: usually preceeded by infection
- chronic: idiopathic or secondary (B cell lymphoma)Search for a
primary cause!!!
Immun hemolysis
R.P, male, b. 1930
• 1933. Heine-medin- right lower limb hypotrophy- needs lots of pain killers
• Cholelithiasis, nephrolithiasis, diverticulosis coli
• 2002. CLL
• 2003- severe AIHA (trigger: NSAID?)- steroid effective
• 2009 sept: AIHA (warm)- steroid – effective, but slower response
• Bone marrow: CLL 50% infiltration- chemoterapy: Leukeran
• 2009. dec. renal terime- FNAB: carcinoma renis- chemoembolisation
• 2012 nov AIHA- rituximab (100mg),-AIHA was thought of CLL activisation-chemotherapy: cyclophosphamid
• 2013, inguinal hernia operation, 2013 pneumonia-
• 2015 febr: anaemia, CLL: complete remission, no hemolysis
• Not AIHA: microcytic anaemia- probably due to renal tumor (urine test: hematuria ++)- transfusion, ferrlecit infusion
• AIHA had not reappeared since 2012, he died in 2016 (due to cc renis)
Messages
• CLL diagnose- by chance- no treatment is necessary if there is no indication
• Several shubs of AIHA later
• Treatment:
– steroid, rituximab, anti- CLL treatment
– Transfusion in case of vital indication
• Anaemia- can be of different origin
– Last time: not AIHA but microcytic anaemia due to renal tumor
Treatment of AIHA• treat the cause
– (e.g. leave the drug, chemotherapy formalignancy)
• Transfusion in case of vital indication
• warm AIHA:• steroid, IVIG, immunsuppressants, splenectomy
• cold AIHA:• avoid cold, steroid/immunsuppr. (less effective),
• Rituximab: anti CD20 antibody
• plasmapheresis
Case report 55-year-old male
• Chronic lymphoid leukaemia, comes to regularcheck-up
• Anaemia• AIHA? – common in CLL• Blood test: LDH, Tbi, haptoglobin norm• ???• Ask the patient: blood in stool? • Answer: Yes: RDV: Weber positive• Gastro-colono:source of bleeding is not found• Capsule endoscopy: small intestine:
angiodysplasia
Message:
Anaemia of a CLL patient
can be due to „ordinary”
Reasons
Anamnesis taking!!
Differential diagnose of anaemias based on mean cell volume (MCV) and mean cell hemoglobin (MCH)
Hypochrom microcyticanaemia
Normochrom normocyticanaemia
Hyperchrom macrocyticanaemia
MCH↓+MCV↓
MCH˂28pg/l
MCH+MCV normalMCH 28-35pg/l
MCH↑+MCV↑
MCH˃35pg/l
Ferritin norm or ↑:Hemoglobinopathy
Iron and ferritin↓:Iron deficiency anaemia
Reticulocyte↑:Haemolytic anaemiaAnaemia due to bleeding
Reticulocyte↓: AplasticanaemiaRenal anaemia
Reticulocyte normal:Megaloblastic anaemia (B12, folic acid deficiency)
Reticulocyte ↓:- myelodysplasia syndrome- drug (eg. hydroxiureatreatment) - pregnancy, hypothyreosis
Iron↓, ferritin↑, ret ↓: anaemia due to inflammation, infection, tumor
Etiology? : decreased RBC, Hb, MCH, (MCV), reticulocyte, ferritin
Ferritin should be evaluated with CRP!Reticulocyte: reflects bone marrow function:
Hyporegenerative: low, hyperregenerative: high
Summary
• Anaemia is a symptom, find the cause!
• Differential diagnose:
– Hypochrom- normochrom- hyperchrom (MCH)
– Reticulocytes
– Iron parameters (ferritin + CRP)
– Other: observe parameters for hemolysis
• Treat the cause
• RBC transfusion is only in case of vital indication in AIHA
Thrombocytopenia
• definition?
• Platelet count below 150G/l
• Risk of bleeding:
– <50G/l spontaneous bleeding which requires treatment
– < 10G/l spontaneous life threatening bleeding
• Vascular constriction: bleedingdiminishes (seconds)
• Primary hemostasis:
– Platelet adhesion- activation-aggregation (3-5 minutes)
• Secondary hemostasis
– Clot formation- fibrin formation
(10-30 minutes)
– fibrinolysis and reconstruction of vessel wall (days, weeks)
Vessel wall damage-exposure of the subendothelium
Clinical charateristics of bleeding disordersClinical symptom Bleeding disorder
Trombocyte defect coagulopathy
Timing of bleeding Immediate (controlled by
pressure)
Delayed (not controlled
by pressure)
Site of bleeding Skin, mucosus
membrane (oral,
gastrointestinal
Deep in soft tissue
(muscle, joint)
Bleeding after small
injuries
Frequent Generally not
Petechiae frequent Generally not
Ecchimosis Small superficial Big palpable
Hemarthros Rare Frequent
Muscle hematome Rare Frequent
Bleeding after surgical
interventions
Immediate, mild Prolonged, severe
Sex of the patient 80-90% female 80-90% male
Positive family history rare frequent
Petechias, purpuras
Etiology of thrombocytopenia
1. Pseudothrombocytopenia:
- EDTA induced aggretation/agglutination
- Satellite formation between leukocytes and thrombocytes
2. Real thrombocytopenia
- Decreased production
- Increased destruction
- Increase storage in spleen
I. Decreased formation and maturation
Bone marrow: Megakariocytenumber is low orabsent
1.Hereditary
Pl. Fanconi anaemia, Wiskott-Aldrich sy, Bernard-Soulier
sy,
2.Acquired
Bone marrow damage:
-drugs (kemoth),
-Chemicals,
-radiation,
- infections
Bone marrow infiltration:
-leukaemia, lymphoma,
-carcinoma
Myelodysplasia, myelofibrosis
Vitamin deficiency (disturbed maturation)
B12 deficiency, folic acid deficiency
Etiology of real thrombocytopenias
II. Inreased damage
Bone marros:
Megakariocyte
number is normal
or elevated
1. Immunthrombocytopenias
Autoimmun Primary:
-Acute and
-Adult chronic ITP (Idiopathic/immun
thrombocytopenic purpura)
secondary:
-drugs (co-trimoxazol, chinidin, HIT),
- infection (HIV, H.pylori),
-autoimmune disease(SLE),
-Malignancy (lymphoma)
-Antiphospholipid syndrome
Alloimmun Posttransfusional purpura
2.Microangiopathic
- Disseminated intravascular coagulation
-Thrombotikus thrombocytopenic purpura
-Hemolytic uraemic syndrome
3. Other:
Valve implantation (mechanic),
Extracorporal circulation (surface)
Etiology of real thrombocytopenias
III. Increased storage in spleen
Bone marrow:
The number of
megakariocytes
depend on the
underlying disease
Portal hypertension (liver cirrhosis)
Myeloproliferative, lymphoproliferative neoplasms
Storage diseases
Etiology of real thrombocytopenias
Thrombocytopenia- diagnosis• 1.Anamnesis
– age
– Family history: inherited- acquired?
– Evolment of symptoms? – acute-chronic
– drugs
– Other diseases (malignant, autoimmun)
– Transfusion history
• 2.physical examination:– Morphology of bleeding (wet
purpuras)
– Size of liver and spleen
– Joints, skin (autoimmune disease)
– Signs of malignancy?
– Signs of infection
• 3. laboratory– Citrate anticoagulated blood as
well
– peripheral blood smear: • thrcyte size (giant: MDS, hereditary)
• Fragmentocyte (microangiopathy)
• Blasts?
• RBC-s with nucelous: (myelofibrosis, bone marrow infiltration)
• Toxic granulation- (infection)
– Special tests can be: • HIV, anti HCV, antiphospholipid AB,
Immuneglobulins, anti TPO, autoantibody screening, (thrcyte antibody is NOT needed)
• H. pylori test
– Bone marrow if: • Atypical case, above 60 years
2019.02.27.
Isolated thrombocytopenia
Probable dg: ITP
Thrombocytopenia with?
White blood cells? Neutrophils? Lymphocytes?
Red blood cells?
Probable diagnose?
Eg. CLL- Cause ot thrombocytopenia?Cause usually:
Splenomegaly
Bone marrow infiltration
Formation of thrombocytes
Thrombopoetin (TPO):- interacts with hemopoetic stem cells and helps them differentiate into megakariocyte precursors
- helps these precursors to proliferate and differentiate into megakariocytes
-Increases peripheral thrombocyte count
ITP –
pathogenesis
Classic theory of ITP: Platelet-death and degradationin spleen due to anti thrombocyte antibodiesBone marrow: increased production, megakariocyte number increases
Thrombocytopenia ITP
Blue arrow represents amount of free or unbound TPO in the system
Spleen
Liver
New theory!:- increased degradation- suboptimal formation: megakariocyte number is relatively LOW
- antibodies against megakariocytes- relatively low TPO:
- TPO is bound to plt- there is less TPO available to stimulate plt prod
- TPO is lost when bound to apoptotic megakariocytes
TPO
Classification of ITP
• Childhood ITP:– Acute ITP: 75% reversible
– Majority is secondary, provoked by infection(morbilli, varicella), allergy, vaccination
• Adult ITP– Newly diagnosed (within 3 months)
– Persistant (3-12months)
– Chronic ITP (50-75%): (over 12 Months): 60% persistant remission, 35% requires continuoustreatment, 1-5% fatal bleeding)
ITP treatment principles
• What is the treatment goal in ITP?
• Treatment is based on the severity of thrombocytopenia AND the clinical signs!
• Normalisation of PLT is not a goal!
• Not to be treated:
• Asymptomatic patient, plt> 30.0 G/l
• Plt transfusion?
– should be omitted if possible
Planned procedures
TCT szám
• dentistry: 10x109/L
• Tooth extraction: 30x109/L
• Regional anaesth.: 30x109/L
• Small surgery: 50x109/L
• Large surgery : 80x109/L
• gynecology:– Sectio Caesarea: 50x109/L
– Sectio Caesarea + epidural anaesth: 80x109/L
BCSH Guidelines. Br J Haematol 2003;120:574–596
Platelet count Risk of bleeding
(x 109/L)
>100 asymptomatic
50-100 invasive intervention
10-50 Purpura, haematoma
<10 Spontaneous severe bleeding
Platelet count and risk of bleeding
ITP treatment modalities
• Inhibit immunological processes:– corticosteroids
– Other immunesuppressive drugs (azathioprin, cyclosporin)
– Killing antibody producing B cells (anti-CD20 monoclonal AB)
• Stopping thrombocyte destruction– Intravenous immunglobulin (IVIG)- „feeds” WBC-s attacking plts
– Anti-D
• Get rid of the site of thrombocyte destruction– Splenectomy
• Get rid of trigger mechanism:– Helicobacter pylori eradication, treat the underlying disease (eg.
Autoimmune)
• Increasing plt production: (at megakariocyte level)– Thrombopoetin analogues (romiplostim- sc., eltrombopag- per os)
T.B., female b.1976.• 1979 diagnose of ITP
• Shubs every 3-4 years, responding to steroids
• 1989. AIHA (AIHA+ ITP= Evans sy)
• 1991. IVIG
• 1997 Vincristin (polyneuropathia)
• 1997. splenectomy (not responding as expected)
• 1998-2007-remission
• 2007 relapse after vaccination- steroid
• 2010-11: 5 relapses, worse and worse response to steroid
• 2011. TPO analogue (romiplostim) (1 month)
• 2013 TPO analogue (elthrombopag) (6 months)
• CVID (common variable immunodeficiency)- regular IVIG supportation
Romiplostim treatment (TB)
1ug/tskg
1ug/tskg
80 48 24 mg Medrol
break
Eltrombopag treatment
50 mg 25mg
50 mg 25mg
50mgbreak break
G/l thrcyta
O.Gy., female b.1949.
• 2002.May ITP
• Steroid resistant
• splenectomy
• 2013 Jan: relapse
• Bone marrow biopsy:
• Cyclosporin treatment
• 2013 TPO analogue treatment (romiplostim)-still on treatment
Romiplostim treatment4ug/tskg
4ug/tskg3ug/tskg
5ug/tskg
BV, female b. 1955• thyreoiditis- hypothyreosis, uterus extirpation,
cyclothymia
• 2000. chronic HCV hepatitis
• 2009. febr. AIHA (cold) with airway infection (Chlamydia IgM pos), flow cytometry: hairy cell leukaemia?
• 2009 apr: bone marrow: splenic marginal zone lymphoma
Message: AIHA came first- hematological malignancy was found
BV, female b. 1955• 2013. thrombopenia 50G/l- but it is a limit to anti HCV treatment- steroid is
not effective
• 2013 june: splenectomy (histology: no MZL infiltration) , cholecystectomy (cholelithiasis)- thrombocyte count elevated
• 2016. may thr 27G/l
– Steroid- not effective….. TPO analogue (elthrombopag)
– Cause of thrombopenia: HCV associtated + lymphoproliferative disease
• 2016 aug: elthrombopag had to be omitted due to liver enzyme elevation
• 2016 sept. Thrombopenia- spontaneously recovered
• 2016.oct: IFN free antiviral treatment initiated
• 2018. sept: severe Anaemia- AIHA (mixed cold-warm)
• Steroid first, then rituximab- cyclophosphamid- vincristin –prednisolon (R-CVP) treatment for SMZL, RBC transfusion with steroid- with vital indication
• 2019.01. 24- 4. R-CVP treatment-
Messages• AIHA came first- so we have to look for it actively
• Then diagnose of SMZL
• ITP- multi etiology
– HCV associated
– Lymphoma associated
• Treatment:
– Steroid, splenectomy for ITP, TPO analogue
– Treatment of underlying disease: lymphoma and HCV
• IFN can not be given in case of autoimmune complication
• General concept- NO transfusion in case of AIHA (ITP)– Except: vital indication
– Anaemia. Angina, shortness of breath etc, ITP: severe bleeding
•Therapeutic supportation:
• Bleeding due to thrombopenia or thrombopathia
(„wet purpuras”, internal beleeding)
•Preventive supportation:
•By critical platelet count (no bleeding)
Indication of platelet transfusion
Preventive supportation Plt count
Stable patient without fever: < 5-10G/l
Accompanying fever, sepsis, DIC, severe anaemia,
extreme leukocytosis, progressive thrombopenia
< 20G/l
Lumbalpunction, intrathecalis chemoth < 30G/l
Surgera, invasive diagnostic intervention (except for
sternum punction, crista biopsy
< 50G/l
Neurosurgery, eye surgery, polytraumatised patient < 100G/l