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