Etiological factor Diagnosis and Therapeutic Principle
Pathogenesis, Difference between aITP and cITP
Idiopathic Thrombocytopenic Purpura ( ITP ):Also named immunologic thrombocytopenic purpura.
The most common(4-8 /100,000) cause of thrombocytopenia in children and a result of immunologically mediated increased platelet destruction
Acute and self-limiting but may be recurrent or chronic disorder.
Etiology and pathogenesis
The etiology is still unknown and the pathogenesis is complex
Etiology a t present
Viral infection (rubella,rubeola,etc,1 to 4 weeks interval)
Immune factor (foreign antigen,drug cross-react with platelet membrane)
Spleen and other parts of reticuloendothelial system
Genetics (None described)
Acute ITP is believed to be a consequence of a disordered immune response during recovery from a viral infection that evokes the formation of antibodies that cause platelet destruction.
Platelet Ab specifically against glycoprotein Ⅱb/Ⅲa
An alternative hypothesis implicates immune complexes derived from primary or underlying disease processes that nonspecifically adsorb to the surface of platelets,resulting in their opsonization and rapid destruction.
antigens on the platelet surface platelet autoantibody platelet mononuclear macrophage Fc receptor
Mainly affects children between 2 and 10 years of age (peak age 2~ 5 yrs).
Boys and girls are equally affected.
A history of an infection prior 1 to 4 weeks, usually an upper respiratory tract infection. Chickenpox, rubella, infectious mononucleosis, hepatitis, mumps, measles, and pertussis have also been associated.
Sudden onset of petechiae or purpura a few days or weeks after an infectious illness. Some may be accompanied by bleeding from mucosal surface,hemorrhagic bullae of gums and lips,nosebleeds(epistaxis).
The most important potential complication is intracranial hemorrhage - rare (<1%)but serious.
Prominent over the legs
The liver and spleen may be palpable in a minority patient.
May be anaemic if they were hemorrhagic severely.
80%~90% of them have spontaneous recovery, the rest recover within 4~8 weeks.
10%~20% of them are chronic ITP.
Case fatality is approximately 0.5~1%, the principal factor is intracranial hemorrhage.
Types of diseases
According to the course of disease, separate ITP into two types
Acute ITP(aITP):the course of disease is shorter or equal to than 6 months.
Chronic ITP(cITP): the course of disease is longer than 6 months.
aITP cITP age A peak incidence between2 and 5 years of age More frequent in adolescents and young adults onste relatively acute relatively chronic degree of hemorrhage relatively severe relatively mild course of disease ≦ 6 months ﹥ 6 months platelet count Mostly,﹤20×10 9 /L Commonly(30~80) ×10 9 /L Numbers of megakaryocytes of bone marrow normal or increased increased markedly Difference between aITP and cITP
Peripheral blood smear : an isolated thrombocytopenia with no other abnormalities. platelet count ＜ 100 ×10 9 /L,the few circulating platelet may be quite large (megathrombocytes)
White blood cell count and morphology are nomal
Hemoglobin values are normal uneless there has been prolonged bleeding
PT and PTT are normal,bleeding time would be prolonged,but testing is unnecessary
Bone marrow:The bone marrow in patients with ITP contains normal or increased numbers of megakaryocytes
Indicating that platelet production is normal and that thrombocytopenia results from increased platelet destruction.
Two mature megakaryocytes; one with a very high N/C ratio, the other with a very low N/C ratio. An almost bare megakaryocyte nucleus lies at 5 o'clock and a stuffed macrophage at 11 o'clock. Idiopathic thrombocytopenic purpura (ITP) marrow
Two bare megakaryocyte nuclear masses. ITP marrow
Measuring antiplatelet antibodies
Including the measurement of the amount of platelet-associated IgG(PAIgG) and direct assay of specific platelet antibodies.
However,these tests lack both specificity and sensitivity in acute ITP of childhood.
Related viral infection may be detected,such as EB virus(EBV), mycoplasma(MP), cytomegalovirus(CMV) and so on.
Helicobacter pylori(HP) infection in cITP
Diagnosis should be based on
the infection history
Failure to perform a bone marrow examination may lead to diagnostic error and delay institution of correct therapy.
Acute leukemia : Acute leukemia patients with normal white blood cell counts may be to confuse,leukemic cell in blood smear or bone marrow can be to make a definite diagnosis.
Aplastic anemia: febril, anaemic, hemorrhagic patients with normal liver and spleen are similar to ITP patients associated with anaemia.but anaemia in aplastic anemia patients are severity, white blood cell counts are decreased, megakaryocytes in bone marrow are also decreased.
Allergic purpura: hemorrhagic erythra , symmetric distribution,always in both lower extremities and haunch.platelet count is normal, it’s easy to differentiate.
( Henoch-Schonlein purpura)
the disease is acute, benign, and self -limiting, and no therapy is required.
Patients should receive in - hospital treatment during acute bleeding.
salicylate-containing medications,antihistamines and nonsteroidal drugs that interfere with platelet function and increase the risk of bleeding and should be avoided.
Therapy is indicated if there is extensive cutaneous and particularly mucosal bleeding and a platlet count ＜ 20 × 10 9 /L
No treatment is usually indicated for patients with platelet counts ＞ 50 × 10 9 /L.
2.Intravenous immunoglobulin ( IVIG) .
Blocking Fc receptor of the RE (reticulo-endothelium) phagocytes
Preventing them from binding and destroying IgG antibody-coated platelets.
Dose: safe dose is 400mg/( kg.d) , using 5 days continuously or 1 g/ (kg.d) for 2 days.
Merit :IVIG appears preferable to corticosteroids because it results in faster elevation of the platelet count and may be indicated in severe disease.
Disadvantage:it is expensive,long infusion time of 6 to 8 hours,allergic reactions,aseptic meningitis with severe headache in 10% to 30%, 50% to 75% have headache,nausea,vomiting,or fever.
Reducing capillary fragility
Inhibiting platelets destruction
Have a rapid,dose-dependent action that reduce RE destruction of antibody-coated platelets
Also more slowly reduces antibody production.
Dose:oral prednisone 2 to 4 mg/kg/d tapered over 2 to 4 weeks.
Children with chronic ITP who have mild or recurrent bleeding are sometimes treated with intermittent courses of IVIG or highdose corticosteroids(intravenous methylprednisolone 20~30mg/kg/d for 3 days,then decrement).
Merit : cheap and convenient.
Disadvantage:Long - term use of corticosteroids should be avoided because of potential toxicity(moodiness,weight gain,etc)
4.Intravenous anti-Rh(D) Immunoglobulin for Rh-positive patient.
Anti- Rh(D) immunoglobulin produces a mild hemolytic anemia that saturates the Fc receptors of the phagocytic elements of the RE system.
Permitting increased survival of antibody-coated platelets.
The immediate goal of therapy is to increase the platelet count to a safe level, usually ＞ 20 × 10 9 /L ,in the hope of reducing the risk of severe hemorrhage.
Dose:IV anti-Rh(D),50 μ g to 75ug/kg for 2 days.
Merit : less expansive than IVIG but more costly than steroids,lower rate of allergic side effects(10%) than IVIG and does not cause aseptic meningitis.
Disadvantage:Cause mild hemolysis with a transient hemoglobin decrease of 10 to 20g/L.
Beneficial in children with chronic,symptomatic ITP.
About 70% of patient with chronic ITP achieve a complete remission following splenectomy,and most of the other show some improvement in platelet counts.
Search for an accessory spleen,depends upon its location,the severity of the thrombocytopenia,the perceived risk of surgery ,and the response to alternative forms of therapy.
Disadvantage:Surgical mobidity and risk of postsplenectomy sepsis with encapsulated organisms.
α -interferon ,danazol(a synthetic androgen),ascorbic acid,cyclosporine,and a variety of immunosupperessive drugs including vincristine(VCR) , azathioprine,and cyclophosphamide(CTX).
No large study of these agent have been describe in children with chronic ITP,and they may have immediate and long-term toxicities.
Adsorption Ab removal have been used with limited success in refractory cases.
Indication: platelets are less than 3 x 10 9 /L , intravenous platelet infusion is necessary to prevent severe hemorrhagic tendency.
Platelet infusions have no role except in life - threatening emergencies.
Because there are a lot of PAIgGs in circulation of patients, infusion platelets will be destroyed quickly.
May be given concomitantly
Is frequently necessary
May also be beneficial
Spontaneous recovery is the norm
60% by 3 months
80% by 6 months
90% by 12 months
The incidence of significiant bleeding-related morbidity and mortality is extremely low
less than 5%
Of patients with cITP
20% will ultimately have spontaneous resolution of their thrombocytopenia