EMAD LAWENDY MDPGY2

October 2009

Aim of this PowerPoint1. Discuss the incidence of neonatal

thrombocytopenia.2. Describe the risks of a low platelet count in

neonates .3. Develop DD for neonate who have

thrombocytopenia based on time of presentation risk factors , signs and symptoms .

4. Explain the potential mechanisms responsible for nonimmune thrombocytopenia.

5. Develop a management plan for neonates who have immune or nonimmune thrombocytopenia.

Classification and incidence of neonatal thrombocytopeniaTraditionally defined as platelet count <

150.000 /mcL ( mild < 100.000 and moderate 50.000-99.000/mcL)

1. 18-35% of all neonates admitted to NICU develop thrombocytopenia at some point during their NICU stays.

2. The incidence of thrombocytopenia is inversely related to the gestational age.

3. 73% of ELBW infants has one or more record during the 1st postnatal week.

4. 85% in neonates less than 800 grams.5. 60% in neonates 801 – 900 grams.

Neonatal platelet functions and risks of ThrombocytopeniaThere is developmental deficiencies in

primary hemostasis in preterm neonates during the first 1 and 2 weeks after birth .

The question of whether ( and to what degree) such haemostatic abnormalities contribute to the pathophysiology of IVH remains unanswered.

Approach to the Neonate who has ThrombocytopeniaTime of presentation is one of the most

helpful pieces in evaluation ( pathologic process in 1st 72 hrs differ than after 72 hrs.

Early onset thrombocytopenia1- Severity of thrombocytopenia2-Clinical presentation 3- Maternal history

If the mother has autoimmune thrombocytopenia -- the most likely diagnosis in an otherwise well appearing neonate is autoimmune thrombocytopenia mediated by the placental passage of maternal autoantibodies .

Mother with preeclampsia or chronic hypertension most common cause of mild thrombocytopenia in healthy appearing neonate . - can be managed with close observation

Thrombocytopenia can be the first presenting sign of a serious condition many clinicians order blood cultures and consider administering antibiotics for well appearing neonates in whom the cause of the thrombocytopenia is not yet clearly defined.

Differential diagnosis of Neonatal Early onset Thrombocytopenia

Clinical presentation

Degree of thrombocytopenia

Differential diagnosis

Ill-appearing Variable Sepsis ( bacterial, Viral)

TORCH infections (HSM)

Birth asphyxia (DIC)

Well appearing Mild - moderate Placental insufficiency

Genetic disorders ( cong. anomalies or dysmorphic features)

Autoimmune

Severe Neonatal alloimmune thrombocytopenia (NAIT)

Autoimmune.

Differential Diagnosis of Neonatal Late-onset ThrombocytopeniaClinical presentation Differential diagnosis

Ill-appearing Sepsis ( bacterial, Viral, Fungal)

NEC

IEM

(Viral = HSV,CMV, enterovirus)

Well appearing Drug induced thrombocytopenia

Thrombosis

Fanconi anemia.

Genetic Disorders Associated With Thrombocytopenia

Category Subtype Other clinical & labs

Chromosomal Trisomy13 Aplasia cutis , CHD, Cleft lip and palate , polydactly

Trisomy18 IUGR, CHD, rocker-bottom feet , overlapping digits, hypertelorism , small mouth , clinodactyly.

Trisomy21 CHD , transverse palmar crease , hypotonia , short neck with redundant posterior folds.

Turner S. CHD, Cutis vulgus ,webbed posterior neck, broad chest with wide spaced nipples , Lower extremity edema

11 q terminal disorder ( Jacobsen S, Paris Trousseau Thrombocytopenia)

CHD, genitourinary anomalies, abnormal brain imaging , Limb anomalies

Category Subtype Other clinical & labs

familial May- Hegglin anomaly,Sebastian syndrome

Giant platelets , Neutrophilic inclusions

Fetcher syndrome Giant platelets , sensorineural hearing loss, cataracts, nephritis, neutrophilic inclusions.

Bernard- soulier Syndrome Giant platelets

X-linked macro thrombocytopenia due to GATA-1 mutation

Anemia, genitourinary abnormalities ( Cryptorchiadism)

Congenital amegakaryocytic thrombocytopenia

Abnormalities of head size and shape. Developmental delay ,CHD,cleft and high arched palate , Abnormal kidneys, optic atrophy, vulgus and varus deformities, Vertebral anomalies , Coloboma,Scoliosis,absent BM,megakaryocytes

Category Subtype Other clinical & labs

familial Wiscott -Aldrich syndrome Immunodeficiency , small palates, eczema

Amegakaryocytic Thrombocytopenia and radioulnar synostosis

Restricted forearm pronation, proximal radioulnar synostosis in forearm, absent BM megakaryocytes

Fanconi anemia Hypopigmeted and hyperpigmented skin lesions. UT abnormalities , microcephaly , upper extermity radial side abnormalities involving the thumb , pancytopenia ( usually with onset in childhood)

Thrombocytopenia and absent radii

Shortened/absent radii bilaterally , normal thumbs, ulnar and hand abnormalities , abnormalities of the humerous.CH defects , Eosinophilia, leukemoid reaction

Neonatal primary hemophagocytic lymphohistiocytosis

Fever, HSM , Hyperferritemia , hypertriglyceridemia, hypofibrogenemia.

Bernard Soulier ( Giant Platelets)

Fanconi anemia

Thrombocytopenia and absent radii

Category Subtype Other clinical & labs

Metabolic Propionic acidemia , methylmalonic acidemia

FTT, developmental delay, Ketoacidosis , hyperglycinemia, hyperammonemia

Isovaleric acidemia Odor of sweaty feet, poor feeing, hypotonia , hyperammonemia, metabolic acidosis

Gausher disease HSM, Gausher cells in BM.

Mechanism of nonimmune thrombocytopeniaNeonatal platelet production

1.Production of thrombopiotin (Tpo).2.Proliferation of megakaryocyte progenitors.3.Megakaryocyte maturation .4.Generation and release of new platelets.

• Tpo concentrations are higher in neonates than adults.

• Neonates who have thrombocytopenia have lower Tpo concentration than similarly affected adults.

• Neonatal megakaryocytes generate fewer platelets than adults predisposition of ill neonates to develop thrombocytopenia.

Mechanism of nonimmune thrombocytopeniaMeasurement of neonatal platelet production

• BM biopsy is the gold standard test for evaluation of thrombocytopenia.

• It is difficult and frequently postponed until the infant is out of the neonatal period.

• Plasma or serum Tpo concentration, circulating megakaryocyte, proginators, reticulated platelet percentages RP% , and glycocalicin concentrations ( research setting).

Mechanism of nonimmune thrombocytopenia• Immature platelet fraction (IPF) part of CBC ( similar to RP% and to retic count in the evaluation of anemia.)

• IPF is elevated in thrombocytopenia associated with increased platelet destruction (e.g. ITP) and decreased in thrombocytopenia due to decreased platelet production (e.g. aplastic anemia , chemotherapy induced thrombocytopenia).

• IPF can predict recovery of the platelet count within the next 24 hours.

Mechanism of nonimmune thrombocytopenia• Mechanisms of thrombocytopenia in specific neonatal illness.

• The use of several tests together can differentiate between disorder of increased platelet destruction and deceased production and clarify the mechanisms of common varieties of neonatal thrombocytopenia.

• Platelet underproduction is the primary mechanism for the thrombocytopenia seen in fetuses and neonates

Mechanism of nonimmune thrombocytopenia1- Chronic intrauterine hypoxia (decreased concentration of megakaryocyte proginators + decreased number of megakaryocytes in bone marrow + lower plasma Tpo concentration)Megakaryocyte proginators from premature neonates are more vulnerable to chronic hypoxia induced suppression than those of term neonate.

2- Sepsis induced thrombocytopenia ( elevated Tpo concentration + increase megakaryocyte proginators concentrations + increase RP%)Neonates with gram negative sepsis have more thrombocytopenia and more sever illness but less thrombopoietic response ( down regulation of thrombopoietic response during sever illness to relative hypoproliferation.

Management of neonatal thrombocytopeniaNeonatal Alloimmne Thrombocytopenia

NAIT should be Considered in any neonate with initial PLT < 50.000/mcl (50 x10^9/L), especially in the absence of other risk factors or clinical symptoms.

Combination of sever neonatal thrombocytopenia with a parenchymal ( rather than interventricular) intracranial hemorrhage is highly suggestive of NAIT.

When NAIT is suspected , rapid blood testing is very important for timely and accurate diagnosis.

Blood should be collected from the mother and the father and submitted for confirmatory testing.

Antigen screening should include human platelet antigen HPA 1,3 and 5.

HPA 9 and 15 ( HPA 4 if parents are Asian ) should be done if the diagnosis is strongly suspected and the initial evaluation results are negative .

If results are positive antibody in the mothers plasma directed against the specific platelet antigen in the father .

The neonates serum can be screened for platelet antibodies if blood from the parents is not available ( may give false negative result).

Imaging of the brain ( US , CT or MRI should be performed as soon as possible when NAIT is suspected .

Large number of infants with NAIT respond to donor PLT transfusion ( first line of therapy)

If the patient is stable + no evidence of ICH PLT transfusion if the PLT count is < 30,000.

If the patient has ICH maintain PLT count > 100,000.

IVIG can be infused to increase the patient own PLT and protect the transfused PLT.

Matched ( antigen negative ) PLT must be given if there is no increase in the PLT count to a save concentration within 1-2 days .

Matched PLT include. 1- Maternal PLT. 2- Donor PLT with known HPA 1b1b and 5a5a ( compatible in > 90% of cases of NAIT).3- Random donor matched PLT ( after the results of typing).

Methylprednisolone might be given on the days that IVIG is used.

NAIT often resolved within 2 weeks . ( frequent PLT count until normal count without treatment).

Management of neonatal thrombocytopeniaAutoimmune thrombocytopenia

Should be considered in any neonate with

1- Early onset moderate to sever thrombocytopenia .

2- Maternal history of ITP or autoimmune disease with or without thrombocytopenia.

In mothers with ITP history 25% of neonates had thrombocytopenia at birth .

Management of neonatal thrombocytopeniaAutoimmune thrombocytopenia

All neonates born to mothers with AID undergo screening PLT count shortly after birth.

1- Normal PLT count no further evaluation.

2- Mild to moderate thrombocytopenia repeat in 2-3 days.

3- PLT < 30,000 IVIG ( first line of therapy).

evidence of active bleeding IVIG + random donor PLT.

Cranial imaging should be done to rule out IVH.

Management of neonatal thrombocytopeniaNon immune thrombocytopenia1- Determine the cause .

2- Provide specific therapy and supportive care.

3- PTs with moderate to sever thrombocytopenia PLT transfusion ( at different thresholds depending on the clinical picture and the signs of hemorrhage) .

Thank You