Contents
6.1 Epidemiology . . . 139
6.2 Etiology . . . 140
6.3 Symptoms and Clinical Signs . . . 140
6.4 Diagnostic Testing . . . 142
6.5 Treatment . . . 143
6.6 Prognosis . . . 144
6.7 Follow-up . . . 145
6.8 Future Perspectives . . . 145
References . . . 145
Bibliography . . . 145
6.1 Epidemiology
A normal platelet count in adults and children ranges from 150,000/mm
3to 450,000/mm
3. Thrombocytope- nia is defined as a platelet count more than two stan- dard deviations below the mean of the general popu- lation, or <150,000/mm
3. Thrombocytopenia is not usually detected clinically until the platelet count falls below 100,000/mm
3, and it is rarely associated with bleeding without trauma until the platelet count falls below 30,000/mm
3. A platelet count below 10,000/mm
3can be associated with severe, often spontaneous, bleeding.
The most common cause of thrombocytopenia in children is immune thrombocytopenia purpura (ITP). The incidence of symptomatic ITP is approxi- mately 3–8 per 100,000 children per year and may be acute or chronic. Acute ITP is defined as ITP that re- solves within 6 months of diagnosis. It is more preva- lent in children younger than 10 years of age and has a peak incidence at 2–5 years of age. In 80–85% of pa- tients with acute ITP, it will resolve spontaneously in 2–6 months. Acute ITP affects males and females equally. It is more prevalent during the late winter and spring months, and 50–80% of cases are preced- ed by a viral illness within the previous 3 weeks. ITP has also been associated with live measles vaccina- tion (Lanzowsky, 2000; Steuber, 2003).
Chronic ITP is defined as the persistence of ITP for longer than 6 months. It is more prevalent in adoles- cents than younger children and affects females more often than males. Up to one-third of patients with chronic ITP will have clinical and laboratory evi- dence of an underlying autoimmune disorder (Buchanan, 2000). Spontaneous remission of chronic
Thrombocytopenia
Cara Simon
ITP after 1 year is uncommon but may occur after 4 or 5 years, with or without treatment (Lanzowsky, 2000; Buchanan, 2000).
Immune thrombocytopenia can occur in the new- born period as maternal ITP or as neonatal alloim- mune thrombocytopenia (NATP). Both diseases are usually self-limiting and resolve within 6 weeks; how- ever, there are significant differences between the two disorders. In maternal ITP the mother usually has a below-normal platelet count, whereas in NATP the mother usually has a normal platelet count. NATP oc- curs in approximately 1 in 5,000 newborns. The platelets of the infant contain different antigens than those of the mother; subsequent formation of mater- nal alloantibodies that cross the placenta result in platelet destruction. Subsequent siblings with NATP are usually more severely affected. NATP is a more se- rious disorder than maternal ITP and has a higher in- cidence of intracranial hemorrhage (10–30% versus 1%) (Fernandes, 2003).
6.2 Etiology
The etiology of thrombocytopenia includes disor- ders of impaired/decreased platelet production, en- hanced platelet destruction, and dilutional or distri- butional thrombocytopenia (Table 6.1). Decreased platelet production occurs when platelet production by the bone marrow is suppressed or damaged, and it can be congenital or acquired. Thrombocytopenia can also occur when the bone marrow produces a normal number of platelets but there is enhanced platelet destruction, which can occur for various rea- sons. Dilutional or distributional thrombocytopenia occurs when circulating platelets are trapped or se- questered in the spleen.
6.3 Symptoms and Clinical Signs
Patients with thrombocytopenia may be asympto- matic; consequently, the low platelet count is detected on a routine blood test. The most common sympto- matic presentation of thrombocytopenia is bleeding, usually mucosal and/or cutaneous (Table 6.2). Mu- cosal bleeding typically manifests as epistaxis, gingi- val bleeding, or wet purpura on the buccal mucosa.
Cutaneous bleeding manifests as petechiae and ec- chymoses. Menorrhagia can occur in adolescent fe- males. Persons with thrombocytopenia may experi- ence profuse bleeding from superficial cuts.
Postsurgical bleeding can be controlled with local measures, but oozing may occur for hours after small injuries such as a minor cut or knee scrape. Bleeding into the central nervous system occurs rarely but is the most common cause of death due to thrombocy- topenia. Bleeding in patients with thrombocytopenia can be distinguished from bleeding in patients with coagulation disorders, as patients with coagulation disorders experience more deep bleeding, less bleeding after minor cuts, and tend not to develop petechiae.
A complete history and physical examination
should be performed on the child with thrombocy-
topenia. The health practitioner should obtain a gen-
eral history (including recent infection, recent immu-
nizations, previously diagnosed hematologic disease,
and family history), a bleeding history (both past and
present), and a history of drug ingestion. The physi-
cal examination should include meticulous examina-
tion of the skin and examination for lymphadenopa-
thy and hepatosplenomegaly.
Table 6.1. Differential diagnosis of thrombocytopenia
Etiology Association Diagnosis
Destructive Immunologic ITP
thrombocytopenias Drug-induced
Infection-induced Post-transfusion purpura Autoimmune disease Post-transplant Hyperthyroidism
Lymphoproliferative disorders
Nonimmunologic Microangiopathic disease
Hemolytic anemia and thrombocytopenia Hemolytic uremic syndrome
Thrombotic thrombocytopenia purpura (TTP) Platelet consumption/destruction Disseminated intravascular coagulation (DIC)
Giant hemangiomas
Cardiac (prosthetic heart valves, repair of intracardiac defects)
Neonatal problems Pulmonary hypertension
Polycythemia
Respiratory distress syndrome (RDS)/infection (viral, bacterial, protozoal, spirochetal) Sepsis/DIC
Prematurity Meconium aspiration Giant hemangioma Neonatal alloimmune
Neonatal autoimmune (maternal ITP) Erythroblastosis fetalis (Rh incompatibility) Impaired production Congenital and hereditary disorders Thrombocytopenia-absent radii (TAR) syndrome
Fanconi’s anemia Bernard-Soulier syndrome Wiskott-Aldrich syndrome Glanzmann’s thromboasthenia May-Hegglin anomaly
Amegakaryocytosis (congenital) Rubella syndrome
Associated with chromosomal defect Trisomy 13 or 18
Metabolic disorders Marrow infiltration: malignancies, storage disease, myelofibrosis
Acquired processes Aplastic anemia
Drug-induced Severe iron deficiency
Dilutional or Hypersplenism (portal hypertension, neoplastic, infectious, glycogen storage disease, distributional cyanotic heart disease)
Hypothermia
Adapted from The Children’s Hospital Oakland: Hematology/Oncology Handbook (2002)
6.4 Diagnostic Testing
Diagnostic testing for thrombocytopenia should start with the evaluation of the complete blood count (CBC) and examination of the peripheral smear. The peripheral smear is evaluated for estimation of platelet numbers, platelet morphology, and the pres- ence or absence of platelet clumping, and is impor- tant to help determine the cause of the thrombocy- topenia. Congenital disorders associated with throm- bocytopenia can often be diagnosed by platelet mor- phology on the peripheral smear. Platelets that are of normal size (Fig. 6.1) or small suggest decreased platelet production or bone marrow failure. Large platelets (Fig. 6.2) suggest platelet destruction.
Table 6.2. Clinical manifestations of thrombocytopenia
Mucosal bleeding Epistaxis Gingival bleeding Wet purpura Menorrhagia Cutaneous bleeding Petechiae
Ecchymoses (bruising)
Figure 6.1
Normal platelets. Reprinted with permission from http://www.wadsworth.org/
chemheme/heme/
microscope/platelets.htm
Table 6.3. Additional studies to be considered in thrombo- cytopenic patients
Viral serologies (EBV, CMV, Parvo) HIV antibody
Antiplatelet antibody (PAIGG) Lupus panel
Antiphospholipid antibody Lupus anticoagulant C3, C4
Lymphocyte panel LDH
Direct Coombs
Quantitative immunoglobulins DEB
PNH Platelet EMs X-ray radii
Family members’ platelet counts
Bone marrow aspiration and biopsy is indicated in patients with unexplained thrombocytopenia. The presence of normal to increased numbers of megakaryocytes in the bone marrow is indicative of increased peripheral destruction of platelets; absent or decreased megakaryocytes in the bone marrow in- dicate decreased platelet production. In a hypercellu- lar marrow, dysplastic changes are indicative of a myelodysplastic disorder. Bone marrow aspiration may also show the presence of infiltration with ma- lignant cells.
Patients with isolated thrombocytopenia who have a normal physical examination and whose pe- ripheral smear does not suggest other etiologies are diagnosed as having ITP and do not need a bone marrow aspiration and biopsy. However, if ITP per- sists longer than 6 months, a bone marrow exam may be warranted (Table 6.3).
6.5 Treatment
Treatment depends upon the cause of the thrombo- cytopenia. Thrombocytopenia that results from de- creased platelet production by the bone marrow is treated by platelet transfusion. Platelet transfusion is
utilized to correct episodes of bleeding. Bone marrow transplant can be used to treat some disorders of congenital thrombocytopenia, such as Wiskott- Aldrich syndrome and Fanconi’s anemia.
Thrombocytopenia that results from increased platelet destruction cannot be treated by platelet transfusion because the immune system will destroy the transfused platelets as well as the patient’s own platelets. Treatments for acute ITP include intra- venous immune globulin (IVIG), corticosteroids, and anti-Rho(D) immune globulin (Table 6.4). All three of these treatments have advantages and disadvan- tages. None is curative but will increase the platelet count as the body recovers.
Treatment for ITP does not need to be continued to maintain a normal platelet count, but rather to de- crease bleeding complications. Patients with chronic ITP who demonstrate persistent significant episodes of bleeding despite frequent and repeated interven- tions may require splenectomy. Splenectomy is effec- tive in improving the platelet count in 60–90% of children with chronic ITP. It is recommended that it not be performed until a child is at least 5 years old, and should not be performed in a child less than 2 years of age if possible. Prior to splenectomy, immu- nizations should be up to date, including Pneu-
Figure 6.2
Giant platelets. Reprinted with permission from http://www.wadsworth.org/
chemheme/heme/
microscope/giantplatelet.htm
movax 23 and Meningovax. The benefit of splenecto- my needs to be carefully weighed against the risk of overwhelming post-splenectomy infection that can be life-threatening.
Patients with thrombocytopenia should be in- structed on thrombocytopenia precautions. These patients should be discouraged from participating in contact sports, such as football and wrestling, or ac- tivities at high altitudes when there is a chance of falling and sustaining a head injury. Children with thrombocytopenia should be instructed to avoid as- pirin, ibuprofen, and other aspirin-containing med- ications that may interfere with platelet function.
The treatment for autoimmune and alloimmune thrombocytopenia in newborns is similar. Both can be treated with IVIG, steroids, platelet transfusions, and exchange transfusions. Platelets should be trans- fused if the platelet count is <20,000/mm
3, but if the infant is premature or ill, they should be given if the platelet count is <50,000/mm
3. An adequate platelet count should be maintained for the first 72–96 hours to prevent intracranial hemorrhage. An important
distinction is that patients with NATP should be transfused with plasmapheresed or washed platelets from the mother because they lack the alloantigen re- sponsible for the formation of the antiplatelet anti- bodies. In contrast, infants born to mothers with ITP should not receive platelets from the mother because they contain the antigens responsible for forming platelet autoantibodies.
6.6 Prognosis
The prognosis of the child with thrombocytopenia depends upon several factors, including the severity and underlying cause of the thrombocytopenia, the response to treatment, and the frequency and severi- ty of bleeding complications. Prognosis also depends on the incidence, quick recognition, and treatment of life-threatening bleeding complications such as in- tracranial hemorrhage.
Table 6.4. Comparison of ITP treatments
Treatment Dose Advantages Disadvantages Side effects
IVIG 400 mg/kg IV per day Faster recovery of Cost (can be as much Nausea, vomiting, for 5 days, or 1 gm/kg platelet count as 70 times more headache, fever, chills
IV per day for 1–2 days expensive than
corticosteroids) Rare: anaphylaxis
Corticosteroids 4 mg/kg/day PO Easy to administer Sharp decrease in Weight gain, hyperten- for 4 days (with or Relatively inexpensive platelet count after sion, Cushing’s
without a taper) or discontinuation syndrome, mood
2 mg/kg/day PO changes
for 2–3 weeks, then tapered over 1 week
Anti-Rho(D) 50–75 mcg/kg/day IV; Infusion time less Must be Rh+ Fever, chills, headache,
immune globulin may be divided and than for IVIG anemia
given over 2 days
Inexpensive 1–1.5 g/dl or greater Rare: anaphylaxis fall in hemoglobin as
a result of hemolysis (occurs 1–2 weeks after administration)
6.7 Follow-up
Follow-up of the child with thrombocytopenia is de- termined by the cause and degree of thrombocytope- nia, the frequency and severity of bleeding complica- tions, and the response to treatment. The child with chronic ITP with few bleeding complications may be followed in clinic every 3–6 months, whereas the child with congenital thrombocytopenia who re- quires frequent platelet transfusions to treat bleeding complications may require more frequent follow-up.
At each clinic visit or with bleeding episodes, a FBC/
CBC should be collected to check the platelet count.
6.8 Future Perspectives
Some medications that are currently being re- searched for the use of chronic ITP include Ritux- imab, vinca alkaloids, danazol, cyclophosphamide, and alpha interferon. Cytokines to stimulate platelet production are being studied and include inter- leukin-3 (IL-3), stem cell factor, IL-6, IL-11, and thrombopoietin.
References
Buchanan GR (2000) ITP: How much treatment is enough?
Contemporary Pediatrics 17(4):112–121
Fernandes CJ (2003) Neonatal thrombocytopenia. www.upto- date.com (06/09/2003)
Lanzowsky P (2000) Disorders in platelets. In: Manual of Pedi- atric Hematology and Oncology, 3rd edn. San Diego: Acad- emic Press, pp. 233–285
Steuber CP (2003) Idiopathic thrombocytopenic purpura in children. www.uptodate.com (06/09/2003)
Bibliography
Chu YW, Korb J, Sakamoto KM (2000) Idiopathic thrombocy- topenic purpura. Pediatrics in Review 21(3):95–104 Hastings C (2002) Immune-mediated thrombocytopenia. In:
The Children’s Hospital Oakland: Hematology/Oncology Handbook. St. Louis: Mosby, pp. 107–116
Hastings C (2002) Non-immune-mediated thrombocytopenia.
In: The Children’s Hospital Oakland: Hematology/Oncolo- gy Handbook. St. Louis: Mosby, pp. 117–118
Landaw SA (2003) Approach to the child with thrombocytope- nia. www.uptodate.com (06/09/2003)
Murphy S, Nepo A, Sills R (1999) Thrombocytopenia. Pedi- atrics in Review 20(2):64–69
