Abstract
This chapter describes the current understanding of a wide variety of platelet pathology, including thrombocytopenia, thrombocytosis, qualitative platelet disorders, and diagnostic approaches to these problems. Autoimmune and alloimmune neonatal thrombocytopenia, immune thrombocytopenia in the older child, as well as other acquired causes of thrombocytopenia including thrombotic thrombocytopenia purpura (inherited and acquired) are described. Classical therapeutics and new agents like the thrombopoietics are reviewed. The discussion of thrombocytosis includes secondary causes of thrombocytosis and familial and hereditary thrombocytosis. Qualitative platelet disorders including various inherited disorders of platelet function and secondary causes of platelet impairment (e.g., drugs) are described. It also includes a section focused on diagnostic tests for platelet function.
Keywords
Immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, neonatal autoimmune thrombocytopenia, neonatal alloimmune thrombocytopenia, thrombocytopenia, thrombocytosis, platelet dysfunction, inherited thrombocytosis, platelet function testing
Platelets are an important component in primary hemostasis. Defects in platelet number or function may lead to bleeding and bruising. Bleeding due to platelet disorders usually involves skin and mucous membranes, presenting as petechiae, purpura, ecchymosis, epistaxis, hematuria, menorrhagia, as well as gastrointestinal and even intracranial hemorrhage (ICH).
Platelet characteristics include:
- •
Size: 1–4 μm (younger platelets are larger). Table 14.1 lists the causes of thrombocytopenia based on platelet size.
Table 14.1
Platelet Diseases Based on Platelet Size
MACROTHROMBOCYTES (MPV RAISED)
ITP or any condition with increased platelet turnover (e.g., DIC)
Bernard–Soulier syndrome
May–Hegglin anomaly and other MYH9-related diseases
Montreal platelet syndrome
Gray platelet syndrome
Various mucopolysaccharidoses
NORMAL SIZE (MPV NORMAL)
Conditions in which marrow is hypocellular or infiltrated with malignant disease
MICROTHROMBOCYTES (MPV DECREASED)
Wiskott–Aldrich syndrome
TAR syndrome
Some storage pool diseases
Cytomegalovirus infection
MPV, mean platelet volume (as determined by automated electronic counters); normal, 8.9±1.5 µm 3 ; ITP, idiopathic thrombocytopenic purpura; DIC, disseminated intravascular coagulation; MYH-9, non-muscle myosin heavy chain 9 gene; TAR, thrombocytopenic absent radii. Inherited thrombocytopenias are not well characterized and may present with normal/large platelet size .
- •
Mean platelet volume (MPV): 8.9±1.5 fl.
- •
Distribution: one-third in the spleen, two-thirds in circulation.
- •
Average lifespan: 9–10 days.
Table 14.2 lists the causes of thrombocytopenia according to pathophysiology and Table 14.3 lists the common and uncommon causes of thrombocytopenia in the neonate and child.
|
a A bone marrow biopsy, in addition to marrow aspiration, should always be carried out to avoid sampling errors and to establish the presence of a decreased number of megakaryocytes in the marrow.
b These conditions are associated with normal or increased bone marrow megakaryocytes.
| Common | Uncommon | |
|---|---|---|
| Neonate | Sepsis | Cardiac (prosthetic heart valves, repair of intracardiac defects, left ventricular outflow obstruction) |
| Asphyxia | ||
| Alloimmune thrombocytopenia | Maternal hypertension | |
| Necrotizing enterocolitis | Infections (rubella, CMV, HIV, hepatitis B, syphilis) | |
| Maternal ITP | Amegakaryocytic thrombocytopenias | |
| Congenital amegakaryocytic thrombocytopenia without anomalies (CAMT) | ||
| Congenital amegakaryocytic thrombocytopenia with bilateral absence of radii (TAR syndrome) | ||
| Amegakaryocytic thrombocytopenia with radio-ulnar synostosis (ATRUS) | ||
| Wiskott–Aldrich and X-linked thrombocytopenia | ||
| Bernard–Soulier syndrome | ||
| MYH9 disorders | ||
| Montreal platelet syndrome | ||
| Quebec syndrome | ||
| Gray platelet syndrome | ||
| Inborn errors of metabolism | ||
| Congenital leukemia (trisomies 13, 18, 21) | ||
| Child | ITP | Type II von Willebrand disease |
| Drug-induced | Autoimmune diseases such as SLE, JIA | |
| Immunodeficiency | Infections | |
| Fanconi anemia | ||
| Leukemia and other malignancies with bone marrow involvement | ||
| Autoimmune hemolytic anemia (Evans syndrome) | ||
| TTP/HUS | ||
| Hyperthyroidism | ||
| Megaloblastic anemias (folate and vitamin B12 deficiencies) | ||
| Severe iron-deficiency anemia | ||
| Cyclic thrombocytopenias | ||
| Lymphoproliferative disorders | ||
| Aplastic anemia | ||
| Drug-induced | ||
| Radiation-induced |
Thrombocytopenia in the Newborn
Neonatal thrombocytopenia is relatively common, occurring in 1–3% of healthy term infants and in 20–30% in the neonatal intensive care unit population. Thrombocytopenia in sick neonates is often secondary to an underlying pathology such as sepsis, disseminated intravascular coagulation (DIC), or respiratory distress syndrome or secondary to maternal factors such as pregnancy-induced hypertension, gestational diabetes, and intrauterine growth retardation (IUGR).
Table 14.4 lists the causes of neonatal thrombocytopenia.
|
Neonatal Alloimmune Thrombocytopenia
Neonatal alloimmune thrombocytopenia (NAIT) is the most common cause of severe thrombocytopenia in the newborn, with an overall incidence of approximately 1 in 1000 births but is perhaps as frequent as 1:3–5000 births when defined as a platelet count <50,000/mm 3 NAIT typically resolves in 2–4 weeks. First-born infants are 25–50% of those affected and subsequent affected pregnancies have increasingly severe presentation and require antenatal treatment.
Pathophysiology
NAIT can be thought of as a platelet analog of Rh incompatibility (i.e., hemolytic disease of the fetus and newborn). It differs from Rh incompatibility because many cases are first-born infants, suggesting the antigenic exposure occurs early in pregnancy unlike in Rh, which occurs primarily at the time of delivery. NAIT occurs when fetal platelets that express platelet-specific antigens inherited from the father, are the target of maternal alloantibodies. Mothers who lack the paternally inherited platelet-specific surface antigen, and who possess the immunologic predisposition to make antibodies to it, can become sensitized when they are expressed on fetal platelets or possibly also from the Α V /B III receptor on the trophoblast. The most common antigen involved is HPA-1a, which accounts for approximately 75% of cases. A further 10–20% of cases are due to maternal sensitization to HPA-5b. More than 20 other antigens are known to be involved in NAIT. HPA-4 is important in Asian populations which do not have the HPA-1A/B polymorphism. Mothers who possess the HLA-DR type DRB30101 represent >90% of cases of sensitization to HPA-1a. These IgG antibodies cross the placenta and attach to the surface of fetal platelets, causing platelet destruction and perhaps inhibition of platelet production.
Clinical Features
- •
Typically infants are otherwise healthy full-term babies, who manifest symptomatic thrombocytopenia with generalized petechiae, ecchymosis, cephalohematomata, umbilical bleeding, oozing from skin puncture sites, and/or gastrointestinal or renal tract bleeding.
- •
Affected neonates have rates of ICH up to 10–20% and, when present, the ICH tends to be severe and intraparenchymal. ICH is now thought to frequently occur in utero and may be detected on ultrasonography during apparently uncomplicated pregnancies. Death in utero may occur.
- •
Platelet count is very low at birth, usually <50,000/mm 3 . Cases of HPA-5b incompatibility are milder.
Diagnosis
NAIT should be considered in all newborns with thrombocytopenia.
Ninety percent of cases of HPA-1a incompatibility NAIT have a platelet count of <50,000/mm 3 , making it a reasonable screening tool for identifying NAIT. Two other reasons to suspect NAIT, even if the neonatal count is >50,000/mm 3 , include:
- •
No clinically apparent etiology of thrombocytopenia.
- •
Family history of transient neonatal thrombocytopenia.
Response to random platelet transfusion or lack thereof is NOT diagnostically useful.
It is important to investigate and establish the diagnosis because of the impact on subsequent pregnancies and hence their management. Laboratory evaluation should include screening for HPA-1, 3, and 5 antibodies, as well as HPA-4 antibodies in those of Asian descent. HPA-9 and 15 are the next most common antigen incompatibilities. To confirm the diagnosis of NAIT, ideally testing must show both platelet antigen incompatibility and antibodies to the discordant antigen.
Additional useful clinical criteria for the diagnosis in addition to severe congenital thrombocytopenia (<50,000/mm 3 ) include:
- •
Normal non-pregnant maternal platelet count and negative history of maternal immune thrombocytopenic purpura (ITP).
- •
Exclusion of alternate diagnoses.
- •
Recovery of normal platelet count within 2–3 weeks.
- •
History of NAIT in a prior pregnancy.
- •
Increased megakaryocytes in bone marrow examination (if performed).
Treatment
The following treatment is recommended:
- 1.
Platelet transfusion 10–20 ml/kg body weight. Maternal or matched platelets are infrequently necessary for effective therapy since there is often good efficacy with transfusion of unmatched platelets.
- 2.
Matched donor platelets or concentrated maternal platelets may be used, if available, especially if unrelated donor platelet transfusions are ineffective.
- 3.
Intravenous immunoglobulin (IVIG) 1 g/kg/day for 1–3 days, especially in combination with random platelet transfusion, depending on response with the goal of platelet count being above 30–50,000/ mm 3 .
- 4.
Methylprednisolone (1 mg IV) every 8 h with IVIG until the IVIG is stopped (no tapering is necessary).
- 5.
Head ultrasound is mandatory for the thrombocytopenic neonate. If there are any abnormal neurological findings, a CT or MRI should also be done. If ICH is present in NAIT on ultrasound, the target platelet count should be greater than 100,000/mm 3 and a head CT or MRI should be performed to better define the hemorrhage. Imaging should be repeated to document stabilization/improvement and then monthly for 3 months to identify early hydrocephalus, along with head circumference measurements.
- 6.
With or without treatment, follow-up until the platelet count is within the normal range will avoid missing inherited causes of thrombocytopenia.
Management of Subsequent Pregnancies
Identification of a family at risk for NAIT is critical to help stratify the antenatal management of future pregnancies with the goal of preventing fetal and neonatal ICH. Previous stratification included the sampling of fetal blood to determine antigen expression and platelet count, but given the invasiveness of this procedure and the risks of serious complications, current approaches are based on noninvasive information. Management of subsequent pregnancies should be undertaken by specialists in maternal fetal medicine, when available.
In cases where there is identification of paternal incompatibility, but not active alloimmunization, the recommendation is for heightened screening. These are potential cases of NAIT and crossmatching paternal platelets and maternal serum for anti-HPA antibodies can be serially performed with initiation of therapy if anti-HPA antibodies (rarely) are detected. With certain incompatibilities (i.e., HPA-3a and -b and HPA-9b) antibodies can be very difficult to detect. Clinical judgment in conjunction with the expertise of the laboratory needs to be combined in these cases.
If a previous affected sibling was serologically diagnosed with severe NAIT, the likelihood of the next fetus being affected depends on the father’s platelet typing. If the father is homozygous for the antigen responsible (as is the case in 75% of men with HPA-1A) then essentially all later fetuses will be affected. If the father is heterozygous, or if typing is unavailable or uncertain, PCR testing via amniocentesis or maternal blood can determine whether the fetus is at risk. If the fetus is affected, stratified antenatal therapy should be initiated.
For mothers with previous NAIT pregnancy without ICH, recommended treatment starts later (20 weeks) and is less intensive than for those in which a previous sibling had an ICH (12 weeks). Even if there was no history of ICH, IVIG 1 g/kg/week by itself may not be sufficient treatment.
Neonatal Autoimmune Thrombocytopenia
Neonatal autoimmune thrombocytopenia is due to a passive transfer of autoantibodies from mothers with ITP to their fetus. It may also be seen in association with other conditions such as maternal systemic lupus erythematosus (SLE) and lymphoproliferative states. Neonates born to mothers who have autoimmune thrombocytopenia are typically well after an uncomplicated delivery. Maternal history and platelet counts can help to distinguish auto- from alloimmune thrombocytopenia, but such a distinction can be confusing in the presence of gestational thrombocytopenia (GTP). However, a history of maternal thrombocytopenia during the pregnancy is not diagnostic of maternal ITP. GTP occurs in 5–10% of pregnancies. By definition it is almost always mild (70–100,000/mm 3 ), is not associated with neonatal thrombocytopenia, and the maternal platelet count normalizes after delivery.
Neonatal thrombocytopenia in infants born to mothers with autoimmune thrombocytopenia is usually less severe than that seen in NAIT. Only 10–15% of these newborns have a platelet count less than 50,000/mm 3 . There is a lower risk of bleeding and only rare reports of ICH. The platelet count may be near normal at delivery (e.g., 90,000/mm 3 ), but then fall to a clinically significant nadir over the next 1–3 days.
Table 14.5 lists the pathogenesis and clinical differences between NAIT and autoimmune thrombocytopenia.
| Alloimmune thrombocytopenia | Autoimmune thrombocytopenia | |
|---|---|---|
| Platelet antigens | Antigens found on fetal platelets not present on maternal platelets (usually HPA-1A or HPA-5b) | Antigens common to both maternal and fetal platelets (usually GPIIB/IIIA and GPIb/IX complexes) |
| Platelet count | Often <20,000/mm 3 | Birth counts often >50,000/mm 3 |
| Time of presentation | Birth | Platelet count can be near normal at birth, and then fall |
| Maternal history | Normal platelet count, no history of ITP, SLE, or hypothyroidism, may have GTP (unrelated) | Low platelet counts (unless mother is splenectomized) |
| History of ITP, SLE, hypothyroidism | ||
| Intracranial hemorrhage | 10–20% | <1–2% |
| Treatment | Random donor platelets | IVIG |
| IVIG | +/– Methylprednisolone | |
| +/– Methylprednisolone | Random platelets (if hemorrhage) | |
| Matched platelets | ||
| Resolution of thrombocytopenia | Usually in 2–4 weeks | Usually 3–12 weeks |
Pathophysiology
Neonatal ITP occurs as a result of passive transfer of maternal antibodies across the placenta, as is seen in neonatal alloimmune thrombocytopenia. However, the target of the antibodies is an antigen present on maternal platelets that is also on fetal platelets (in contrast to alloimmune thrombocytopenia, where the antigen is not present on maternal platelets). The most frequently targeted antigens are the GPIIB/IIIA or GPIb/IX complexes. Differences in glycosylation of fetal and maternal platelets may explain mothers with normal or near normal counts having thrombocytopenic neonates. A careful history must be obtained to identify mothers who have previously undergone splenectomy for ITP and may still pass antibodies transplacentally.
Diagnosis
Pregnant women with the following conditions may give birth to a neonate with autoimmune thrombocytopenia:
- •
History of previously affected infant.
- •
Mother who was previously splenectomized for ITP (mother may have platelet antibodies without being thrombocytopenic).
- •
Mother with thrombocytopenia (<100,000/mm 3 ) in current pregnancy especially if the platelet count is <50,000/mm 3 .
- •
Mother with SLE, hypoythyroidism, preeclampsia—HELPP syndrome (hemolytic anemia, elevated liver enzymes, and low platelets).
- •
Maternal drug ingestion (e.g., thiazide).
Treatment
Follow the platelet count (as the initial count may be near normal) until 3–7 days of life to capture nadir and monitor until stable or a rising count to >150,000/mm 3 without intervention. All infants with severe thrombocytopenia should have a head ultrasound to exclude ICH.
Treatment is required when the infant’s platelet count falls below 30,000/mm 3 or if significant bleeding is present. The regimen is similar to that of NAIT, utilizing IVIG and IV methylprednisolone but unrelated donor platelet transfusion is used only if indicated by severe bleeding symptoms or a platelet count that remains <30,000/mm 3 despite maximal care.
The duration of neonatal thrombocytopenia is usually about 3 weeks. If persistent in an infant of a breastfeeding mother, a trial of discontinuation of breastfeeding may be considered. Unlike NAIT, there is no need for maternal treatment during pregnancy except under extraordinary circumstances.
General Diagnostic Approach to a Newborn with Thrombocytopenia
If the maternal platelet count is low, this suggests maternal ITP or another etiology for the maternal thrombocytopenia such as inherited thrombocytopenias. If the maternal platelet count is normal but the mother has had a splenectomy for ITP, the neonatal ITP can still be seen from circulating antiplatelet antibodies. Gestational thrombocytopenia, which complicates up to 10% of all normal deliveries, may have a platelet count as low as 50–70,000/mm 3 but hardly ever results in neonatal thrombocytopenia.
If the platelet count is <50,000/mm 3 on the first day of life in an otherwise normal neonate, NAIT should be considered and appropriate laboratory testing performed; imaging is required based on the platelet count and clinical findings. Platelet transfusion and possibly IVIG should be given. The next most common cause of early severe neonatal thrombocytopenia is a TORCH infection (toxoplasmosis, rubella, cytomegalovirus or herpes virus) which presents as a variably sick newborn with associated fever, microcephaly, IUGR, conjunctivitis, hearing loss, hepatosplenomegaly, or occasionally blueberry muffin rash. If the baby is sick and the platelet count is >50,000/mm 3 , it is likely that the underlying illness (e.g., respiratory distress syndrome, sepsis, DIC) is the cause of the low platelet count and the underlying condition should be treated with the expectation that with the resolution of the underlying illness resolution of the thrombocytopenia will occur.
If there is persistent severe thrombocytopenia, congenital amegakaryocytic thrombocytopenia (CAMT) and other inherited thrombocytopenias should be considered (see Chapter 8 ).
Thrombocytopenia Associated with Hemolytic Disease of Fetus and Neonate
Newborns with severe erythroblastosis frequently develop petechiae and purpura in the first few hours after birth. Thrombocytopenia with red cell alloimmunization may be due to an alloimmune mechanism, decreased production and overlap with known risk factors for thrombocytopenia such as SGA, lower birth weight, and maternal factors (e.g., hypertension/hypoxic-ischemic encephalopathy).
Exchange transfusion, the emergent treatment for hemolytic disease of the newborn, is an independent risk factor for transient thrombocytopenia because of the absence of platelets in stored, reconstituted blood, although this may be balanced somewhat by procoagulant alterations in endogenous thrombin generation from adult blood used for the exchange transfusion.
Thrombocytopenia Secondary to Chronic Fetal Hypoxia, Maternal Diabetes, Pregnancy-Induced Hypertension, or IUGR
Neonatal thrombocytopenia may be caused by chronic intrauterine hypoxia resulting in placental insufficiency in association with pregnancy-induced hypertension, preeclampsia, HELLP ( h emolysis, e levate l iver enzymes, l ow p latelet count) syndrome, maternal diabetes mellitus, and IUGR. These may be due in part to increased platelet destruction, but typically there is impaired megakaryopoiesis and an elevated thrombopoietin level. Neonates can increase the number of megakaryocytes, but not their size, therefore potentially limiting their platelet-producing capability. Thrombocytopenia is usually not severe and is self-limited. The nadir tends to occur around days 3–4 with recovery by days 7–10. Often no treatment is required, but it may be appropriate to treat if there is sufficient asphyxia and thrombocytopenia raising the risk of ICH, in which case platelet transfusions are indicated.
Thrombocytopenia Secondary to Congenital Infections
Perinatal viral, bacterial and fungal infection may present with early- or late-onset thrombocytopenia. Often the presentation may be in an ill neonate with accompanying low birth weight, microcephaly, hepatosplenomegaly, chorioretinitis, and impaired hearing. Infections to consider include: toxoplasmosis, rubella, cytomegalovirus, or herpes simplex (TORCH), group B Streptococcus , Listeria monocytogenes , Escherichia coli , or HIV. Of the TORCH infections, cytomegalovirus (CMV) infection most commonly causes severe thrombocytopenia in 50–77% of affected infants. Thrombocytopenia in early-onset neonatal sepsis can occur because of:
- •
Platelet consumption associated with disseminated intravascular coagulation.
- •
Bacteria, viruses, or immune complexes that adhere to platelets and are cleared by the mononuclear phagocyte system.
- •
Sequestration secondary to hepatosplenomegaly.
- •
Impaired thrombopoiesis—often there is insufficient compensation for platelet destruction or increased platelet clearance. In these infants, thrombocytopenia resolves with effective treatment of the underlying infection.
Late-Onset Thrombocytopenia Secondary to Late-Onset Infections, Necrotizing Enterocolitis, or Thrombosis
Thrombocytopenia occurring at greater than 72 h after birth is more likely to be related to late-onset sepsis, necrotizing enterocolitis (NEC), thrombosis, or liver disease. NEC presents with feeding intolerance, abdominal distension, bloody stools, and pneumatosis. Severe thrombocytopenia, when present, has been associated with poor outcomes.
The causes of this type of thrombocytopenia are varied and often multifactorial including:
- •
Consumption related to infection (as in NEC).
- •
Deficient platelet production.
- •
DIC.
- •
Consumption secondary to thrombosis (e.g., renal vein or hepatic vein thrombosis).
Thrombocytopenia due to Aneuploidy
Thrombocytopenia is common in Down syndrome, occurring in up to 85% of cases. Some of these cases may represent a transient myeloproliferative disorder (TMD). TMD occurs in 10% of trisomy 21 cases and is associated with mutations in the second exon of GATA-1 transcription factor. TMD may present in the first month of life with thrombocytopenia, leukocytosis, hepatosplenomegaly, and hepatic fibrosis from megakaryotic infiltration. The majority of TMD will resolve with observation, but ~30% will progress, often later, to AMKL (see Chapter 19 ). Thrombocytopenia may also be seen in trisomies 13 and 18 and in Turner syndrome and triploidy, in which case other congenital anomalies suggest the diagnosis. In these cases bleeding complications are not frequent and thrombocytopenia may not become obvious for 3–4 days. Other medical problems in these patients far outweigh thrombocytopenia in their importance.
Rare Bone Marrow Disease or Inborn Errors of Metabolism
The following marrow diseases, many relatively rare, may be associated with thrombocytopenia in the newborn:
- •
Osteopetrosis—generalized hyperostosis of bone and obliteration of bone marrow cavity resulting in extramedullary hematopoiesis and pancytopenia.
- •
Metastatic neuroblastoma.
- •
Gaucher disease, often including hypersplenism and other coagulopathies.
- •
Niemann–Pick disease.
- •
Hemophagocytic lymphohistiocytosis (HLH), autosomal recessive, patients present with hepatosplenomegaly, fever, cytopenia, jaundice, tachypnea, hyperferritinemia, hypofibrinogenemia, hypertriglyceridemia, elevated soluble IL-2 receptor and absent NK cell activity.
- •
Congenital leukemia—more commonly with AML. It may be associated with skin infiltrates, hepatosplenomegaly, and megakaryoblasts in the peripheral blood smear. Congenital leukemia carries a poor prognosis unless associated with Down syndrome. Classic “blueberry muffin” rash, which is not actually petechial or purpuric in nature, but rather represents sites of extramedullary hematopoiesis in the skin. These skin lesions may also be seen in other etiologies of bone marrow infiltration and replacement, TORCH infections, or severe hemolysis.
Metabolic Causes
Hyperglycinemia with ketosis and the closely related metabolic disorder of methylmalonic acidemia may cause periodic thrombocytopenia, as well as neutropenia, during infancy. Infants with these metabolic disorders present with lethargy, vomiting, and ketosis during the neonatal period. A similar disorder, isovaleric acidemia , is associated with a “sweaty feet odor” but may present with a generalized marrow hypoplasia causing thrombocytopenia and neutropenia. Thrombocytopenia has been reported in rare infants born with neonatal Graves disease, resulting from maternal transfer of thyroid-stimulating antibodies with associated symptoms of tachycardia, cardiac dysfunction, liver disease, and hepatosplenomegaly.
Vascular Anomalies
Vascular anomalies are heterogeneous disorders involving the skin, subcutaneous tissues, and visceral organs. Current classification divides lesions into proliferative neoplasms and malformations. Included within this classification of proliferative neoplasms are infantile hemangioma, congenital hemangioma, and kaposiform hemagioendothelioma/tufted angioma (previously known as giant capillary hemangioma). Kaposiform hemagioendothelioma, a rapidly proliferating neoplasm, usually presents as a >5 cm red-purple indurated plaque with a pebbled texture and ill-defined margins typically occurring on the lateral neck, axilla, groin, extremities, or trunk. Kaposiform hemagioendothelioma can be associated with high morbidity and mortality secondary to the association with Kasabach–Merritt phenomenon. Infantile hemangiomas, the most common tumor of infancy, are not associated with the complication of Kasabach–Merritt phenomenon.
Kasabach–Merritt phenomenon is a form of localized intravascular microangiopathic anemia presenting with severe thrombocytopenia, hypofibrinogenemia, and elevated fibrin split products or D-dimers in the setting of this proliferative vascular anomaly. Platelet trapping and fibrinogen consumption has been demonstrated through immunohistochemistry and radiolabeling and leads to the consumption of coagulation factors and increased risk for hemorrhage and high-output cardiac failure. MRI imaging of the lesion is used to determine the extent of dermal, lymphatic and muscular involvement as well identifying the arterial supply and venous drainage which may help to direct therapy. CT, x-ray, and ultrasound are of limited utility in determining the extent of the lesion and directing appropriate therapy. Since these vascular anomalies often require time to grow after birth, they may not present until after the first month of life.
Treatment
- 1.
Supportive care with transfusions of platelets and other coagulation factors (e.g., fibrinogen concentrates, fresh frozen plasma, cryoprecipitate, and antifibrinolytic drugs) have only transient effects. These modalities may help with acute management and stabilization in cases of intralesional or systemic bleeding. Prophylactic platelet transfusions are not recommended as they may lead to increased trapping and pain with tumor enlargement. Antiplatelet agents (aspirin, ticlopidine, and clopidogrel) have been used with mixed results. Low-dose heparinization may be useful.
- 2.
Surgical resection, the gold standard for cure, is often difficult given the extent of tumor infiltration and coagulopathy at presentation.
- 3.
Embolization may be an adjunctive therapy to minimize bleeding but is often a temporizing measure that may improve the thrombocytopenia rather than be a curative modality.
- 4.
Radiation therapy is not recommended.
- 5.
Pharmacologic therapy:
- a.
Steroids: Corticosteroids are the most commonly used first-line therapy at high oral doses (2–3 mg/kg/d of oral prednisone) or equivalent intravenous doses. There is limited evidence supporting their effectiveness as a single agent therapy.
- b.
Chemotherapy: Vincristine, a vinca alkaloid and inhibitor of endothelial proliferation has shown successful response in tumor regression. Doses of vincristine 0.05 mg/kg weekly have been used. Barriers to its use include the need for IV access and risk of neurologic side effects. Other reports have looked at cyclophosphamide and actinomycin-D in refractory disease, with less clear data for efficacy, safety, and dosing.
- c.
Interferon α-2a has been shown to be effective. It inhibits angiogenesis, in part by inhibiting the proliferation of endothelial cells, smooth muscle cells, and fibroblasts that have been stimulated by fibroblast growth factor, decreasing collagen production and increasing endothelial prostacyclin production. Despite its efficacy, use of this therapy has been limited due to concerns over its association with spastic diplegia in infants <8 months of age.
- d.
New agents:
- e.
Propranolol, a non-selective beta-blocker, has been used successfully in the management of infantile hemangioma. The proposed mechanism is multifactorial with vasoconstriction, antiangiogenesis, and apoptosis of capillary endothelial cells contributing to the clinical outcome. Isolated case reports have demonstrated successful patient outcomes.
- f.
Sirolimus, an inhibitor of m-TOR, targets antiangiogenesis pathways and results in apoptosis as the proposed mechanism of action. Due to multiple case reports with good outcomes, Sirolimus is currently in an ongoing prospective trial.
- a.
Inherited Thrombocytopenias
Thrombocytopenias due to inherited causes are usually distinguished by characteristic clinical features including family history, platelet morphology, long-term stable low counts, and lack of response to therapies of immune thrombocytopenia, for example, IVIG. Most of the syndromes are associated with ‘‘giant’’ platelets ( Table 14.1 ). In general, the thrombocytopenia is not severe and often there are characteristic features that define each syndrome other than the thrombocytopenia. In certain cases (i.e., Wiskott–Aldrich), bleeding symptoms can be more severe than would be expected by the platelet count alone, due to platelet dysfunction.
Table 14.6 lists the characteristics of congenital thrombocytopenic syndromes.
| Clinical features | TACC | TAR | ATRUS | FA | AMT | HH (DC) | WAS | BS | MH | Trisomies 13, 18, 21 |
|---|---|---|---|---|---|---|---|---|---|---|
| Agenesis of corpus callosum | 1 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
| Hypoplasia of cerebellar vermis | 1 | 2 | 2 | 2 | 2 | 1 | 2 | 2 | 2 | 2 |
| Low birth weight | 1 | 1 | 2 | 1 | 2 | 1 | 2 | 2 | 2 | 1 |
| Growth delay | 1 | 1 | 2 | 1 | 1 | 1 | 2 | 2 | 2 | 1 |
| Dysmorphic face | 1 | 1 | 2 | 1 | 2 | 1 | 2 | 2 | 2 | 1 |
| Developmental delay | 1 | 2 | 2 | 6 | 1 | 1 | 2 | 2 | 2 | 1 |
| Thrombocytopenia | 1 | 1 | 1 | 6 | 1 | 1 | 1 | 1 | 1 | 6 |
| Platelet size | N | N | N | N | N | N | ↓ | ↑ | ↑ | N |
| Pancytopenia | 2 | 2 | 1 | 1 | 6 | 1 | 2 | 2 | 2 | 2 |
| Immunodeficiency | 2 | 2 | 2 | 2 | 2 | 1 | 1 | 2 | 2 | 2 |
| Megakaryocytes, bone marrow | N/↓ | ↓ | ↓ | ↓ | ↓ | ↓ | N/↑ | N/↑ | N/↑ | N/↑ |
| Skeletal deformities | ||||||||||
| Radial x-ray | 2 | 1 | 2 | 6 | 2 | 2 | 2 | 2 | 2 | 2 |
| Clinodactyly/syndactyly | 6 | 2 | 1 | 6 | 2 | 2 | 2 | 2 | 2 | 6 |
| Enamel hypoplasia | 6 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
| Cardiac defects | 6 | 6 | 2 | 6 | 6 | 2 | 2 | 2 | 2 | 6 |
| Renal malformations | 6 | 2 | 2 | 6 | 6 | 2 | 2 | 2 | 2 | 6 |
| Cutaneous abnormalities | 2 | 1 | 2 | 1 | 2 | 1 a | 1 | 2 | 2 | 2 |
| Karyotypic abnormalities | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 1 |
| Chromosome breaks | 2 | 2 | 2 | 1 | 2 | 2 | 2 | 2 | 2 | 2 |
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