INTRODUCTION — This review will discuss the evaluation of purpura in children. The evaluation of bleeding in children and adults is discussed separately. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)
TERMINOLOGY — Bleeding under the skin or into mucosal membranes is called purpura and may be an innocent finding related to mild childhood trauma or may be the presenting sign of a life threatening disease. Purpura can be subdivided based on size into petechiae (picture 1) and ecchymoses (picture 2) [1]. Pinpoint areas (less than 2 mm) of hemorrhage, which are reddish-purple lesions are called petechiae (picture 1), while larger confluent lesions are referred to as ecchymoses (picture 2). Ecchymoses are commonly called bruises. In some cases, ecchymoses may be tender or raised. In contrast to other erythematous or vascular skin lesions, purpuric lesions do not blanch when pressure is applied to the skin.
Careful evaluation of any patient with purpura is important for early diagnosis and treatment, particularly in children who are ill-appearing. The type, location, and extent of the purpura, along with the overall appearance of the child, will help guide the initial evaluation.
CAUSES — Purpura may result from disruptions in vascular integrity (trauma, infection, vasculitis, collagen disorders) or may be due to abnormalities in primary or secondary hemostasis (thrombocytopenia, abnormal platelet function, clotting factor deficiency, or abnormal clotting factor function) [2].
Complex mechanisms maintain vascular integrity and limit the flow of blood when a blood vessel is damaged:
●Vitamin C and other factors that affect collagen synthesis are required for normal formation of connective tissue within the vessel walls. When a blood vessel is injured, vasoconstriction and retraction usually occur immediately and decrease the flow of blood to the affected area.
●Formation of a platelet plug, also referred to as primary hemostasis, is initiated upon injury to a blood vessel wall:
•Circulating platelets recognize subendothelial collagen and von Willebrand factor, and adhere to the injured area.
•Following adhesion to the vascular subendothelium, platelets are rapidly activated, resulting in the release of platelet granules.
•This granule release attracts other circulating platelets, which bind to activated platelets causing platelet aggregation, and the formation of a platelet plug.
●The platelet plug alone is not sufficient, and requires the second phase of hemostasis to form a stable fibrin clot. This second phase is initiated when tissue factor (which is exposed on the endothelial cell after injury) binds to factor VII. This proteolytic TF-VIIa complex activates factor X to Xa and factor IX to IXa, initiating a series of cascading reactions whose central purpose is to generate thrombin from prothrombin (II) at the site of injury. There are multiple coagulation proteins that are necessary for this cascade. Thrombin can then cleave fibrinogen to fibrin, which is cross-linked and forms a clot. These reactions occur on the phospholipid surface of platelets. The coagulation cascade is shown in the figure (figure 1).
DISRUPTIONS IN VASCULAR INTEGRITY
Trauma — Trauma is the most common etiology of purpura in children.
Non-blanching purpura from unintentional trauma vary in size from a few millimeters to several centimeters and are frequently located over extensor surfaces of the lower legs, bony prominences including the knees and elbows, and the forehead. It is not possible to reliably predict the age of an ecchymoses based on its color. However, red, blue, or purple bruises suggest recent lesions. Yellow, brown, or green bruises tend to be older, healing lesions. (See "Physical child abuse: Recognition", section on 'Inflicted bruises'.)
In contrast, the presence of purpura on the face, back, upper arms, or soft tissue areas including buttocks, genitals, and upper thigh may suggest the possibility of intentional trauma. Bruising is the most common presenting feature of physical abuse in children. Other patterns of bruising that are suggestive of non-accidental trauma are listed in the table (table 1). (See "Physical child abuse: Recognition", section on 'Inflicted bruises'.)
Infection — Purpura fulminans (PF) is an acute life-threatening disorder that most commonly occurs following infection with Neisseria meningitidis, but may also occur in association with other infections (eg, varicella, Group A Streptococcus, Streptococcus pneumoniae). It is a result of microvascular thrombosis that leads to tissue necrosis, skin infarction and hemorrhage. Patients with PF are extremely ill-appearing, with fever, hypotension, and bleeding. Laboratory evidence of disseminated intravascular coagulation (DIC) is often present. (See "Clinical manifestations of meningococcal infection", section on 'Purpura fulminans' and "Disseminated intravascular coagulation in infants and children".)
The lesions of PF have a characteristic appearance, which helps to distinguish them from other purpuric lesions. Erythema is followed by central areas of blue or black hemorrhagic necrosis with a surrounding erythematous border (picture 3). The lesions are painful and indurated.
Viral infections, including parvovirus, adenovirus, and enterovirus, and Rickettsial infections have also been associated with the development of purpuric lesions in children. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Hand, foot, and mouth disease and herpangina".)
Immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]) — IgAV (HSP) is the most common cause of vasculitis in children, occurring at a mean age of six years [3]. The clinical manifestations of IgAV (HSP)are due to IgA1 deposition in blood vessel walls and the renal mesangium. Cutaneous purpura is an essential component in the diagnosis of IgAV (HSP) and is characterized by palpable purpuric lesions 2 to 10 mm in diameter that often coalesce (picture 4). The purpura tend to be concentrated on the buttocks and lower extremities. Other clinical manifestations of IgAV (HSP) include arthritis (commonly of the knees and ankles), abdominal pain with or without gastrointestinal bleeding, and nephritis. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)
Drug-induced vasculitis — Numerous drugs have been associated with vasculitis and purpura. These include sulfonamides, penicillins, chloral hydrate, and phenytoin [4]. Drug induced vasculitis usually develops within 7 to 21 days of starting the drug and may be confined to the skin.
Neonatal purpura fulminans — Neonatal purpura fulminans usually occurs on the first day of life and is caused by congenital severe deficiency of protein C or protein S. Affected infants present with ecchymoses, extensive venous and arterial thromboses, laboratory evidence of disseminated intravascular coagulation, and extremely low levels of protein C antigen (less than 1 percent of normal).
Administration of exogenous protein replacement (Protein C concentrate or fresh frozen plasma) appears to be critical for the treatment of neonatal purpura fulminans, while heparin and antiplatelet agents are ineffective. (See "Protein C deficiency", section on 'Neonatal purpura fulminans'.)
Severe acquired deficiency of the anticoagulant proteins, protein C and protein S, may also present with non-infectious purpura fulminans or in association with infectious disseminated intravascular coagulopathy. (See 'Infection' above.)
Vitamin C deficiency — Dietary deficiency of Vitamin C (scurvy) is relatively rare in developed countries. It may occur in individuals with severely restricted diets (anorexia, neurodevelopmental delay, and/or hyperalimentation without vitamin C supplementation). Vitamin C deficiency results in impaired collagen synthesis.
The typical pathologic manifestations of vitamin C deficiency are noted in collagen-containing tissues and in organs and tissues such as skin, cartilage, dentin, osteoid, and capillary blood vessels. Scurvy may present with gum bleeding, petechiae or ecchymoses. In addition, the prominence of hair follicles on the thighs and buttocks and the eruption of coiled, fragmented hair with a characteristic corkscrew appearance are specific features of vitamin C deficiency. Petechiae found on the skin have a characteristic pale halo ring around a central erythematous core (picture 5). These lesions heal rapidly after the administration of vitamin C. (See "Overview of water-soluble vitamins", section on 'Vitamin C (ascorbic acid)'.)
Ehlers-Danlos syndrome — Ehlers-Danlos syndrome (EDS) is the name given to a group of inherited disorders that involve genetic defects in collagen and connective-tissue synthesis and structure. This heterogeneous group is characterized by joint hypermobility, cutaneous fragility, and hyperextensibility. Fragility of dermal skin is common, with frequent bruises and delayed wound healing. In some cases, abnormal blood vessel structure causes capillary hemorrhage.
Pigmented purpuric dermatoses (PPDs) — The PPDs, also known as capillaritis, purpura simplex, and inflammatory purpura without vasculitis, are a group of chronic, benign, cutaneous eruptions characterized by the presence of petechiae, purpura, and increased skin pigmentation. PPDs most commonly occur on the lower extremities and may be asymptomatic or pruritic. The presence of discrete or circumscribed purpuric macules, papules, patches, or plaques (particularly on the lower extremity) with petechiae and yellow-brown pigmentation suggests the possibility of PPDs. The diagnosis is usually made through clinical inspection and the recognition of classic clinical features. A skin biopsy is useful when the diagnosis remains uncertain following clinical examination. Biopsies may help to distinguish PPD from disorders in the differential diagnosis, such as cutaneous vasculitis. There are several different subtypes of PPD, although Schamberg’s disease (picture 6) is the most common. (See "Pigmented purpuric dermatoses (capillaritis)".)
DISORDERS OF HEMOSTASIS
Thrombocytopenia — Conditions that result in decreased platelet number may present with purpura. These conditions may be inherited or acquired. The normal platelet count is >150,000/mm3. In most situations, thrombocytopenia is acquired. In general, patients do not develop bleeding until the platelet count drops below 20,000/mm3, unless there is associated trauma or surgery.
Thrombocytopenia may be a result of increased platelet destruction, decreased platelet production, or sequestration (table 2). Several of the most important causes of purpura due to thrombocytopenia are provided below. The approach to unexplained thrombocytopenia and causes of thrombocytopenia in children are discussed in detail separately. (See "Approach to the child with bleeding symptoms" and "Causes of thrombocytopenia in children".)
Immune thrombocytopenia (ITP) — ITP is one of the most common causes of thrombocytopenia in children. This immune mediated disorder is characterized by the sudden development of petechiae and ecchymoses in an otherwise healthy child, although symptoms may occasionally develop more gradually. Epistaxis occurs in 10 to 20 percent, and although more serious bleeding may occur, it is uncommon. ITP occurs most frequently in children between the ages of one to five years, but also occurs in older children and adults. In young children, the development of ITP is often preceded by a mild viral illness. The diagnosis of ITP is based upon two clinical features:
●Isolated thrombocytopenia, with otherwise normal blood counts and peripheral blood smear
●No clinically apparent associated conditions that may cause thrombocytopenia
(See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)
Hemolytic uremic syndrome (HUS) — HUS is a disease that primarily affects young children and is characterized by the triad of thrombocytopenia, microangiopathic anemia, and acute renal failure. Patients may rarely manifest purpura. HUS can be divided into two forms based upon clinical presentation: Typical HUS is most common and usually follows a prodromal infectious disease, most commonly diarrhea, and less frequently an upper respiratory infection. This syndrome is classically associated with Escherichia coli serotype O157:H7 (see "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children", section on 'Thrombocytopenia'). Atypical HUS is a heterogeneous disorder characterized by the absence of diarrhea. (See "Complement-mediated hemolytic uremic syndrome in children".)
Thrombotic thrombocytopenic purpura (TTP) — TTP is most common in adults but is occasionally seen in children. The classic pentad includes thrombocytopenia, microangiopathic hemolytic anemia, fever, renal dysfunction, and neurologic abnormalities. It is a usually a result of deficiency of the ADAMTS-13 protease, which is responsible for cleaving von Willebrand factor (VWF) multimers. Without this cleavage, ultra large VWF multimers circulate, stimulating microvascular platelet thrombi which cause microangiopathic hemolytic anemia and thrombocytopenia. TTP is most often a result of antibody mediated destruction of ADAMTS-13. However, a rare autosomal recessive inherited deficiency of ADAMTS-13 can cause TTP in young children. (See "Diagnosis of immune TTP" and "Hereditary thrombotic thrombocytopenic purpura (TTP)".)
Disseminated intravascular coagulation — Thrombocytopenia may be an early manifestation of disseminated intravascular coagulation. (See 'Disseminated intravascular coagulation (DIC)' below and "Disseminated intravascular coagulation in infants and children".)
Bone marrow infiltration — Diseases associated with decreased amounts of functional bone marrow also may present with thrombocytopenia and purpura. Most notable in this group in children are acute leukemia and neuroblastoma. In the majority of cases, hematologic abnormalities other than thrombocytopenia are also present (eg, anemia, leukopenia, or leukocytosis), but occasionally a decrease in the platelet count may be the only abnormality. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Laboratory studies' and "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma".)
Neonatal alloimmune thrombocytopenia — Neonatal alloimmune thrombocytopenia (NAIT) occurs when fetal platelets contain an antigen inherited from the father that the mother lacks. The mother forms IgG class antiplatelet antibodies against the "foreign" antigen; these cross the placenta and destroy fetal platelets, resulting in fetal and neonatal thrombocytopenia. Plasma levels of thrombopoietin in these patients are normal because the megakaryocytes and platelets that are produced bind to this growth factor. In contrast to Rh sensitization, NAIT often develops in the first pregnancy of an at-risk couple.
NAIT can result in severe thrombocytopenia in the fetus because platelet antigens form early in gestation and maternal antibodies cross the placenta in early midtrimester. The most serious complication is intracranial hemorrhage, which occurs in approximately 10 to 20 percent of affected newborns; one-quarter to one-half of these occur in utero. The risk of severe thrombocytopenia and intracranial hemorrhage is greater in alloimmune than in autoimmune thrombocytopenia. (See "Neonatal thrombocytopenia: Etiology".)
Inherited thrombocytopenias — True hereditary isolated thrombocytopenia is an extremely rare cause of bleeding. (See "Neonatal thrombocytopenia: Etiology", section on 'Genetic disorders' and "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders'.):
●Congenital amegakaryocytic thrombocytopenia is characterized by severe thrombocytopenia that is present at birth and may be associated with skeletal abnormalities.
●The thrombocytopenia with absent radii (TAR) syndrome has an autosomal recessive inheritance. The thrombocytopenia in TAR is variable in severity, but tends to improve over time.
●Wiskott-Aldrich syndrome is an X-linked recessive disorder characterized by thrombocytopenia, eczema, and immunodeficiency. Infants with Wiskott-Aldrich may present with thrombocytopenic purpura beginning in the newborn period. Shortened platelet survival in this disease comes from an intrinsic platelet abnormality.
●Patients with inherited giant-platelets may have Bernard-Soulier syndrome or one of the MYH-9 related syndromes (May-Hegglin anomaly, Sebastian, Fechtner, or Epstein). The MYH-9 related disorders may be associated with sensorineural hearing loss, glomerulonephritis and cataracts. The bleeding phenotype is variable.
Drug induced thrombocytopenia — Numerous drugs have been reported to cause thrombocytopenia due to the formation of antibodies directed against platelets with resultant increased platelet destruction. The drugs causing immune-mediated thrombocytopenia that are most commonly used in children include sulfa compounds (eg, trimethoprim-sulfamethoxazole), valproic acid, and phenytoin. (See "Drug-induced immune thrombocytopenia".)
Alternatively, drugs may also cause thrombocytopenia as a result of decreased platelet production. Any drug capable of causing general bone marrow suppression can produce thrombocytopenia (eg, carbamazepine, chloramphenicol). Valproic acid causes dose-related suppression of platelet production in addition to sporadic, immune-mediated platelet destruction. (See "Treatment of acquired aplastic anemia in children and adolescents".)
Bone marrow failure — Aplastic anemia (AA) is a rare disorder of hematopoiesis characterized by pancytopenia and bone marrow hypoplasia. The majority of cases are acquired and this appears to be an immune mediated condition. In some patients with the acquired form, AA is preceded by hepatitis, viral infection, or toxin exposure; though there is no identifiable etiologic agent in the majority. Patients with one of the rare, congenital bone marrow failure syndromes (Fanconi's anemia, dyskeratosis congenital, cartilage-hair hypoplasia) often have other abnormalities on physical exam. (See "Treatment of acquired aplastic anemia in children and adolescents", section on 'Classification of severity' and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)
Sequestration — Splenomegaly that comes from numerous causes (eg, portal hypertension, storage diseases) can result in sequestration of platelets and thrombocytopenia. The spleen is markedly enlarged and very firm in these disorders. Purpura that comes from platelet sequestration alone is rare because the platelet count usually does not fall below 40,000/mm3. Bleeding may occur, however, when the platelet sequestration is associated with liver disease and clotting abnormalities. Platelet sequestration and consumption also can occur in large hemangiomas (Kasabach Merritt syndrome).
Platelet function abnormalities — Platelet function disorders may be acquired or inherited; acquired platelet function abnormalities are much more common:
●Acquired – Drugs are the most common cause of acquired platelet dysfunction. Aspirin is the best known of the drugs that cause platelet dysfunction. A single dose of aspirin can irreversibly alter platelet function by blocking the normal pathway of thromboxane-induced platelet aggregation. Nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, have a similar mechanism of action, but the effects are reversible and the disruption of platelet function is less pronounced. Platelet dysfunction also has been associated with antihistamines, serotonin-specific reuptake inhibitors, beta-lactam antibiotics, phenothiazines, valproic acid, and guaifenesin. Myeloproliferative and myelodysplastic syndromes and uremia are other important acquired causes of platelet dysfunction in children. Patients with uremia often develop platelet function abnormalities that may result in purpura (see "Uremic platelet dysfunction"). A more extensive discussion of acquired platelet function abnormalities in children is provided separately. (See "Congenital and acquired disorders of platelet function".)
●Inherited – Inherited platelet function disorders are an uncommon cause of bleeding. There are several disorders which range in severity. The most severe, but also quite rare, are Glanzmann thrombasthenia and Bernard-Soulier syndrome.
In Glanzmann thrombasthenia, the platelet count is normal and there is a deficiency of the glycoprotein IIb/IIIa complex. Bernard-Soulier syndrome results from a deficiency of platelet glycoprotein protein complex GPIb/IX/V, which mediates the initial interaction of platelets to the subendothelial components via the von Willebrand protein. In Bernard-Soulier syndrome the platelet count may be decreased, but, characteristically, the platelets are large, often the size of red blood cells, and may be missed because most automatic counters do not count them as platelets. Both Bernard-Soulier syndrome and Glanzmann thrombasthenia are characterized by life-long bleeding.
Other more common, but less severe, platelet function abnormalities include storage pool defects (eg, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome) or mild secretion defects. (See "Congenital and acquired disorders of platelet function".)
Clotting factor deficiencies — Purpura can be the presenting symptom of a congenital or acquired deficiency of coagulation factors. The most commonly encountered congenital deficiencies are von Willebrand disease, hemophilia A (factor VIII deficiency), and hemophilia B (factor IX deficiency). Although the latter two disorders have an X-linked recessive mode of inheritance, the de novo appearance of coagulopathy is not uncommon, particularly in children with severe hemophilia A (factor VIII activity less than 1 percent). Therefore, a family history of affected males may be helpful in establishing the diagnosis of hemophilia, but the absence of such a history does not eliminate this diagnostic possibility.
Von Willebrand disease (VWD) — VWD is the most common congenital bleeding disorder, present in approximately 1 percent of the population. It is actually a collection of disorders characterized by either quantitative or qualitative abnormalities of von Willebrand factor (vWf). VWD affects males and females equally and is generally inherited as an autosomal dominant trait with variable penetrance. VWD should be suspected in patients with a history of easy bruising, mucous membrane bleeding (epistaxis, heavy menstrual bleeding), or prolonged bleeding after a surgical procedure (eg, post-tooth extraction). In contrast to hemophilia, joint and muscle bleeds are very uncommon in VWD. (See "Clinical presentation and diagnosis of von Willebrand disease".)
Hemophilia — Hemophilia, the most common inherited severe bleeding disorder, is an X-linked disorder that affects males of all ethnic groups. Hemophilia A (deficiency of factor VIII) occurs in approximately 1 in 5000 live male births and is five to six times more common than Hemophilia B (deficiency of factor IX). The severity of hemophilia is classified according to the amount of circulating functional clotting factor:
●Less than 1 percent – Severe disease
●1 to 5 percent – Moderate disease
●Greater than 5 percent – Mild disease
Patients with severe hemophilia experience frequent spontaneous bleeding episodes, in contrast to those with moderate or mild hemophilia in whom trauma or surgery is usually required to provoke hemorrhage. Although bleeding can occur in almost any site, hemarthrosis (intra-articular bleeding) is the most common clinical manifestation, and the ankles, knees, and elbows are most frequently affected.
Children with hemophilia often come to medical attention when they develop purpura either spontaneously or after mild trauma. The ecchymoses in boys with hemophilia are often quite pronounced and palpable for the degree of trauma. The diagnosis of hemophilia should also be entertained in newborns who develop excessive bleeding after circumcision and in infants with prolonged bleeding from lacerations of the lip, tongue, or frenulum. Prompt recognition of the disorder at this early age allows for careful surveillance, appropriate treatment, and early genetic counseling for parents. (See "Clinical manifestations and diagnosis of hemophilia".)
Other congenital factor deficiencies — While VWD and hemophilia A and B represent the majority of inherited bleeding disorders, hereditary deficiencies of other clotting factors may also be encountered. Deficiencies of the following factors result in clinical bleeding: II, V, X, VII, XI, XIII, and fibrinogen. These are all autosomal traits, and are usually symptomatic only in patients with homozygous deficiencies. Most patients with the above deficiencies will have an abnormal PT or aPTT. The diagnosis requires specific factor assays. Patients with factor XIII deficiency will have normal screening tests and can be diagnosed with a factor XIII functional assay that assays clot solubility. (See "Rare inherited coagulation disorders".)
Vitamin K deficiency — Vitamin K is an essential fat-soluble vitamin that is required for the post-translational gamma-carboxylation of several of the clotting factors. The clotting factors that are vitamin K dependent are: II, VII, IX, and X. Deficiency of vitamin K leads to low levels of these clotting factors which may present with purpura or more systemic bleeding. (See "Overview of vitamin K", section on 'Vitamin K deficiency'.)
Hemorrhagic disease of the newborn, with clinical manifestations that range from purpura to intracranial hemorrhage, may occur in infants who do not receive prophylactic vitamin K at birth. This important step in normal newborn care may be overlooked when infants are born at home, or when problems develop in the delivery room and vitamin K is not given. The classic form presents in the first week of life, and the late form presents between two weeks and six months of life. The deficiency is the result of inadequate stores of vitamin K due to maternal deficiency or exclusive breastfeeding. (See "Overview of vitamin K", section on 'Vitamin K-deficient bleeding in newborns and young infants' and "Overview of the routine management of the healthy newborn infant".)
Vitamin K deficiency may occur in older children with malabsorption or chronic diarrhea. Ingestion of warfarin or long-acting superwarfarin rat poisons (eg, brodifacoum), which interferes with the metabolism of vitamin K, may also present with purpura.
Liver disease — The majority of clotting factors are produced in the liver. As a result, impaired hepatic synthesis, due to either inherited or acquired liver dysfunction may lead to a coagulopathy and purpura.
Disseminated intravascular coagulation (DIC) — DIC is a complex consumptive coagulopathy that is characterized by diffuse intravascular activation of coagulation resulting in thrombocytopenia and clotting factor deficiencies. It is associated with a variety of infectious and noninfectious disease states (table 3).
Thrombocytopenia from shortened platelet survival may occur due to fibrin deposition and platelet consumption. In addition, the intravascular consumption of clotting factors may cause purpura because of factor depletion and, in severe cases, may lead to widespread, rapidly progressing purpuric lesions (purpura fulminans) associated with thrombosis or emboli.
Infections are the most common cause of DIC in children (table 3). Although other signs of serious illness are usually present in the child with purpura caused by DIC, fever and purpura may be the only significant findings in the early stages of severe bacterial infections such as meningococcemia. Further investigations and appropriate therapy should proceed rapidly in such instances. (See 'Infection' above and 'Disseminated intravascular coagulation' above.)
EVALUATION — The evaluation of a child with purpura must combine speed and skill. Purpura can be the initial sign of a life threatening meningococcal infection, requiring immediate treatment, or the first sign of child abuse, requiring patient, thorough investigation. The initial approach should be dictated by the general appearance of the child and the presenting vital signs. A well-appearing child with purpura and normal vital signs can be approached with less urgency than a febrile, lethargic child with purpura.
History — By taking into account the patient's age, sex, clinical presentation, past medical history, and family history, the most likely causes of purpura can usually be determined.
●Fever – Serious infection is an important cause of purpura in children and is usually associated with fever.
●Age of patient – Severe congenital bleeding disorders usually present in the first year of life.
●Sex of patient – Hemophilia is X-linked and only affects males (with rare-exception). Von Willebrand is autosomal dominant and is seen with equal frequency in boys and girls.
●Onset of symptoms – The patient's recent and past medical history should be reviewed carefully with the parents and child. Acute onset of purpura after a recent viral illness or immunization is consistent with an acquired disorder such as ITP. Recurrent purpura since infancy, however, suggests an inherited abnormality of platelets or clotting factors.
●Location and type of purpura – The site and type of bleeding manifestation may be helpful in establishing the alteration in the hemostatic mechanisms (table 4). Petechiae are most commonly seen in patients with thrombocytopenia and platelet disorders, mucosal bleeding (heavy menstrual bleeding, epistaxis) is common in platelet disorders and von Willebrand disease, and bleeding into the joints (hemarthroses) is common in patients with hemophilia.
●Prior bleeding history – Specific inquiries about past surgeries (including circumcision), dental extractions, or significant trauma should be made because the absence of bleeding under these conditions would be unusual in most inherited disorders of even moderate severity. When previous bleeding has occurred, the site of bleeding may be helpful in establishing the alteration in the hemostatic mechanisms.
●Family history of bleeding – The family history should be reviewed for purpura or bleeding disorders. A positive family history in male relatives on the maternal side suggests factor VIII or factor IX deficiency. A history of bleeding or bruising in numerous family members of both sexes suggests a condition with dominant inheritance such as von Willebrand's disease. As noted earlier, however, a negative family history does not preclude the diagnosis of von Willebrand disease or hemophilia. (See "Clinical manifestations and diagnosis of hemophilia" and "Clinical presentation and diagnosis of von Willebrand disease".)
●Recent medications – The clinician should note exposure to aspirin and other drugs known to affect platelet function. (See 'Drug induced thrombocytopenia' above.)
●Exploratory or intentional overdose of prescription anticoagulant or rat poison (warfarin or superwarfarin) ingestion – In general, oral intake of small amounts of rat poison (eg, single handful of superwarfarin product) or prescription anticoagulant would be unlikely to result in purpura. Thus, patients with purpura in whom these ingestions are confirmed have likely had a large ingestion. (See 'Vitamin K deficiency' above and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Superwarfarin poisoning'.)
●Dietary history – Patients with severe malnutrition or restricted diets may be at risk for scurvy or vitamin K deficiency.
●Past medical history – Patients with underlying conditions such as uremia, hepatic disease, congenital heart disease, and malabsorption are predisposed to a coagulopathy that may present with purpura and bleeding.
Physical examination
●General examination – The overall appearance of a child will help guide further management. Patients who have purpuric lesions and are ill-appearing and/or hemodynamically unstable need to be rapidly assessed to determine the underlying etiology. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)
●Skin – The child should be examined carefully to assist in the diagnosis of the specific bleeding disorder and to evaluate hidden areas of hemorrhage. The distribution and size of purpura should be noted. It is not possible to reliably predict the age of an ecchymoses based on its color. However, red, blue, or purple bruises suggest recent lesions. Yellow, brown, or green bruises tend to be older, healing lesions [5]. Ecchymotic lesions may take weeks to resolve.
Petechiae indicate disorders associated with thrombocytopenia or platelet dysfunction. Clotting disorders typically cause mucosal bleeding or ecchymoses without petechiae (table 4).
Bruising in a recognizable pattern, such as a loop mark (picture 7 and picture 8), ligature mark, belt or hand print (picture 9), indicates child abuse. Bruises in multiple stages of healing in areas atypical for unintentional trauma are also suspicious (picture 10). (See "Physical child abuse: Recognition", section on 'Inflicted bruises'.)
Purpura localized to the lower body (buttocks, legs, ankles), with or without joint swelling in the hands or feet, suggests immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]).
●Lymph nodes – Lymphadenopathy may be present in certain malignancies (leukemias) or viral infections (infectious mononucleosis, CMV) that can present with purpura.
●Abdominal examination – Hepatomegaly may signal an underlying hepatic disorder or leukemia.
Splenomegaly can be seen in infectious mononucleosis, leukemia, hepatic disease, and the storage diseases.
●Extremities and joints – Inflammation or synovial thickening of the large joints is consistent with the hemarthroses seen in hemophilia or the swollen, painful joints associated with IgAV (HSP).
●Neurologic evaluation – Complete neurologic assessment is mandatory when there is suspicion of head trauma in the face of a bleeding diathesis. The eyes should be examined for the presence of conjunctival, scleral, or retinal hemorrhage.
Laboratory evaluation — Initial screening tests in a patient with purpura should include [6]:
●Complete blood count (CBC), including a platelet count and a peripheral smear
●Prothrombin time (PT) with an international normalized ratio (INR)
●Activated partial thromboplastin time (aPTT)
The CBC establishes abnormalities in platelet number, the presence of abnormalities in other hematologic cell lines (eg, anemia, leukopenia), and provides evidence for intravascular hemolysis. The PT tests the extrinsic clotting pathway (factors VII, IX, II, X, V, fibrinogen). The aPTT tests the intrinsic pathway (factors HWMK, kallikrein, XII, XI, IX, VIII, II, X, V, fibrinogen) (figure 1). Details of testing, including nonmedical causes for abnormal results, are discussed separately. (See "Clinical use of coagulation tests" and "Approach to the child with bleeding symptoms", section on 'Initial laboratory evaluation'.)
The bleeding time is not routinely recommended in children. It is subject to significant variation based on the experience of the technician and cooperation of the patient.
In patients with a suspected bleeding disorder, discriminating laboratory studies should be obtained based on the results of the initial screening tests and the clinical setting (table 5):
●Thrombocytopenia:
•Inspection of blood smear (screening for bone marrow diseases, platelet size and platelet clumping)
•Mean platelet volume (elevated in destructive causes, low in Wiskott-Aldrich syndrome)
•Bone marrow aspiration (in cases where malignancy or bone marrow failure is suspected)
●PT and aPTT prolonged and thrombocytopenia (suspect DIC):
•Fibrinogen
•D-dimer or fibrin split products
•Peripheral smear inspection for RBC fragments (schistocytes)
●Prolonged PT and aPTT with normal platelet count:
•Factor assays: II (prothrombin), V, VII, VIII and fibrinogen to help distinguish between hepatic dysfunction and vitamin K deficiency
•Hepatic enzymes and serum albumin to assess hepatic function
●Prolonged aPTT only:
•Inhibitor screen (50:50 mixing study of patient's and normal plasma)
•If aPTT fully corrects:
Specific factors: VIII, IX, XI, XII, VW Ag, VW Activity
•If partial or no correction after mixing study:
Inhibitor is present
Confirmatory test for the presence of a lupus anticoagulant
●Prolonged PT only:
•Factor VII level
●Initial CBC, smear, PT, and aPTT normal:
•Qualitative platelet defect suspected. There is controversy regarding the usefulness of the PFA-100, a screening assay for platelet function. If a platelet defect is strongly suspected, consider platelet aggregometry. (See "Platelet function testing", section on 'Platelet aggregometry'.)
•von Willebrand disease (VWD) suspected. The clinician should obtain factor VIII, von Willebrand factor antigen and von Willebrand factor activity. If the VW antigen or activity are low, vWf multimeric analysis should be performed to aid in subtype determination. The normal ranges of these tests depend on the patient's ABO blood group type; values fluctuate over time and may periodically be normal in affected individuals. Thus, diagnosis may require repeated testing to make the diagnosis. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Laboratory testing'.)
DIAGNOSTIC APPROACH — A systematic approach to the evaluation of a child with purpura helps guide the workup and identify the appropriate treatment (algorithm 1).
Appears ill — Children with purpura who are ill-appearing or febrile require rapid evaluation and treatment for serious hemorrhage, disseminated intravascular coagulopathy, or infection. Patients with abnormal vital signs warrant emergent attention and stabilization of the airway, breathing, and circulation. (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)", section on 'Resuscitation' and "Physical child abuse: Diagnostic evaluation and management" and "Trauma management: Approach to the unstable child".)
A directed history, physical exam, and pertinent laboratory studies should target likely underlying etiologies including serious trauma, child abuse, and bacterial sepsis (meningococcemia). Empiric antibiotic treatment is usually warranted. (See "Physical child abuse: Diagnostic evaluation and management" and "Trauma management: Approach to the unstable child" and "Septic shock in children: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric antibiotic therapy'.)
Fibrinogen, D-dimer or fibrin split products (FSP), peripheral smear, and liver testing (albumin and liver enzymes) should be performed in addition to screening coagulation studies (CBC, PT, aPTT). (See 'Laboratory evaluation' above.)
Appears well — Well-appearing children with purpura should undergo a detailed history, physical examination, and screening coagulation studies (CBC, PT, aPTT) to establish the most likely diagnosis.
Thrombocytopenia — Children with severe, isolated thrombocytopenia (PT, aPTT normal) who are well-appearing and previously healthy with physical exam abnormalities consisting solely of petechiae and/or ecchymoses, usually have immune-mediated thrombocytopenia (ITP). (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)
Other causes of thrombocytopenia are suggested by the clinical setting:
●Young infants with thrombocytopenia may have an inherited thrombocytopenia or alloimmune thrombocytopenia due to maternal antibodies.
●Patients with thrombocytopenia and other abnormalities on CBC (eg, anemia, leukopenia) may have malignancy (leukemia, neuroblastoma), bone marrow failure (congenital or acquired), hemolytic-uremic syndrome (HUS), or thrombotic thrombocytopenic purpura (TTP).
●Children with thrombocytopenia and evidence for microangiopathic hemolytic anemia (eg, schistocytes on peripheral blood smear) may have HUS or TTP.
Normal platelet count, abnormal PT or aPTT — Patients with purpura and abnormal initial coagulation tests require further investigation to determine the etiology of the abnormal PT or aPTT. (See 'Laboratory evaluation' above and "Clinical use of coagulation tests" and "Approach to the child with bleeding symptoms", section on 'Initial laboratory evaluation'.)
Normal platelet count, PT, and aPTT — Children in whom trauma (unintentional or intentional) is the primary etiology of purpura will have normal screening tests in the absence of massive hemorrhage or transfusion. Petechiae are unusual as a primary presentation of trauma except in traumatic asphyxia. These screening tests are also usually normal in patients with vascular causes of purpura. (See "Physical child abuse: Recognition", section on 'Inflicted bruises'.)
In addition, some patients with von Willebrand disease or platelet function disorders will have normal screening tests. Further laboratory studies (platelet aggregation testing and von Willebrand testing) is often necessary to diagnose these conditions. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Congenital and acquired disorders of platelet function".)
SUMMARY AND RECOMMENDATIONS
●Purpura may result from disruptions in vascular integrity (trauma, infection, vasculitis, collagen disorders) or due to abnormalities in primary or secondary hemostasis (thrombocytopenia, abnormal platelet function, or clotting factor deficiency). (See 'Disruptions in vascular integrity' above and 'Disorders of hemostasis' above.)
●The initial approach should be dictated by the general appearance of the child and the presenting vital signs. The patient's age, sex, clinical presentation, past medical history, and family history usually determine the most likely cause. The site and type of bleeding manifestation may also help establish the alteration in the hemostatic mechanisms (table 4). (See 'Evaluation' above.)
●Initial screening tests in a child with purpura should include the following (see 'Laboratory evaluation' above):
•Complete blood count with a peripheral smear
•Prothrombin time (PT) with an international normalized ratio (INR)
•Activated partial thromboplastin time (aPTT)
In patients with a suspected bleeding disorder, discriminating laboratory studies should be obtained based upon the results of the initial screening tests and the clinical setting (table 5).
●A systematic approach to the evaluation of a child with purpura helps guide the work-up and identify the appropriate treatment (algorithm 1):
•Children with purpura who are ill-appearing or febrile require rapid evaluation and treatment for serious hemorrhage, disseminated intravascular coagulopathy, or infection. Patients with abnormal vital signs warrant emergent attention and stabilization of the airway, breathing, and circulation. A directed history, physical exam, and pertinent laboratory studies should target likely underlying etiologies including serious trauma, child abuse, and bacterial sepsis (meningococcemia). Empiric antibiotic treatment is usually warranted. (See 'Appears ill' above.)
•Well-appearing children with purpura should undergo a detailed history, physical examination, and screening coagulation studies (CBC, PT, aPTT) to establish the most likely diagnosis. (See 'Appears well' above.)
