Bleeding and Purpura
Kim Smith-Whitley
INTRODUCTION
Purpura, that is, petechiae and ecchymoses (bruises), and excessive bleeding are caused by disruptions in one or more of the three stages of normal hemostasis:
Vascular phase— vasoconstriction
Primary hemostasis— platelet plug formation
Secondary hemostasis— fibrin thrombus formation
Disruptions in vascular integrity are characterized by purpuric lesions; laboratory tests demonstrate normal platelet number and function as well as normal coagulation. Disorders of primary hemostasis are also characterized by purpuric lesions, but laboratory test results are not normal. Disorders of secondary hemostasis are characterized by hemarthroses and deep bleeding and abnormal coagulation studies. Unexplained excessive bruising and bleeding occurring in children with normal hemostasis requires a thorough investigation for nonaccidental trauma.
DIFFERENTIAL DIAGNOSIS LISTThrombocytopenia Increased Platelet Destruction
Immune-Mediated Thrombocytopenia
Idiopathic (immune) thrombocytopenic purpura (ITP)
Evans syndrome
Autoimmune lymphoproliferative syndrome
Neonatal, isoimmune, and autoimmune
Posttransfusion purpura
Drug related
HIV infection
Systemic lupus erythematosus (SLE)
Microangiopathic Process
Hemolytic uremic syndrome
Disseminated intravascular coagulation (DIC)
Thrombotic thrombocytopenic purpura
Decreased Platelet Production
Congenital amegakaryocytic thrombocytopenia
Thrombocytopenia with absent radii
Inherited bone marrow failure syndromes (Fanconi anemia, dyskeratosis congenital, cartilage-hair hypoplasia)
Aplastic anemia
Vitamin B12 or folate deficiency
Viral infection—varicella-zoster virus, measles virus, rubella, cytomegalovirus, Epstein-Barr virus
Drugs
Bone Marrow Infiltration
Leukemia
Malignancy metastatic to bone marrow
Myelofibrosis
Storage diseases
Osteopetrosis
Platelet Sequestration
Splenomegaly
Large hemangiomas (Kasabach-Merritt syndrome)
Disorders of Platelet Function
Bernard-Soulier disease
Glanzmann thrombasthenia
Wiskott-Aldrich syndrome
May-Hegglin anomaly
Platelet granule defects
Drug-induced abnormalities (e.g., aspirin, ibuprofen)
Uremia
Disruption in Vascular Integrity
Trauma (accidental or nonaccidental)
Henoch-Schönlein purpura (HSP)
Telangiectasia syndromes
Drug-induced vasculitis
Purpura fulminans
Bacterial (e.g., Neisseria meningitidis, streptococcal toxins)
Viral (e.g., measles, influenza)
Rickettsial—Rocky Mountain spotted fever
Parasitic—malaria
Connective tissue disorders
Ehlers-Danlos syndrome
Osteogenesis imperfecta
Vitamin C deficiency
Clotting Factor Deficiencies
von Willebrand disease (vWD)
Hemophilia—factor VIII or IX deficiency
Other congenital factor deficiencies
Vitamin K deficiency
Liver disease
Disseminated intravascular hemolysis
Anticoagulants (heparin, warfarin)
DIFFERENTIAL DIAGNOSIS DISCUSSION I: BLEEDING AND PURPURA IN CHILDREN
Idiopathic (Immune) Thrombocytopenic Purpura
ITP, the most common cause of low platelet counts in childhood, can be categorized as newly diagnosed (thrombocytopenia resolves within 3 months of diagnosis), persistent (thrombocytopenia for 3 to 12 months), or chronic (thrombocytopenia for >12 months). Although ITP can occur at any age, the peak incidence in children is between the ages of 2 and 6 years. The most recent definitions of ITP use a platelet count of less than 100 × 103/µL (100 × 109/L). Primary ITP occurs in situations where the cause of thrombocytopenia is not known and secondary ITP when the cause of thrombocytopenia is known.
Etiology
The exact cause of primary ITP is unknown, but the disorder is thought to be due to immune-mediated destruction of platelets. Although the stimulus inciting this immunologic response is often not known, in children, a viral illness may precede the signs and symptoms of ITP.
Clinical Features
Children with ITP appear otherwise well but have rapid onset of purpuric lesions. They rarely have signs and symptoms of significant bleeding such as intracranial hemorrhage, but epistaxis occurs in about a third of patients. Clinical findings of lymphadenopathy and hepatosplenomegaly should alert the physician to a diagnosis other than ITP (e.g., malignancy, metabolic disorder).
Evaluation
A complete blood count (CBC) often demonstrates isolated thrombocytopenia. Hemoglobin values may be low due to significant blood loss or immune-mediated red cell destruction. Additional laboratory studies (depending on the situation) should include a direct antibody test (DAT) and a reticulocyte count. The peripheral blood smear may demonstrate large platelets, but prominent schistocytes or immature lymphocytes should lead the physician to consider other diagnoses such as thrombotic thrombocytopenic purpura or acute leukemia. Other causes of thrombocytopenia (e.g., SLE) should be considered, particularly in adolescent girls. Immunoglobulin levels should be performed when common variable immune deficiency is suspected.
HINT: Evans syndrome (autoimmune hemolytic anemia with immunemediated thrombocytopenia) should be suspected in patients with thrombocytopenia and anemia. Patients with Evans syndrome have a positive DAT, evidence of hemolysis, and usually require more intensive intervention than those with ITP alone.Routine bone marrow aspiration to evaluate acute ITP is usually not necessary. Increased platelet precursors (megakaryocytes) are often present on histologic examination of bone marrow aspirate in patients with ITP.
Treatment
Many believe that treating patients with newly diagnosed ITP and isolated skin manifestations (petechiae and bruising) is unnecessary as the disease process often will resolve over a short period of time without major sequelae. However, if a child experiences significant bleeding such as prolonged epistaxis, treatment is warranted. Treatment options include intravenous immunoglobulin (IVIG) (800 to 1,000 mg/kg), steroids (2 mg/kg/day), and, in Rh-positive children, anti-D immune globulin (50 to 75 µg/kg). Rapidity of response and drug side effects should be considered when considering therapeutic options. IVIG or anti-D immune globulin administration may be associated with a more rapid increase in platelet count than steroid therapy. However, aseptic meningitis has been associated with IVIG and significant intravascular hemolysis with anti-D immune globulin. Anti-D administration should be avoided in children with severe anemia, evidence of immune-mediated red cell destruction such as a positive DAT, those who are Rh-negative, and those with a history of splenectomy. The Food and Drug Administration recommends close monitoring for hemolysis in all patients
treated with anti-D immune globulin. If steroids are initiated, they should be tapered as quickly as possible to avoid long-term side effects. In situations where a patient with known ITP requires therapy, it is best to use whatever therapy has been beneficial for that patient in the past.
treated with anti-D immune globulin. If steroids are initiated, they should be tapered as quickly as possible to avoid long-term side effects. In situations where a patient with known ITP requires therapy, it is best to use whatever therapy has been beneficial for that patient in the past.
TABLE 18-1 Causes of Disseminated Intravascular Coagulation (DIC) | ||||||||||||||
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Intracranial hemorrhage and life-threatening hemorrhage, although rare in patients with ITP, may be fatal. Therefore, treatment is mandatory if the ITP patient has major head trauma, abnormal neurologic examination, or copious blood loss. High-dose steroid therapy with IVIG administration should be initiated rapidly before more detailed evaluations. In patients with ongoing lifethreatening bleeding, continuous platelet transfusions, emergent splenectomy, or both may be necessary.
Disseminated Intravascular Coagulation
Etiology
DIC is a consumptive coagulopathy characterized by intravascular coagulation and fibrinolysis resulting in clotting factor deficiencies and thrombocytopenia in association with an underlying disease (Table 18-1).
HINT: Sepsis should be considered an etiology for any critically ill child until proven otherwise.Clinical Features
Children with DIC usually appear ill and bleed from multiple sites. In neonates, DIC usually manifests as gastrointestinal bleeding or oozing from skin puncture sites.
Evaluation
In patients with DIC, laboratory values show a normal or decreased platelet count, increased prothrombin time (PT) and partial thromboplastin time (PTT), decreased fibrinogen, and increased fibrin split products or D-dimer levels. A peripheral blood smear is significant for schistocytes, fragmented red blood cells, and normal or decreased platelets.
Treatment
Treatment is directed toward managing the underlying disorder and replacing coagulation factors and platelets.
Henoch-Schönlein Purpura
Etiology
HSP is an acquired inflammatory small-vessel vasculitis due to immunoglobulin A subclass 1 (IgA1), C3 and immune complex deposition in blood vessel walls and the renal mesangium. HSP is most common in early childhood and often is a self-limited benign illness.
Clinical Features
Diffuse inflammation of the small vessels causes abdominal pain, joint pain or arthritis, and palpable purpura. Renal involvement occurs in 50% of patients. Most patients have a prodromal upper respiratory infection 1 to 3 weeks before the onset of illness. The hallmark of this disorder on physical examination is a symmetric pattern of purpura, primarily involving the buttocks and lower extremities. In some patients, purpura are also found on the extensor surfaces of the arms but the palms and soles are spared.
Evaluation
Hematuria, proteinuria, and cellular casts on urinalysis confirm nephritis in patients with HSP. The CBC, PT, and PTT are normal unless major gastrointestinal blood loss has occurred, in which case the patient may be anemic.
Treatment
HSP, a self-limited disorder, usually resolves in 1 to 6 weeks. Treatment primarily involves supportive therapy. Corticosteroids, used to manage renal complications, may be helpful to alleviate persistent or severe gastrointestinal and musculoskeletal symptoms but should be used cautiously in patients with suspected renal insufficiency.
Von Willebrand Disease
Etiology
vWD, the most common inherited bleeding disorder, is characterized by quantitative or qualitative abnormalities in von Willebrand factor (vWF). Patients with vWD can be classified as having type 1, type 2, and type 3 vWD, according to the clinical history and laboratory test results. Type 1, occurring in approximately 65% to 80% of vWD patients, is due to a quantitative decrease in vWF and is inherited in an autosomal dominant fashion with variable penetrance. Type 2, occurring in 15% to 20% of patients, is due to a qualitative change in vWF and is inherited in an autosomal dominant or recessive pattern. Type 3 (autosomal recessive) is a rare and more severe bleeding disorder in which vWF levels and factor VIII:coagulant (factor VIII:C) are significantly decreased.
Clinical Features
Evaluation
Screening coagulation studies may demonstrate a prolonged PTT, although this may be normal in patients with mild vWD. Specific laboratory studies for vWD include vWF activity (ristocetin cofactor), factor VIII-related antigen (vWF), and factor VIII:C evaluation. Patients with vWD may have decreased factor VIII:C activity, decreased vWF, decreased ristocetin cofactor, or a combination of the three findings (see section on “Etiology”).
Treatment
Multiple treatment options are available for patients with vWD, depending on the type of vWD and the reason for treatment. Desmopressin acetate, an analog of vasopressin, is often used to treat or prevent bleeding episodes in patients with type 1 vWD, although its use is controversial in patients with type 2B and platelettype vWD. Type 2B and type 3 patients can receive factor VIII concentrate with retained vWF activity, and those with the rare platelet-type vWD may need platelet transfusions, depending on their past experience with blood products.
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