Ecchymosisek-i-mbcsis A purplish patch caused by extravasation of blood into the skin, differing from petechiae only in size (larger than 3 mm diameter).Purpura p\rcpa-r^ A condition characterized by hemorrhage into the skin. Appearance of the lesions varies with the type of purpura, the duration of the lesions, and the acuteness of the onset. The color is first red, gradually darkens to purple, fades to a brownish yellow, and usually disappears in 2 or 3 weeks; color of residual permanent pigmentation depends largely on the type of unabsorbed pigment of the extravasated blood; extravasations may occur also into the mucous membranes and internal organs. Syn: peliosis.petechiae, sing. Petechia pe-tTckT-T, pT-tekc-; pe-tTckT-^ Minute hemorrhagic spots, of pinpoint to pinhead size, in the skin, which are not blanched by diascopy.Hematoma hT-m^-tbcm^, hem-^- A localized mass of extravasated blood that is relatively or completely confined within an organ or tissue, a space, or a potential space; the blood is usually clotted (or partly clotted), and, depending on how long it has been there, may manifest various degrees of organization and decolorization.Bruise braz An injury producing a hematoma or diffuse extravasation of blood without rupture of the skin.Pada kemerahan pada kulit terdapat 3 kemungkinan, eritema, purpura, atau telangiektasis. Cara membedakannya dengan menekannya. Eritema warna kemerahan akan hilang dan warna kemerahan akan kembali setelah jari dilepaskan karena kembali setelah jari dilepaskan karena terjadi vasodilatasi kapiler. Purpura tidak bisa menghilang sebab terjadi perdarahan di kulit, telangiektasis tidak bisa menghilang karena terjadi pelebaran kapiler yang menetapReticulocyte re-tikcya-lb-sUt A young red blood cell with a network of precipitated basophilic substance representing residual polyribosomes, and occurring during the process of active blood regeneration. See Also: erythroblast. Syn: reticulated corpuscle, skein cell.Idiopathic Thrombocytopenic Purpura Acquired immune deficiency syndrome evaluation battery, Diagnostic (for HIV antibody)

Bleeding time, Duke, Blood

Bleeding time, Ivy, Blood

Bone marrow aspiration analysis, Diagnostic

Capillary fragility test, Diagnostic

Complete blood count, Blood

Computed tomography of the body (Spleen), Diagnostic

Differential leukocyte count, Peripheral blood

Histopathology, Specimen

Mean platelet volume, Blood

Platelet antibody, Blood

Platelet count, Blood

Red blood cell, Blood

Reticulocyte CountBlood Norm. Constitutes 1%2% of the total RBC count.SI Units

Adult females0.5%2.5%0.0050.025 10-3

Adult males0.5%1.5%0.0050.015 10-3

Cord blood3.0%7.0%0.0300.070 10-3

Newborn1.1%4.5%0.0110.045 10-3

Neonates0.1%1.5%0.0010.015 10-3

Infants0.5%3.1%0.0050.031 10-3

Children >6 months0.5%4.0%0.0050.040 10-3

Immature reticulocyte fraction (IRF)0.13%0.31%0.0010.004 10-3

Increased Total Reticulocyte Count. Acquired autoimmune hemolytic anemia, Di Guglielmo's disease, erythemic myelosis (chronic), erythroblastosis fetalis, hemolytic anemias, hemoglobin C disease, hemorrhage (chronic), hereditary spherocytosis, infants, leukemia, malaria, metastatic carcinoma, myxoma of left heart atrium, paroxysmal nocturnal hemoglobinuria, polycythemia, posthemorrhagic anemia (acute), pregnancy, sickle cell disease, thalassemia major, thrombotic thrombocytopenic purpura, transfusion therapy, treatment of iron-deficiency anemia, vitamin B12 deficiency, or folic acid deficiency.Increased Immature Reticulocyte Fraction. Anemia (hemolytic), blood loss, bone marrow regeneration, folic acid/folate deficiency, iron deficiency, myelodysplasia, and thalassemia.Decreased Total Reticulocyte Count. Alcoholism, anemia (aplastic, hemolytic [aplastic crisis], iron deficiency, megaloblastic, pernicious, pure red cell), anoxia, aregenerative crisis, blood loss, bone marrow regeneration, chronic infection, myxedema, and radiation therapy. Drugs include carbamazepine and chloramphenicol.Children 1 episode of rejection treatment and who have mild or moderate RSV pneumonia. Evidence-based documentation for treatment of other groups of clients is lacking.Description. Reticulocytes are nonnucleated red blood cells containing a basophilic network of granules or filaments characteristic of an immature cell of the erythrocyte class. Formed in the bone marrow, reticulocytes reach maturity after 1 day in the circulating blood and are an index of bone marrow function. The reticulocyte count is the number of reticulocytes per 1000 erythrocytes and is significant only when reported as a percentage of the total number of erythrocytes. This test helps differentiate bone marrow depression from anemias, hemorrhage, hemolysis, or radiation, and helps evaluate bone marrow activity and response to therapeutic interventions. Some test results include an immature reticulocyte fraction (IRF), determined by the staining abilities of the reticulocytes. Young reticulocytes have a higher degree of RNA staining. Higher than normal amounts of immature reticulocytes can indicate conditions in which there is more red blood cell production, such as after erythropoietin administration. The IRF is also useful in detecting new or increasing erythropoiesis after bone marrow or stem cell transplant.Abnormalities of Platelet Number or FunctionThrombocytopenia in the pediatric age range is often immune-mediated (eg, idiopathic thrombocytopenic purpura, neonatal auto- or alloimmune thrombocytopenia, heparin-induced thrombocytopenia), but is also caused by consumptive coagulopathy (eg, DIC, Kasabach-Merritt syndrome), acute leukemias, rare disorders such as Wiskott-Aldrich syndrome and type IIb von Willebrand disease, and artifactually in automated cytometers (eg, Bernard-Soulier syndrome), where giant forms may not be enumerated as platelets by automated cell counters.Platelet AntibodyBlood Norm. Negative or 38.3 degrees C).

3. Results are normally available within 24 hours.

Factors That Affect Results 1. A uniform incision is difficult to make without considerable skill.

2. Pressing too hard on the blood with the filter paper disturbs the platelet plug and prolongs bleeding time.

Other Data 1. The depth of the puncture with the lancet is difficult to standardize and results in difficulty reproducing bleeding times.

2. Healthy pregnant women given 75 mg of aspirin for 2 weeks have an increased bleeding time by Ivy tests.

3. Nitric oxide does not affect IV bleeding time.

Bone Marrow Aspiration AnalysisSpecimen (Biopsy, Bone Marrow Iron Stain, Iron Stain, Bone Marrow) Norm. Red marrow contains connective tissue, fat cells, and hematopoietic cells. Yellow marrow contains connective tissue and fat cells. Interpretation of cell count and histopathology by a hematologist, pathologist, or oncologist is required.Response to Staining. Iron stain for hemosiderin: 2+.Periodic AcidSchiff (PAS) Glycogen Reactions. Negative.Sudan Black B (SBB) Granulocyte. Negative.Differential Cell Count Adult (%)Child (%)Infant (%)

Basophils0.10.060.07

Eosinophils3.13.62.6

Hemocytoblasts0.11.0

Lymphocytes (all stages)2.7241649

Megakaryocytes0.030.50.10.05

Plasmacytes0.11.50.40.02

Promyelocytes0.58.01.40.76

Reticulum cells0.12.0

Undifferentiated cells0.00.1

Neutrophils, total56.557.132.4

Metamyelocytes9.624.623.311.3

Neutrophilic1032

Eosinophilic0.33.7

Basophilic00.3

Monocytes (all stages)02.7

Myeloblasts0.15.01.20.62

Myelocytes4.21518.42.5

Neutrophilic5.020

Eosinophilic0.13.0

Basophilic00.5

Segmented granulocytes6.012.012.93.6

Neutrophilic7.030

Eosinophilic0.24.0

Basophilic00.7

Band cells9.515.3014.1

Neutrophilic1035

Eosinophilic0.22.0

Basophilic00.3

Erythroid series

Normoblasts, total25.623.18.0

Pronormoblasts0.24.00.50.1

Basophilic normoblasts1.55.81.70.34

Polychromatophilic normoblasts5.026.418.26.9

Orthochromic normoblasts3.6212.70.54

Promegaloblasts0

Basophilic megaloblasts0

Polychromatic megaloblasts0

Orthochromic megaloblasts0

M:E Ratio. The myeloid:erythroid ratio is the ratio of white blood cells to nucleated red blood cells.Adult6:1 to 2:1

Birth1.85:1

2 weeks11:1

12 months5.5:1

120 years2.95:1

Usage. Helps to distinguish primary and metastatic tumors. Assists in the identification, classification, and staging of neoplasias. Aids evaluation of the progress or response to the treatment of neoplasias. Assists in the definitive diagnosis of blood disorders. Culture of an aspirated sample can aid in the identification of infections such as histoplasmosis or tuberculosis. Histologic examination aids in the diagnosis of carcinoma, granulomas, lymphoma, or myelofibrosis. Iron stain showing decreased hemosiderin levels may indicate iron deficiency or malnutrition from anorexia nervosa, and SBB stain differentiates acute granulocytic leukemia from acute lymphocytic leukemia.Increased Eosinophils. Bone marrow carcinoma, eosinophilic leukemia, hypereosinophilic syndrome, lymphadenoma, myeloid leukemia, and pernicious anemia (relapse).Increased Lymphocytes. Aplastic anemia, hypoplasia of the bone marrow, infectious lymphocytosis or mononucleosis, lymphatic leukemoid reactions, lymphocytic leukemia (B-cell and T-cell), lymphoma, macroglobulinemia, myelofibrosis, and viral infections.Increased Megakaryocytes. Acute hemorrhage, aging, chronic myeloid leukemia, hypersplenism, idiopathic thrombocytopenia, infection, megakaryocytic myelosis, myelofibrosis, pneumonia, polycythemia vera, and thrombocytopenia.Increased Plasma Cells. Agranulocytosis, amyloidosis, aplastic anemia, carcinomatosis, collagen disease, hepatic cirrhosis, Hodgkin's disease, hypersensitivity reactions, infection, irradiation, macroglobulinemia, malignant tumor, multiple myeloma, rheumatic fever (acute), rheumatoid arthritis, serum sickness, syphilis, and ulcerative colitis.Increased Granulocyte. Hypoplasia of the bone marrow, infections, myelocytic leukemia, myelocytic leukemoid reaction, and myeloproliferative syndrome.Increased Normoblasts. Anemia (iron deficiency, hemolytic, megaloblastic), blood loss (chronic), erythema, erythroid-type myeloproliferative disorders, hypoplasia of the bone marrow, and polycythemia vera.Increased M:E Ratio Above 7:1. Decreased hematopoiesis, erythroid hypoplasia, infection, leukemoid reactions, and myeloid leukemia.Increased Diffuse Bone Marrow Hyperplasia. Myeloproliferative syndromes and pancytopenia reactions.Decreased Megakaryocytes. Anemia (aplastic, pernicious), bone marrow hyperplasia (with carcinomatous or leukemic deposits), cirrhosis, irradiation (excessive), and thrombocytopenia purpura. Drugs include benzene, chlorothiazides, and cytotoxic drugs.Decreased Granulocyte. Agranulocytosis, barbiturate coma, hyperplasia of the bone marrow, and ionizing radiation.Decreased Normoblasts. Anemia (aplastic, hypoplastic), folic acid or vitamin B12 (cyanocobalamin) deficiency.Decreased M:E Ratio Below 2:1. Agranulocytosis, anemia (iron deficiency, normoblastic, pernicious, posthemolytic, posthemorrhagic), erythroid activity (increased), hepatic disease, myeloid formation (decreased), polycythemia vera, sprue, and steatorrhea.Decreased Diffuse Bone Marrow Hypoplasia. Aging, cellular infiltrations, dengue fever, hepatitis C virus, myelofibrosis, myelosclerosis, myelotoxic agents, osteoporosis, rubella, and viral infections.Description. Bone marrow is the soft, organic, spongelike material contained in the medullary cavities, long bones, and some haversian canals and within the spaces between trabeculae of cancellous bone. It is composed of red and yellow marrow, with the chief function being production of erythrocytes, leukocytes, and platelets. Only the rusty, red marrow produces blood cells. The yellow marrow is formed of connective tissue and fat cells, which are inactive. During infancy and childhood, bone marrow is primarily red marrow, but in the adult, 50% is red marrow. The bone marrow aspiration procedure is a way to obtain a sample of bone marrow by needle. A stained blood smear of the sample is evaluated for bone marrow morphology and examination of blood cell erythropoiesis, cellularity, differential cell count, bone marrow iron stores, and M:E ratios. This test is used mainly in the diagnosis and management of anemia, fever, leukemia, lymphoma, pancytopenia, and thrombocytopenia.Professional Considerations Consent form IS required.Risks Bleeding, heart damage (with sternal biopsy), hemorrhage, infection, and meningitis.Contraindications Bone marrow aspiration is contraindicated in hemophilia, hemostasis, and coagulation defects; also contraindicated in clients receiving anticoagulants.

Preparation 1. Obtain a bone marrow aspiration tray, laboratory slides and stains, and a lavender-topped or green-topped tube.

2. Obtain a sterile container of Zenker's acetic acid solution if a bone marrow biopsy is to be performed.

3. Pain medication may be given to lessen procedure discomfort.

4. Just before beginning the procedure, take a time out to verify the correct client, procedure, and site.

Procedure 1. The most common sites for bone marrow aspiration include the sternum (preferred for bone marrow biopsy), the posterior superior iliac spine (for needle biopsy), and the anterior iliac crest and vertebral spinous process in the adult. For infants under 18 months, the anterior tibia site is used, and for children, the iliac crest is preferred.

2. The designated site is prepped, shaved, and draped. After a local anesthetic is injected and under sterile technique, a -inch stab wound is made. A Jamshidi needle with the stylet in place is inserted until the outer surface of the bone is impinged. The needle guard is engaged, and the outer needle is inserted with a boring motion, about 3 mm deep, into the bone marrow cavity.

3. For bone marrow aspiration: The stylet is removed, and a 10-mL syringe is attached to the needle. When aspiration of 0.2 to 0.5 mL of bone marrow has entered the syringe, it is removed and given to a technician for preparation of a stained blood smear. A second syringe may be attached and a 2-mL sample of bone marrow withdrawn and placed into a lavender-topped tube containing EDTA or a heparinized green-topped tube.

4. For bone marrow biopsy: The stylet is removed, and a biopsy or inner needle with a trephine tip is inserted. A tissue plug is removed and placed into a container of Zenker's acetic acid solution.

5. The needle is withdrawn.

Postprocedure Care 1. Apply a pressure dressing to the bone marrow aspiration site.

2. Observe the aspiration site for bleeding.

Client and Family Teaching 1. Bone marrow aspiration is painful, but only for a few moments. Preprocedure pain medicine may be used to lessen the discomfort. It is also normal to experience a deep pressure feeling as the bone marrow is withdrawn.

2. It is important to lie very still during the procedure.

3. Results are normally available within 2472 hours.

4. Call the physician if there are signs of infection at the procedure site: increasing pain, redness, swelling, purulent drainage, or temperature >101 degrees F (>38.3 degrees C).

Factors That Affect Results 1. Cytotoxic drugs, folic acid, iron, liver or vitamin B12 agents, and recent blood transfusions should be noted before the biopsy.

2. Chloramphenicol causes higher frequency (90%) of marrow hypocellularity.

3. Send the specimen to the laboratory immediately.

Other Data 1. The presence of normal bone marrow at one site does not eliminate the possibility of disease elsewhere in the bone marrow.

2. Normal M:E ratio may be associated with aplastic anemia, myeloma, and myelosclerosis.

Activated Partial Thromboplastin Time (APTT) and Partial Thromboplastin Time (PTT)Plasma Note: Activated partial thromboplastin time (APTT) is the current method of this test, which is still commonly referred to as PTT.Norm. Standardized times should be reported by each laboratory because results depend on the type of activator used. In general, standards are less than 35 seconds and vary by 2036 seconds.Premature infants 6 months' duration) occurs in 1020% of affected patients. The thrombocytopenia results from clearance of circulating IgM- or IgG-coated platelets by the reticuloendothelial system. The spleen plays a predominant role in the disease by forming the platelet cross-reactive antibodies and sequestering the antibody-bound platelets.Clinical FindingsSymptoms and SignsOnset of ITP is usually acute, with the appearance of multiple petechiae and ecchymoses. Epistaxis is also common at presentation. No other physical findings are usually present. Rarely, concurrent infection with EBV or CMV may cause hepatosplenomegaly or lymphadenopathy, simulating acute leukemia.Laboratory FindingsBloodThe platelet count is markedly reduced (usually < 50,000/L and often < 10,000/L), and platelets frequently are of larger size on peripheral blood smear, suggesting accelerated production of new platelets. The white blood count and differential are normal, and the hemoglobin concentration is preserved unless hemorrhage has been significant.Bone MarrowThe number of megakaryocytes is increased. Erythroid and myeloid cellularity is normal.Other Laboratory TestsPlatelet-associated IgG or IgM, or both, may be demonstrated on the patient's platelets or in the serum. PT and aPTT are normal.Differential DiagnosisTable 287 lists common causes of thrombocytopenia. ITP is a diagnosis of exclusion. Family history or the finding of predominantly giant platelets on the peripheral blood smear is helpful in determining whether thrombocytopenia is hereditary. Bone marrow examination should be performed if the history is atypical (ie, the child is not otherwise healthy, or if there is a family history of bleeding), if abnormalities other than purpura and petechiae are present on physical examination, or if other cell lines are affected on the CBC. The importance of performing a bone marrow examination prior to using corticosteroids in the treatment for ITP is controversial.Table 287. Common Causes of Thrombocytopenia.

Increased TurnoverDecreased Production

Antibody-MediatedCoagulopathyOtherCongenitalAcquired

Idiopathic thrombocytopenic purpuraDisseminated intravascular coagulopathyHemolytic-uremic syndromeFanconi anemiaAplastic anemia

InfectionSepsisThrombotic thrombocytopenic purpuraWiskott-Aldrich syndromeLeukemia and other malignancies

Immunologic diseasesNecrotizing enterocolitisHypersplenismThrombocytopenia with absent radiiVitamin B12 and folate deficiencies

ThrombosisRespiratory distress syndrome

Cavernous hemangiomaWiskott-Aldrich syndromeMetabolic disorders

Osteopetrosis

ComplicationsSevere hemorrhage and bleeding into vital organs are the feared complications of ITP. Intracranial hemorrhage is the most serious (but rarely seen) complication, occurring in less than 1% of affected children. The most important risk factors for hemorrhage are a platelet count less than 10,000/L and mean platelet volume less than 8 fL.TreatmentGeneral MeasuresTreatment is optional in most children in the absence of bleeding. Aspirin and other medications that compromise platelet function should be avoided. Bleeding precautions (eg, restriction from physical contact activities, use of helmets, etc) should be observed. Platelet transfusion should be avoided except in circumstances of life-threatening bleeding, in which case emergent splenectomy is to be pursued. In this setting, administration of corticosteroids and IVIG is also advisable.CorticosteroidsPatients with clinically significant but nonlife-threatening bleeding (ie, epistaxis, hematuria, and hematochezia) and those with a platelet count of less than 10,000/L may benefit from prednisone at 24 mg/kg orally per day for 35 days, decreasing to 12 mg/kg/d for a total of 14 days. The dosage is then tapered and stopped. No further prednisone is given regardless of the platelet count unless significant bleeding recurs, at which time prednisone is administered in the smallest dose that achieves resolution of bleeding episodes (usually 2.55 mg twice daily). Follow-up continues until the steroid can again be discontinued, spontaneous remission occurs, or other therapeutic measures are instituted.Intravenous Immunoglobulin (IVIG)IVIG is the treatment of choice for severe, acute bleeding, and may also be used as an alternative or adjunct to corticosteroid treatment in both acute and chronic ITP of childhood. IVIG may be effective even when the patient is resistant to corticosteroids; responses are prompt and may last for several weeks. Most patients receive 1 g/kg/d for 13 days. Infusion time is typically 46 hours. Platelets may be given simultaneously during life-threatening hemorrhage but are rapidly destroyed. Adverse effects of IVIG are common, including transient neurologic complications (eg, headache, nausea, and aseptic meningitis) in one third of patients. These symptoms may mimic those of intracranial hemorrhage and necessitate radiologic evaluation of the brain. A transient decrease in neutrophil number may also be seen.Anti-Rho(D) ImmunoglobulinThis polyclonal immunoglobulin binds to the D antigen on red blood cells. The splenic clearance of anti-Dcoated red cells interferes with removal of antibody-coated platelets, resulting in improvement in thrombocytopenia. This approach is effective only in Rh(+) patients with a functional spleen. The time required for platelet increase is slightly longer than with IVIG. However, approximately 80% of Rh(+) children with acute or chronic ITP respond well. Significant hemolysis may occur transiently with an average hemoglobin concentration decrease of 0.8 g/dL. However, severe hemolysis occurs in 5% of treated children, and clinical and laboratory evaluation approximately 5 days following administration is warranted in all patients. Rho(D) immunoglobulin is less expensive and infused more rapidly than IVIG, but is more expensive than corticosteroids.SplenectomyMost children with chronic ITP have platelet counts greater than 30,000/L. Up to 70% of such children spontaneously recover with a platelet count greater than 100,000/L within 1 year. For the remainder, corticosteroids, IVIG, and anti-D immunoglobulin are typically effective treatment for acute bleeding. Splenectomy produces a response in 7090%, but it should be considered only after persistence of significant thrombocytopenia for at least 1 year. Preoperative treatment with corticosteroids, IVIG, or anti-D immunoglobulin is usually indicated. Postoperatively, the platelet count may rise to 1 million/L, but is not often associated with thrombotic complications in the pediatric age group. The risk of overwhelming infection (predominantly with encapsulated organisms) is increased after splenectomy, particularly in the young child. Therefore, the procedure should be postponed, if possible, until age 5 years. Administration of pneumococcal and H influenzae type b vaccines at least 2 weeks prior to splenectomy is recommended. Meningococcal vaccine, although controversial, may be considered. Penicillin prophylaxis should be started postoperatively and continued for 13 years.Rituximab (Anti-CD20 Monoclonal Antibody)The efficacy of treating childhood chronic ITP in several series and a phase I/II trial has been demonstrated; remission was observed in 40%. Because of significant adverse events, this therapy may be reserved for refractory cases with significant bleeding.PrognosisNinety percent of children with ITP will have a spontaneous remission. Features associated with the development of chronic ITP include female gender, age greater than 10 years at presentation, insidious onset of bruising, and the presence of other autoantibodies. Older child- and adolescent-onset ITP is associated with an increased risk of chronic autoimmune diseases. Appropriate screening by history and laboratory studies (eg, antinuclear antibody) is warranted.Franchini M: Rituximab for the treatment of childhood chronic idiopathic thrombocytopenic purpura and hemophilia with inhibitors. Pediatr Blood Cancer 2007;49:6. [PMID: 17311349]

Imbach P: Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS). Pediatr Blood Cancer 2006;46:351. [PMID: 16086422]

Tarantino MD: The pros and cons of drug therapy for immune thrombocytopenic purpura in children. Hematol Oncol Clin North Am 2004;18:1301. [PMID: 15511617]

Thrombocytopenia in the NewbornThrombocytopenia is one of the most common causes of neonatal hemorrhage and should be considered in any newborn with petechiae, purpura, or other significant bleeding. Defined as a platelet count less than 150,000/L, thrombocytopenia occurs in approximately 0.9% of unselected neonates. Several specific entities may be responsible (see Table 287); however, half of such neonates have alloimmune thrombocytopenia. Infection and DIC are the most common causes of thrombocytopenia in ill full-term newborns and in preterm newborns. In the healthy neonate, antibody-mediated thrombocytopenia (alloimmune or maternal autoimmune), viral syndromes, hyperviscosity, and major-vessel thrombosis are frequent causes of thrombocytopenia. Management is directed toward the underlying etiology.Thrombocytopenia Associated with Platelet Alloantibodies (Neonatal Alloimmune Thrombocytopenia)Platelet alloimmunization occurs in 1 in approximately 350 pregnancies. Unlike in Rh incompatibility, 3040% of affected neonates are first-born. Thrombocytopenia is progressive over the course of gestation and worse with each subsequent pregnancy. Alloimmunization occurs when a platelet antigen of the infant differs from that of the mother and the mother is sensitized by fetal platelets that cross the placenta into the maternal circulation. In Caucasians, alloimmune thrombocytopenia is most often due to human platelet antigen (HPA)-1a incompatibility. Sensitization of a mother homozygous for HPA-1b to paternally acquired fetal HPA-1a antigen results in severe fetal thrombocytopenia in 1 in 1200 fetuses. Only 1 in 20 HPA-1apositive fetuses of HPA-1anegative mothers develop alloimmunization. The presence of antenatal maternal platelet antibodies on more than one occasion and their persistence into the third trimester is predictive of severe neonatal thrombocytopenia; a weak or undetectable antibody does not exclude thrombocytopenia. Severe intracranial hemorrhage occurs in 1030% of affected neonates as early as 20 weeks' gestation. Petechiae or other bleeding manifestations are usually present shortly after birth. The disease is self-limited, and the platelet count normalizes within 4 weeks.If alloimmunization is associated with clinically significant bleeding, transfusion of platelet concentrates harvested from the mother is more effective than random donor platelets in increasing the platelet count. Transfusion with HPA-matched platelets from unrelated donors or treatment with IVIG or methylprednisolone has also been successful in raising the platelet count and achieving hemostasis. If thrombocytopenia is not severe and bleeding is absent, observation alone is often appropriate.Intracranial hemorrhage in a previous child secondary to alloimmune thrombocytopenia is the strongest risk factor for severe fetal thrombocytopenia and hemorrhage in a subsequent pregnancy. Amniocentesis or chorionic villus sampling to obtain fetal DNA for platelet antigen typing is sometimes performed if the father is heterozygous for HPA-1a. If alloimmunization has occurred with a previous pregnancy, irrespective of history of intracranial hemorrhage, screening cranial ultrasound for hemorrhage should begin at 20 weeks' gestation and be repeated regularly. In addition, cordocentesis should be performed at approximately 20 weeks' gestation, with prophylactic transfusion of irradiated, leukoreduced, maternal platelet concentrates. If the fetal platelet count is less than 100,000/L, the mother should be treated with weekly IVIG. Delivery by elective cesarean section is recommended if the fetal platelet count is less than 50,000/L, to minimize the risk of intracranial hemorrhage associated with birth trauma.

Disorders of Platelet FunctionIndividuals with platelet function defects typically develop skin and mucosal bleeding similar to that occurring in persons with thrombocytopenia. Historically, platelet function has been screened by measuring the bleeding time. If this is prolonged, in-vitro platelet aggregation is studied using agonists, such as adenosine diphosphate, collagen, arachidonic acid, and ristocetin, and simultaneous comparison with a normal control subject. While labor-intensive, platelet aggregometry remains important in selected clinical situations. The PFA-100 has become available to evaluate platelet dysfunction and von Willebrand disease, and has replaced the template bleeding time in many clinical laboratories. Unfortunately, none of these tests of platelet function is uniformly predictive of clinical bleeding severity.Platelet dysfunction may be inherited or acquired, with the latter being more common. Acquired disorders of platelet function may occur secondary to uremia, cirrhosis, sepsis, myeloproliferative disorders, congenital heart disease, and viral infections. Many pharmacologic agents decrease platelet function. The most common offending agents in the pediatric population are aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), synthetic penicillins, and valproic acid. In acquired platelet dysfunction, the PFA-100 closure time is typically prolonged with collagen-epinephrine, but normal with collagen-ADP.The inherited disorders are due to defects in platelet-vessel interaction, platelet-platelet interaction, platelet granule content or release (including defects of signal transduction), thromboxane and arachidonic acid pathway, and platelet-procoagulant protein interaction. Individuals with hereditary platelet dysfunction generally have a prolonged bleeding time with normal platelet number and morphology by light microscopy. PFA-100 closure time, in contrast to that in acquired dysfunction, is typically prolonged with both collagen-ADP and collagen-epinephrine.Congenital causes of defective plateletvessel wall interaction include Bernard-Soulier syndrome. This condition is characterized by increased platelet size and decreased platelet number. The molecular defect in this autosomal recessive disorder is a deficiency or dysfunction of glycoprotein Ib-V-IX complex on the platelet surface resulting in impaired von Willebrand factor (vWF) binding, and hence, impaired platelet adhesion to the vascular endothelium.Glanzmann thrombasthenia is an example of platelet-platelet dysfunction. In this autosomal recessive disorder, glycoprotein IIb-IIIa is deficient or dysfunctional. Platelets do not bind fibrinogen effectively and exhibit impaired aggregation. As in Bernard-Soulier syndrome, acute bleeding is treated by platelet transfusion.Disorders involving platelet granule content include storage pool disease and Quebec platelet disorder. In individuals with storage pool disease, platelet-dense granules lack adenosine dinucleotide phosphate and adenosine trinucleotide phosphate and are often found to be low in number by electron microscopy. These granules are also deficient in Hermansky-Pudlak, Chdiak-Higashi, and Wiskott-Aldrich syndromes. Whereas deficiency of -granules results in the gray platelet syndrome, Quebec platelet disorder is characterized by a normal platelet -granule number, but with abnormal proteolysis of -granule proteins and deficiency of platelet -granule multimerin. Epinephrine-induced platelet aggregation is markedly impaired.Platelet dysfunction has also been observed in other congenital syndromes, such as Down and Noonan syndromes, without a clear understanding of the molecular defect.TreatmentAcute bleeding in many individuals with acquired or selected congenital platelet function defects responds to therapy with desmopressin acetate, likely due to an induced release of vWF from endothelial stores. If this therapy is ineffective, or if the patient has Bernard-Soulier syndrome or Glanzmann syndrome, the mainstay of treatment for bleeding episodes is platelet transfusion. Recombinant VIIa has variable efficacy and may be helpful in platelet transfusion-refractory patients.

Factor VIII Deficiency (Hemophilia A, Classic Hemophilia)Essentials of Diagnosis & Typical Features Bruising, soft-tissue bleeding, hemarthrosis. Prolonged activated partial thromboplastin time (aPTT). Reduced factor VIII activity.General ConsiderationsFactor VIII activity is reported in units per milliliter, with 1 U/mL equal to 100% of the factor activity found in 1 mL of normal plasma. The normal range for factor VIII activity is 0.51.5 U/mL (50150%). Hemophilia A occurs predominantly in males as an X- linked disorder. One third of cases are due to a new mutation. The incidence of factor VIII deficiency is 1:5000 male births.Clinical FindingsSymptoms and SignsPatients with severe hemophilia A (< 1% plasma factor VIII activity) have frequent spontaneous bleeding episodes involving skin, mucous membranes, joints, muscles, and viscera. In contrast, patients with mild hemophilia A (540% factor VIII activity) bleed only at times of trauma or surgery. Those with moderate hemophilia A (1% to < 5% factor VIII activity) typically have intermediate bleeding manifestations. The most crippling aspect of factor VIII deficiency is the tendency to develop recurrent hemarthroses that incite joint destruction.Laboratory FindingsIndividuals with hemophilia A have a prolonged aPTT, except in some cases of mild deficiency. The prothrombin time (PT) is normal. The diagnosis is confirmed by finding decreased factor VIII activity with normal vWF activity. In two thirds of families of hemophilic patients, the females are carriers and some are mildly symptomatic. Carriers of hemophilia can be detected by determination of the ratio of factor VIII activity to vWF antigen and by molecular genetic techniques. In a male fetus or newborn with a family history of hemophilia A, cord blood sampling for factor VIII activity is accurate and important in subsequent care.ComplicationsIntracranial hemorrhage is the leading disease-related cause of death among patients with hemophilia. Most intracranial hemorrhages in moderate to severe deficiency are spontaneous (ie, not associated with trauma). Hemarthroses begin early in childhood and, if recurrent, result in joint destruction (ie, hemophilic arthropathy). Large intramuscular hematomas can lead to a compartment syndrome with resultant muscle and nerve death. Although these complications are most common in severe hemophilia A, they may be experienced by individuals with moderate or mild disease. A serious complication of hemophilia is the development of an acquired circulating antibody to factor VIII after treatment with factor VIII concentrate. Such factor VIII inhibitors develop in 1525% of patients with severe hemophilia A, and may be amenable to desensitization with regular factor VIII infusion with or without immunosuppressive therapy. In recent years, recombinant factor VIIa has become a therapy of choice for treatment of acute hemorrhage in patients with hemophilia A and a high-titer inhibitor.In prior decades, therapy-related complications in hemophilia A have included infection with the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Through more stringent donor selection, the implementation of sensitive screening assays, the use of heat- or chemical viral inactivation methods, and the development of recombinant products, the risk of these infections is minimal. Inactivation methods do not eradicate viruses lacking a lipid envelope, however, so that transmission of parvovirus and hepatitis A remains a concern with the use of plasma-derived products. Immunization with hepatitis A and hepatitis B vaccines is recommended for all hemophilia patients.TreatmentThe general aim of management is to raise the factor VIII activity to prevent or stop bleeding. Some patients with mild factor VIII deficiency may respond to desmopressin via release of endothelial stores of factor VIII and vWF into plasma; however, most patients require administration of exogenous factor VIII to achieve hemostasis. The in-vivo half-life of factor VIII is generally 812 hours but may exhibit considerable variation among individuals depending on comorbid conditions. Nonlife-threatening, nonlimb-threatening hemorrhage is treated initially with 2030 U/kg of factor VIII, to achieve a rise in plasma factor VIII activity to 4060%. Large joint hemarthrosis and life- or limb-threatening hemorrhage is treated initially with approximately 50 U/kg of factor VIII, targeting a rise to 100% factor VIII activity. Subsequent doses are determined according to the site and extent of bleeding and the clinical response. Doses are rounded to the nearest whole vial size. In circumstances of suboptimal clinical response, recent change in bleeding frequency, or comorbid illness, monitoring the plasma factor VIII activity response may be warranted. For most instances of nonlife-threatening hemorrhage in experienced patients with moderate or severe hemophilia A, treatment can be administered at home, provided adequate intravenous access exists and close contact is maintained with the hemophilia clinician team.Prophylactic factor VIII infusions (eg, two or three times weekly) may prevent the development of arthropathy in severe hemophiliacs, and this approach is becoming more common in pediatric hemophilia care.PrognosisThe development of safe and effective therapies for hemophilia A has resulted in improved long-term survival in recent decades. In addition, more aggressive management and the coordination of comprehensive care through hemophilia centers have greatly improved quality of life and level of function.Gouw SC: Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: The CANAL cohort study. Blood 2007;109:4648. [PMID: 17289808]

Manco-Johnson MJ: Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357:535. [PMID: 17687129]

Factor IX Deficiency (Hemophilia B, Christmas Disease)The mode of inheritance and clinical manifestations of factor IX deficiency are the same as those of factor VIII deficiency. Hemophilia B is 1520% as prevalent as hemophilia A. As in factor VIII deficiency, factor IX deficiency is associated with a prolonged aPTT, but the PT and thrombin time are normal. However, the aPTT is slightly less sensitive to factor IX deficiency than factor VIII deficiency. Diagnosis of hemophilia B is made by assaying factor IX activity, and severity is determined similarly to factor VIII deficiency. In general, clinical bleeding severity correlates less well with factor activity in hemophilia B than in hemophilia A.The mainstay of treatment in hemophilia B is exogenous factor IX. Unlike factor VIII, about 50% of the administered dose of factor IX diffuses into the extravascular space. Therefore, 1 U/kg of plasma-derived factor IX concentrate or recombinant factor IX is expected to increase plasma factor IX activity by approximately 1%. Factor IX typically has a half-life of 2022 hours in vivo, but due to variability, therapeutic monitoring may be warranted. As for factor VIII products, viral inactivation techniques for plasma-derived factor IX concentrates appear effective in eradicating HIV, HBV, and HCV. Only 13% of persons with factor IX deficiency develop an inhibitor to factor IX, but patients may be at risk for anaphylaxis when receiving exogenous factor IX. The prognosis for persons with factor IX deficiency is comparable to that of patients with factor VIII deficiency. Gene therapy research efforts are ongoing for both hemophilias.Shapiro AD: Hemophilia B (factor IX deficiency). In Goodnight SH, Hathaway WE (editors): Disorders of Hemostasis & Thrombosis: A Clinical Guide, 2nd ed. McGraw-Hill, 2001:140148.

Shapiro AD: The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B. Blood 2005;105:518. [PMID: 15383463]

Factor XI Deficiency (Hemophilia C)Factor XI deficiency is a genetic, autosomally transmitted coagulopathy, typically of mild to moderate clinical severity. Cases of factor XI deficiency account for less than 5% of all hemophilia patients. Homozygotes generally bleed at surgery or following severe trauma, but do not commonly have spontaneous hemarthroses. In contrast to factor VIII and IX deficiencies, factor XI activity is least predictive of bleeding risk. Although typically mild, pathologic bleeding may be seen in heterozygous individuals with factor XI activity as high as 60%. The aPTT is often considerably prolonged. In individuals with deficiency of both plasma and platelet-associated factor XI, the PFA-100 may also be prolonged. Management typically consists of perioperative prophylaxis and episodic therapy for acute hemorrhage. Treatment includes infusion of fresh frozen plasma (FFP); platelet transfusion may also be useful for acute hemorrhage in patients with deficiency of platelet-associated factor XI. Desmopressin has been used in some cases. The prognosis for an average life span in patients with factor XI deficiency is excellent.

von Willebrand DiseaseEssentials of Diagnosis & Typical Features Easy bruising and epistaxis from early childhood. Menorrhagia. Prolonged PFA-100 (or bleeding time); normal platelet count; absence of acquired platelet dysfunction. Reduced activity or abnormal structure of vWF.General Considerationsvon Willebrand disease (vWD) is the most common inherited bleeding disorder among Caucasians, with a prevalence of 1%. vWF is a protein present as a multimeric complex in plasma, which binds factor VIII and is a cofactor for platelet adhesion to the endothelium. An estimated 7080% of all patients with vWD have classic vWD (type 1), which is caused by a partial quantitative deficiency of vWF. vWD type 2 involves a qualitative deficiency of (ie, dysfunctional) vWF, and vWD type 3 is characterized by a nearly complete deficiency of vWF. The majority (> 80%) of individuals with type 1 disease are asymptomatic. vWD is most often transmitted as an autosomal dominant trait, but can be autosomal recessive. The disease can also be acquired, developing in association with hypothyroidism, Wilms tumor, cardiac disease, renal disease, or systemic lupus erythematosus and in individuals receiving valproic acid. Acquired vWD is most often caused by the development of an antibody to vWF or increased turnover of vWF.Clinical FindingsSymptoms and SignsA history of increased bruising and excessive epistaxis is often present. Prolonged bleeding also occurs with trauma or at surgery. Menorrhagia is often a presenting finding in females.Laboratory FindingsPT is normal, and aPTT is sometimes prolonged. Prolongation of the PFA-100 or bleeding time is usually present since vWF plays a role in platelet adherence to endothelium. Platelet number may be decreased in type 2b vWD. Factor VIII and vWF antigen are decreased in types 1 and 3, but may be normal in type 2 vWD. vWF activity (eg, ristocetin cofactor or collagen binding) is decreased in all types. Since normal vWF antigen levels vary by blood type (type O normally has lower levels), blood type must be determined. Complete laboratory classification requires vWF multimer assay. The diagnosis requires confirmation of laboratory testing and bleeding history is often helpful when present.TreatmentThe treatment to prevent or halt bleeding for most patients with vWD types 1 and 2 is desmopressin acetate, which causes release of vWF from endothelial stores. Desmopressin may be administered intravenously at a dose of 0.3 mcg/kg diluted in at least 2030 mL of normal saline and given over 2030 minutes. This dose typically elicits a three- to fivefold rise in plasma vWF. A high-concentration desmopressin nasal spray (150 mcg/spray), different than the preparation used for enuresis, may alternatively be used. Because response to vWF is variable among patients, factor VIII and vWF activities are typically measured before and 60 minutes after infusion, if no recent response has been measured. Desmopressin may cause fluid shifts, hyponatremia, and seizures in children younger than 2 years of age. Because release of stored vWF is limited, tachyphylaxis often occurs with desmopressin.If further therapy is indicated, vWF-replacement therapy (eg, plasma-derived concentrate) is recommended; such therapy is also used in patients with type 1 or 2a vWD who exhibit suboptimal laboratory response to desmopressin, and for all individuals with type 2b or 3 vWD. Antifibrinolytic agents (eg, -aminocaproic acid) may be useful for control of mucosal bleeding. Topical thrombin and fibrin glue may also be of benefit, although antibodies that inhibit clotting proteins have been described. Estrogen-containing contraceptive therapy may be helpful for menorrhagia.PrognosisWith the availability of effective treatment and prophylaxis for bleeding, life expectancy in vWD is normal.Cox Gill J: Diagnosis and treatment of von Willebrand disease. Hematol Oncol Clin North Am 2004;18:1277. [PMID: 15511616]

Mannucci PM: Treatment of von Willebrand's disease. N Engl J Med 2004;351:683. [PMID: 15306670]

Acquired Bleeding DisordersDisseminated Intravascular Coagulation (DIC)Essentials of Diagnosis & Typical Features Presence of disorder known to trigger DIC. Evidence for consumptive coagulopathy (prolonged aPTT, PT, or thrombin time; increase in FSP (fibrin-fibrinogen split products); decreased fibrinogen or platelets).General ConsiderationsDIC is an acquired pathologic process characterized by tissue factormediated diffuse coagulation activation in the host. DIC involves dysregulated, excessive thrombin generation, with consequent intravascular fibrin deposition and consumption of platelets and procoagulant factors. Microthrombi, composed of fibrin and platelets, may produce tissue ischemia and end-organ damage. The fibrinolytic system is frequently activated in DIC, leading to plasmin-mediated destruction of fibrin and fibrinogen; this results in fibrin-fibrinogen degradation products (FDPs) which exhibit anticoagulant and platelet-inhibitory functions. DIC commonly accompanies severe infection and other critical illnesses in infants and children. Conditions known to trigger DIC include endothelial damage (eg, endotoxin, virus), tissue necrosis (eg, burns), diffuse ischemic injury (eg, shock, hypoxia acidosis), and systemic release of tissue procoagulants (eg, certain cancers, placental disorders).Clinical FindingsSymptoms and SignsSigns of DIC may include (1) signs of shock, often including end-organ dysfunction, (2) diffuse bleeding tendency (eg, hematuria, melena, purpura, petechiae, persistent oozing from needle punctures or other invasive procedures), and (3) evidence of thrombotic lesions (eg, major vessel thrombosis, purpura fulminans).Laboratory FindingsTests that are most sensitive, easiest to perform, most useful for monitoring, and best reflect the hemostatic capacity of the patient are the PT, aPTT, platelet count, fibrinogen, and fibrin-fibrinogen split products. The PT and aPTT are typically prolonged and the platelet count and fibrinogen concentration may be decreased. However, in children, the fibrinogen level may be normal until late in the course. Levels of fibrin-fibrinogen split products are increased, and elevated levels of D-dimer, a cross-linked fibrin degradation byproduct, may be helpful in monitoring the degree of activation of both coagulation and fibrinolysis. However, D-dimer is nonspecific and may be elevated in the context of a triggering event (eg, severe infection) without concomitant DIC. Often, physiologic inhibitors of coagulation, especially antithrombin III and protein C, are consumed, predisposing to thrombosis. The specific laboratory abnormalities in DIC may vary with the triggering event and the course of illness.Differential DiagnosisDIC can be difficult to distinguish from coagulopathy of liver disease (ie, hepatic synthetic dysfunction), especially when the latter is associated with thrombocytopenia secondary to portal hypertension and hypersplenism. Generally, factor VII activity is decreased markedly in liver disease (due to deficient synthesis of this protein, which has the shortest half-life among the procoagulant factors), but only mildly to moderately decreased in DIC (due to consumption). Factor VIII activity is often normal or even increased in liver disease, but decreased in DIC.TreatmentTherapy for Underlying DisorderThe most important aspect of therapy in DIC is the identification and treatment of the triggering event. If the pathogenic process underlying DIC is reversed, often no other therapy is needed for the coagulopathy.Replacement Therapy for Consumptive CoagulopathyReplacement of consumed procoagulant factors with FFP and of platelets via platelet transfusion is warranted in the setting of DIC with hemorrhagic complications, or as periprocedural bleeding prophylaxis. Infusion of 1015 mL/kg FFP typically raises procoagulant factor activities by approximately 1015%. Cryoprecipitate can also be given as a rich source of fibrinogen; one bag of cryoprecipitate per 3 kg in infants or one bag of cryoprecipitate per 6 kg in older children typically raises plasma fibrinogen concentration by 75100 mg/dL.Anticoagulant Therapy for Coagulation ActivationContinuous intravenous infusion of unfractionated heparin is sometimes given in order to attenuate coagulation activation and consequent consumptive coagulopathy. The rationale for heparin therapy is to maximize the efficacy of, and minimize the need for, replacement of procoagulants and platelets; however, clinical evidence demonstrating benefit of heparin in DIC is lacking. Heparin dosing is provided in the section on thrombosis treatment.Specific Factor ConcentratesA nonrandomized pilot study of antithrombin concentrate in children with DIC and associated acquired antithrombin deficiency demonstrated favorable outcomes, suggesting that replacement of this consumed procoagulant may be of benefit. Protein C concentrate has also shown promise in two small pilot studies of meningococcal-associated DIC with purpura fulminans. Activated protein C has reduced mortality in septic adults in a large randomized multicenter trial; an international pediatric trial is ongoing.

Liver DiseaseThe liver is the major synthetic site of prothrombin, fibrinogen, high molecular weight kininogen, and factors V, VII, IX, X, XI, XII, and XIII. In addition, plasminogen and the physiologic anticoagulants (antithrombin III, protein C, and protein S) are hepatically synthesized. 2-Antiplasmin, a regulator of fibrinolysis, is also produced in the liver. Deficiency of factor V and the vitamin Kdependent factors (II, VII, IX, and X) is most often a result of decreased hepatic synthesis and is manifested by a prolonged PT and often a prolonged aPTT. Extravascular loss and increased consumption of clotting factors may contribute to PT and aPTT prolongation. Fibrinogen production is often decreased, or an abnormal fibrinogen (dysfibrinogen) containing excess sialic acid residues may be synthesized, or both. Hypofibrinogenemia or dysfibrinogenemia is associated with prolongation of thrombin time and reptilase time. FDPs and D-dimers may be present because of increased fibrinolysis, particularly in the setting of chronic hepatitis or cirrhosis. Thrombocytopenia secondary to hypersplenism may occur. DIC and coagulopathy of liver disease also mimic vitamin K deficiency; however, vitamin K deficiency has normal factor V activity. Treatment of acute bleeding in the setting of coagulopathy of liver disease consists of replacement with FFP and platelets. Desmopressin may shorten the bleeding time and aPTT in patients with chronic liver disease, but its safety has not been well established. Recombinant VIIa also is efficacious for life-threatening hemorrhage.Vitamin K DeficiencyThe newborn period is characterized by physiologically depressed activity of the vitamin Kdependent factors (II, VII, IX, and X). If vitamin K is not administered at birth, a bleeding diathesis previously called hemorrhagic disease of the newborn, now termed vitamin K deficiency bleeding (VKDB), may develop. Outside of the newborn period, vitamin K deficiency may occur as a consequence of inadequate intake, excess loss, inadequate formation of active metabolites, or competitive antagonism.One of three patterns is seen in the neonatal period:1. Early VKDB of the newborn occurs within 24 hours of birth and is most often manifested by cephalohematoma, intracranial hemorrhage, or intra-abdominal bleeding. Although occasionally idiopathic, it is most often associated with maternal ingestion of drugs that interfere with vitamin K metabolism (eg, warfarin, phenytoin, isoniazid, and rifampin). Early VKDB occurs in 612% of neonates born to mothers who take these medications without receiving vitamin K supplementation. The disorder is often life-threatening.2. Classic VKDB occurs at 24 hours to 7 days of age and usually is manifested as gastrointestinal, skin, or mucosal bleeding. Bleeding after circumcision may occur. Although occasionally associated with maternal drug usage, it most often occurs in well infants who do not receive vitamin K at birth and are solely breast fed.3. Late neonatal VKDB occurs on or after day 8. Manifestations include intracranial, gastrointestinal, or skin bleeding. This disorder is often associated with fat malabsorption (eg, in chronic diarrhea) or alterations in intestinal flora (eg, with prolonged antibiotic therapy). Like classic VKDB, late VKDB occurs almost exclusively in breast-fed infants.

The diagnosis of vitamin K deficiency is suspected based on the history, physical examination, and laboratory results. The PT is prolonged out of proportion to the aPTT (also prolonged). The thrombin time becomes prolonged late in the course. The platelet count is normal. This laboratory profile is similar to the coagulopathy of acute liver disease, but with normal fibrinogen level and absence of hepatic transaminase elevation. The diagnosis of vitamin K deficiency is confirmed by a demonstration of noncarboxlyated proteins in the absence of vitamin K in the plasma and by clinical and laboratory responses to vitamin K. Intravenous or subcutaneous treatment with vitamin K should be given immediately and not withheld while awaiting test results. In the setting of severe bleeding, additional acute treatment with FFP or recombinant factor VIIa may be indicated.

Vascular Abnormalities Associated with BleedingHenoch-Schnlein Purpura (Anaphylactoid Purpura)Essentials of Diagnosis & Typical Features Purpuric cutaneous rash. Migratory polyarthritis or polyarthralgias. Intermittent abdominal pain. Nephritis.General ConsiderationsHenoch-Schnlein purpura (HSP), the most common type of small vessel vasculitis in children, primarily affects boys 27 years of age. Occurrence is highest in the spring and fall, and upper respiratory infection precedes the diagnosis in two thirds of children.Leukocytoclastic vasculitis in HSP principally involves the small vessels of the skin, gastrointestinal tract, and kidneys, with deposition of IgA immune complexes. The most common and earliest symptom is palpable purpura, which results from extravasation of erythrocytes into the tissue surrounding the involved venules. Antigens from group A -hemolytic streptococci and other bacteria, viruses, drugs, foods, and insect bites have been proposed as inciting agents.Clinical FindingsSymptoms and SignsSkin involvement may be urticarial initially, progresses to a maculopapules, and coalesces to a symmetrical, palpable purpuric rash distributed on the legs, buttocks, and elbows. New lesions may continue to appear for 24 weeks, and may extend to involve the entire body. Two thirds of patients develop migratory polyarthralgias or polyarthritis, primarily of the ankles and knees. Intermittent, sharp abdominal pain occurs in approximately 50% of patients, and hemorrhage and edema of the small intestine can often be demonstrated. Intussusception may develop. From 2550% of those affected develop renal involvement in the second or third week of illness with either a nephritic or, less commonly, nephrotic picture. Hypertension may accompany the renal involvement. In males, testicular torsion may also occur, and neurologic symptoms are possible due to small vessel vasculitis.Laboratory FindingsThe platelet count is normal or elevated, and other screening tests of hemostasis and platelet function are typically normal. Urinalysis frequently reveals hematuria, and sometimes proteinuria. Stool may be positive for occult blood. The antistreptolysin O (ASO) titer is often elevated and the throat culture positive for group A -hemolytic streptococci. Serum IgA may be elevated.Differential DiagnosisThe rash of septicemia (especially meningococcemia) may be similar to skin involvement in HSP, although the distribution tends to be more generalized. The possibility of trauma should be considered in any child presenting with purpura. Other vasculitides should also be considered. The lesions of thrombotic thrombocytopenic purpura are not palpable.TreatmentGenerally, treatment is supportive. NSAIDs may be useful for the arthritis. Corticosteroid therapy may provide symptomatic relief for severe gastrointestinal or joint manifestations but does not alter skin or renal manifestations. If culture for group A -hemolytic streptococci is positive or if the ASO titer is elevated, a therapeutic course of penicillin is warranted.PrognosisThe prognosis for recovery is generally good, although symptoms frequently (2550%) recur over a period of several months. In patients who develop renal manifestations, microscopic hematuria may persist for years. Progressive renal failure occurs in less than 5% of patients with HSP, with an overall fatality rate of 3%.Ronkainen J: Early prednisone therapy in Henoch-Schnlein purpura: A randomized, double-blind, placebo-controlled trial. J Pediatr 2006;149:241. [PMID: 16887443]