IDIOPATHIC TROMBOCYTOPENIC PURPURA ITP CHILDHOOD IDIOPATHIC IMMUNE THROMBOCYTOPENIA

IDIOPATHIC TROMBOCYTOPENIC PURPURA ITP

CHILDHOOD IDIOPATHIC (IMMUNE) THROMBOCYTOPENIA (ITP) Definition Idiopathic (or immune) thrombocytopenia (ITP) is a condition in which platelet destruction is increased due to circulating antiplatelet antibodies which are presents in plasma, platelet count is less than 50, 000/mm 3 , platelet survival is shortened and megacaryocytes are increased in bone marrow. Acute ITP generally lasts less than 6 months. It mainly occurs in children, both boys and girls, and is the most common type of ITP. It typically occurs following an infection caused by a virus. This type of ITP often goes away on its own within a few weeks or months and does not return. Treatment may not be needed. Chronic ITP is a long-lasting (6 months or longer) type of ITP that mostly affects adults. However, some teenagers and even younger children get this type of ITP. Chronic ITP affects women 2 to 3 times more often than men. Treatment depends on how severe the bleeding symptoms are and the platelet count. In mild cases, treatment may not be needed. Recurrent form in which platelets number is decreased, but there are periods when they can turn to normal

Incidence/Etiology Incidence of ITP is approximately 4. 0 to 5. 3 per 100, 000 population. In Denmark and England, childhood ITP occurs in approximately 10 -40 cases per 1, 000 per year. A study in Kuwait reported a higher incidence of 125 cases per 1, 000 per year. New cases of chronic refractory ITP comprise approximately 10 cases per 1, 000 per year. Approximately 40% of all patients are younger than 10 years. While ITP affects both genders equally, it affects white children more frequently than black children ITP commonly occurs about 1 to 4 weeks after a nonspecific viral illness in 50 -80% cases. In 20% rubella, measles, varicella, pertussis, mumps, mononucleosis hepatitis A, B, C, bacteraemia can be involved. In acute ITPdistribution is equal between males and females, in chronic ITP the female-to-male ratio is 2. 6: 1. More than 72% of patients older than 10 years are female.

Patogeny Cause is unknown but believed to be related to immune factors; theories include a viral-induced, disordered immune response resulting in the formation of plateletdestroying antibodies. Alternatively, immune complexes from the underlying disease nonspecifically adsorb to platelets resulting in their destruction Platelet destruction occurs in the spleen. Ig. G antibody or Ig. G-containing immune complexes are involved in the destruction of host platelets in this disease. Autoantibodies are against platelet membrane glycopreoteins GPIIb/IIIa, GP Ib/IX, GP IV. The spleen contains large numbers of Fc receptor (Fc-gamma-R)– bearing phagocytic cells, such as monocytes and macrophages. These cells can bind and destroy opsonized platelets. Although platelets are destroyed in many different organs, splenectomy is a successful treatment for many cases of ITP. +

Purpura; the purple color of the skin after blood has "leaked" under it. A bruise is blood under the skin. Children with ITP may have large bruises from no known trauma. Bruises can appear at the joints of elbows and knees just from movement. Nonpalpable petechiae (tiny red dots under the skin that are a result of very small bleeds which mostly occur in dependent regions) Hemorrhagic bullae on mucous membranes Gingival bleeding Nose bleeding

Cines D and Blanchette V. N Engl J Med 2002; 346: 995 -1008

Signs of GI bleeding Hematuria Menometrorrhagia, menorrhagia Retinal hemorrhages Evidence of intracranial hemorrhage, with possible neurologic symptoms Headache, diziness ( neurosurgical exam can be necessary ) Nonpalpable spleen: The prevalence of palpable spleen in patients with ITP is approximately the same as that in the non-ITP population ( 12% in children). Spontaneous bleeding when platelet count is less than 20, 000/mm 3.

CBC: Isolated thrombocytopenia, under 50, 000/mm 3 is the key finding regarding laboratory evaluation. Anemia can be present as a consequence of hemorrhage Ig G anti trombocytes can be found ( radiolabeled Coombs antiglobulin test ) ITP platelets usually survive only a few hours, in comparison to normal platelets which have a lifespan of 7 to 10 days. Test with Chromium 51 labeled platelets show this. Bleeding time is prolonged Clotting retraction is modified Bone marrow aspirate shows enhancement of platelet production, megacaryocytes are increased, often immature with absence of budding Urine and stools must be checked for blood presence Prothrombin time (PT), activated partial thromboplastin time ( APTT) and fibrinogen level are normal

Differential diagnosis Other types of thrombocytopenia ( central mechanism) as in congenital thrombocytopenia, aplastic anemia where bone marrow aspirate makes the difference Drug induced thrombocytopenia (alcohol, heparin, quinine/quinidine, aceta-minophen, sulfonamides, antituberculous, piroxicam, penicillin, ceftazidime, anticonvulsivants, captopril, digitoxin, furosemide, motphine) Immune thrombocytopenias secondary to a collagen vascular disorder (eg, SLE) or to lymphoproliferative disease. LES: ANA, anti DNA , other autoimmune (antimitocondrial, anti smooth muscle) antibodies are absent, clinics: skin, liver, lung, myocardial, haematological involvment

Evans syndrome The combination of direct Coombs-positive hemolytic anemia and immune thrombocytopenia with no known underlying etiology now defines patients with Evans syndrome. The CBC and reticulocyte count show anemia, thrombocytopenia, neutropenia, or combined cytopenias; the reticulocyte count increases if the patient has anemia. Phisical there are signs of thrombocytopenia include purpura, petechiae, and ecchymoses, signs of anemia with pallor, fatigue, and light-headedness, jaundice that may indicate hemolysis

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening multisystem disorder described by Moschowitz characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever, and renal dysfunction where mortality rate is approximately 95% for untreated cases Hemolytic uremic syndrome. HUS is characterized by acute renal failure, microangiopathic hemolytic anemia, fever, and thrombocytopenia precipitated by iarrhea and/or upper respiratory infection. Petechiae, purpura, and fever may accompany gastrointestinal involvement together with hypertension and oliguria.

Disseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelets. It is characterized by signs of spontaneous and lifethreatening hemorrhage, nonspecific altered consciousness/stupor, hypotension, tachycardia, circulatory collapse

Acute leukaemia Severe disease with thrombocytopenia, neutropenia, anemia and adenohepato-splenomegaly caused by a clonal proliferation of a blast cell in bone marrow and ather organs Trombocytopenia with large platelets on smear of congenital type HIV infection and AIDS: immunosupresion CD 4, associated bacterian, fungal, viral recurrent infection, positive tests for HIV

Complication Hemorrhage represents the most serious complication; intracranial hemorrhage is the most significant. The mortality rate from hemorrhage is approximately 1% in children and 5% in adults, spontaneous remission occurs in more than 80% of cases in children. Life threatening hemorrhage is treted with Platelet transfusion Methylprednisolone 500 mg/m 2 per day IV, three days IV Ig. G 2 g/kg Emergency splenectomy

Treatment Children who have platelet counts >30, 000/mm 3 and are asymptomatic or have only minor purpura do not require routine treatment. Children who have platelet counts <20, 000/mm 3 and significant mucous membrane bleeding and those who have platelet counts <10, 000/mm 3 and minor purpura should receive specific treatment. Platelet transfusion is indicated for controlling severe hemorrhage, better transfused immediately after IVIg infusion. Dose is 6 -8 U of platelet concentrate, or 1 U/10 kg. 1 U of platelets increase count of an 18 -kg child by 20, 000/mm 3

Intravenous immune globulin (IVIG) was initially shown to be effective in autoimmune idiopathic thrombocytopenic purpura (ITP) in 1981 (Imbach, 1981). IVIG is an immunomodulating agent that has multiple activities. These include modulation of complement activation; suppression of idiotypic antibodies; saturation of Fc receptors on macrophages; and suppression of various inflammatory mediators. Blockade of macrophage Fc receptors is considered the primary mechanism of action of immune globulin in persons with ITP. The standard dose of IVIG is 400 mg/kg 5 times daily. A new dosing level is 1 g/kg twice a day, which is more effective. Undesirable effects from IVIG occur in less than 5% of patients. The most common adverse effects occur soon after infusions and can include headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension; patient can be premedicated with antihistamines and intravenous hydrocortisone. An uncommon but potentially irreversible adverse event is acute renal failure, rare cases of thrombosis. It has caused disseminated intravascular coagulation, transient serum sickness, and transient neutropenia. Life-threatening human parvovirus B 19 infection and hepatitis C have been transmitted by IVIG. IV anti-(Rh)D, also known as IV Rh immune globulin (IG) increases at 24 hours faster than medicating with steroids and at 72 hours similar to IVIg. Dose is 50 -75 mcg/kg IV infusion 3 -5 minute, repeat at 3 -8 week interval. Hemoglobin level must be checket one week after the treatment

Steroid therapy Methylprednisolone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased permeability. Used as alternative glucocorticoid of choice for all patients with severe, lifethreatening bleeding or children with platelet counts <30, 000/mm>3. Loading dose is 2 mg/kg IV, maintenance dose: 0. 5 -1 mg/kg/dose q 6 h for up to 5 days. Side effects are: hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections. IV corticosteroid can be followed by Prednisone which is useful in treating inflammatory and allergic reactions; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Dose is from 1 -2 mg/kg daily , divided in 2 -3 to 4 -8 mg/kg/d PO for severe, life-threatening bleeding with platelet counts <50, 000/ mm 3, or for all patients with platelet counts <30, 000/mm 3

Combination of weekly vincristine, weekly methylprednisolone, both until platelet counts reached 50, 000/mm 3, and cyclosporine orally twice daily until the platelet count is normal for 3 -6 months Splenectomy is reserved for patients in whom medical therapy fails. Emergent splenectomy is indicated in patients with life-threatening bleeding in whom medical therapy fails. Patients should be immunised with antipneumococcus anti haemophilus influentzae vaccine. Otherapies, such as vinblastin, cyclophosphamide, danazol, dapsone, interferon alfa, azathioprine, rituximab, vinca alkaloids, accessory splenectomy, and splenic radiation have been studied. Steroid use and immunosuppressives and splenectomy may be undesirable because of their associated complications. For long-term steroid use, osteoporosis, glaucoma, cataracts, loss of muscle mass, and an increased risk of infection can appear. For immunosuppressive therapy and splenectomy, risks include worsening immunosuppression and infection or sepsis.

Rituximab is a human monoclonal antibody against B cell surface antigen CD 20 and eliminates autoreactiva B cells. Dose is 375 mg/kg IV per week and adverse reactions are chills, headache, nausea, hypotensionmucocutaneous reaction Plasmapheresis may accelerate the clearance of circulating antiplatelet antibodies

Follow up Preventing bleeding: For the young child, make the environment as safe as possible: wearing helmets, and providing protective clothing are necessary when platelet counts are low. Contact sports, riding bicycles, and rough play may need to be restricted. Avoid medications which contain aspirin, as they may interfere with the body's ability to control bleeding.

Prognosis Complete remission is seen in about 80 -90% of children within 6 to 9 months of diagnosis About 10 -20% of affected children remain symptomatic and are classified as having chronic ITP; chronic ITP is seen more commonly in children older than 7 years of age is associated with insidious onset, female gender, age older than 10. 50% of all cronic patients stabilize the disease without any therapy.

VON WILLEBRANDT DISEASE

HAEMOPHILIA COAGULATION DISORDERS

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Hemophilia A ( lack of F VIII) and hemophilia B ( lack of F IX) are the most common severe inherited bleeding disorders X linked diseases Clinical Manifestations Approximately 30% of male infants with hemophilia have bleeding with circumcision In the majority of patients hemophilia is diagnosed at birth because of a family history, although in approximately a third of patients the occurrence of hemophilia represents a new mutation

The usual initial symptoms include easy bruising; oral bleeding, especially from a torn frenulum; hemarthrosis intramuscular hemorrhage. When the diagnosis of hemophilia is suspected on the basis of either clinical findings or a positive family history, the initial diagnostic studies should include determination of the prothrombin time, partial thromboplastin time (PTT), bleeding time, and fibrinogen or thrombin time; a platelet count; and studies to identify VWD

the hallmark of hemophilia is deep bleeding into joints and muscles. bleeding occurs most commonly into the joint space, a condition referred to as hemarthrosis. As the toddler attempts to maintain an upright position, the ankle becomes particularly prone to hemorrhage. Thus, in toddlers the ankle is the most common site of hemorrhage, with the knee being the second most common. As the child grows older, the most frequent bleeding sites are the knees and elbows. hemarthrosis usually first note an aura of tingling or warmth, followed shortly thereafter by increasing pain and decreased range of motion of the joint as the joint capsule becomes progressively distended. on examination, pain and limitation of range of motion followed by the development of warmth, swelling, and tenderness Severe chronic arthropathy may develop in older children and adults who have not received aggressive early treatment

A, Grade I. 4 -year-old boy with severe hemophilia who presented with early chronic synovitis. Note the popliteal soft-tissue fullness indicative of synovial thickening and osteopenia of the tibial epiphysis B, Grade II. Anteroposterior radiograph of an 11 -year-old boy with severe hemophilia, normal cartilage interval, early joint surface erosions, widened epiphyses, and juxta-articular osteopenia. C, Grade III. Anteroposterior radiograph moderate hemophilia. The medial compartment has surface irregularity, subchondral cysts, reactive sclerosis, and partially narrowed cartilage interval. D, Grade IV. Anteroposterior radiograph in a severe, adult hemophiliac with complete loss of cartilage interval, extensive surface erosions, a large synovial cyst, tibiofemoral subluxation, and lateral subluxation of the patella 28

Iliopsoas bleeding is a particularly troublesome form of intramuscular hemorrhage. A patient with an iliopsoas hemorrhage is generally seen with vague symptoms of lower abdominal or upper thigh discomfort

If the PTT is prolonged, assays for factor VIII and factor IX should be performed. The severity of bleeding manifestations in hemophilia is generally correlated with the clotting factor level. Severe hemophilia Moderate hemophilia Mild < 1% factor level 1 to 5% > 5% SEVERE: Spontaneous, hemarthrosis MODERATE: Mild-to-moderate trauma MILD: Major trauma or surgery

Diagnosis Hemophilia is diagnosed based on medical history, a physical examination and tests of blood clotting factors. Laboratory testing is needed for initial diagnosis and long-term monitoring. • Easy bruising in early childhood; • Spontaneous bleeding (particularly into the joints and soft tissue); and • Excessive bleeding following trauma or surgery

Treatment World Federation of Hemophilia (WFH) has various programs to improve care for people with hemophilia worldwide and has standard guidelines appropriate for countries where economic resources are limited, to ensure a basic level of care. The general principles of care for hemophilia management: • Prevention of bleeding • Acute bleeds should be treated early • Home therapy should be managed only uncomplicated mild/moderate bleeding episodes.

Factor VIII concentrates Commercially prepared, lyophilized FVIII is distributed under a variety of brand names. Recombinant products; Monoclonal antibody purified products Intermediate and high purity FVIII products Each FVIII unit per kilogram of body weight infused intravenously will raise the plasma FVIII level approximately 2%. The half-life is approximately 8– 12 hours. Verify the calculated dose by measuring the patient’s factor level. • Calculate the dosage by multiplying the patient’s weight in kilograms by the factor level desired multiplied by 0. 5. This will indicate the number of factor units required. Example: (20 kg x 40 (% level desired) x 0. 5 = 400 units of FVIII).

1. Joint hemorrhage Raise the factor level to 40% with first symptoms or after trauma. Immobilize the joint as soon as possible until pain subsides. Adjunctive care: ice, temporary rest, and elevation. Pain control: Aspirin-free medication. 2. Throat and neck hemorrhage and severe tonsillitis Immediately raise factor level to 80 to 100% when symptoms or significant trauma occur. Maintain at least a 50% factor level for one to two weeks until the hemorrhage resolves. 3. Acute gastrointestinal (GI) hemorrhage Immediately raise the factor level to 80 to 100%. Maintain at least a 50% factor level until the etiology is defined. 4. Central nervous system (CNS) hemorrhage/head trauma Treat all post-traumatic head injuries and significant headaches as a head bleed. Raise factor level immediately to 80 to 100%.

. Acute abdominal hemorrhage Iliopsoas hemorrhage should be ruled out; raise the factor level to 80 to 100%. Maintain at least a 50% factor level until the etiology can be defined. 6. Renal hemorrhage Avoid use of antifibrinolytic agents; painless hematuria should be treated with complete bed rest and vigorous hydration; in persistent gross hematuria, give factor to raise the level to 50%; prednisone is often utilized in these instances. 7. Epistaxis a) Factor replacement therapy is usually not required because the formation of a platelet plug often is adequate; place his head forward to avoid swallowing blood and have him gently blow out weak clots. Apply firm pressure to the fleshy part of the nose for at least 10 to 20 minutes; try Neo-Synephrine®. 5%-1%, two drops each nostril b. i. d. for 5 days, use of a cold mist vaporizer and petroleum jelly in the nares may be helpful, watch for anemia if bleeding is prolonged, ear, nose, and throat (ENT) consultation may be indicated, 4% cocaine solution may be advised; if persistent raise the factor level to 20 to 30%.

Dental extractions require a prior infusion of factor concentrate that raises the level to 50% to 100%. The dose for EACA, which should be started prior to the procedure, is 50 -100 mg/kg every four to six hours, for seven to ten days (maximum 24 grams per 24 hours) 9. An inhibitor should be suspected if the patient does not respond to the usual dose of factor. -Prophylactic administration of clotting factor concentrates is advisable prior to engaging in activities with higher risk of injury to prevent bleeding. Profilaxis: the most commonly suggested protocol for prophylaxis is the infusion of 25 -40 IU/kg of clotting factor concentrates three times a week. -Patients should avoid trauma by adjusting their lifestyle and avoid use of drugs that affect platelet function, particularly acetylsalicyclic acid (ASA) and non-steroidal anti-inflamma-tory drugs (NSAIDs).

Cryoprecipitate is prepared by slow thawing of fresh frozen plasma (FFP) at 4°C for 10– 24 hours. . The use of this product in hemofilia is justified in situations where clotting factor concentrates are not available. Fresh frozen plasma (FFP) FFP should not be used for these patients unless faced with a life-threatening emergency and only if FVIII products are not available !!

-Desmopressin (1 -deamino-8 -D-arginine vasopressin, also known as DDAVP) is a synthetic analogue of antidiuretic hormone (ADH). The compound boosts the plasma levels of FVIII and v. WF after administration, iv infusion at a dose of 0. 3 micrograms/kg body weight can be expected to boost the level of FVIII three to sixfold. -Tranexamic acid is an antifibrinolytic agent that competitively inhibits the activation of plasminogen to plasmin. It promotes clot stability; for 5 -10 days is effective as adjunctive treatment for mucosal bleeds (e. g. , epistaxis, mouth bleed). These drugs should be avoided in renal bleeding as unlysed clots in the renal pelvis

-Intramuscular injections must be avoided. -Regular exercise should be encouraged to promote strong muscles -Contact sports should be avoided, swimming and cycling are allowed. Professional orientation of children in schools towards “safe” jobs is required -Home therapy allows immediate access to treatment, and early treatment. This is ideally achieved with clotting factor concentrates or other lyophilized products.

Complications Musculoskeletal complications: chronic hemophilic arthropathy, chronic synovitis, deforming arthropathy; contractures, pseudotumour formation (soft tissue and bone); fracture; Inhibitors against FVIII/FIX; Transfusion-related infections of concern in people with hemophilia: Human immunodeficiency virus (HIV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Hepatitis A virus (HAV), Parvovirus B 19;