DISORDERS OF HEMOSTASIS Dept.of Hematology ZhongShan Hospital,FuDan University Prof. JlAN-MIN XU General Considerations Disorders of hemostasis defects in platelet number or function problems in fibrin clot (coagulation) Bleeding due to platelet disorders is typically mucosal or dermatologic include epistaxis, gum bleeding, menorrhagia, gastrointestinal bleeding, purpura, and petechiae Thrombocytopenic Purpura Dept.of Hematology ZhongShan Hospital,FuDan University Prof. JlAN-MIN XU Brief 1.definition ：bleeding of skin 、mucous and  organs 2.cause ：（1）production  ：drug, tumor, infection, radiation （2）destruction  ：ITP,DIC,TTP （3）abnormal distribution ：splenomegaly 3.classification ：primary ,secondary IDIOPATHIC (AUTOIMMUNE) THROMBOCYTOPENIC PURPURA (ITP) General Considerations ITP is an autoimmune disorder in which an IgG autoantibody is formed that binds to platelets It is not clear which antigen on the platelet surface is involved. Although the antiplatelet antibody may bind complement, platelets are not destroyed by direct lysis  General Considerations  Rather, destruction takes place in the spleen, where splenic macrophages with Fc receptors bind to antibody-coated platelets Since the spleen is the major site both of antibody production and platelet sequestration, splenectomy is highly effective therapy  General Considerations 1.definition ：thrombocyte unrelated to a drug, an infection, or autoimmune disease is generally classified as ITP 2.character ：shortened span of platelet increased megakaryocyte in bone marrow 3.classification ：acute, chronic Mechanism 1.Immunity  （1）acute ：postviral infection immune complex (viral Ag and Ab) connect with platelet Fc-R  viral components banding with platelet auto Ab generation  （2）chronic ：not affected by foreign Ag Mechanism 2.liver and spleen ：（1）1/3 platelets are held within the spleen （2）spleen produces platelet associated Ab （3）liver and spleen erase platelet ：7-11 days  in normal persons, 1-3 days in patients Mechanism 3.else ：（1）estrogen: ITP often seen in female patient hold down platelet production augment platelet clearance （2）more delicate capillary wall Clinical Findings Symptoms and Signs: occurs ：in childhood, frequently precipitated by viral infection and usually self-limited. In adult form is usually a chronic disease and only infrequently follows a viral infection.  Clinical Findings age ：It is a disease of young persons, with peak incidence between ages 20 and 50 sex ：there is a 2:1 female predominance  Clinical Findings presenting complaint ：mucosal or skin bleeding. Common types ：epistaxis, oral bleeding, menorrhagia, purpura, and petechiae. Patients are systemically well and not febrile. Clinical Findings On examination ：no abnormal findings other than those related to bleeding. An enlarged spleen should lead one to doubt the diagnosis. Common signs of bleeding are purpura, petechiae, and hemorrhagic bullae in the mouth. Clinical Findings 1. occurs ：（1）acute ：children, fever  viral infection history  fervent uprise,  （2）chronic ：young or middle-aged female  dormant uprise  Clinical Findings 2.  bleeding ：（1）manifestation ：a. petechial and purpuric 、epistaxis gum bleeding b. menorrhagia 、digestive tract 、urotract bleeding c. retina hemorrhage—blindness intracranial hemorrhage--death Clinical Findings （2）characteristic ：a. acute ：severe 、self-limited (4-6w ）seldom relapse  b. chronic ：less severe 、ofter relapse longterm else ：anemia (severe bleeding) mild splenomegaly  Laboratory Findings Laboratory Findings: Peripheral blood ：counts ：The hallmark is thrombocytopenia, which may be less than 10,000/mL.  Other counts are usually normal except for occasional mild anemia  Laboratory Findings cell morphology ：normal except that platelets are slightly enlarged (megathrombocytes). These larger platelets are young platelets produced in response to enhanced platelet destruction. Laboratory Findings Evans‘s syndrome ：Approximately 10% of patients will have coexistent autoimmune hemolytic anemia will see anemia, reticulocytosis, and spherocytes on peripheral smear. Red blood cell fragmentation should not be seen.  Laboratory Findings bone marrow ：appear normal, with a normal or increased number of megakaryocytes. Tests ：Coagulation studies will be entirely normal. Quantitate platelet-associated IgG may help the diagnosis ，highly sensitive (95%) but very nonspecific(50%) Essentials of Diagnosis Isolated thrombocytopenia. Other hematopoietic cell lines normal. No systemic illness. Spleen not palpable. Normal bone marrow with normal or increased megakaryocytes Differential Diagnosis Thrombocytopenia may be produced either by abnormal bone marrow function or by peripheral destruction. bone marrow disorders ：diagnoses such as myelodysplasia can only be excluded by examining the bone marrow.  Differential Diagnosis peripheral destruction ：Can be ruled out by initial evaluation.  Disorders such as DIC 、TTP 、HUS 、hypersplenism, and sepsis are easily excluded by the absence of systemic illness. Patients with isolated thrombocytopenia with no other abnormal findings almost certainly have immune thrombocytopenia. Differential Diagnosis Patients should be questioned regarding drug use, especially sulfonamides, quinine, thiazides, cimetidine, gold, and heparin. Heparin is now the most common cause of drug-induced thrombocytopenia in hospitalized patients. SLE 、Cll are common causes of secondary thrombocytopenic purpura, hematologically identical to ITP. Treatment Few adults with ITP will have spontaneous remissions, most will require treatment. Prednisone ：Primarily by decreasing the affinity of splenic macrophages for antibody-coated platelets. High-dose also reduces the binding of antibody to the platelet surface.  Long-term therapy decrease antibody production Treatment Initial treatment is 1–2 mg/kg/d. Bleeding will often diminish within 1 day The platelet count will usually begin to rise within a week Responses are almost always seen within 3 weeks. About 80% of patients will respond, and the platelet count will usually return to normal. Treatment High-dose therapy should be continued until the platelet count is normal, and the dose should then be gradually tapered. In most, thrombocytopenia will recur if prednisone is completely withdrawn, and one aims to find a dose that will maintain an adequate platelet count. Treatment It is not necessary for the platelet count to be entirely normal the risk of bleeding is small with platelet counts above 50,000/mL.  Treatment Splenectomy ：the most definitive treatment for ITP, and most adult patients will ultimately undergo splenectomy High-dose prednisone therapy should not be continued indefinitely in an attempt to avoid surgery.  Treatment Indicated ：If patients do not respond to prednisone initially or require unacceptably high doses to maintain an adequate platelet count. Other patients may be intolerant of prednisone or may simply prefer the surgical alternative. Treatment Safety ：performed safely even with platelet counts less than 10,000/mL. Efficacy ：Eighty percent of patients benefit from splenectomy with either complete or partial remission.  Treatment High-dose intravenous immunoglobulin Reserved for bleeding emergencies or situations such as preparing a severely thrombocytopenic patient for surgery  This treatment is expensive Treatment 400 mg/kg/d for 3–5 days highly effective in rapidly raising the platelet count. The response rate is 90% The platelet count rises within 1–5 days. The beneficial effect lasts only 1–2 weeks. Treatment Danazol ：patients who fail to respond to prednisone and splenectomy ，600 mg/d, with responses obtained in about half of cases. Immunosuppressive agents ：employed in refractory cases include vincristine, vinblastine infusions, azathioprine, cyclosporine, and cyclophosphamide. Treatment Platelet transfusions ：Rarely used in the treatment of ITP Since exogenous platelets will survive no better than the patient's own and will survive less than a few hours. Platelet transfusion reserved for cases of life-threatening bleeding in which even fleeting hemostasis may be of benefit.  Prognosis The prognosis for remission is good. In most cases, the disease is initially controlled with prednisone splenectomy offers definitive therapy.  Prognosis The major concern during the initial phases is cerebral hemorrhage, which becomes a risk when the platelet count is less than 5000/mL. These patients usually exhibit warning signs of mucosal bleeding. However, even at these very low platelet counts, fatal bleeding is rare. * *