Bleeding

A careful history is the most effective way to determine the presence and significance of a bleeding disorder. Abnormal hemostasis may result from liver disease, uremia, malignancy, or systemic lupus erythematous. The history should include medications, including over-the-counter products (aspirin), family history of abnormal bleeding, epistaxis, menorrhagia, excessive prolonged bleeding from minor cuts, bruising, prolonged or profuse bleeding after dental extraction, excessive bleeding after major surgery or obstetric delivery, and trauma followed by bleeding considered excessive relative to the injury. The timing and type of bleeding have diagnostic significance. For example, if bleeding following dental extraction is immediate and lasts >24 hours, a problem with primary hemostatic plug formation may be present. Therefore, this may suggest a platelet disorder. If initial hemostasis seemed normal but prolonged bleeding developed 2-3 days later, a problem in the coagulation phase is suspected. Spontaneous mucus membrane bleeding (e.g., gum bleeding, nose bleeding) and petechiae are suggestive of a vascular disorder, thrombocytopenia. or abnormal platelet function. On the other hand, hemarthrosis, deep hematomas, and retroperitoneal bleeding more likely reflect a severe coagulation abnormality, such as hemophilia, if problems have been lifelong, or spontaneous inhibitor of factor VIII, if problems appear later in life. Vascular disorders such as vascular purpura present with bleeding from mucus membranes and the appearance of petechiae, but usually the platelet count and the coagulation profile (PT and PIT) are normal.

The causes of thrombocytopenia can be divided into (a) decreased platelet production, (b) decreased platelet survival, (c) sequestration (hypersplenism), and (d) dilutional. Automated cell counters report spurious thrombocytopenia in approximately 0.1 % of patients. This is generally a result of platelet clumping after drawing blood into the anticoagulant ethylenedi-aminetetraacetic acid (EDTA). Confirmation can be obtained by identifying platelet aggregates on peripheral blood smear and by obtaining a normal platelet count after using citrate or heparin as an anticoagulant. Therefore, reviewing the peripheral blood smear is very important for identifying spurious thrombocytopenia. Impaired platelet production is caused by a bone marrow abnormality, such as infiltration caused by malignancy or myelofibrosis, marrow hypoplasia as a result of chemicals, drugs, or radiation, and viruses. In these cases, a deficit of platelet production is rarely seen without abnormalities in the production of white cells and red cells. Therefore, when impaired platelet production is the result of a bone marrow abnormality, we also expect abnormalities in the number of leukocytes and red cells. Decreased platelet survival is another cause of thrombocytopenia. Decreased platelet survival can be a result of increased destruction of platelets, such as ITP (caused by immunoglobulin [Ig|G antibody against the platelets), drug-induced thrombocytopenic purpura, secondary immunologic purpura (as in lymphoma, lupus, infection with human immunodeficiency virus type 1). and posttransfusion purpura. DIC, HUS, cavernous hemangioma, and acute infections are also in this category.

Increased platelet destruction is seen in idiopathic thrombocytopenic purpura as a result of destruction in the spleen after autoantibody adherence to platelets, which may also impair platelet production in the bone marrow. Acute ITP is most common in early childhood, often following an antecedent upper respiratory infection, and usually is self-limiting. In children, ITP usually resolves spontaneously within 3-6 months. ITP in adults is more likely to have an insidious or subacute presentation, is most likely to occur in women ages 2(1-40 years old. and is more likely to persist for months to years, with uncommon spontaneous remission. The patient will present with the clinical manifestations of thrombocytopenia, such as petechiae and mucosal bleeding, but with no systemic toxicity, no enlargement of nodes or abdominal organs, and a normal blood count and normal peripheral blood smear except for thrombocytopenia. In ITP. tests for antiplatelet antibodies are of limited use because false-positive results are common. Bone marrow examination often reveals increased megakaryocytes but otherwise normal findings.

Several immunologic disorders may mimic true ITP. When a patient presents with a clinical picture of ITP. any drug that the patient is using should be considered a possible cause. Discontinuation of the medication should lead to improvement in the platelet count within a time frame consistent with the drug's metabolism. Many drugs are known to cause thrombocytopenia, such as H, blockers and heparin. In general, the diagnosis is made by clinical observation of the response to drug withdrawal. Thrombocytopenia can be found in patients with systemic lupus erythematosus, Hodgkin disease, and non-Hodgkin lymphoma. These patients may have splenomegaly and lymphadenopathy, and because these physical findings are not part of the true ITP. organ enlargement should suggest the possibility of a different disease. A patient with AIDS and individuals with HIV-1 infection also have an increased incidence of thrombocytopenia. Posttransfusion purpura is a rare clinical syndrome in which marked thrombocytopenia occurs 5-10 days after a routine red cell transfusion. Most patients are women who previously have been pregnant or have been transfused, with the suspected mechanism being antiplatelet antibody.

A number of nonimmunologic disorders mimic true ITP. These disorders are characterized by accelerated platelet consumption, as in DIC. DIC can be distinguished from true ITP because of the low level of plasma coagulation factors and elevated levels of fibrin and fibrinogen split products. A low fibrinogen level is especially helpful, because such reduction is rare except in DIC. Prolongation of PT and PTT also are helpful but are less specific. DIC usually is associated with infections, obstetric catastrophes such as abruptio placentae and retained dead fetus syndrome, malignancy, and vascular abnormalities such as giant hemangiomas. Usually, the cause of DIC is obvious, and treatment should be directed towards correcting the underlying cause. Another known immunologic disorder that mimics true ITP is

TTP/HUS, which is a clinical syndrome characterized by the formation of microscopic thrombi composed of platelets that are rapidly consumed in the process. TTP has a subacute onset with five main findings seen in various combination: (a) thrombocytopenia; (b) microangiopathic hemolytic anemia with elevated lactate dehydrogenase (LDH) level, and poikilocytosis and schistocytosis in the peripheral blood smear: (c) fever; (d) fluctuating central nervous system deficits with altered mental status; and (e) renal failure. Table 58-1 compares DIC. TTP. and ITP.

Von Willebrand Disease Patients who appear to have impaired primary hemostasis (i.e.. petechiae. easy bruising, mucosal bleeding, menorrhagia) yet have normal platelet counts should be suspected of having impaired platelet function, as in vWI). vWD is the most common inherited bleeding disorder. It may occur as often as I in 1000 individuals. It is an autosomal dominant disorder but often is not recognized because of relatively mild bleeding symptoms or because of excessive bleeding attributed to other causes, for example, menorrhagia attributed to uterine fibroids, von Willebrand factor (vWF) is a large complex multimeric protein that has two major functions: it allows for platelet adhesion to endothelium at sites of vascular injury, and it is the carrier protein for coagulation factor VIII. which stabilizes the molecule. vWD is a heterogenous group of disorders, but a common feature is deficiency in the amount or function of vWF. Clinical features are those of primary hemostasis as discussed. Typical laboratory features are reduced levels of vWF. reduced vWF activity as measured by ristocetin cofactor assay, and reduced factor VIII activity. Treatment is desmopressin acetate (DDAVP), which causes release of stored vWF before surgery, or use of factor VIII concentrate, which contains large amount of vWF.

Treatment of Thrombocytopenia Identifying the underlying etiology of the thrombocytopenia is paramount in rendering the correct treatment. If ITP is diagnosed after careful investigation, the treatment is fairly straightforward. In 80% of children affected with ITP, spontaneous remission occurs within 6 weeks, but spontaneous recovery in adults is less common. Many physicians elect to treat affected patients, especially adults, with oral steroids, such as prednisone 1-2 mg per kilogram of body weight. Platelet transfusions usually are unnecessary and should be reserved for rare life-threatening situations because survival of transfused platelets in ITP may be as short as a few minutes. Because the spleen removes the antibody-bound platelets, patients who do not respond to steroids may be candidates for splenectomy. Intravenous immunoglobulin (IVI«) is often used when platelet counts are <10,000 and is used concurrently with steroids. Immunosuppressive agents can be used if splenectomy is ineffective.

Table 58-1

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