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HEMOSTASIS AND BLEEDING DISORDERS
Hemostasis is a sequence of events leading to the cessation of bleeding by the forma-tion of a stable fibrin-platelet hemostatic plug. It involves interactions between the vascular wall, platelets, and the coagulation system.
Transient vasoconstriction is mediated by endothelin-1. Thrombogenic factors include a variety of processes:
· Changes in blood flow cause turbulence and stasis favor clot formation.
· Release of tissue factor from injured cells activates factor VII (extrinsic pathway).
· Exposure of thrombogenic subendothelial collagen activates factor XII (intrin-sic pathway).
· Release of von Willebrand factor (vWF) binds to exposed collagen and facili-tates platelet adhesion.
· Decreased endothelial synthesis of antithrombogenic substances (prostacy-clin, nitric oxide [NO2], tissue plasminogin activator, and thrombomodulin)
Platelets are derived from megakaryocytes in the bone marrow. They form a throm-bus through a series of steps.
· Step 1: Platelet adhesion occurs when vWF adheres to subendothelial collagenand then platelets adhere to vWF by glycoprotein Ib.
· Step 2: Platelet activation occurs when platelets undergo a shape change anddegranulation occurs. Platelets synthesize thromboxane A2. Platelets also show membrane expression of the phospholipid complex, which is an impor-tant substrate for the coagulation cascade.
· Step 3: Platelet aggregation occurs when additional platelets are recruited fromthe bloodstream. ADP and thromboxane A2 are potent mediators of aggrega-tion. Platelets bind to each other by binding to fibrinogen using GPIIb-IIIa.
Laboratory tests for platelets include platelet count (normal 150,000–400,000 mm3) and platelet aggregometry.
Bernard-Soulier syndrome and Glanzmann thrombasthenia present as mucocutane-ous bleeding in childhood.
Immune thrombocytopenia purpura (ITP) is an immune-mediated attack (usuallyIgG antiplatelet antibodies) against platelets leading to decreased platelets (throm-bocytopenia) which result in petechiae, purpura (bruises), and a bleeding diathesis (e.g., hematomas).
The etiology involves antiplatelet antibodies against platelet antigens such as GPIIb-IIIa and GPIb-IX (type II hypersensitivity reaction). The antibodies are made in the spleen, and the platelets are destroyed peripherally in the spleen by macrophages, which have Fc receptors that bind IgG-coated platelets.
Forms of ITP include:
· Acute ITP, seen in children following a viral infection and is a self-limited disorder.
· Chronic ITP, usually seen in women in their childbearing years and may be the first manifestation of systemic lupus erythematosus (SLE). Clinically, it is characterized by petechiae, ecchymoses, menorrhagia, and nosebleeds.
Lab studies usually show decreased platelet count and prolonged bleeding time but normal prothrombin time and partial thromboplastin time. Peripheral blood smear shows thrombocytopenia with enlarged immature platelets (megathrombocytes). Bone marrow biopsy shows increased numbers of megakaryocytes with immature forms.
Treatment is corticosteroids, which decrease antibody production; immunoglobulin therapy, which floods Fc receptors on splenic macrophages; and/or splenectomy, which removes the site of platelet destruction and antibody production.
Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of hemostasis inwhich there is widespread intravascular formation of fibrin-platelet thrombi. It is sometimes associated with an acquired or inherited deficiency of the enzyme ADAMTS13, responsible for cleaving large multimers of von Willebrand factor.
Clinically, TTP most often affects adult women. The inclusion criteria are microan-giopathic hemolytic anemia and thrombocytopenia, with or without renal failure or neurologic abnormalities. Pathology includes widespread formation of platelet thrombi with fibrin (hyaline thrombi) leading to intravascular hemolysis (throm-botic microangiopathy).
Lab studies typically show decreased platelet count and prolonged bleeding time but normal prothrombin time and partial thromboplastin time. Peripheral blood smear shows thrombocytopenia, schistocytes, and reticulocytosis. Treatment is plasma exchange.
Hemolytic uremic syndrome (HUS) is a form of thrombotic microangiopathy due toendothelial cell damage. It occurs mostly in children, typically after a gastroenteritis (typically due to Shiga toxin-producing E. coli 0157:H7).
Typical HUS presents with abdominal pain, diarrhea (an atypical variant is diar-rhea-negative), microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Renal involvement is seen more commonly than in TTP. The kidney shows fibrin thrombi in the glomeruli. Renal glomerular endothelial cells are targeted by the bacterial toxin. Glomerular scarring may ensue.
Treatment is supportive (fluid management, dialysis, erythrocyte transfusions); plasma exchange is only used for atypical cases.
Coagulation factors.The majority of the clotting factors are produced by the liver.The factors are proenzymes that must be converted to the active form. Some con- versions occur on a phospholipid surface, and some conversions require calcium.
· The intrinsic coagulation pathway is activated by the contact factors, which include contact with subendothelial collagen, high molecular weight kinino-gen (HMWK), and kallikrein.
· The extrinsic coagulation pathway is activated by the release of tissue factor.
Lab tests for coagulation include the following:
· Prothrombin time (PT), which tests the extrinsic and common coagulation pathways (more specifically, it tests factors VII, X, V, prothrombin, and fibrin-ogen). The international normalized ratio (INR) standardizes the PT test so that results throughout the world can be compared. A longer time means blood takes longer to clot.
· Partial thromboplastin time (PTT), which tests the intrinsic and common coagulation pathways (more specifically, it tests factors XII, XI, IX, VIII, X, V, prothrombin, and fibrinogen).
· Thrombin time (TT), which tests for adequate fibrinogen levels.
· Fibrin degradation products (FDP), which tests the fibrinolytic system (increased with DIC).
Hemophilia A (classic hemophilia) is an X-linked recessive condition resulting froma deficiency of factor VIII. Clinically, hemophilia A predominately affects males. Symptoms vary depending on the degree of deficiency.
· Newborns may develop bleeding at the time of circumcision.
· Other problems include spontaneous hemorrhage into joints (hemarthrosis), easy bruising and hematoma formation after minor trauma, and severe pro-longed bleeding after surgery or lacerations.
Laboratory studies typically show normal platelet count and normal bleeding time, normal PT and prolonged PTT. Treatment is factor VIII concentrate.
Hemophilia B (Christmas disease) is an X-linked recessive condition resulting froma deficiency of factor IX that is clinically identical to hemophilia A. Treatment is recombinant factor IX.
Acquired coagulopathies include vitamin K deficiency (decreased synthesis of fac-tors II, VII, IX, X, and protein C & S) and liver disease (decreased synthesis of virtually all clotting factors).
Von Willebrand disease is an autosomal dominant bleeding disorder characterizedby a deficiency or qualitative defect in von Willebrand factor. vWF is normally produced by endothelial cells and megakaryocytes. Clinical features include spon-taneous bleeding from mucous membranes, prolonged bleeding from wounds, and menorrhagia in young females. Hemarthrosis is uncommon.
Lab studies show normal platelet count, a prolonged bleeding time, normal PT, and often prolonged PTT. Abnormal platelet response to ristocetin (adhesion defect) is an important diagnostic test. Treatment for mild classic cases (type I) is desmo-pressin (an antidiuretic hormone analog), which releases vWF from Weibel-Palade bodies of endothelial cells.
Disseminated intravascular coagulation (DIC) is always secondary to another dis-order. Causes are diverse.
· Obstetric complications can cause DIC because placental tissue factor activates clotting.
· Gram-negative sepsis can cause DIC because tumor necrosis factor activates clotting.
· Microorganisms (especially meningococcus and rickettsiae)
· AML M3 (cytoplasmic granules in neoplastic promyelocytes activate clotting)
· Adenocarcinomas (mucin activates clotting)
DIC causes widespread microthrombi with consumption of platelets and clotting factors, causing hemorrhage. Laboratory studies show decreased platelet count, pro-longed PT/PTT, decreased fibrinogen, and elevated fibrin split products (D dimers). Treat the underlying disorder.
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