Abnormal bleeding Excessive Bleeding Unusual or excessive bleeding may be indicated by several different signs and symptoms. Patients may present with Unexplained nosebleeds (epistaxis) Excessive or prolonged menstrual blood flow... read more can result from disorders of the coagulation system Overview of Hemostasis Hemostasis, the arrest of bleeding from an injured blood vessel, requires the combined activity of Vascular factors Platelets Plasma coagulation factors Regulatory mechanisms counterbalance... read more , of platelets Overview of Platelet Disorders Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes... read more , or of blood vessels Overview of Vascular Bleeding Disorders Bleeding may result from abnormalities in Platelets Coagulation factors Blood vessels Vascular bleeding disorders result from defects in blood vessels, typically causing cutaneous or mucosal... read more . Disorders of coagulation can be acquired or hereditary.
The major causes of acquired coagulation disorders are
Development of circulating anticoagulants Coagulation Disorders Caused by Circulating Anticoagulants Circulating anticoagulants are usually autoantibodies that neutralize specific clotting factors in vivo (eg, an autoantibody against factor VIII or factor V) or inhibit phospholipid-bound proteins... read more
Disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC)
Severe liver disease (eg, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more , fulminant hepatitis Fulminant Hepatitis Fulminant hepatitis is a rare syndrome of rapid (usually within days or weeks), massive necrosis of liver parenchyma and a decrease in liver size (acute yellow atrophy); it usually occurs after... read more , acute fatty liver of pregnancy Fatty liver of pregnancy Hepatic disorders in pregnancy may be Unique to pregnancy Preexisting Coincident with pregnancy and possibly exacerbated by pregnancy Jaundice may result from nonobstetric or obstetric conditions. read more ) may disturb hemostasis Overview of Hemostasis Hemostasis, the arrest of bleeding from an injured blood vessel, requires the combined activity of Vascular factors Platelets Plasma coagulation factors Regulatory mechanisms counterbalance... read more by impairing clotting factor synthesis. Because all coagulation factors are made in the liver (by hepatocytes and hepatic sinusoidal endothelial cells), both the prothrombin time (PT) and partial thromboplastin time (PTT) are prolonged in severe liver disorders. (PT results are typically reported as INR [international normalized ratio].) Occasionally, decompensated liver disease also causes excessive fibrinolysis and bleeding due to decreased hepatic synthesis of alpha 2-antiplasmin.
The most common hereditary disorder of hemostasis is
The most common hereditary coagulation disorders are
Testing for Coagulation Disorders
Patients in whom a coagulation disorder is suspected require laboratory evaluation beginning with
Prothrombin time (PT) and partial thromboplastin time (PTT)
Complete blood count (CBC) with platelet count
Peripheral blood smear
Results of these tests narrow the diagnostic possibilities and guide further testing.
Normal results on initial tests exclude many bleeding disorders. The main exceptions are
Von Willebrand disease is a common entity in which the associated deficiency of factor VIII is frequently insufficient to prolong the PTT. Patients who have normal initial test results, along with symptoms or signs of bleeding and a positive family history, should be tested for von Willebrand disease by measuring plasma von Willebrand factor (VWF) antigen, ristocetin cofactor activity (an indirect test of VWF function), VWF multimer pattern, and factor VIII levels.
Hereditary hemorrhagic telangiectasia (also called Osler-Weber-Rendu syndrome) is a hereditary disorder of vascular malformation. Patients with this disorder have small red-to-violet lesions on the face, lips, oral and nasal mucosa, and tips of the fingers and toes. They may experience recurrent bleeding from the nasal mucosa and gastrointestinal tract and may have other potentially serious consequences of arteriovenous malformations.
If thrombocytopenia Overview of Platelet Disorders Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes... read more is present, the peripheral blood smear often suggests the cause.
If the smear is normal, patients should be tested for HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more and hepatitis C Hepatitis C, Chronic Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more . If these tests are negative and the patient is not pregnant and has not taken a medication known to cause platelet destruction, then immune thrombocytopenia Immune Thrombocytopenia (ITP) Immune thrombocytopenia (ITP) is a bleeding disorder usually without anemia or leukopenia. Typically, it is chronic in adults, but it is usually acute and self-limited in children. Spleen size... read more (ITP) is likely.
If the smear also shows signs of hemolysis Diagnosis At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more (fragmented red blood cells), thrombotic thrombocytopenic purpura Thrombotic Thrombocytopenic Purpura (TTP) Thrombotic thrombocytopenic purpura (TTP) is an acute, fulminant disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia. Other manifestations may include alterations... read more (TTP) or hemolytic-uremic syndrome Hemolytic-Uremic Syndrome (HUS) Hemolytic-uremic syndrome (HUS) is an acute, fulminant disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS usually occurs in children... read more (HUS) should be suspected. "Classic" HUS occurs in patients with Shiga-like toxin-induced hemorrhagic colitis that occurs during infections with several Escherichia coli serotypes. An "atypical" form of HUS occurs uncommonly in individuals with congenital abnormalities of the alternative complement pathway. The Coombs test is negative in TTP and HUS.
If the CBC and peripheral blood smear demonstrate other cytopenias or immature white blood cells, a hematologic abnormality affecting multiple cell types should be suspected. Bone marrow aspiration and biopsy are then necessary for diagnosis.
Prolonged PTT with normal platelets and PT
A prolonged PTT with a normal platelet count and PT suggests hemophilia A or B Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more , and factor VIII and IX assays are indicated. Inhibitors that specifically prolong the PTT include an autoantibody against factor VIII and antibodies against protein-phospholipid complexes (lupus anticoagulant). Clinicians suspect one of these inhibitors when a prolonged PTT does not correct after 1:1 mixing with normal plasma. In patients with normal factor VIII and factor IX levels, factor XI deficiency (hemophilia C, or Rosenthal disease) should also be considered. Factor XI deficiency is particularly common in patients with Ashkenazi Jewish ancestry.
Prolonged PT with normal platelets and PTT
A prolonged PT with a normal platelet count and PTT suggests factor VII deficiency. Congenital factor VII deficiency is rare; however, the short half-life of factor VII in plasma causes factor VII to decrease to low levels more rapidly than other vitamin K–dependent coagulation factors in patients beginning warfarin anticoagulation, in patients with early vitamin K deficiency Vitamin K Deficiency Vitamin K deficiency results from extremely inadequate intake or fat malabsorption. Risk of bleeding is increased by use of coumarin anticoagulants. Deficiency is particularly common among breastfed... read more , or in patients with incipient liver disease.
Prolonged PT and PTT with thrombocytopenia
A prolonged PT and PTT with thrombocytopenia suggests DIC Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more , especially in patients with obstetric complications, sepsis, cancer, or shock.
Confirmation is by finding elevated levels of D-dimer (or fibrin degradation products) and decreasing plasma fibrinogen levels on serial testing.
A prolonged PT, prolonged PTT, and thrombocytopenia can also result from liver disease because hepatocytes synthesize most coagulation factors (except factor VIII) as well as thrombopoietin, the primary platelet growth factor. In patients with liver disease and portal hypertension, thrombocytopenia also results from splenic sequestration. Many patients with liver disease and thrombocytopenia also have leukopenia Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to < 4000/mcL (9/L). It is usually the consequence of a reduced number of circulating neutrophils, although... read more and anemia Etiology of Anemia Anemia is a decrease in the number of red blood cells (RBCs), which leads to a decrease in hematocrit and hemoglobin content. (See also Red Blood Cell Production.) The RBC mass represents the... read more . Testing for hepatitis C Hepatitis C, Acute Hepatitis C is caused by an RNA virus that is often parenterally transmitted. It sometimes causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice but may be asymptomatic... read more is recommended.
Prolonged PT or PTT with normal platelet count
A prolonged PT or PTT with a normal platelet count can occur with liver disease or vitamin K deficiency Vitamin K Deficiency Vitamin K deficiency results from extremely inadequate intake or fat malabsorption. Risk of bleeding is increased by use of coumarin anticoagulants. Deficiency is particularly common among breastfed... read more , or during anticoagulation with warfarin, unfractionated heparin, direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban), or direct thrombin inhibitors (argatroban, bivalirudin—see table ).
Liver disease is suspected based on history or physical examination findings (eg, jaundice, hepatomegaly, splenomegaly, telangiectasia) and is confirmed by finding elevations of serum aminotransferases and bilirubin.
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