Bleeding Disorders
Overview of Coagulation Disorders
Abnormal bleeding can result from disorders of the coagulation system, of platelets, or of blood vessels. Disorders of coagulation can be acquired or hereditary.
The major causes of acquired coagulation disorders are
• Vitamin K deficiency
• Liver disease
• Disseminated intravascular coagulation (DIC)
• Development of circulating anticoagulants
Severe liver disease (eg, cirrhosis, fulminant hepatitis, acute fatty liver of pregnancy) may disturb hemostasis by impairing clotting factor synthesis. Because all coagulation factors are made in the liver (by hepatocytes and endothelial cells), both the PT and PTT are prolonged in severe liver disorders. (PT results are typically reported as INR.) 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
• von Willebrand disease (VWD)
The most common hereditary coagulation disorders are
• The hemophilias
Testing
Patients in whom a coagulation disorder is suspected require laboratory evaluation beginning with
• Prothrombin time (PT) and partial thromboplastin time (PTT)
• CBC with platelet count
• Peripheral blood smear
Results of these tests narrow the diagnostic possibilities and guide further testing.
Normal results
Normal results on initial tests exclude many bleeding disorders. The main exceptions are
• von Willebrand disease
• Hereditary hemorrhagic telangiectasia
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 VWD by measuring plasma von Willebrand factor (VWF) antigen, ristocetin cofactor activity (an indirect test for large VWF multimers), VWF multimer pattern, and factor VIII levels.
Hereditary hemorrhagic telangiectasia (also called Osler-Weber-Rendu Syndrome) is a hereditary disorder of vascular malformation. People with this disorder have small red-to-violet telangiectatic lesions on the face, lips, oral and nasal mucosa, and tips of the fingers and toes. They may experience recurrent bleeding from nasal mucosa and GI tract and may have other potentially serious consequences of arteriovenous malformations.
Thrombocytopenia
If thrombocytopenia is present, the peripheral blood smear often suggests the cause.
If the smear is normal, patients should be tested for HIV infection. If the result of the HIV test is negative and the patient is not pregnant and has not taken a drug known to cause platelet destruction, then immune thrombocytopenia (ITP) is likely.
If the smear shows signs of hemolysis (fragmented RBCs on smear, decreasing Hb level), thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS) is 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 abnormal WBCs, a hematologic abnormality affecting multiple cell types is suspected. A bone marrow aspiration and biopsy are then necessary for diagnosis.
Prolonged PTT with normal platelets and PT
Prolonged PTT with normal platelets and PT suggests hemophilia A or B. 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.
Prolonged PT with normal platelets and PTT
Prolonged PT with normal platelets 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 or in patients with incipient liver disease.
Prolonged PT and PTT with thrombocytopenia
Prolonged PT and PTT with thrombocytopenia suggest DIC, especially in patients with obstetric complications, sepsis, cancer, or shock.
Confirmation is by finding elevated levels of D-dimers (or fibrin degradation products) and decreasing plasma fibrinogen levels on serial testing.
Prolonged PT or PTT with normal platelet count
Prolonged PT or PTT with normal platelet count occurs with liver disease, vitamin K deficiency, or during anticoagulation with warfarin, unfractionated heparin, or a direct oral inhibitor of thrombin or factor Xa. Liver disease is suspected based on history and is confirmed by finding elevations of serum aminotransferases and bilirubin. Hepatitis testing is then recommended.
Bleeding Disorders
When tissues are injured, blood cell fragments called platelets gather at the wound, providing a foundation for coagulation (clotting). Platelets are bound together by a glue-like protein named von Willebrand factor. Once the initial platelet plug is built, clotting factors gather at the injury site to seal the wound, stop bleeding, and begin the healing process. The clotting factors work in a carefully timed sequence, resulting in a sturdy clot and healed wound.
Overview of Coagulation Disorders
Abnormal bleeding can result from disorders of the coagulation system, of platelets, or of blood vessels. Disorders of coagulation can be acquired or hereditary.
The major causes of acquired coagulation disorders are
• Vitamin K deficiency
• Liver disease
• Disseminated intravascular coagulation (DIC)
• Development of circulating anticoagulants
Severe liver disease (eg, cirrhosis, fulminant hepatitis, acute fatty liver of pregnancy) may disturb hemostasis by impairing clotting factor synthesis. Because all coagulation factors are made in the liver (by hepatocytes and endothelial cells), both the PT and PTT are prolonged in severe liver disorders. (PT results are typically reported as INR.) 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
• von Willebrand disease (VWD)
The most common hereditary coagulation disorders are
• The hemophilias
Testing
Patients in whom a coagulation disorder is suspected require laboratory evaluation beginning with
• Prothrombin time (PT) and partial thromboplastin time (PTT)
• CBC with platelet count
• Peripheral blood smear
Results of these tests narrow the diagnostic possibilities and guide further testing.
Normal results
Normal results on initial tests exclude many bleeding disorders. The main exceptions are
• von Willebrand disease
• Hereditary hemorrhagic telangiectasia
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 VWD by measuring plasma von Willebrand factor (VWF) antigen, ristocetin cofactor activity (an indirect test for large VWF multimers), VWF multimer pattern, and factor VIII levels.
Hereditary hemorrhagic telangiectasia (also called Osler-Weber-Rendu Syndrome) is a hereditary disorder of vascular malformation. People with this disorder have small red-to-violet telangiectatic lesions on the face, lips, oral and nasal mucosa, and tips of the fingers and toes. They may experience recurrent bleeding from nasal mucosa and GI tract and may have other potentially serious consequences of arteriovenous malformations.
Thrombocytopenia
If thrombocytopenia is present, the peripheral blood smear often suggests the cause.
If the smear is normal, patients should be tested for HIV infection. If the result of the HIV test is negative and the patient is not pregnant and has not taken a drug known to cause platelet destruction, then immune thrombocytopenia (ITP) is likely.
If the smear shows signs of hemolysis (fragmented RBCs on smear, decreasing Hb level), thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS) is 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 abnormal WBCs, a hematologic abnormality affecting multiple cell types is suspected. A bone marrow aspiration and biopsy are then necessary for diagnosis.
Prolonged PTT with normal platelets and PT
Prolonged PTT with normal platelets and PT suggests hemophilia A or B. 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.
Prolonged PT with normal platelets and PTT
Prolonged PT with normal platelets 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 or in patients with incipient liver disease.
Prolonged PT and PTT with thrombocytopenia
Prolonged PT and PTT with thrombocytopenia suggest DIC, especially in patients with obstetric complications, sepsis, cancer, or shock.
Confirmation is by finding elevated levels of D-dimers (or fibrin degradation products) and decreasing plasma fibrinogen levels on serial testing.
Prolonged PT or PTT with normal platelet count
Prolonged PT or PTT with normal platelet count occurs with liver disease, vitamin K deficiency, or during anticoagulation with warfarin, unfractionated heparin, or a direct oral inhibitor of thrombin or factor Xa. Liver disease is suspected based on history and is confirmed by finding elevations of serum aminotransferases and bilirubin. Hepatitis testing is then recommended.
Coagulation disorders
Coagulation disorders are disruptions in the body’s ability to control blood clotting. Coagulation disorders can result in either a hemorrhage (too little clotting that causes an increased risk of bleeding) or thrombosis (too much clotting that causes blood clots to obstruct blood flow).These clotting disorders develop due to several conditions.
Major causes of coagulation disorders resulting in bleeding include:
• Hemophilia. This condition is a bleeding disorder in which blood does not clot normally. Children with hemophilia have low levels of a clotting factor protein necessary for clotting.
• Von Willebrand disease. This condition takes its name from a clotting factor protein in the blood called von Willebrand factor. This disorder is often genetic (passed down from parent to child) and causes excessive bleeding when von Willebrand factor is low.
• Other clotting factor deficiencies. Low levels of clotting factor proteins other than those leading to hemophilia may also result in bleeding.
• Disseminated intravascular coagulation. This condition causes overactive clotting that obstructs blood vessels.
• Liver Disease. Liver disease comprises a number of conditions in which liver function is impaired.
• Overdevelopment of circulating anticoagulants. This condition causes diminished clotting that creates a condition with symptoms similar to hemophilia.
• Vitamin K deficiency. A deficiency in this vitamin, which is common in breast-fed infants, can impair blood clotting.
• Platelet dysfunction. Platelets are important cells needed to make blood clots. If platelets are too low or if they do not work properly, bruising and bleeding may occur.
Major causes of coagulation disorders resulting in too much clotting include:
• Factor V Leiden. In this genetic disorder, a blood clotting protein called factor V Leiden overreacts causing the blood to clot too often or too much.
• Antithrombin III (ATIII) deficiency. ATIII helps to regulate the bleeding and clotting system. Also a genetic disorder, low levels of ATIII cause the blood to clot too much.
• Protein C or protein S deficiency. Protein C and protein S help to regulate the bleeding and clotting system. Low levels of either protein cause the blood to clot too much.
• Prothrombin (PT) gene mutation. This is also called factor II mutation. PT gene mutation is a genetic disorder. This mutation results in too much clotting factor being made, and too much clotting factor can result in too much clotting.
• Antiphospholipid antibody syndrome. This is an autoimmune disorder resulting in an increase in certain blood proteins that may increase the risk of clotting.