Etiology

Patients may be born with a deficiency of one of the factors needed for blood coagulation—for example, factor VIII deficiency as in hemophilia A or factor IX deficiency as in hemophilia B or Christmas disease. Congenital deficiencies of the other coagulation factors have been reported but are rare ( Table 25.1 ). When congenital deficiency of a coagulation factor occurs, only a single factor is affected.

In von Willebrand disease, the primary problem involves lack of various sizes of von Willebrand factor (vWF), which are needed to attach platelets to damaged vascular wall tissues and to carry factor VIII in circulation. In the most severe form of the disease, bleeding occurs as a consequence of lack of platelet adhesion and deficiency of factor VIII. Bernard-Soulier disease is a disorder of platelet adhesion to vWF caused by a lack of glycoprotein (GP) Ib on the platelet membrane. These platelets are unable to bind to vWF and thus are unable to adhere to the subendothelium. Glanzmann thrombasthenia is a disorder of platelet aggregation due to abnormality of the platelet membrane complex GP IIb/IIIa. The platelets can adhere to the subendothelium but cannot bind to fibrinogen.

Hereditary hemorrhagic telangiectasia is a disorder consisting of multiple telangiectatic lesions involving the skin and mucous membranes. Bleeding occurs because of the inherent mechanical fragility of the affected vessels. Problems with the construction of connective tissue components of the vessel wall are the underlying weakness in Ehlers-Danlos disease, osteogenesis imperfecta, pseudoxanthoma elasticum, and Marfan syndrome. Readers are referred to other sources for further information on these latter diseases.

Pathophysiology and Complications

The three phases of hemostasis for controlling bleeding are vascular, platelet, and coagulation. The vascular and platelet phases are referred to as primary, and the coagulation phase is secondary. The coagulation phase is followed by the fibrinolytic phase, during which the clot is dissolved. These hemostatic mechanisms are discussed in detail in Chapter 24 , on acquired bleeding disorders.

Signs and Symptoms

The most common objective findings in patients with genetic coagulation disorders are ecchymoses, hemarthrosis, and dissecting hematomas ( Figs. 25.1 and 25.2 ). The signs seen most commonly in patients with abnormal platelets or thrombocytopenia are petechiae and ecchymoses ( Fig. 25.3 ). The signs seen most commonly in patients with vascular defects are petechiae and bleeding from the skin or mucous membrane.

Large area of subcutaneous ecchymoses caused by trauma in a patient with hemophilia.

(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 4, London, 2010, Mosby.)

Acute hemarthrosis of the knee is a common complication of hemophilia. It may be confused with acute infection unless the patient’s coagulation disorder is known because the knee is hot, red, swollen, and painful.

(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)

Purpura (petechiae), in this case, thrombocytopenia purpura. The patient was a 15-year-old boy whose antiepileptic treatment regimen had recently been modified to include sodium valproate. This is just one of a number of drugs that may induce thrombocytopenia purpura, but the disorder is almost always reversible if the drug therapy is stopped.

(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)

Laboratory and Diagnostic Findings

Three tests are recommended for use in initial screening for possible bleeding disorders: activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet count ( Fig. 25.4 ). If no clues are evident as to the cause of the bleeding problem and the dentist is ordering the tests through a commercial laboratory, an additional test can be added to the initial screen: thrombin time (TT).

Organization of the coagulation system based on current screening assays. The intrinsic coagulation system consists of the protein factors XII, XI, IX, and VIII; prekallikrein (PK); and high-molecular-weight kininogen (HK). The extrinsic coagulation system consists of tissue factor and factor VII. The common pathway of the coagulation system consists of factors X, V, and II and fibrinogen (I). The activated partial thromboplastin time requires the presence of every protein except tissue factor and factor VII. The prothrombin time requires tissue factor; factors VII, X, V, and II; and fibrinogen. The thrombin clotting time only tests the integrity of fibrinogen.

(From McPherson RA, Pincus MR, editors: Henry’s clinical diagnosis and management by laboratory methods, ed 22, London, 2012, Saunders.)

Patients with positive results on screening tests should be evaluated further so that the specific deficiency can be identified and the presence of inhibitors ruled out. A hematologist orders these tests, establishes a diagnosis that is based on the additional testing, and makes recommendations for treatment of the patient who is found to have a significant bleeding problem. The screening laboratory tests are discussed in detail in Chapter 24 .

In patients with prolonged aPTT, PT, and TT, the defect involves the last stage of the common pathway, which is the activation of fibrinogen to form fibrin to stabilize the clot. The plasma level of fibrinogen is determined, and if it is within normal limits, then tests for fibrinolysis are performed. These tests, which detect the presence of fibrinogen, fibrin degradation products, or both, consist of staphylococcal clumping assay, agglutination of latex particles coated with antifibrinogen antibody, and euglobulin clot lysis time.

Signs and Symptoms

The most common objective findings in patients with genetic coagulation disorders are ecchymoses, hemarthrosis, and dissecting hematomas ( Figs. 25.1 and 25.2 ). The signs seen most commonly in patients with abnormal platelets or thrombocytopenia are petechiae and ecchymoses ( Fig. 25.3 ). The signs seen most commonly in patients with vascular defects are petechiae and bleeding from the skin or mucous membrane.

Large area of subcutaneous ecchymoses caused by trauma in a patient with hemophilia.

(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 4, London, 2010, Mosby.)

Acute hemarthrosis of the knee is a common complication of hemophilia. It may be confused with acute infection unless the patient’s coagulation disorder is known because the knee is hot, red, swollen, and painful.

(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)

Purpura (petechiae), in this case, thrombocytopenia purpura. The patient was a 15-year-old boy whose antiepileptic treatment regimen had recently been modified to include sodium valproate. This is just one of a number of drugs that may induce thrombocytopenia purpura, but the disorder is almost always reversible if the drug therapy is stopped.

(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)

Laboratory and Diagnostic Findings

Three tests are recommended for use in initial screening for possible bleeding disorders: activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet count ( Fig. 25.4 ). If no clues are evident as to the cause of the bleeding problem and the dentist is ordering the tests through a commercial laboratory, an additional test can be added to the initial screen: thrombin time (TT).

Organization of the coagulation system based on current screening assays. The intrinsic coagulation system consists of the protein factors XII, XI, IX, and VIII; prekallikrein (PK); and high-molecular-weight kininogen (HK). The extrinsic coagulation system consists of tissue factor and factor VII. The common pathway of the coagulation system consists of factors X, V, and II and fibrinogen (I). The activated partial thromboplastin time requires the presence of every protein except tissue factor and factor VII. The prothrombin time requires tissue factor; factors VII, X, V, and II; and fibrinogen. The thrombin clotting time only tests the integrity of fibrinogen.

(From McPherson RA, Pincus MR, editors: Henry’s clinical diagnosis and management by laboratory methods, ed 22, London, 2012, Saunders.)

Patients with positive results on screening tests should be evaluated further so that the specific deficiency can be identified and the presence of inhibitors ruled out. A hematologist orders these tests, establishes a diagnosis that is based on the additional testing, and makes recommendations for treatment of the patient who is found to have a significant bleeding problem. The screening laboratory tests are discussed in detail in Chapter 24 .

In patients with prolonged aPTT, PT, and TT, the defect involves the last stage of the common pathway, which is the activation of fibrinogen to form fibrin to stabilize the clot. The plasma level of fibrinogen is determined, and if it is within normal limits, then tests for fibrinolysis are performed. These tests, which detect the presence of fibrinogen, fibrin degradation products, or both, consist of staphylococcal clumping assay, agglutination of latex particles coated with antifibrinogen antibody, and euglobulin clot lysis time.

Vascular Defects

Hereditary hemorrhagic telangiectasia, also referred to as Osler-Weber-Rendu syndrome, is a rare autosomal dominant disorder that is characterized by multiple telangiectatic lesions involving the skin, mucous membranes, and viscera. One form of the disorder, characterized by a high frequency of symptomatic pulmonary arteriovenous malformations and cerebral abscesses, has been identified. Both ENG and ALK-1 encode putative receptors for transforming growth factor-beta (TGF-β) superfamily that play a critical role for proper development of the blood vessels.

The telangiectasias consist of focal dilation of postcapillary venules with connections to dilated arterioles, initially through capillaries and later directly. Perivascular mononuclear cell infiltrates also are observed. The vessels of HHT show a discontinuous endothelium and an incomplete smooth muscle cell layer. The surrounding stroma lacks elastin. Thus, the bleeding tendencies are thought to be because of mechanical fragility of the abnormal vessels. Lesions usually appear in affected persons by the age of 40 years, and they increase in number with age.

Clinical Findings.

On clinical examination, venous lakes and papular, punctate, matlike, and linear telangiectasias appear on all areas of the skin and mucous membranes, with a predominance of lesions on and under the tongue and on the face, lips, perioral region, nasal mucosa, fingertips, toes, and trunk. Recurrent epistaxis is a common finding in patients with this disorder; symptoms tend to worsen with age. Thus, the severity of the disorder often can be gauged by the age at which the nosebleeds begin, with the most severely affected patients experiencing recurrent epistaxis during childhood. Cutaneous changes usually begin at puberty and progress throughout life. Bleeding can occur in virtually every organ, with GI, oral, and urogenital sites most commonly affected ( Fig. 25.5 ). In the GI tract, the stomach and duodenum are more frequent sites of bleeding than is the colon. Other features may include hepatic and splenic arteriovenous shunts, as well as intracranial, aortic, and splenic aneurysms. Pulmonary arteriovenous fistulas are associated with oxygen desaturation, hemoptysis, hemothorax, brain abscess, and cerebral ischemia caused by paradoxical emboli. Cirrhosis of the liver has been reported in some families.

Hereditary hemorrhagic telangiectasia (HHT). HHT is a condition in which occult blood loss in the gut may lead to severe iron deficiency anemia. The diagnosis usually is clear from a careful clinical examination, although the telangiectases are not always as obvious, as in this patient with multiple lesions on the face, lip, and tongue. The patient had received multiple blood transfusions over many years because of HHT-associated gastrointestinal blood loss, and he had developed cirrhosis associated with hepatitis B antigen positivity, probably as a result of transmission of hepatitis B in transfused blood.

(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)

Laboratory and Diagnostic Findings

The diagnosis is based on clinical (Curacao) criteria; there are no reliable laboratory tests to determine the tendency for bleeding to occur in affected persons. Clinical findings and a history of bleeding problems are the only effective means to identify patients at risk.