Signs and Symptoms

Signs associated with bleeding disorders may appear in the skin or mucous membranes or after trauma or invasive procedures. Jaundice ( Fig. 24.5 ), spider angiomas ( Fig. 24.6 ), and ecchymoses ( Fig. 24.7 ) may be seen in individuals with liver disease. A fine tremor of the hands when held out also may be observed in these patients. In about 50% of persons with liver disease, a reduction in platelets occurs because of hypersplenism that results from the effects of portal hypertension; these patients may show petechiae on the skin and mucosa.

Jaundice of the skin in a patient with chronic liver disease.

A, Spider angioma on the skin of a patient with chronic liver disease. B, Note how the spider legs of the angioma blanch with pressure on the central arteriole.

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

Ecchymoses on the mucosa of the hard and soft palate in a patient with chronic liver disease.

Petechiae ( Fig. 24.8 ) and ecchymoses are the signs seen most commonly in patients with abnormal platelets or thrombocytopenia.

The arm of a patient with thrombocytopenia showing numerous petechiae.

Patients with acute or chronic leukemia may reveal one or more of the following signs: ulceration of the oral mucosa, hyperplasia of the gingivae ( Fig. 24.9 ), petechiae of the skin or mucous membranes ( Fig. 24.10 ), ecchymoses of skin or mucous membranes, and lymphadenopathy. Chapter 23 discusses these findings in greater detail.

Hyperplastic gingiva in a patient with leukemia.

Palatal petechiae in a patient with leukemia.

(From Hoffbrand AV: Color atlas of clinical hematology, ed 3, St. Louis, 2000, Mosby.)

A number of patients with bleeding disorders may show no objective signs that suggest the underlying problem. Severe or chronic bleeding can lead to anemia with features of pallor, fatigue, and so forth. Anemia is discussed in detail in Chapter 22 .

Laboratory and Diagnostic Findings

Several tests are available to screen patients for bleeding disorders and to help pinpoint the specific deficiency. In general, screening is done in dentistry when the patient reveals a history of a bleeding problem or a family member with a history of a bleeding problem or when signs of bleeding disorders are found during the clinical examination. The dentist can order the screening tests, or the patient can be referred to a hematologist for screening. In medicine, routine screening is done for patients before major surgical procedures such as open heart surgery are performed.

The Ivy bleeding time (BT) has been used to screen for disorders of platelet function and thrombocytopenia. It has been found to be unreliable and is no longer used as a screening test. The platelet function analyzer (PFA-100), an instrument that measures platelet-dependent coagulation under flow conditions, is more sensitive and specific for platelet disorders and von Willebrand disease than the bleeding time; however, it is not sensitive enough to rule out underlying mild bleeding disorders. The relationship between bleeding time test and postextraction bleeding in a healthy control population was evaluated by Brennan et al in 2002. The mean cutaneous BT was 5.9 minutes (range, 1.5–10.0 minutes). The mean oral BT was 7.5 minutes (range, 0–20 minutes). Cutaneous BT did not correlate with oral BT or any measures of postoperative bleeding. Therefore, the BT and PFA-100 are not recommended as screening tests to be used by dentists.

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. 24.11 ). In the absence of clues to the cause of the bleeding problem, if the dentist is ordering the tests through a commercial laboratory, an additional test can be added to the initial screen: the thrombin time (TT).

Coagulation cascade indicating the intrinsic pathway measured by activated partial thromboplastin time (aPTT); the extrinsic pathway measured by prothrombin time (PT); and the conversion of fibrinogen to fibrin, which is measured by thrombin time (TT). Other proteins—prekallikrein and high-molecular-weight (HMW) kininogen—participate in the contact activation phase but are not considered coagulation factors. Ca ²⁺ , Calcium; PL, phospholipid.

(From Rick ME: Coagulation testing. In Young NS, Gerson SL, High KA, editors: Clinical hematology, St. Louis, 2006, Mosby.)

Patients with positive screening test results should be evaluated further so 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.

Screening Tests.

Partial Thromboplastin Time. The partial thromboplastin time (PTT) is used to check the intrinsic system (factors VIII, IX, XI, and XII) and the common pathways (factors V and X, prothrombin, and fibrinogen). It also is the best single screening test for coagulation disorders. A phospholipid platelet substitute is added to the patient’s blood to initiate the coagulation process via the intrinsic pathway. When a contact activator, such as kaolin, is added, the test is referred to as activated PTT (aPTT). A control sample must be run with the test sample. In general, aPTT ranges from 25 to 35 seconds, and results in excess of 35 seconds are considered abnormal or prolonged. The aPTT is prolonged in cases of mild to severe deficiency of factor VIII or IX. The test result is abnormal when a given factor is 15% to 30% below its normal value.

Prothrombin Time.

The PT is used to check the extrinsic pathway (factor VII) and the common pathway (factors V and X, prothrombin, and fibrinogen). For this test, tissue thromboplastin is added to the test sample to serve as the activating agent. Again, a control must be run, and results vary from one laboratory to another. In general, the normal range is 11 to 15 seconds. PT is prolonged when the plasma level of any factor is below 10% of its normal value. When the test is used to evaluate the level of anticoagulation with coumarin-like drugs the international normalized ratio (INR) format is recommended. INR, a method that standardizes PT assays, is defined later in this chapter. In this book, the term INR is used only for PT tests from patients taking coumarin-like drugs.

Platelet Count.

The platelet count is used to screen for possible bleeding problems caused by thrombocytopenia. A normal platelet count is 150,000 to 450,000/µL of blood. Patients with a platelet count of between 50,000 and 100,000/µL manifest excessive bleeding only with severe trauma. Patients with counts below 50,000/µL demonstrate skin and mucosal purpura and bleed excessively with minor trauma. Patients with platelet counts below 20,000/µL may experience spontaneous bleeding.

Thrombin Time.

In this test, thrombin is added to the patient’s blood sample as the activating agent. It converts fibrinogen in the blood to insoluble fibrin, which makes up the essential portion of a blood clot. Again, a control must be run, and results vary from laboratory to laboratory. This test bypasses the intrinsic, extrinsic, and most of the common pathway. For example, patients with hemophilia A or factor V deficiency have a normal TT. Generally, the normal range for the TT test is 9 to 13 seconds, and results in excess of 16 to 18 seconds are considered abnormal or prolonged. Abnormal test results usually are caused by excessive plasmin or fibrin split products.

Diagnostic Tests Performed by the Hematologist.

When one or more of the screening tests yield an abnormal result, the hematologist runs additional tests to pinpoint the specific defect of the bleeding disorder.

Platelet Disorders.

The platelet count is very effective for identifying patients with thrombocytopenia. It is not effective for identifying patients with disorders of platelet function such as von Willebrand disease, Bernard-Soulier disease, Glanzmann disease, uremia, and drug-induced platelet release defects. BT may be prolonged in these patients, but test results are inconsistent. Platelet aggregation tests, ristocetin-induced agglutination, platelet release reaction, and other tests may have to be performed for the nature of the clinical bleeding problem to become apparent.

Additional laboratory tests are needed to establish the diagnosis and to identify the type of von Willebrand disease. These consist of ristocetin cofactor activity, ristocetin-induced platelet aggregation, immunoassay of vWF, multimeric analysis of vWF, and specific assays for factor VIII.

Disorders of the Intrinsic Pathway. Screening tests show prolonged aPTT, normal PT, and normal platelet count (except in some cases of von Willebrand disease). The next step is to mix (mixing tests) the patient’s blood with a sample of pooled plasma and repeat the aPTT. If this test is normal, then the specific missing factor is identified by specific assays. If the mixing test result is abnormal, tests for inhibitor activity (antibodies to the factor) are performed. Some acquired coagulation disorders can produce prolonged aPTT along with normal PT. These include the lupus inhibitor, antibodies to factor VIII, and heparin therapy.

Disorders of the Extrinsic Pathway. A normal aPTT and a prolonged PT suggest a factor VII deficiency, which is very rare, or inhibitors to factor VII. Factor VII deficiency is confirmed by specific assay. Mixing studies are used to rule out factor VII inhibitors.

Disorders of the Common Pathway. A prolonged aPTT and a prolonged PT in a patient with a history of a congenital bleeding disorder indicate a common pathway factor deficiency. Congenital deficiency of factors V and X, prothrombin, or fibrinogen is rare. When both of these test results are prolonged, an acquired common pathway factor deficiency is usually indicated. Often, multiple factors are found to be deficient. Conditions that can cause both tests to be abnormal are vitamin K deficiency, liver disease, and DIC. When both test results are prolonged in a patient with a history suggestive of a congenital bleeding problem, the next step is to exclude or identify an abnormality of fibrinogen in the laboratory. This involves measuring the plasma fibrinogen level and performing tests for D-dimer of FDPs. After a problem involving fibrinogen has been ruled out, the next step is to perform mixing studies to rule out inhibitor activity. If these test result are negative, then specific assays for deficiency of factor V or X or prothrombin are performed.

Degradation Products of Fibrin or Fibrinogen. 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, FDPs, or both, consist of staphylococcal clumping assay, agglutination of latex particles coated with antifibrinogen antibody, and euglobulin clot lysis time.

Disorders with Normal Primary Screening Results. Patients with vascular abnormalities that can cause clinical bleeding may not be identified through the use of recommended screening tests. BT is the only finding that might be abnormal in these patients. However, it has clearly been shown that BT is inconsistent in these patients. Thus, this test is not reliable for identifying these patients. In most cases, the diagnosis must be based on history and clinical findings.

Three known defects in the coagulation system do not affect PT, aPTT, or TT. These are rare and include factor XIII deficiency, α ₂ plasmin inhibitor deficiency, and plasminogen activator inhibitor-1 deficiency (major inhibitor of plasminogen activators). Patients with a strong clinical history of bleeding and normal coagulation test results (PT, aPTT, and TT) require additional testing, such as the use of 5M urea.

Another small group of patients with a history of significant bleeding problems will have negative test results when screened by means of currently recommended methods. It appears that current methods are unable to reveal whatever disorder these patients may have. A clear-cut history of prolonged bleeding after trauma or surgical procedures is always more significant than negative laboratory data.