Causes and Symptoms Patients with bleeding abnormalities are commonly encountered in medicine. Such patients may be evaluated because of previous bleeding episodes, a family history of uncontrollable bleeding, or sometimes abnormalities detected during preliminary studies before surgery or other invasive procedures. Bleeding episodes are often described as local (the source of bleeding is pinpointed to a specific part of the body) or generalized (abnormal bleeding occurring at multiple, distinct anatomic sites). It is important to distinguish between these two possibilities because treatment may differ markedly. Localized bleeding disorders may be correctable with surgery, while the treatment of generalized bleeding disorders may be more complex and long-term. The evaluation of patients with suspected bleeding disorders includes a detailed medical history, a thorough physical examination, and appropriate screening tests for hemostatic functioning. Subsequently, more specific laboratory tests are usually required to define the nature of a bleeding abnormality. Abnormal bleeding may result from blood vessel abnormalities (vascular defects), low platelet counts (thrombocytopenia), excessively high platelet counts (thrombocytosis), platelet function abnormalities, deficiencies or abnormalities of plasma coagulation factors, excessive breakdown of blood clots (excessive fibrinolysis), or a combination of these abnormalities. Bleeding disorders may be inherited or acquired.
Generalized bleeding abnormalities are suggested by several characteristics. Bleeding from multiple sites, bleeding in the absence of a known causative event (often termed spontaneous bleeding), and bleeding following trauma that is much more severe than expected for the degree of injury are all characteristics of generalized bleeding defects. An unexplained increase in bleeding severity may be a sign of a newly acquired generalized bleeding abnormality.
Inherited disorders. There are numerous inherited disorders of hemostasis (hemostasis is the normal process by which bleeding stops). Fortunately, most of these disorders are quite rare. The two most common inherited bleeding disorders are von Willebrand’s disease and
hemophilia A. Inherited bleeding disorders usually become evident in infancy or early childhood. There is often a family history of abnormal bleeding, and abnormal bleeding may have been experienced in association with surgery or trauma. Bleeding from the umbilical cord at birth or bleeding following circumcision may provide evidence of inherited hemostatic disorders. In contrast, a lack of abnormal bleeding following surgery such as tonsillectomy or dental procedures such as tooth extraction lowers the likelihood that even a mild inherited hemostatic disorder is present. There are, however, exceptions to such trends. Inherited disorders of hemostasis such as Ehlers-Danlos syndrome or hereditary hemorrhagic telangiectasia may not become evident until later in life. Idiopathic (or immune) thrombocytopenic purpura (ITP) is an acquired hemostatic abnormality that may occur in childhood, usually as a result of an infection. Hemorrhagic disease of the newborn is a short-lived bleeding abnormality caused by a transient deficiency of coagulation factors (known as the vitamin K dependent factors) in the newborn period.
Family history is helpful in the evaluation of hemostatic disorders because a pattern of bleeding among family members may be revealed. If only male members of a family are affected, this suggests an X-linked recessive pattern of inheritance (transmitted by the X sex chromosome). Such diseases are usually transmitted from female carriers of the trait. Hemophilia A, hemophilia B, and Wiskott-Aldrich syndrome are transmitted as X-linked recessive traits. Inherited bleeding disorders such as von Willebrand’s disease occur in both sexes through non-sex-linked, or autosomal, transmission. Some bleeding disorders occur because of a gene mutation. Some individuals, therefore, are the first members of their family to have an inherited bleeding disorder.
Acquired disorders. These may first become evident in adulthood. A negative family history for bleeding may exist, and diseases may be present that are associated with bleeding abnormalities, such as kidney or liver disease. Liver disease may lead to abnormal bleeding for numerous reasons. Causes of abnormal bleeding include decreases in plasma coagulation factors (most coagulation factors are manufactured by the liver), low platelet counts, platelet function abnormalities, production of abnormal coagulation factors (such as abnormal fibrinogen), vulnerability to a condition called disseminated intravascular coagulation (DIC), and abnormal lysis (breakdown) of blood clots. Platelet function abnormalities are associated with kidney failure and many blood diseases (for example, dysproteinemias, leukemias, and myeloproliferative disorders). Vitamin K is necessary for the production of numerous functional plasma coagulation factors. A deficiency of vitamin K, therefore, may lead to abnormal bleeding. Poor nutrition or antibiotic therapy may lead to vitamin K deficiency, which may also occur in newborns. One source of vitamin K is bacteria located in the gastrointestinal (GI) tract. Because the newborn GI tract is sterile, newborns have no bacterial source of vitamin K. Some medical conditions, such as sprue or biliary obstruction, may lead to inadequate absorption of vitamin K from the GI tract.
Numerous drugs and medications may cause abnormal bleeding. Drugs or medications may cause low platelet counts or platelet dysfunction or may affect coagulation factors. Oral anticoagulant therapy (warfarin therapy), which is used in the treatment of blood clots in the legs, causes a reduction of functional vitamin K dependent coagulation factors and is a common cause of drug-induced bleeding.
Nutritional deficiency, a major problem in many parts of the world, may result in bleeding disorders. One example is severe protein deficiency, a syndrome known as kwashiorkor, which produces severe liver damage. Vitamin C deficiency may cause scurvy, which may result in skin hemorrhages, bleeding gums, and bleeding beneath the lining of the bones (subperiosteal bleeding).
Evaluating hemostatic functioning. Dental extractions are a good measure of hemostatic functioning because bleeding occurs over rigid bone. The bleeding sites, therefore, are not easily compressible. Persistent and excessive bleeding after incisor removal is more significant as a diagnostic indicator than such bleeding following molar removal. (Even patients with normal hemostasis may experience persistent bleeding after molar extractions.) Tonsillectomy is evaluated in a similar manner. Because tonsillectomy may lead to persistent bleeding in the setting of normal hemostasis, the significance of excessive bleeding following tonsillectomy may be difficult to interpret. The lack of bleeding following tonsillectomy, however, implies normal hemostasis.
Investigation of trauma-related bleeding is an important component of hemostatic evaluation. When considering trauma-related bleeding, it is important to determine other details related to the events: Were blood transfusions required? What methods were used to bring bleeding under control? How easily was bleeding brought under control? Was there clearly a local cause of bleeding? Were any medications being taken which could lead to abnormal bleeding? A lack of abnormal bleeding with prior trauma does not absolutely exclude inherited bleeding disorders. Patients with milder forms of hemophilia may bleed abnormally only following severe trauma. Oral contraceptives or pregnancy influence the hemostatic reaction to a degree that may mask von Willebrand’s disease in women.
Diagnosis by type of bleeding. In diagnosis, the type of abnormal bleeding may provide important clues. In vascular or platelet abnormalities, bleeding typically occurs in the skin or mucous membranes. Bleeding usually starts within seconds of the time of injury and may continue for hours; however, once the bleeding stops it may not recur. Posttraumatic bleeding in coagulation disorders may be delayed for many hours after a traumatic episode; recurrent episodes of bleeding following trauma are also a characteristic of such disorders.
Petechiae, small, red spots about the size of a pinhead, represent tiny hemorrhages from small blood vessels, such as capillaries. These spots are a sign of platelet or vascular abnormalities. Petechiae caused by vasculitis (the inflammation of blood vessels) are often elevated lesions that are distinct to the touch (palpable) as well as being evident visually. Petechiae associated with low platelet counts or abnormalities of platelet function are not palpable and, while often widespread, may first appear on the lower extremities, such as the ankles, or on mucous membranes, such as in the mouth.
Ecchymoses (bruises) are larger lesions caused by the leakage of blood into tissue of the skin or mucous membranes, usually as the result of trauma. Ecchymoses can be seen with all hemostatic disorders. Spontaneous ecchymoses, bruises appearing in the absence of prior trauma, may be a sign of a hemostatic problem. The location of the ecchymoses may provide diagnostic information. Bruises occurring only on the limbs, which are at greater risk for minor trauma, are less indicative of a possible bleeding abnormality than bruising that occurs on the trunk. Easy bruising in a man also warrants further study.
Hematomas are collections of blood that accumulate in organs, body cavities, or tissues. They produce deformity of the area in which they develop and may be quite painful. Hematomas tend to be associated with abnormalities in the coagulation mechanism, such as hemophilia. Bleeding into joint spaces is known as hemarthrosis. Hemarthroses are characteristic of severe coagulation disorders such as hemophilia. Telangiectases and angiomata, caused by vascular malformations, are red spots or patches caused by the presence of blood in abnormally dilated vessels. Unlike the other lesions previously discussed, these vascular lesions blanch with pressure.
Epistaxis
(nose bleeding) is most frequently caused by mild trauma (for example, nose blowing) to dilated vessels of the nose in individuals with normal hemostasis. Epistaxis in the setting of bleeding disorders is often associated with low platelet counts, the vascular abnormality called hereditary hemorrhagic telangiectasia, and von Willebrand’s disease. Epistaxis consistently occurring on one side may be the result of a local abnormality, as opposed to a generalized hemostatic defect.
Abnormal bleeding may also be seen in other areas. Gingival bleeding (gum bleeding)
may be caused by gum disease; however, it is also seen in association with low platelet counts, platelet dysfunction, and scurvy, and in conditions where there are abnormally high levels of proteins in the blood (hyperviscosity syndrome). Hematuria (blood in the urine) may be caused by low platelet counts, platelet dysfunction, coagulation factor abnormalities, and oral anticoagulant therapy. Hematuria is a serious medical symptom that requires immediate medical investigation to determine the cause. Bleeding from the GI tract can be seen with all types of hemostatic disorders. GI bleeding must be completely investigated to determine whether there is local cause for the bleeding or the bleeding is part of a generalized hemostatic defect. Menorrhagia (abnormal bleeding during menstrual periods) is associated with low platelet counts, platelet dysfunction, von Willebrand’s disease, and coagulation factor abnormalities. Information such as the number and type of sanitary pads or tampons needed, period duration, the necessity of sanitary pad changes at night, the passage of clots, and the requirement of iron for anemia may be helpful in quantifying menstrual blood loss.
Laboratory tests. Laboratory evaluation of hemostatic functioning consists of screening tests, to aid in the detection of abnormalities, and confirmatory tests, to characterize the disorders. Microscopic examination of a blood smear is a simple screening procedure that may provide valuable information. A disease process associated with abnormal bleeding, such as leukemia, may be detected. Numerous red cell fragments may be present in hemostatic disorders such as DIC or thrombotic thrombocytopenic purpura (TTP). An estimate of the number of platelets and an evaluation of their size and shape can be made. Abnormally low and high platelet counts can lead to abnormal bleeding. Large platelets can be seen in conditions in which they are being destroyed rapidly, such as ITP. Large platelets are also seen in Bernard-Soulier syndrome, an inherited platelet function disorder.
The automated platelet count and bleeding time are screening tests for the evaluation of platelets. A normal interaction between platelets and damaged blood vessels is a necessary first step to control bleeding. This step is often termed primary hemostasis. An adequate number of normally functioning platelets are necessary to provide normal primary hemostasis. A representative normal range for the platelet count is 150,000 to 400,000 platelets per microliter of blood. In the absence of platelet dysfunction, spontaneous bleeding is rare when the platelet count is greater than 20,000 per microliter. The risk of life-threatening hemorrhage does not markedly increase until the platelet count drops below 10,000 per microliter. The bleeding time is primarily used to screen for platelet dysfunction, although it may also indicate some vascular abnormalities. The bleeding time measures the interval required for bleeding to cease following a standard skin incision on the forearm. A blood pressure cuff on the arm is inflated to a pressure of 40 millimeters of mercury during the procedure. A representative normal range for the bleeding time is four to seven minutes. A prolonged bleeding time may be a sign of a platelet or vascular abnormality.
The
plasma coagulation system is composed primarily of a set of proteins that interact to produce clotting of blood (fibrin clots). This system is often referred to as secondary hemostasis. Most plasma coagulation factors are identified by a roman numeral (for example coagulation factor VIII). For ease of analysis, the plasma coagulation system has been divided into groups of proteins known as the intrinsic pathway, the extrinsic pathway, and the final common pathway. Screening tests for the plasma coagulation system include the thrombin time (TT), the prothrombin time (PT), and the activated partial thromboplastin time (aPTT). The screening tests detect significant deficiencies or abnormalities of plasma coagulation factors and help localize the defects within the pathways.
Specific, and often more complex laboratory studies of hemostasis are performed based on information derived from the medical history, physical examination, and screening laboratory tests. The goal of specific tests is to pinpoint the diagnosis of hemostatic abnormalities.
Platelet disorders. Thrombocytopenia, a low platelet count in the blood, has numerous causes. Platelets are produced in the bone marrow and subsequently released into the blood.
Bone marrow damage may result in inadequate numbers of platelets. Drugs, toxins, radiation, and infections may damage the bone marrow. Certain diseases, such as leukemia or other cancers, may lead to the replacement of bone marrow cells with abnormal cells or fibrous tissue. Some diseases result in inadequate release of platelets from the bone marrow. Inadequate platelet release may be the result of nutritional deficiencies, such as vitamin B12 or folic acid deficiencies, or it can be seen in some rare hereditary disorders, such as May-Hegglin anomaly or Wiscott-Aldrich syndrome. Individuals with an enlarged spleen may develop thrombocytopenia because of the pooling of platelets within the organ. Massive transfusion may result in thrombocytopenia when the blood volume is replaced with transfused solutions that do not contain platelets.
Certain disorders result in the rapid destruction or consumption of platelets. If the production of platelets by the bone marrow does not compensate for the rate of destruction, thrombocytopenia occurs. Platelet consumption with resultant thrombocytopenia is a component of DIC. Thrombocytopenia caused by accelerated destruction may also occur with prosthetic heart valves, blood infections (sepsis), and vascular defects called hemangiomas. The development of antibodies against one’s own platelets (such as with ITP) causes platelet consumption. ITP can be a self-limited disorder with a complete return to normal (acute ITP) or a prolonged thrombocytopenic condition (chronic ITP). Acute ITP is seen most frequently in children between two and six years of age. The disease is preceded by a viral infection in about 80 percent of cases. The platelet count returns to normal within six months in more than 80 percent of patients; the usual period of thrombocytopenia is four to six weeks. Mortality from acute ITP occurs in about 1 percent of cases. Chronic ITP typically occurs in young and middle-aged adults, and the disorder is about three times more common in women than in men. As many as 50 percent of
children born to mothers with ITP have thrombocytopenia at birth as a result of the transfer of antiplatelet antibodies across the placenta. Isoimmune neonatal thrombocytopenia and post-transfusion purpura are other conditions in which thrombocytopenia is caused by antiplatelet antibodies.
Numerous drugs have been associated with thrombocytopenia. Examples of such drugs include gold salts, quinine, quinidine, sulfonamide drugs, and heparin. Thrombocytopenia may occur within twenty-four hours following exposure to an offending drug. All nonessential medications should be discontinued in patients suspected of having drug-induced thrombocytopenia.
Platelet function defects may be inherited or acquired. They may occur without evidence of an associated disease or be secondary to a recognizable clinical disorder. Platelet function defects are suspected when there is abnormal skin or mucous membrane bleeding, a prolonged bleeding time, and a normal platelet count. Bleeding disorders caused by the inability of platelets to stick to damaged blood vessel walls in a normal manner are called platelet adhesion defects; Bernard-Soulier syndrome and von Willebrand’s disease are examples of such defects.
Certain molecules necessary for normal platelet function are contained within platelets (that is, in the storage pool). Deficiencies or defects of these molecules lead to platelet dysfunction and are called storage pool defects. Examples of storage pool defects include gray platelet syndrome and dense granule deficiency. Platelet release defects occur when there is a failure to release storage pool contents normally. Hereditary deficiency of the enzymes cyclooxygenase or thromboxane synthetase causes platelet release defects. Aspirin causes a platelet release defect by inactivating cyclooxygenase.
Disorders that render platelets unable to interact with one another to form large clumps at the site of vascular injury are known as platelet aggregation defects. Ganzmann’s thrombasthenia and hereditary afibrinogenemia are examples of such defects.
Platelets also play a key role in secondary hemostasis by providing a surface on which many coagulation factors can interact. A bleeding disorder results if the platelet surface is incapable of supporting secondary hemostasis. Hereditary bleeding disorders caused by this type of platelet defect are quite rare.
Acquired platelet dysfunction is quite common. Renal failure (uremia) may cause acquired platelet dysfunction. Liver disease can cause multiple bleeding abnormalities, including platelet dysfunction. A vast number of drugs and medications, such as aspirin and penicillin, cause platelet dysfunction. Acquired platelet function defects are seen with cardiopulmonary bypass procedures and in association with numerous blood diseases.
Coagulation disorders. The overall incidence of inherited coagulation factor disorders is about one in 10,000. In such conditions, either there is a failure to make a sufficient amount of a coagulation factor (quantitative disorder) or a dysfunctional factor is made (qualitative disorder). An inherited disorder exists for every coagulation factor, although most are quite rare. Symptoms range from serious spontaneous bleeding, which occurs in the severe forms of hemophilia A (factor VIII disorder) or hemophilia B (factor IX disorder), to an absence of abnormal bleeding in other inherited conditions (factors XII, prekallikrein, and high molecular weight kininogen). In general, for disorders that cause bleeding, the more profound the coagulation factor defect, either quantitatively or qualitatively, the more severe the bleeding. Severe disorders are usually easily identified. Moderate or mild disorders are more common and may go undetected until there is a significant hemostatic challenge, such as surgery.
Von Willebrand’s disease is probably the most common inherited bleeding disorder. It is caused by deficiencies or defects in a vital group of hemostatic proteins known collectively as von Willebrand factor. Manifestations include epistaxis, menorrhagia, prolonged bleeding after trauma or surgery, frequent ecchymoses, and persistent gum bleeding. Severe episodes of epistaxis may occur during childhood, and such episodes may cease during puberty. In women, epistaxis may recur after the menopause. Important diagnostic clues include a family history of abnormal bleeding, affected members in every generation (male and female), and marked worsening of bleeding following the ingestion of aspirin or other drugs that impair platelet function. Von Willebrand’s disease consists of a very diverse spectrum of abnormalities: At least twenty-one distinct subtypes of von Willebrand’s disease have been recognized.
Hemophilia A and hemophilia B are clinically indistinguishable; laboratory testing is required for their diagnosis. Hemophilia A is an inherited disorder of a portion of coagulation factor VIII. Hemophilia A is typically seen in men, while women are carriers of the abnormal gene and can transmit the disease. Approximately 20 percent of affected individuals have a negative family history and likely developed their disease because of a mutation of the factor VIII gene. Once the abnormal gene is established in a family, the severity of the disease is the same for all affected male relatives. Hemophilia A is divided into severe, moderate, and mild subtypes based on the amount of functional factor VIII present. Bleeding in hemophiliac patients may be spontaneous or posttraumatic. Spontaneous bleeding tends to occur only in severe hemophilia. It characteristically affects joints and muscles, and it may lead to crippling injury without prompt and adequate treatment. Posttraumatic bleeding may occur in mild, moderate, or severe hemophilia A. Such episodes are often prolonged and dangerous. Bleeding into the head (intracranial bleeding) remains a common cause of severe disability and death in hemophilia A. Modern treatment, however, has reduced the incidence of this severe complication. Antibodies (inhibitors) directed against factor VIII develop in approximately 12 to 15 percent of patients who require transfusions to provide factor VIII. The development of inhibitors is a serious complication that may compromise the effectiveness of therapy. Factor VIII inhibitors may occur in nonhemophiliac patients, leading to serious bleeding in affected men and women.
Acquired coagulation factor disorders may be caused by reduced or absent factor production (for example, in liver disease), the production of defective or inactive factors (such as in liver disease or vitamin K deficiency), factor inhibitors, or accelerated consumption or clearance of factors. Examples in the latter group include DIC (accelerated consumption), kidney disease (factors lost in the urine), and the attachment of factors to abnormal tissue, which occurs in a disease called amyloidosis.
DIC is a hemostatic disorder that arises as part of a disease or medical condition. Examples of associated conditions include obstetrical accidents, abnormal destruction of red blood cells within blood vessels, infections, malignancies, burns, severe injuries, liver disease, and diseases of blood vessels. DIC may be a life-threatening syndrome (high-grade DIC) or a troublesome, less dramatic feature of a disease (low-grade DIC). Conditions associated with DIC cause abnormal activation of the hemostatic response, resulting in the widespread formation of blood clots in the vascular system. The clots obstruct the blood supply to vital organs (the kidneys, heart, lungs, and brain), leading to impaired organ function. Abnormal bleeding may develop if coagulation factors and platelets become depleted because of their incorporation into widespread blood clots. The breakdown of blood clots may also become inadequately controlled and contribute further to abnormal bleeding.
