This 4 year old female is referred to the hematology department with a chief complaint of acute onset of easy bruising and "rash" for 3 days. She has not had epistaxis, oral bleeding, gross blood in urine or stools. She has never had palpable bruises, hemarthroses or deep muscle bleeds in the past. She has no history of fever or appetite changes. She had upper respiratory infection symptoms approximately 2 weeks ago. There is no travel history. She has 2 older brothers, neither of whom have had bleeding symptoms. Family history is negative for frequent nosebleeds, oral bleeding, menorrhagia or excessive bleeding with surgery or trauma. There is no history of malignancies, or autoimmune disorders.
Exam: VS are normal. Height and weight are at the 50th percentile. She is a healthy appearing, cooperative girl in no acute distress. HEENT exam demonstrates no signs of bleeding or bruising. Heart and lung exams are normal. Her abdomen demonstrates no hepatosplenomegaly. A diffuse petechial rash is noted on her neck, trunk, extremities and groin. Nonpalpable ecchymoses of varying ages are present on shins and arms. Her neurologic examination demonstrates no deficits.
CBC shows Hgb 12.8, Hct 38.5, WBC 6,000 with a normal differential. Platelet count is low at 5,000. PT and PTT 12.0 and 32 seconds, respectively. Review of the peripheral smear shows normal morphology of red and white blood cell lines. The platelets are reduced in number and the majority of them are increased in size. A bone marrow aspirate is not performed.
She is diagnosed with immune thrombocytopenic purpura. She is followed closely with weekly CBCs. Her bruises and petechiae fade by her next visit and her platelet count returns to 240,000 one month later.
Bleeding disorders can either be inherited or acquired and are due to defects in either primary or secondary hemostasis. While evaluating a child with a bleeding tendency, the history and physical examination should be directed at differentiating between these. An appropriate history can be more helpful in evaluating these children than any laboratory test. Bruising with or without preceding trauma can be due to a defect in either primary or secondary hemostasis although deep palpable bruises are usually due to a clotting factor defect. Petechiae are usually due to a platelet or blood vessel defect. One should ask about a history of mucosal bleeding (including epistaxis, oral bleeding, gastrointestinal, genitourinary and menstrual bleeding), bleeding from injury or following procedures such as circumcision and tonsillectomy, and deep tissue or musculoskeletal bleeding. Age of onset, frequency and severity of each bleeding complaint should be determined and an extensive family history and medication history should be obtained.
The child should be examined for signs of bleeding, such as petechiae, bruising, mucosal bleeding, and oozing from venipuncture sites. Differentiate between superficial bruises and deep palpable ecchymoses, making note of their location. Special attention should be made to the joints and large muscle areas, looking for deep tissue bleeding.
Laboratory studies assist in confirming suspicions raised from the history and physical. Routine screening laboratory studies should include complete blood count (CBC) with a platelet count, prothrombin time (PT) and activated partial thromboplastin time (PTT). Further specific testing should be performed based on the working diagnosis. These include a PTT mixing study (which helps differentiate a factor deficiency from an acquired inhibitor), bleeding time, factor assays, von Willebrand studies, and platelet aggregation tests. The bleeding time is an uncommonly ordered test during which a standardized small laceration is created on the patient's forearm and the time for the bleeding to stop is measured and compared to standard times. This test is prolonged in conditions of thrombocytopenia and platelet dysfunction. Platelet aggregation studies are special studies that can be done to test the aggregation of platelets in response to several known agents which induce platelet aggregation in vitro such as adenosine diphosphate (ADP), epinephrine and collagen.
The more commonly encountered bleeding disorders are discussed in further depth in this chapter.
I. Primary Hemostasis (platelets)
. . . . A. Quantitative (thrombocytopenia)
. . . . . . . . 1. ITP
. . . . . . . . 2. Hemolytic uremic syndrome (HUS)
. . . . . . . . 3. Thrombotic thrombocytopenic purpura (TTP)
. . . . . . . . 4. Medications
. . . . . . . . 5. Marrow failure (leukemia, aplastic anemia)
. . . . . . . . 6. Platelet sequestration, consumption and dilution
. . . . B. Qualitative (poor platelet function)
. . . . . . . . 1. Inherited platelet aggregation defect
. . . . . . . . 2. Drug effect
II. Secondary Hemostasis (coagulation)
. . . . A. Congenital factor deficiency
. . . . . . . . 1. Hemophilia A and B
. . . . . . . . 2. von Willebrand disease
. . . . . . . . 3. Other factor deficiencies (rare)
. . . . B. Acquired factor deficiency
. . . . . . . . 1. Vitamin K deficiency
. . . . . . . . 2. Liver failure
. . . . C. Antiphospholipid antibody
Defects in Primary Hemostasis
Quantitative platelet disorders result in thrombocytopenia, either due to decreased bone marrow production or increased platelet destruction.
Immune Thrombocytopenic Purpura
Immune or idiopathic thrombocytopenic purpura (ITP) is one of the most common acquired bleeding disorders of childhood. Usually, it is a benign, self-limited disease that occurs in previously healthy children. The typical course in an untreated child is resolution of bleeding symptoms 3 to 10 days after diagnosis, regardless of the platelet count and an increase in the platelet count within 1 to 3 weeks. The platelet count returns to normal in 4 to 8 weeks in approximately half of patients and two thirds of children have resolution by 3 months after diagnosis. By 6 months, platelet counts have returned to normal (>150,000 per cubic mm) in 80% of patients. The remainder are defined as having chronic ITP (1,2). Most children follow a course consistent with acute ITP, in which the platelet counts are very low, but they recover as noted above. Adults more commonly follow a course consistent with chronic ITP, in which the platelet counts are usually moderately low, but the thrombocytopenia persists for long periods of time and often for life. If patients with chronic ITP sustain significant consequences from recurrent bleeding, a splenectomy is sometimes necessary to raise their platelet count.
ITP is an immune-mediated disorder in which circulating antiplatelet antibodies target epitopes on the platelet membrane (1). The antibody-coated platelets are subsequently destroyed by macrophages in the reticuloendothelial system. Children with ITP present with sudden onset of bruising, petechiae and occasionally epistaxis. There may be a history of a preceding viral infection or a recent live-virus immunization (1). There should be no evidence of other disorders causing thrombocytopenia, such as systemic lupus erythematosus or HIV infection. These children appear well except for bruises and petechiae. A minority of patients have mucous membrane hemorrhage, such as menorrhagia, gastrointestinal bleeding or oral blood blisters. They do not have jaundice, pallor, or hepatosplenomegaly.
The most important laboratory assessment in the evaluation of ITP is the CBC and peripheral blood smear. The platelet count is typically very low (<20,000 per cubic mm) and unless there is appreciable bleeding, the hemoglobin concentration is normal as is the leukocyte count. The peripheral smear shows normal morphology of all cell lines except the platelets are reduced in number and tend to be large. PT and PTT are normal and do not need to be performed. The bleeding time is predictably prolonged and unnecessary in the evaluation of a child with ITP. When indicated by the medical history and physical examination, evaluation for HIV, systemic lupus erythematosus, or Evan's syndrome should be considered. Bone marrow aspiration should be considered in patients with lymphadenopathy, hepatosplenomegaly, or other abnormalities on the CBC.
Management of ITP in a child includes education and reassurance of the child's parents. The child's activities should be limited, and aspirin and NSAID containing medications should not be used. Children without significant clinical bleeding may be closely observed with CBCs once or twice weekly. Once the platelet count begins to increase, it may be measured every 2 to 3 weeks until it returns to normal (>150,000). Once the platelet count has normalized, recurrence is rare and follow-up platelet counts are unnecessary (1,2). A few children with ITP have bleeding significant enough to warrant medical management. Standard therapy options include oral or IV corticosteroids (which block the reticuloendothelial system's destruction of antibody-coated platelets and reduce synthesis of antiplatelet antibodies), IVIG (IV gamma globulin which inhibits Fc receptors on phagocytes, allowing antibody-coated platelets to circulate and alters T-lymphocyte subsets and B-cell function and reduces autoantibody production), and Anti-D (which is the anti-serum against the Rh(D) antigen on erythrocytes and by coating Rh(D) positive erythrocytes, it decreases platelet destruction).
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)
HUS and TTP are closely related disorders caused by microvascular occlusion of arterioles and capillaries producing ischemia of multiple organs. HUS is a combination of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure (4). It occurs mostly in children and has a fairly good prognosis. TTP is characterized by a pentad of features which include: thrombocytopenia, microangiopathic hemolytic anemia, neurologic disturbances, renal dysfunction and fever (4). It occurs in young adults and teenagers and carries a high mortality if unrecognized and not treated. Table 1 compares both disorders.
Table 1: Comparison of HUS and TTP
A variety of drugs have been reported to cause thrombocytopenia either by drug-induced platelet destruction or bone marrow suppression. Heparin merits special emphasis because it is so commonly used. Heparin does not inhibit platelet function but it may sometimes cause thrombocytopenia. There are two types of heparin-induced thrombocytopenia (HIT). The first occurs 2 to 5 days after initiation of heparin. Platelet counts rarely fall below 100,000 per cubic mm and normalize within 1 to 5 days. This type is thought to result from platelet aggregation secondary to a direct heparin effect (4). The second type of HIT occurs 3 to 15 days after the initiation of heparin (4). Platelet counts fall below 40,000. Arterial thrombosis may occur. The mechanism is immune mediated. Treatment involves discontinuation of heparin.
Decreased numbers of platelets result from impaired platelet production due to leukemia, aplastic anemia or bone marrow suppression due to viral infection or drugs. These are discussed in separate chapters. May-Hegglin anomaly is characterized by mild to moderate thrombocytopenia and the presence of Dohle bodies in the leukocytes. Kasabach-Merritt (giant hemangioma) syndrome is due to localized intravascular coagulation from low blood flow through the abnormal vascular tissue and is associated with thrombocytopenia (4). Foreign bodies in the circulation (central venous catheters and prosthetic valves) are sites for platelet consumption. Platelet loss also results from extracorporeal circulation and exchange transfusions. Massive plasma and blood transfusions lead to a dilutional thrombocytopenia. Finally, platelet counts may be low as a result of sequestration when the spleen is enlarged.
Qualitative platelet disorders (defects in platelet aggregation) are very rare. Most are inherited as autosomal recessive traits. Patients present with bleeding similar to that seen with thrombocytopenia. They complain of skin and mucous membrane bleeding, recurrent epistaxis, gastrointestinal bleeding, menorrhagia, and prolonged bleeding with injury or surgery (5). Aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) are common causes of temporary platelet dysfunction. Laboratory evaluation usually demonstrates a normal platelet count, prolonged bleeding time and abnormal platelet aggregation studies. Coagulation studies (PT, PTT) are usually normal. The most common platelet aggregation defects are described in table 2 below.
Table 2: Platelet aggregation defects
Defects in Secondary Hemostasis
Hemophilia is an X-linked inherited bleeding disorder transmitted from female carriers to their male children. It is due to a deficiency of factor VIII (Hemophilia A or "Classic hemophilia") or factor IX (Hemophilia B or "Christmas disease"). Hemophilia A is more common, occurring in 1/5000 male births while hemophilia B occurs in 1/15,000 (6). Signs and symptoms vary depending on the severity of the hemophilia. Severity is defined by baseline factor levels: severe <1%, moderate 1-5%, mild >5% (6,7). Children with severe hemophilia usually present in the first year of life with a history of extensive deep palpable ecchymoses. There may be a history of bleeding from the circumcision. After the age of 2 years, they begin to develop spontaneous hemarthroses or deep muscle bleeds. They can have mucosal bleeds, such as oral bleeding with procedures and hematuria. The bleeding is usually not catastrophic. Instead, it is prolonged and continuous without therapy. A head injury is considered an emergency since it is potentially life threatening if not treated appropriately. Children with milder forms of hemophilia may present later in life with a history of easy bruising or prolonged bleeding following injury. They usually do not have spontaneous bleeding. Laboratory findings include a markedly prolonged PTT (>100 seconds) and a decreased factor VIII or IX activity. Other screening tests (PT, platelet count and bleeding time) should be normal.
The mainstay of therapy is replacing the deficient clotting factor with factor VIII or IX concentrate (6,7). Both human derived and recombinant factor concentrates are available. In the past, factor replacement carried a risk of transmission of viral infections, especially hepatitis B and C, and HIV. This risk has been reduced with current viral inactivation techniques and with the availability of recombinant factor. Each unit of factor VIII will increase the factor VIII level by 2% and has an 8 to 12 hour half-life. Each unit of factor IX will increase the factor IX level by 1% and has an 18 to 24 hour half-life (6,7). Dosing depends on the location and severity of the bleed. In addition to factor replacement, males with hemophilia benefit from supportive measures, physical therapy and often require orthopedic intervention. Aminocaproic acid is an oral antifibrinolytic and can be used adjunctively to treat mucous membrane bleeding. Mild factor VIII deficient patients may be treated with intravenous or highly concentrated intranasal desmopressin (DDAVP) which causes a release in endogenous factor VIII stores. These boys need to be cautioned to avoid contact sports such as tackle football, boxing or wrestling. It is nationally recognized that hemophilia treatment centers have improved the prognosis of patients with hemophilia. Patients and their families have a home supply of factor and infuse themselves promptly at the earliest sign of a bleed. Prophylaxis has been instituted in most severely affected individuals where they infuse themselves regularly two to three times a week and/or prior to a sports activity in order to prevent spontaneous bleeds. This has reduced much of the chronic arthropathy in this population. Today, young people with hemophilia can lead independent and nearly normal lives.
von Willebrand Disease
von Willebrand disease (vWD) is the most common inherited bleeding disorder. It affects 1% to 2% of the population. von Willebrand factor is a cofactor for platelet adhesion and a carrier protein for factor VIII (8,9). The most common form is transmitted as an autosomal dominant trait. Severity of bleeding symptoms depends on the type and subtype. Types 1 and 3 result in quantitative defects of the von Willebrand protein (i.e., deficiency) while Type 2 is due to a qualitative defect in the von Willebrand protein. The vWD types are listed in table 3.
Table 3 - von Willebrand disease subtypes
Patients with vWD often have a positive family history of bleeding and easy bruisability in addition to the personal bleeding history. The bleeding symptoms can be similar to that seen with thrombocytopenia or platelet dysfunction and usually involve the mucous membranes and patients present with complaints of recurrent epistaxis, oral bleeding with dental care, and menorrhagia. In addition, they often have a history of easy or spontaneous bruising and post-operative bleeding. More rarely, one may elicit a history of gastrointestinal or genitourinary bleeding. Types 2N and 3 may also have deep tissue bleeding, similar to the bleeding seen in moderate or severe hemophiliacs.
The most useful screening tests in patients with suspected vWD are bleeding time, PTT and von Willebrand factor activity (ristocetin cofactor). Ristocetin cofactor is a functional assay of the von Willebrand protein. At least one of these screening tests will be abnormal in 97% of patients with vWD (10). Other useful studies include platelet count, von Willebrand factor (vWF) antigen and factor VIII activity. Once the diagnosis of vWD is made, the vWF multimeric assay and platelet aggregation studies will determine the type of vWD. With deficient or defective von Willebrand factor, there will be abnormal platelet aggregation to ristocetin. Other platelet aggregation studies should be normal.
It is important to keep in mind that vWF is an acute phase reactant and therefore, studies for vWD can be affected by cigarette smoking, stress, exercise, pregnancy, corticosteroids, birth control pills, etc. In addition, people who are blood group O have a lower normal range for vWF antigen and ristocetin cofactor activity. When there is a strong suspicion that a patient has vWD, the laboratory evaluation may need to be repeated up to 3 times.
In most cases of vWD the bleeding symptoms are quite mild, and therapy includes education and measures for local control of bleeding. Aminocaproic acid is useful in treating mucous membrane bleeding. Desmopressin (DDAVP) causes a release of factor VIII and vWF from storage sites and is useful in treating bleeding symptoms in patients with mild (type 1) vWD. Patient with severe forms of vWD (type 3) or a qualitative defect of the vWF (types 2A, 2B, 2N) may need replacement with Humate-P (a factor VIII product containing vWF) (8,9). Once diagnosed and followed and treated in a comprehensive hemophilia treatment center, people with vWD can lead normal lives.
Other Factor Deficiencies
Deficiencies in other fluid factors are much more rare than deficiencies in factors VIII, IX or vWF. Factor XI deficiency presents with variable bleeding and a prolonged PTT. Bleeding symptoms do not correlate with the factor level (11). It is more common in the Ashkenazi Jewish population. Deficiencies of the contact factors (factor XII-Hageman factor, high molecular weight kininogen, and prekallikrein) are associated with a significantly prolonged PTT without bleeding symptoms (11). Deficiencies of factors II, V, VII, X and XIII are very rare. For most of these, bleeding symptoms occur in those whose factor levels are <5% to 10% (11). Factor VII deficiency should be considered with isolated prolongation of the PT. Factors II, V, and X are common pathway factors and present with prolongation of both PT and PTT. Factor XIII deficiency is associated with bleeding from the umbilical stump and intracranial hemorrhage with a normal PT and PTT. It is only symptomatic in patients whose level is <1%. Treatment consists of replacement of the deficient factor with fresh frozen plasma or, if available, specific factor concentrate (11).
Acquired Defects of Secondary Hemostasis
Vitamin K is needed for the synthesis of factors II, VII, IX and X. Vitamin K is vital to the carboxylation of glutamic acid residues which is needed for the calcium and phospholipid-dependent activation of these factors (1). The most common circumstance in which vitamin K deficiency leads to bleeding is hemorrhagic disease of the newborn. Without vitamin K supplementation, significant GI and cutaneous hemorrhage may develop within a few days (1). After the newborn period, vitamin K is absorbed from the GI tract. Deficiency may then result from nutritional deficits, malabsorption, or alteration in intestinal flora. Treatment must be directed at the underlying disorder and vitamin K supplementation.
Decreased synthesis of coagulation proteins occurs in severe liver disease. Abnormalities in the liver's capacity to synthesize one or more clotting factors may result in problems with hemostasis. Treatment involves replacement of the decreased factor(s) with fresh frozen plasma. Liver disease may also lead to portal hypertension and platelet sequestration in the spleen.
Disseminated intravascular coagulation (DIC) occurs in patients who are critically ill and therefore, rapid diagnosis is essential. Fever, hypotension, acidosis, oliguria, or hypoxia may be present. In addition, petechiae, purpura, and oozing from wounds and venipuncture sites may develop. Although not always clinically evident, microvascular and large vessel thrombosis may occur. The platelet count is typically decreased due to consumption and platelet destruction. The PT and PTT are prolonged from depletion of factors V, VIII, IX, and XI. Fibrinogen is decreased. Fibrin degradation products and the D-dimer assay are increased. The mainstay of therapy is to treat the underlying disease. However, this may not always be enough to correct serious bleeding or thrombosis. Additional therapy consists of replacing clotting factors and platelets and possibly the use of heparin and antifibrinolytic agents (1).
Circulating inhibitors such as heparin and the lupus anticoagulant (antiphospholipid antibody) often lead to abnormalities in screening coagulation laboratory values. These cause a prolonged PTT which is not corrected with 1:1 dilution with normal plasma (the PTT mixing study). If the patient has a factor deficiency such as hemophilia, adding normal plasma to the patient's plasma, will partially correct the factor deficiency and the PTT will normalize. If the PTT does not normalize by adding normal plasma, this implies that an anticoagulant is present in the patient's plasma. The term “lupus anticoagulant” is misleading because it can occur in many clinical settings other than in SLE and the anticoagulant effects are only observed in vitro with prolongation of the PTT, but not with excessive bleeding. Instead, when it occurs in adults, it may be associated with spontaneous abortion, and thromboembolism. In the pediatric population, it usually occurs in otherwise healthy children, often following a viral illness and is transient with rare clinical sequelae (1).
A summary of laboratory studies for bleeding disorders is listed below. Routine tests are commonly ordered by non-hematologists. Special tests are not ordered routinely and are only ordered (most commonly by hematologists and other subspecialists) when a bleeding disorder is highly suspected.
1. What is the mechanism for the thrombocytopenia in ITP?
2. What is the classic triad associated with hemolytic uremic syndrome?
3. How is hemophilia inherited?
4. Describe some indications for factor VIII administration in a patient with hemophilia A.
5. What are the functions of von Willebrand factor?
6. What combination of laboratory tests are good screening studies for von Willebrand disease?
7. Why is it important to test for blood type in a person with suspected von Willebrand disease?
8. Name the vitamin K dependent factors.
9. Explain why the addition of normal plasma to a patient's PTT test, will help to identify a circulating anticoagulant such as the lupus anticoagulant.
1. Medeiros D, Buchanan GR. Idiopathic thrombocytopenic purpura: beyond consensus. Curr Opin Pediatr 2000;12(1):4-9.
2. Medeiros D, Buchanan GR. Current controversies in the management of idiopathic thrombocytopenic purpura during childhood. Pediatr Clin North Am 1996;43(3):757-772.
3. Medeiros D, Buchanan GR. Major hemorrhage in children with idiopathic thrombocytopenic purpura: immediate response to therapy and long-term outcome. J Pediatr 1998;133(3):334-339.
4. Medeiros D, Buchanan GR. Chapter 47 - Disseminated Intravascular Coagulation and Other Acquired Bleeding Disorders. In: Levin DL, Morriss FC (eds). Essentials of Pediatric Intensive Care, second edition. 1997, New York: Churchill Livingstone Inc., pp. 473-482.
5. Hardisty RM. Platelet Functional Disorders. In: Lilleyman J, Hann I, Blanchette V (eds). Pediatric Hematology, second edition. 1999, London: Churchill Livingstone Inc., pp. 465-496.
6. DiMichele D. Hemophilia 1996: New approach to an old disease. Pediatr Clin North Am 1996;43(3):709-736.
7. Lusher JM. Chapter 29 - Hemophilia A and B. In: Lilleyman J, Hann I, Blanchette V (eds). Pediatric Hematology, second edition. 1999, London: Churchill Livingstone Inc., pp. 585-600.
8. Lillicrap D, Dean J, Blanchette VS. Chapter 30 - von Willebrand Disease. In: Lilleyman J, Hann I, Blanchette V (eds). Pediatric Hematology, second edition. 1999, London: Churchill Livingstone Inc., pp 601-610.
9. Werner EJ. von Willebrand disease in children and adolescents. Pediatr Clin North Am 1996;43(3):683-708.
10. Werner EJ, Abshire TC, Giroux DS, Tucker EL, Broxson EH. Relative value of diagnostic studies for von Willebrand disease. J Pediatr 1992;121(1):34-38.
11. Blanchette VS, Dean J, Lillicrap D. Chapter 31 - Rare Congenital Hemorrhagic Disorders. In: Lilleyman J, Hann I, Blanchette V (eds). Pediatric Hematology, second edition. 1999, London: Churchill Livingstone Inc., pp. 611-628.
Answers to questions
1. ITP is an immune-mediated disorder in which circulating antiplatelet antibodies target epitopes on the platelet membrane. The antibody-coated platelets are subsequently destroyed by macrophages in the reticuloendothelial system.
2. Thrombocytopenia, microangiopathic hemolytic anemia, and uremia.
3. X-linked recessive.
4. Following trauma or injury, especially head injury; to treat spontaneous bleeding, such as hemarthrosis or deep muscle bleeding, and prior to procedures, including dental work.
5. von Willebrand factor is a cofactor for platelet adhesion and carrier protein for factor VIII.
6. Bleeding time, PTT, and ristocetin cofactor.
7. Patients who have blood group O have a lower normal range for von Willebrand studies.
8. Factors II, VII, IX, and X.
9. If the prolonged PTT is due to a factor deficiency, then the addition of factors from the "normal plasma", will correct the PTT. However, if the PTT is due to a circulating anticoagulant such as heparin or a lupus anticoagulant, the circulating antibody will inhibit the "normal" factors and the PTT will remain prolonged. Failure to normalize the PTT after the addition of normal plasma, implies the presence of a circulating anticoagulant.