Evaluation of Bleeding Problems and Abnormal Bleeding Studies

The problems of bleeding encountered in the office setting range from abnormal results on screening studies to easy bruising, petechial rashes, and recurrent episodes of unexplained frank blood loss. Sometimes, the only manifestation is a low platelet count, prolonged prothrombin time (PT), or a delay in the bleeding time. When the volume of blood loss is small, the rate of bleeding is slow, and the risk for serious hemorrhage is low, evaluation may take place in the outpatient setting. The workup involves examination of the intrinsic and extrinsic clotting systems in addition to an evaluation of blood vessels, platelet function, and platelet quantity to identify which part of the hemostatic apparatus is at fault. Often, a careful history and physical examination, supplemented by a few simple laboratory studies, can yield a clinically meaningful answer and guide therapy. An important objective is to determine whether the problem is inherited or acquired. At times, an anatomic lesion coexists with a bleeding diathesis; the clinician always needs to address this possibility, especially when the bleeding originates from the lung, gastrointestinal tract, vagina, or urinary tract (see Chapters 42, 63, 111, and 129, respectively).

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11)

Overview

Hemostasis is achieved by the interplay of the coagulation cascade, platelets, and vessel wall. The platelets provide the initial primary hemostatic plug in response to vascular injury, followed secondarily by the generation of fibrin at the site of damage. Blood coagulation is a carefully controlled process, limited by endogenous anticoagulants. Normal hemostasis represents a delicate balance between coagulant and anticoagulant factors. Any upset in this system of checks and balances may result in bleeding or thrombosis.

Disorders of Primary Hemostasis

These involve platelets and/or the vessel wall and present as spontaneous bleeding or bleeding into superficial tissues (skin and mucous membranes, including the lining of the bowel and the genitourinary tract). The appearance of petechiae and slow oozing after trauma, rather than brisk bleeding, is typical. Menorrhagia or epistaxis may be a presenting complaint.

Disorders of Secondary Hemostasis

These involve the clotting factors or the fibrinolytic system and lead to bleeding that is characteristically deep and visceral, causing such problems as hemarthrosis, retroperitoneal hemorrhage, and deep hematomas.

Disorders of Primary Hemostasis: Qualitative Platelet Disorders

Platelet function defects can be classified according to the step in platelet activity that is affected: adhesion, aggregation, activation, secretion, or acceleration of coagulation. Patients with isolated qualitative platelet defects have a prolonged bleeding time in conjunction with normal-appearing platelets that are adequate in number.

Defective Adhesion

The most important cause of impaired adhesion is von Willebrand disease; acquired forms are seen in the setting of malignancy and connective tissue disease or with high-dose antibiotic administration.

von Willebrand Disease.

This is inherited in an autosomal dominant pattern and is associated with decreased secretion or abnormal synthesis of a glycoprotein (GP) polymer (von Willebrand factor) needed for platelet adherence to a site of vascular endothelial injury. The release of von Willebrand factor in the classic form of the disease can be stimulated by (DDAVP). Rarer forms of the disease are not corrected by DDAVP. In addition, because of a deficiency of factor VIII procoagulant, the partial thromboplastin time (PTT) is prolonged. Platelet agglutination fails to occur in the presence of the antibiotic ristocetin, a laboratory characteristic of this disease that is useful for its detection. Mucous membrane bleeding is a frequent manifestation. The severity of bleeding is variable and most severe among homozygous persons, who may bleed from the gastrointestinal tract; hemarthrosis is rare. Cryoprecipitate can also correct the problem.

Acquired Forms.

Acquired forms of von Willebrand disease are seen in lymphoma, other malignancies, and connective tissue disease. High doses of semisynthetic penicillins or cephalosporins can produce an acquired adhesion defect by coating the platelet surface and reducing binding to GP.

Defective Activation and Release

Patients with activation problems have an impaired production or an impaired response to prostaglandin-dependent activators such as thromboxane A2, which attracts platelets and constricts vessels. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) affect platelet activation and secretion by inhibiting cyclooxygenase-2 (COX-2), which helps to convert arachidonic acid to thromboxane. In addition, such NSAIDs inhibit the release of adenosine diphosphate, which is needed for platelet aggregation. (Some of the more selective NSAIDs that inhibit COX-2 do not impair thromboxane formation, a feature that may contribute to their suspected prothrombotic potential.)

Aspirin, unlike NSAIDs, produces irreversible inhibition of COX even with single small doses; the effect persists for the life span of the platelet (7 days). Reversible inhibition is seen with the use of NSAIDs and omega-3 fatty acids (found in oily fish). Severe bleeding does not result, but an underlying bleeding diathesis may be aggravated.

In patients with storage pool disease, the adenosine diphosphate and serotonin contents of platelet granules are reduced or released prematurely, as occurs in patients who have undergone cardiopulmonary bypass. Bleeding is typically mild, and the bleeding time is only mildly prolonged.

Defective Aggregation

Patients with a rare hereditary defect in platelet aggregation, Glanzmann thrombasthenia, are missing a bridging protein called GPIIb/IIIa. The platelets of such persons cannot bind to fibrinogen and thus fail to aggregate by way of fibrinogen cross-links. Clot retraction is abnormal; the bleeding time is markedly prolonged. Serious bleeding can occur. Patients taking high doses of semisynthetic penicillins or cephalosporins also demonstrate reduced binding to fibrinogen.

Defective Acceleration of Coagulation

When platelets bind factors V and × on their surface, the rate of prothrombin conversion is greatly accelerated. Patients whose platelets cannot bind these clotting factors have a mildly prolonged PT, normal bleeding time, and normal platelet aggregation.

Mixed or Unknown Defects in Function

A number of conditions are associated with poorly defined but potentially important qualitative defects in platelet function. Uremia is the most important and is believed to be related to a dialyzable toxin. In addition to dialysis, the correction of anemia and administration of DDAVP, conjugated estrogens, and cryoprecipitate can reduce the prolongation in bleeding time. Dysproteinemias and myeloproliferative diseases also produce complex defects in platelet function, as can high parenteral doses of β-lactam antibiotics.

Disorders of Primary Hemostasis: Quantitative Platelet Defects

A normal platelet count ranges from 150,000 to 300,000/mm³. The presence of too many or too few platelets can impair primary hemostasis.

Thrombocytosis

Thrombocyte counts greater than 400,000/mm³ may interfere with platelet function; thrombosis is the more likely consequence, but occasionally, mucous membrane bleeding or hemorrhage may occur, especially following trauma or surgery. In most instances, the bleeding is inconsequential, but it is more likely when there is underlying myeloproliferative disease. Thrombocytosis may be primary or secondary.

Essential thrombocythemia is the primary myeloproliferative form of thrombocytosis. Like polycythemia, there is evidence of autonomous clonal hematopoiesis due to an acquired clonal somatic mutation (JAK2 617F—see Chapter 80). Thrombopoietin levels are inappropriately normal or elevated. Although the mean age of onset is 60 years, young women may develop the condition, which can cause miscarriage. Overall, the clinical course in the first 10 years after diagnosis is relatively indolent, especially when compared to polycythemia vera and myelofibrosis. The risk of thrombosis is about 15% to 25%; risk factors include age at diagnosis greater than 60 years, leukocytosis, and history of thrombosis. The risk of bleeding is considerably less. Transformation to polycythemia, myelofibrosis, or leukemia is rare in the first decade after diagnosis (1.4%) and is seen mostly in persons with mutations in the JAK2 gene; the risk increases over time to 24% after three decades. Vasoocclusive symptoms due to transient excessive platelet aggregation include migraine headache, dysesthesias, and redness in the hands and feet.

Secondary thrombocytosis occurs in the context of inflammatory disease, infection, or malignancy.

Thrombocytopenia

A platelet count of less than 100,000/mm³ is associated with a prolonged bleeding time. The diagnosis requires confirmation with a peripheral smear because spurious forms occur caused by in vitro clumping of platelets in response to citrate or small amounts of circulating cold agglutinin. The risk for serious bleeding from true thrombocytopenia does not occur until the platelet count falls to well less than 50,000/mm³. Easy bruising is seen with counts of 30,000 to 50,000/mm³; spontaneous bruising, menorrhagia, and prolonged bleeding with trauma arise as the count drops to less than 20,000/mm³. At less than 10,000/mm³, spontaneous epistaxis, gastrointestinal and genitourinary bleeding, and an increased risk for central nervous system hemorrhage occur. A petechial rash of the lower legs may be an initial manifestation. The lesions differ from those of vasculitis in that they are painless, flat, nonpruritic, and without an erythematous blush. Hemorrhagic bullae in the buccal mucosa are another characteristic finding. Bleeding may begin from the gastrointestinal or urinary tract. Thrombocytopenia develops when platelet destruction is increased (trauma, immune injury, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura [TTP]), production is decreased (marrow failure), or abnormal pooling occurs (hypersplenism).

Increased Destruction

Accelerated destruction is the most common cause of thrombocytopenia. The primary mechanism is immunologic, occurring in association with drugs, viruses, lymphoproliferative disorders, and connective tissue diseases, as well as idiopathically.

Immune (Idiopathic) Thrombocytopenic Purpura.

Immune (idiopathic) thrombocytopenic purpura (ITP) is a major cause of platelet destruction, mediated by the production of immunoglobulin G (IgG) autoantibodies directed against platelets. The idiopathic form is most common in young adults, children, and women. In adults, the condition is more chronic, characterized by a waxing and waning course with few spontaneous remissions. It may present as bleeding in the context of aspirin or NSAID use, as an incidental finding on routine blood count, or as menorrhagia, epistaxis, or purpuric rash following a viral infection. The physical examination findings are otherwise normal, and the spleen usually is not palpable, although it may be slightly enlarged. No lymphadenopathy, hepatomegaly, or sternal tenderness is present, which helps to distinguish the condition form secondary forms. Mild fever is sometimes noted.

Secondary Immune Thrombocytopenias.

Immune-mediated thrombocytopenia can occur in the context of concurrent illness and with drugs.

Concurrent Illness.

Immune thrombocytopenia is seen with a number of disease, including lymphoproliferative disorders, systemic lupus erythematosus, HIV, and hepatitis C. The clinical picture follows a pattern similar to that for ITP, except that there might also be findings indicative of the underlying cause (e.g., recent new drug exposure or lymphadenopathy, hepatomegaly, splenomegaly, arthritis, arthralgias, skin rash, renal dysfunction). Platelet counts drop to less than 100,000/mm³ in about 15% of cases. The prevalence of thrombocytopenia is 10% among asymptomatic HIV patients and up to 30% in those with symptomatic disease.

Drug-Induced Immune Thrombocytopenias.

These are idiosyncratic reactions, most often occurring among persons taking histamine₂ blockers, quinidine, sulfonamides, or anticonvulsants, although any drug may be responsible, as may herbal remedies and over-the-counter medications (e.g., acetaminophen,
NSAIDs). Usually, 5 to 7 days of use is needed to allow time for sensitization if there is no prior exposure. A rapid fall in the platelet count to less than 20,000/m³ is characteristic, and acute hemorrhage may ensue. A prompt return of the count to safe levels is typical as soon as the responsible drug is withheld.

Heparin-Induced Thrombocytopenia.

This form of druginduced thrombocytopenia differs from others in that thrombosis rather than bleeding dominates the clinical picture in the 20% to 50% of patients who become symptomatic. The problem is seen most often with use of unfractionated heparin (less likely with low molecular weight heparin if no recent exposure to unfractionated heparin). Risk increases with duration of unfractionated heparin therapy and is greatest after orthopedic or cardiac surgery and uncommon in obstetrical and long-term hemodialysis settings. Onset depends on history of exposure: 5 to 10 days if no recent exposure and within hours if recent exposure. Antibodies form against complexes of platelet factor 4 (PF4) and heparin, leading to platelet activation and increased thrombin production, believed responsible for the marked increase in risk of thrombosis. Platelet counts can decline rapidly by 50% or more but rarely to less than 10,000/mm³ and usually recover within 4 to 10 days of stopping therapy, although, even after the platelet count has returned to normal, thrombotic risk may persist for up to several weeks. Diagnosis depends on finding PF4-heparin antibodies in the serum (high sensitivity, low specificity), confirmed by functional assay of platelet activation (provides increased specificity).

Thrombotic Thrombocytopenic Purpura.

TTP causes platelet consumption, rather than outright destruction, as hyaline-platelet complexes form in small vessels, trapping platelets. Microangiopathic hemolytic anemia ensues, fever develops, and microvascular damage to the kidneys and the central nervous system may become manifest, producing the findings of hemolytic-uremic syndrome, which is considered a component of TTP and not a separate condition. Unlike disseminated intravascular coagulation, there is no consumption of clotting factors.

The precise mechanism is unknown, but vascular endothelial damage appears to be pathophysiologically important. Precipitants include food poisoning due to a Shiga toxin-producing organism (e.g., Escherichia coli 0157:H7 or Shigella species), adverse drug response (quinine, ticlopidine, clopidogrel, mitomycin C), autoimmune disorders, and pregnancy or postpartum state. The combination of anemia, a peripheral smear showing schistocytes, and thrombocytopenia in conjunction with fever, neurologic symptoms, and renal dysfunction constitutes the clinical syndrome. Serum lactic dehydrogenase can rise markedly. Patients with the acute fulminant form of the disease are unlikely to present in the outpatient setting, but those with the chronic relapsing form may do so.

Decreased Production

The bone marrow may be suppressed by drugs, depressed after a viral infection, or replaced by tumor. Thrombocytopenias associated with conditions causing marrow failure or a myelophthisic process usually occur in the context of a generalized pancytopenia (see Chapter 80). On occasion, individual drugs cause selective inhibition of platelet production. Chlorothiazide, tolbutamide, and ethanol are among the best documented. Megakaryocyte production is reduced in megaloblastic anemia, and quick recovery is noted with replacement therapy. Transient thrombocytopenia may follow influenza, hepatitis, rubella, and other viral diseases. The thrombocytopenia of HIV disease involves viral invasion of megakaryocytes in addition to increased peripheral destruction.

Increased Pooling

Pooling may occur in disorders associated with an abnormally enlarged spleen. Splenomegaly results in excessive trapping and a decrease in the number of circulating platelets.

Disorders of Secondary Hemostasis: Defects of the Intrinsic Pathway

These conditions prolong the PTT (the PT remains normal) by impairing the synthesis or functioning of intrinsic pathway clotting factors. Detection may be difficult because the PTT will not become prolonged until the reduction in the concentration of a functioning intrinsic clotting factor exceeds 75%. Fortunately, many clotting factor deficiencies do not cause serious bleeding, but the most common ones—the hemophilias—do.

Deficiencies of Factors VIII and IX: Hemophilias A and B

Hemophilias A and B represent deficiencies of factors VIII and IX, respectively. They account for more than 80% of patients with an inherited bleeding diathesis and, because they are X-linked, affect only male individuals. The risk for bleeding depends on the degree of factor deficiency. Patients with concentrations as low as 5% of normal experience little bleeding, except after surgery or major trauma; those with concentrations that are 1% to 5% of normal may bleed after minor trauma; and those with concentrations that are less than 1% of normal undergo spontaneous hemorrhage, typically into muscle and weight-bearing joints. Bleeding can also occur into the central nervous system, genitourinary tract, and retroperitoneum. As noted, detection may be difficult if factor levels are greater than 25% of normal because the PTT will be normal. Chromosomal mapping is being developed to help to detect female carriers. Relatively early prenatal detection is available by DNA analysis of chorionic villi tissue, provided that tissue is also available from other affected family members. Fetal blood may be sampled for the determination of antihemophilic factor levels later in pregnancy by ultrasonographically guided aspiration.

Factor Xi Deficiency

Factor Xi deficiency occurs mostly among Ashkenazi Jews and is inherited as an autosomal recessive disorder. A severe insult such as major trauma or surgery is needed to precipitate bleeding.

Other Deficiencies

Other deficiencies of intrinsic pathway factors may cause a prolongation of the PTT but do not lead to clinical bleeding, even in the setting of major surgery or serious trauma.

Inhibitors

The lupus anticoagulant is an IgG antibody elicited in the setting of connective tissue disease and phenothiazine use. Bleeding complications are rare, but a hypercoagulable state is sometimes seen in patients with this anticoagulant that leads to an increased risk for venous thrombosis and spontaneous abortion (see Chapter 22). Both the PTT and the PT are prolonged because the antibody is directed against the phospholipids used in both assays. Hemophiliacs who have had multiple transfusions of antihemophilic factor have close to a 15% risk for the development of antihemophilic factor inhibitors, IgG antibodies against the replaced factors. Such antibodies are also noted
in patients with connective tissue or lymphoproliferative disease, those who are pregnant, and persons of advanced age.

Disorders of Secondary Hemostasis: Defects of the Extrinsic Pathway

The major clotting factors of the extrinsic pathway (II, VII, X) depend for their synthesis and modification on a healthy liver and an adequate dietary intake of vitamin K. Some vitamin K also derives from bacterial production by gut flora. Hereditary deficiencies of extrinsic pathway factors are rare. Most bleeding traced to the extrinsic pathway is the consequence of impaired vitamin K production or liver disease. Causes include hepatocellular insufficiency, cholestasis (which impairs absorption of lipid-soluble vitamin K), poor dietary intake, and the use of broadspectrum antibiotics that kill normal gut flora. The characteristic laboratory finding is a prolongation of the PT. Prolongation of the PT also occurs with warfarin anticoagulant therapy. Warfarin inhibits the vitamin K-dependent postsynthetic modification of factors II, VII, IX, and X; this prevents them from being able to bind calcium and achieve biologic activity (see Chapter 83).

Vascular Defects

Vascular defects are characterized by purpuric bleeding into the skin and mucous membranes in the absence of a detectable clotting factor or platelet abnormality. Ecchymoses and petechiae are the predominant manifestations. The most common form occurs as a result of aging—the so-called senile purpura. Atrophy of connective and fatty tissues makes the vessels fragile and subject to ecchymotic bleeding, especially in areas of constant sun exposure (face, neck, dorsum of hands, forearms). The skin fragility and easy bruising seen with Cushing syndrome are believed to have a similar basis, the catabolic effects of prolonged corticosteroid excess. Scurvy causes defective collagen synthesis; affected patients may present with gingival bleeding or hemorrhage into subcutaneous tissue and muscle. Perifollicular bleeding is characteristic. Purpura simplex is a mild condition seen in otherwise healthy women; they experience ecchymoses mostly in the lower extremities (sometimes colorfully referred to as “devil’s pinches”), especially during menstrual periods. Most cases are believed to be acquired, and some have been linked to the use of NSAIDs.

Hereditary Disorders

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