Patrick F. Fogarty
INTRODUCTION
In addition to thrombocytopenia (Chapter 19) and primary deficiencies in the activity of coagulation proteins (Chapter 20), disseminated intravascular coagulation (DIC), von Willebrand disease, and qualitative abnormalities of platelets can also result in bleeding.
DISSEMINATED INTRAVASCULAR COAGULATION
Although it frequently manifests as bleeding, DIC begins as a result of an uncontrolled local or systemic activation of coagulation due to an underlying disorder. DIC may be acute or chronic, limited or diffuse, and accompanied by hemorrhage or (less commonly) thrombosis. Conditions that are associated with DIC are listed in Table 21.1.
Pathophysiology
The inciting events are numerous but generally involve either overwhelming release of tissue factor (see Chapter 20) by cellular, vascular, or hypoxemic injury, or the presence of endogenously or exogenously derived procoagulant molecules (bacterial lipopolysaccharide proteins produced by neoplastic cells).1 As coagulation is inappropriately and systemically activated, clotting factors and platelets are consumed, leading to bleeding. If activation of coagulation is chronic and low grade, however, clotting factors and platelets may be replenished and hypercoagulability may occur, manifesting as thrombosis (as in Trousseau syndrome).
Presentation
The appearance of DIC always indicates a serious underlying condition. A typical presentation of DIC involves a patient who has been hospitalized due to another disorder (Table 21.1) when unexplained bleeding and/or abnormalities in routine coagulation are observed.
The hemorrhage of DIC is typically diffuse and may involve bleeding at sites of surgical incisions or vascular access catheters, as well as urinary, gastrointestinal, pulmonary, central nervous system, or cutaneous hemorrhage. Acral cyanosis and petechial and ecchymotic lesions may also occur. Widespread DIC-associated truncal and extremity bruising (Purpura fulminans) usually is limited to children or follows a viral infection. 2
Severe systemic DIC may lead to widespread tissue hypoxia and multiorgan dysfunction; hepatic, neurologic, cardiac, renal impairment may occur. The development of multiorgan dysfunction is associated with a high mortality rate.
Diagnosis
Typically, acute DIC is suspected when a patient with a predisposing condition (Table 21.1) develops bleeding or thrombosis and/or a perturbation in laboratory tests indicative of DIC. DIC is a dynamic condition, especially in the acutely ill patient; considerable variation in laboratory markers from timepoint to timepoint is possible, and analysis of trends rather than isolated values is crucial. Laboratory parameters may show the following:
Increased (prolonged) activated partial thromboplastin time (aPTT), prothrombin time (PT), or thrombin time—due to consumption of clotting factors and/or fibrinogen (most patients).
Decreased fibrinogen (compared to baseline)*—due to consumption of fibrinogen.
Increased products of fibrinogen and fibrin degradation (FDPs; D-dimer assay)—due to plasminmediated cleavage of fibrinogen and fibrin. The D-dimer assay measures fibrin products that have been cross-linked by activated factor XIII.
Decreased platelet count (compared to baseline)*—due to clearance resulting from activation and aggregation at the sites of local prothrombotic reactions (most patients). DIC rarely produces a platelet count less than 20,000/μL. Patients with thrombosis and chronic DIC due to malignancy may have a normal or even elevated platelet count.
Fragmented red cells (schistocytes) on peripheral blood smear—due to microvascular hemolysis (25%–50% of patients with DIC).
Treatment
The clinical and laboratory manifestations of DIC are expected to resolve with correction of the inciting disorder. This might entail effective administration of antimicrobials to a patient with sepsis, treatment of malignancy, surgery to repair an aneurysmal dilatation, removal of conceptus and placenta, or another intervention as dictated by the clinical scenario. If the DIC is severe enough to have eventuated in multiorgan dysfunction, management in an intensive care unit is required.
Blood products should not be administered to patients with acute DIC unless clinically significant bleeding is present or if the risk of bleeding is felt to be high (as with thrombocytopenia in a patient who has sustained major trauma); there is, however, no reason to withhold blood products for fear of “fueling the fire.”
If bleeding is present, platelet transfusions may be administered to stop clinical bleeding; a target platelet count of 20,000 to 30,000/μL (most cases) or >50,000/μL (intracranial or life-threatening hemorrhage) is reasonable. Higher target ranges may be desired for patients who are to undergo invasive procedures such as major surgery, but the consumptive process may make achieving the goal difficult.
Cryoprecipitate may be administered for bleeding in the setting of fibrinogen levels that are consistently less than 80 to 100 mg/dL. Fresh frozen plasma (FFP) should be given only to patients with significant bleeding and a prolonged PT and aPTT.
Due to its potential to exacerbate hemorrhage, heparin should be considered in acute DIC only in cases of bleeding, when DIC is ongoing despite appropriate treatment (blood product infusion). Heparin should not be administered unless the platelet count can be supported to 50,000/μL or higher and there is no central nervous system or diffuse gastrointestinal bleeding. If heparin is to be used, a low-dose infusion (6–10 U/kg/h) with no bolus dose is recommended. An improving platelet count and fibrinogen concentration signifies that the treatment is effective. Heparin is contraindicated in patients with placental abruption or other obstetric conditions that will require surgical management, because the anticoagulation is likely to complicate the curative treatment.
Fibrinolysis inhibitors may have a role in patients with profuse bleeding who have failed to respond to other management, in whom FDPs are felt to be inhibiting platelets.
Due to questionable efficacy and worsened bleeding in some subjects, activated protein C concentrate (APC, drotrecogin alfa) is no longer recommended for patients with severe sepsis and DIC.3 Use of antithrombin concentrates is controversial. 4
Laboratory parameters (PT, PTT, fibrinogen, and platelet count) should be monitored at least every 6 hours in the acutely ill patient with DIC, and clinical bleeding should be followed to assess efficacy of therapeutic measures.
HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) affects women in the peri-partum period and produces clinically significant hemolytic anemia, hepatocellular injury, and low platelets. It may be difficult initially to distinguish the disorder from thrombotic thrombocytopenia purpura (TTP). Hepatic dysfunction (leading to elevated transaminases) may distinguish the diagnosis from TTP, which also may complicate pregnancy (see Chapter 19). Introduction of placental proteins into the maternal circulation has been thought to be etiologic; potential biomarkers have been identified.5 Gross hemoglobinuria with renal dysfunction and hypotension is common; the mortality rate is high. Management must include evacuation of the uterus, either by delivery of a term or near-term infant, or by dilatation and curettage to remove retained placental or fetal tissue.
Acute promyelocytic leukemia (APL) is frequently accompanied by DIC, potentially due to procoagulant molecules (tissue factor and others) contained within circulating promyelocytes. Bleeding commonly occurs in the lungs and brain and is frequently fatal. In addition to the appropriate use of blood products (FFP, cryoprecipitate, platelets) upon detection of APL-associated DIC, emergent initiation of treatment with all-trans-retinoic acid (ATRA) is recommended (see Chapter 11).6
Trousseau syndrome is a form of chronic DIC in which recurrent episodes of venous thromboembolism (VTE) complicate an underlying malignancy, especially adenocarcinomas. Experience in the management of the disorder has suggested that anticoagulation with warfarin is not effective in preventing further VTE; instead, subcutaneous low molecular weight heparin in therapeutic doses is usually necessary to prevent recurrence of thromboembolism (see Chapter 23).7
VON WILLEBRAND DISEASE
Epidemiology
von Willebrand disease (VWD) is the most common inherited bleeding disorder.8
Pathophysiology and Classification
Von Willebrand factor (VWF) is an extremely large multimeric glycoprotein that is synthesized in endothelial cells and megakaryocytes. Binding of VWF to its receptor, platelet glycoprotein Ib (GPIb), tethers platelets to one another and to the subendothelial collagen matrix, localizing them to the site of injury. This interaction is especially important to assure primary hemostasis in vessels such as arterioles, where a “high shear” state is present (Fig. 21.1). VWF also binds factor VIII (FVIII) in the circulation, protecting it from clearance.
Type 1 (quantitative defect in VWF) includes approximately 75% to 80% of patients, the majority of whom do not have an identified causal mutation in the VWF gene, which is located on chromosome 12. Patients may have mild or moderate bleeding. Autosomal dominant inheritance is typical.
Type 2 (qualitative defect in VWF) includes four subtypes; patients usually have moderate bleeding symptoms and present before adulthood. Type 2A (10% to 15% of VWD) involves mutations in VWF that cause either a defect in intracellular transport (2A, type 1) or render the molecule more susceptible to proteolysis (2A, type 2). Laboratory testing (Table 21.2) typically shows a marked decrease in VWF activity relative to antigen (a ratio of ≤0.6 is typical). Type 2B (5% of VWD) mutations result in an abnormal structure in the binding site for platelet GPIb (A1 domain of VWF), and are responsible for a “gain-of-function” defect that allows spontaneous binding of the abnormal VWF to platelets in the circulation. Patients typically have thrombocytopenia due to removal of VWF-bound platelet aggregates. The ristocetin-induced platelet aggregation (RIPA) (Table 21.2) shows an increase in platelet aggregation to low concentrations of ristocetin.† Type 2N (uncommon) features mutations in VWF that decrease its ability to bind and protect FVIII from clearance, resulting in decreased FVIII levels in the plasma and a phenotype similar to hemophilia A. Soft tissue and joint bleeding are common. The presence of affected females in the family is an important clue to consider this diagnosis. Laboratory studies show decreased FVIII (2% to 10%), and normal VWF function and antigen. Type 2M (very uncommon) results from mutations affecting the A1 domain in an area different from those mutations in type 2B. These result in decreased binding of platelets to VWF.
Type 3 VWD (rare) is caused by a variety of mutations of the VWF molecule, including larger deletions; patients may be homozygous for a given mutation or double heterozygotes. Severe bleeding manifests in childhood. FVIII is usually about 5%, and VWF levels usually are too low to detect.
Presentation
Bleeding symptoms usually involve mucous membranes. Epistaxis, oral bleeding, menorrhagia, and gastrointestinal bleeding are common. Individuals with marked abnormalities of VWF usually present earlier in life with bleeding at the time of mucous membrane-related procedures (tooth extractions, tonsillectomy), or at menarche.
FIGURE 21.1. Primary hemostasis. A. Normal conditions. Under physiologic conditions, platelets do not interact with the endothelium. B. Adhesion. Upon disruption of the blood vessel wall, subendothelial collagen and fibronectin are exposed, leading to platelet adhesion. In the arterial/arteriolar circulation, subendothelial von Willebrand factor (VWF) assists in the adherence of platelets to the site of injury via binding to the platelet glycoprotein (GP) Ib receptor. C. Aggregation. Tissue factor interacts with factor VIIa, present locally, to catalyze the formation of thrombin.Thrombin, collagen, and other molecules bind to receptors on the platelet membrane, leading to platelet activation. Fibrinogen cross-links platelets via their GPIIb/IIIa receptors, promoting formation of an occlusive plug that prevents additional blood loss through the break in the vessel wall.VWF also bridges between platelets, via their GPIb and GPIIb/IIIa receptors.
Diagnosis
The diagnosis of VWD is based on a typical history of bleeding (i.e., mucous membrane-related) and confirmatory laboratory testing.9 The diagnosis can be difficult, given the large number of individuals (estimated up to 1% of the population) whose VWF levels fall below the laboratory reference range, many of whom do not experience abnormal bleeding.
The personal and family history of bleeding should be carefully documented.
A complete blood count and routine coagulation studies should be performed, to exclude other diagnoses and assess for anemia.
Initial testing for VWD (Table 21.2). A VWF antigen level (by ELISA) and a VWF activity (by ristocetin cofactor assay) should be performed. The latter involves addition of ristocetin at 1.2 mg/mL to a mixture of patient plasma (the VWF source) and washed normal platelets. Ristocetin binds VWF, allowing it to bind GPIb on the platelet membrane, causing platelet aggregation. The factor VIII activity may be abnormal.
Secondary testing. A VWF multimer study detecting the distribution of multimers is performed once a diagnosis of VWD has been made, to assess for type 2 VWD.
VWF levels <30% are regarded by most clinicians as diagnostic of VWD. If borderline results are obtained, testing may need to be repeated up to three times to exclude the diagnosis. Menstruating females generally have the lowest VWF levels in the first 4 days of menstruation. Exogenous estrogens increase VWF levels, and testing may need to be repeated off of the hormones. Testing of family members also may aid in the diagnosis of patients with borderline results.
“Low VWF.” This classification was developed to encompass VWF levels in the 30% to 50% range, which are too high to be considered a definitive criterion for diagnosis but may indicate a tendency for bleeding in selected patients. Hemostatic agents (see “Treatment” ) may be used if bleeding (or a high risk of bleeding) is present.
Treatment
The patient’s type of VWD, past response to bleeding challenges, current medications, and general medical condition should be considered (Table 21.3).9
DDAVP (desmopressin acetate) indirectly causes release of VWF and factor VIII from storage sites (primarily the endothelium). After intravenous administration, levels of both factors are increased 2 to 7-fold for about 6 to 12 hours. Prior to use of DDAVP for clinically significant bleeding or as prophylaxis prior to invasive procedures, patients should undergo a therapeutic trial to document responsiveness to the medication (as assessed by increased VWF levels into the hemostatic range and lack of worsening thrombocytopenia [type 2B patients]). More than two doses, given 12 to 24 hours apart, generally should be avoided in a 24 to 48-hour period, as tachyphylaxis and serious hyponatremia (due to fluid retention) can occur after repeated doses. Nonsteroidal anti-inflammatory (NSAIDs) agents may aggravate this latter effect.
VWF concentrates are used when bleeding is not controlled with DDAVP, or as prophylaxis prior to a major invasive procedure, or for clinically significant bleeding in patients who are less likely to be responsive to DDAVP (type 3 and some type 1 and 2 patients). Humate-P®, Alphanate, and Wilate are antihemophilic factors that contain VWF. Cryoprecipitate generally is not recommended because of its lack of viral inactivation.
Antifibrinolytic agents such as epsilon aminocaproic acid (Amicar®) and topical agents (including topical thrombin, Gelfoam, and fibrin sealant) are used adjunctively, especially in cases of mucosal bleeding (e.g., dental).
Pregnancy and Von Willebrand Disease
All pregnant women with VWD should be managed in consultation with a hematologist and should deliver at a specialized center for bleeding disorders. VWF levels increase 2 to 3-fold during the last two trimesters of pregnancy; type 1 VWD patients whose VWF levels have reached the normal range during the third trimester may not require treatment during delivery. In more severely affected patients, VWF concentrates can be administered prophylactically, beginning usually after the onset of labor. Peripartum DDAVP use warrants caution due to the risk for hyponatremia and seizures. The risk of postpartum hemorrhage may persist for up to a month after delivery.10
QUALITATIVE PLATELET DISORDERS
Introduction
Most disorders of platelet function are acquired. Heritable qualitative platelet disorders are individually rare (occurring in 0.01–1/100,000 population) but in aggregate may not be uncommon.11 Because of redundancy of biochemical and receptor pathways that mediate the function of platelets, certain defects may be detectable only on laboratory testing, whereas other qualitative defects characteristically produce clinically significant bleeding.
Review of Hemostasis and the Role of Platelet Biochemistry
Primary hemostasis describes the formation of a platelet plug at the site of vascular injury (Fig. 21.1). In a variety of reactions that are not entirely sequence-specific, individual circulating platelets must adhere to the denuded endothelial surface, undergo activation through receptor-ligand interactions, release the contents of their granules (i.e., platelet secretion), and aggregate to form a physical barrier to continued blood loss.12
Adhesion
Subendothelial molecules such as VWF, collagen, and fibronectin mediate adhesion of platelets to the exposed subendothelial matrix at sites of vessel wall compromise. In “high-shear” states such as arterioles, VWF is especially important, because it tethers the platelet to the endothelial surface via interaction with its receptor, GPIb.
Activation
Subendothelial collagen activates platelets; thrombin, which has been generated locally in reactions following the interaction of factor VIIa and tissue factor (provided by the membranes of cells), also activates platelets by binding to receptors on the platelet surface and initiating a series of signal transduction events.
Secretion
Agonists such as collagen, thrombin, Adenosine Diphosphate (ADP), and epinephrine bind to their receptors on the platelet membrane and induce a series of biochemical events that cause platelets to release the contents of their granules (Table 21.4), which act to promote further activation and aggregation.
Aggregation
Binding of agonists also promotes a conformational change in the platelet GP IIb/IIIa receptor, exposing its binding sites for fibrinogen and VWF; these molecules can then bridge between individual platelets at the site of vascular injury, promoting the formation and stability of the platelet plug.
Participation in Coagulation Reactions
The platelet membrane is rich in phospholipid, which is a required component for reactions involving clotting factor complexes.
Platelet Function Testing
Platelet Aggregation Studies (Platelet-Rich Plasma System)
According to the classical method, platelets in a suspension of platelet-rich plasma (PRP) impede transmission of light. When any of a variety of agonists (collagen, thrombin, ADP, epinephrine) is added, aggregation occurs, consolidating the platelets and allowing the passage of light through the plasma. The increase in light transmission as aggregation occurs is plotted as a function of time (Fig. 21.2).
Ideally, the waveform shows two physiologic processes: a primary wave represents initial aggregation as platelet receptors are activated and become available to bind proaggregatory molecules such as fibrinogen.
A secondary wave indicates further aggregation that is stimulated by the release of platelet granule contents.
Routinely, secretion of platelet granule contents (Table 21.4) is assessed in tandem with platelet aggregation; per one methodology, after stimulation of platelets with an agonist, release of adenosine triphosphate into solution is measured through a chemiluminescence procedure, and plotted as a function of time.
Platelet Function Analyzer
The Platelet Function Analyzer (PFA-100™, Dade Behring, Inc.) device assesses the formation of a platelet plug after citrated whole blood is aspirated through an aperture in a collagen-impregnated membrane, leading to platelet activation and aggregation; the time to occlusion of the aperture is measured and compared with a normal range. Though it may be helpful for assessing aspirin-associated platelet inhibition,13 the test lacks sufficient sensitivity and specificity to be used in screening for inherited platelet disorders.14
Measurement of Granule Contents (Rarely Indicated)
Centrifugation of PRP produces a platelet pellet; the platelet membranes are then disrupted, liberating intracellular/intragranular proteins into the lysate. The molecule of interest is then assessed (VWF, by ristocetin co-factor assay, for intra-granular VWF).
Acquired Disorders
Drugs
The most common acquired qualitative platelet disorders are caused by the use of medications that directly or indirectly impair platelet function; of these, aspirin and the NSAIDs are most frequently responsible (Table 21.5). Patients who present with bruising or platelet-type bleeding and whose platelet function testing shows abnormal aggregation or secretion should be questioned regarding current medications, especially recently initiated drugs including over-the-counter, naturopathic, and herbal agents. Treatment of clinically significant bleeding due to drug-induced platelet dysfunction first involves discontinuation of the offending agent, and may require additional measures (Table 21.6).
FIGURE 21.2. Platelet aggregation studies. Platelet aggregation studies involve the addition of agonists (collagen, thrombin, ADP, arachidonic acid, or epinephrine) to a suspension of platelet-rich plasma (PRP); the agonist induces aggregation of platelets and allows transmission of light through the plasma component of the PRP. A. In the normal scenario, the binding of an agonist to its platelet receptor initiates a shape change that temporarily decreases light transmission; subsequently, a primary wave of platelet aggregation is recorded (as increased light transmission) as fibrinogen binds its receptor, GPIIb/IIIa, and begins to cross-link platelets. Unlike the other agonists, collagen does not induce a primary wave. A secondary wave occurs as signal transduction events (resulting from platelet activation) eventuate in augmented binding of GPIIb/ IIIa by fibrinogen and release of platelet granules, whose contents are able to induce further aggregation. B. In storage pool disease (SPD), platelet aggregation to ADP and other agonists typically shows an initial wave of aggregation, but the aggregates subsequently dissociate due to reduced or absent release of platelet granule contents. Because release of granules is largely dependent on thromboxane, the aspirin effect produces a similar platelet aggregation profile to that of SPD when ADP or epinephrine is used, but stronger agonists such as thrombin and collagen can circumvent the thromboxane pathway and produce a normal aggregation curve. C. Due to lack of GP IIb/IIIa expression on the platelet surface, platelets from patients with Glanzmann thrombasthenia show absent aggregation to all agonists except ristocetin.
Aspirin irreversibly inhibits the platelet cyclooxygenase (COX-1) enzyme, which is responsible for the conversion of membrane-associated arachidonic acid to thromboxane A2 (TxA2); the inhibition is constant for the entire life span of the platelet (7–10 days). Platelet aggregation studies (Fig. 21.2) show decreased reactivity to most agonists, including low concentrations of thrombin and collagen, and normal aggregation with high concentrations of thrombin and collagen. Using the PFA-100 system, aspirin-induced platelet dysfunction is evident in an increased time to aperture occlusion with the epinephrine/collagen reagent, while that of the ADP/collagen reagent is unaffected. 13
NSAIDs reversibly inhibit platelet COX-1; their inhibitory effect persists only as long as the drug is present in the circulation. Selective inhibitors of COX-2 do not bind or impair platelet COX-1.
Platelet glycoprotein IIb/IIIa inhibitors are used in the management of patients with acute coronary syndromes or before or following percutaneous coronary intervention, frequently in conjunction with heparin. Eptifibatide is a small molecule that binds the GP IIb/IIIa receptor, inhibiting the binding of its ligands, fibrinogen, VWF, and others, hindering platelet aggregation. Abciximab is a monoclonal antibody against GP IIb/IIIa that also inhibits binding of these proaggregatory ligands. Abciximabbound platelets can be cleared at an accelerated rate due to interaction between the Fc portion of the antibody and Fc receptors on reticuloendothelial macrophages in the liver and spleen, producing thrombocytopenia that in some cases (<1.0%) is severe.
Table 21.5 Substances Associated with Platelet Dysfunction*
Platelet-Directed Agents
Aspirin
NSAIDS (except COX-2 inhibitors)
Dipyridamole (Aggrenox ®)
Clopidogrel (Plavix ®)
Ticlopidine (Ticlid ®)
Prasugrel (Effient ®)
Abciximab (ReoPro ®)
Eptifibatide (Integrilin ®)
Tirofiban (Aggrastat ®)
Anesthetics
Dibucaine
Procaine
Halothane
Antibiotics
Penicillins (penicillin G, ticarcillin, nafcillin, piperacillin, methicillin, ampicillin)
Cephalosporins (cefazolin, cefotaxime)
Nitrofurantoin
Chemotherapeutic Drugs
Car-mustine
Daunorubicin
Mithramycin
Psychiatric Medications
Selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline)
Tricyclic antidepressants (e.g., imipramine, amytriptyline, nortriptyline)
Other Agents
Nitrates
Antihistamines (diphenhydramine, chlorpheniramine)
Ethanol
Omega-3 fatty acids (eicosapentaenoic acid)
“Wood ear” mushrooms
Radiographic contrast dye
* Most of these agents have been reported to cause abnormalities in platelet aggregation or the bleeding time, rather than bleeding. Adapted from George JN, Shattil SJ. Acquired disorders of platelet function. In: Hoffman R, Benz EJ, Shattil SJ, et al., eds. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:2174.
Ticlopidine, clopidogrel, and prasugrel irreversibly inhibit the binding of ADP to its receptor on the platelet membrane, impairing the ADP-dependent binding of fibrinogen to GP IIb/IIa, decreasing platelet aggregation. Neutropenia and aplastic anemia have been reported with increased frequency in patients taking ticlopidine; TTP has been described with use of ticlopidine and less frequently with clopidogrel. 15
Dipyridamole is used to prevent recurrent stroke or transient ischemic attack, usually in conjunction with aspirin. It inhibits ADP- and collagen-induced platelet aggregation via an effect on intracellular cyclic Adenosine Monophosphate (AMP).
Other substances. Serotonin reuptake inhibitors may impair the function of platelets by reducing the serotonin content of platelet-dense granules.16 Omega-3 fatty acids may disrupt the phospholipid membrane of the platelet and interfere with reactions of coagulation that normally take place on the platelet surface. 17
Myelodysplasia/Myeloproliferative Diseases
The platelets that are produced in myelodysplasia and the myeloproliferative disorders (chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, and idiopathic myelofibrosis) may show abnormal receptor-ligand interactions, ineffective signal transduction, or decreased secretion of platelet granule contents; in a minority of patients these abnormalities lead to bleeding.18
Renal Failure/Uremia
Platelets from individuals with impaired kidney function frequently show abnormalities upon aggregation testing. Although plasma urea itself may not be causative, other factors, such as dysfunctional VWF and increased levels of nitric oxide and cyclic GMP, may lead to clinically important bleeding, especially gastrointestinal. DDAVP (standard doses), cryoprecipitate, and high-dose estrogens (Premarin, 50 mg single dose) have been suggested to be of benefit in uremia-related bleeding.19 Because the presence of adequate numbers of intravascular red cells may facilitate interaction of platelets with the vessel wall, red cell transfusions or erythropoietin are recommended in patients with anemia related to renal failure who are bleeding, to keep the hematocrit above 30%.19 Platelet transfusion may be beneficial temporarily if other measures fail and bleeding persists. If a dialyzable substance in the uremic plasma is responsible for the defect in platelet function, hemodialysis also may be beneficial, albeit temporarily.19
Cardiac Bypass
Cardiac bypass causes defects in both platelet number and function.20 As platelets pass through the extracorporeal oxygenating circuit, they contact the artificial surfaces of the system and are activated; they also are fragmented by distortional trauma. Both phenomena lead to their accelerated clearance. Following bypass, a decrease in the platelet count, abnormalities in platelet morphology on the blood smear, and impaired in vitro platelet aggregation are observed in most patients; but these effects typically persist for 24 to 48 hours following bypass. Platelet transfusion may be given for serious bleeding.
Inherited Disorders
Inherited disorders of platelet function are rare and produce varying degrees of platelet-type bleeding, usually beginning within the first decade of life.11 Heritable disorders of platelet function may also remain clinically silent until unmasked by a significant hemostatic challenge. Prophylaxis prior to invasive procedures or treatment of significant hemorrhage (Table 21.6) typically involves transfusion of normal platelets. Early use of antifibrinolytic agents may decrease transfusion requirements. DDAVP may be effective in platelet disorders characterized by normal dense granules, whereas recombinant factor VIIa may be helpful as only an adjunctive measure to platelet transfusion when transfusions alone have been ineffective (Table 21.6).
Bernard-Soulier Syndrome
Bernard-Soulier syndrome (BSS) comprises a triad of large platelets, moderate thrombocytopenia, and a prolonged bleeding time; individuals with this disorder have reduced or abnormal expression of platelet glycoprotein Ib/IX (the receptor for VWF) on the surface of their platelets. BSS is autosomal recessively inherited. Platelet aggregation studies are normal with all agonists except ristocetin. BSS is distinguished from VWD in that the reduced RIPA in BSS is corrected by the addition of normal platelets whereas in VWD, it is corrected by the addition of normal plasma (which contains adequate VWF). The diagnosis can be confirmed by platelet flow cytometry.
Glanzmann Thrombasthenia
Glanzmann thrombasthenia is a recessively inherited qualitative or quantitative abnormality in GP IIb/IIIa expression on the platelet surface.21 Without adequate functional IIb/IIIa to bind fibrinogen and VWF (both of which cross-link platelets), platelet aggregation is markedly impaired (Fig. 21.2). Patients may present with mucocutaneous bleeding in infancy. In pregnant patients, the condition is associated with maternal and fetal hemorrhage, and a third of women experience primary postpartum hemorrhage (up to 20 days after delivery).22 Isoantibodies against the missing or defective platelet integrin may neutralize transfused platelets in some cases, suggesting a role for rVIIa as a platelet-sparing measure.23 The diagnosis can be confirmed by platelet flow cytometry.
Storage Pool Disease
Storage pool disease (SPD) is characterized by abnormalities in number or content of platelet granules.24 Defects in alpha-granules, dense granules, or both (Table 21.4) may be present. Platelet aggregation to ADP (Fig. 21.2) typically shows an initial wave of aggregation, but the aggregates subsequently dissociate due to reduced or absent release of granule contents, which reinforce the aggregatory response. Most patients have a prolonged bleeding time. A variable bleeding diathesis results. More commonly, patients may have release defects wherein granules are present, but signaling necessary for release of granule contents is defective.
Albinism-associated SPD occurs in the context of disorders characterized by oculocutaneous albinism, such as the Hermansky-Pudlak and Chediak-Higashi syndromes. Impaired biogenesis of dense granules, lysosomes, and melanosomes may be responsible for the reduced number of dense granules in these patients.
Non-albinism-associated SPD occurs in a variety of other conditions (TAR syndrome, Ehlers-Danlos syndrome, Wiskott-Aldrich syndrome, Osteogenesis imperfecta). Defects in dense granules may relate more to granular content rather than number and may occur in conjunction with alpha-granule abnormalities (alpha-delta SPD).25 Decreased or empty dense granules can be visualized on electron microscopy.
The Gray Platelet Syndrome: The gray platelet syndrome is a rare, inherited disorder characterized by abnormalities of platelet alpha granules, thrombocytopenia, and fibrosis in the bone marrow; consanguinity is common. A lifelong history of mild to moderate mucocutaneous bleeding usually is present. Review of the blood smear typically shows agranular platelets that appear “gray” on Wright staining due to a lack of azurophilic granules. In contrast to dense granule deficiency, platelet aggregation to epinephrine, ADP, and arachidonic acid is often normal, while thrombin and collagen produce variable results. The diagnosis is confirmed with electron microscopy.
Quebec Platelet Disorder26: The Quebec platelet disorder is an extremely rare disorder that is characterized by abnormal alpha-granule content and mild thrombocytopenia, leading to a moderate bleeding diathesis. Bleeding is unresponsive to platelet transfusion. Increased intraplatelet urokinase-type plasminogen activator results from a tandem duplication of the PLAU gene.
Scott Syndrome
Scott syndrome is an extremely rare disorder characterized by spontaneous bleeding due to a defect in scramblase, which is necessary for adequate expression of phosphatidylserine on the outer leaflet of the platelet membrane and normal binding of coagulation factors.27 Patients may show a loss-of-function mutation in TMEM16F.28
Congenital Disorders of Signal Transduction
These include defects in receptor-agonist interactions, G-protein activation, platelet enzymatic activity, and phosphorylation of signaling proteins.12
Isolated Laboratory-Specific Defects
Individuals with phenotypically normal hemostasis occasionally demonstrate reduced or (less frequently) absent aggregation to one or more agonists on platelet aggregation testing. These abnormalities, which may be genetically determined, probably reflect inter-individual differences in the reactivity of platelets to certain ligands and do not necessarily indicate an increased risk for spontaneous or traumainduced hemorrhage, unless a tendency to bleed has been previously demonstrated.
Other Conditions
The May-Hegglin anomaly29 features mild to moderate thrombocytopenia, large platelets, and characteristic leukocyte azurophilic inclusions (Dohle bodies). While the large size of the platelets implies a qualitative abnormality, patients generally do not bleed excessively and aggregation studies are normal. An autosomal dominantly inherited disorder, it is a manifestation of mutated non-muscle myosin heavy chain IIA, which has been implicated in the related disorders Sebastian syndrome, Fechtner syndrome, and Epstein syndrome; these feature varying degrees of sensorineural hearing loss, nephritis, cataracts, and leukocyte inclusions. Eltrombopag has been used in some patients with severe thrombocytopenia with a resulting decrease in bleeding manifestations.30
References
*Especially in early [Q21]DIC, the platelet count and fibrinogen may be reduced from the baseline value but still remain within the normal laboratory reference range.
† Pseudo or platelet type VWD is caused by a defect in the platelet GPIb molecule, allowing it to bind to the patient’s normal VWF with increased avidity and leading to a type 2B clinical phenotype. Mixing studies using a modified RIPA (patient’s platelets and control plasma) distinguish it from type 2B VWD.