Published: January 2009
Platelet disorders can be divided into disorders of platelet function and number.
Thrombocytopenia is defined as a platelet count of less than 150,000/mm3. With normal platelet function, thrombocytopenia is rarely the cause of bleeding unless the count is less than 50,000/mm3. Thrombocytopenia should always be confirmed by examination of a peripheral smear. It can be caused by decreased platelet production, increased destruction, sequestration, or a combination of these causes.
The hallmark of platelet underproduction is decreased marrow megakaryocytes or, when available, a decreased peripheral blood reticulated platelet count.2 Common causes include infections (including HIV), drugs (frequently chemotherapeutic agents or alcohol, but other medications in rare cases), radiotherapy, vitamin deficiency (e.g., folate, vitamin B12), or marrow infiltration by tumor, storage diseases, or marrow failure syndromes (e.g., aplastic anemia). In addition, the myelodysplastic syndromes are a frequently overlooked group of disorders associated with thrombocytopenia in older adults.
Management involves treatment of the underlying condition and supportive platelet transfusions if needed. More recently, two recombinant thrombopoietin (TPO) agents have made their way into the clinical arena for the treatment of chemotherapy-induced thrombocytopenia (recombinant human thrombopoietin, rhuTPO, and pegylated recombinant human megakaryocyte growth and development factor, PEG-rhuMGDF).3 A single dose of rhuTPO or PEG-rhuMGDF increases the platelet count after about 5 days and the peak effect is observed about 10 to 12 days later; rhuTPO increases the nadir platelet count, reduces the duration of thrombocytopenia, and results in a decrease in platelet transfusion for patients receiving dose-intense chemotherapy for ovarian cancer.3 These agents remain the subjects of investigation and recommendations for their use have not been defined.
Hypersplenism from a variety of causes, including liver disease or malignancy, may result in platelet sequestration (Box 1). Mild to moderate thrombocytopenia is caused by platelet sequestration when there is an associated mild reduction in neutrophil count and hemoglobin and with minimal impairment of hematopoiesis on bone marrow examination. If physical examination fails to detect splenomegaly, evaluation with ultrasonography or radionuclide imaging is recommended to document splenomegaly.
|Box 1: Causes of Splenomegaly|
|Portal or hepatic venous thrombosis|
|Malignancies and hematologic disorders, including lymphoma, acute and chronic leukemias, myeloproliferative disorders, metastatic solid tumors, and hemolytic anemias|
|Infectious disorders, including infection with Epstein-Barr virus, cytomegalovirus, Salmonella, Brucella, tuberculosis, malaria, Toxoplasma, and leishmania|
|Infiltrative disease, including Gaucher's disease, amyloidosis, and glycogen storage diseases|
|Miscellaneous disorders, including sarcoidosis, systemic lupus erythematosus, and Felty's syndrome|
Management includes treatment of the underlying condition and platelet transfusion, as needed. Cytopenias secondary to hypersplenism are often not sufficiently severe to warrant treatment in the form of total or partial splenectomy, partial splenic embolization, or transjugular intrahepatic portosystemic shunting for congestive splenomegaly.4
The hallmark of increased platelet destruction is increased marrow megakaryocytes or, when available, high reticulated platelet count. Platelet destruction results from various immune conditions, including the following:
The incidence of ITP in a Danish study was 100 cases per 1,000,000 person-years, with 50% of cases occurring in the pediatric age group. It can be of adult or childhood onset. Adult onset is more likely to be chronic and insidious. Adult-onset ITP is more common in females than males (with a female-to-male ratio of 1.7 : 1), whereas childhood onset has equal gender distribution.5
ITP is subdivided into chronic or acute, with the latter being of 6 months or less in duration.5
ITP can be primary or secondary. Causes of secondary ITP include systemic lupus erythematosus, antiphospholipid antibody syndrome, immunoglobulin A (IgA) deficiency, common variable hypogammaglobulinemia, lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, lymphomas), viral (e.g., HIV, hepatitis C), or drug-induced—many drugs have been linked to thrombocytopenia, but those known to be associated with immune thrombocytopenia are heparin and quinidine. Patients with drug-induced ITP usually present within 1 to 2 weeks from the initiation of the offending drug with petechiae and a platelet count of less than 20,000/mm3. Recovery usually occurs 5 to 7 days after discontinuation of the offending agent but can occasionally be more prolonged.
Here we will focus on primary ITP. The guidelines are derived from recommendations of the consensus guideline of the American Society of Hematology.6
The pathophysiology of primary ITP involves the formation of antiplatelet antibodies, frequently directed at platelet glycoproteins IIb/IIIA, IIb/IX, Ia/IIa, and V, or multiple platelet antigens.
On history and physical examination, the absence of systemic symptoms is helpful in ruling out secondary causes. Evidence of platelet-type (mucosal) bleeding should be noted, and the absence of splenomegaly supports the diagnosis. Bleeding is often less pronounced than in cases of decreased production with similar platelet counts.
The complete blood cell (CBC) count should be unremarkable except for thrombocytopenia or easy to account for anemia. The peripheral smear must confirm thrombocytopenia, and large immature platelets are often noted. A bone marrow biopsy or aspirate is required when one of the following features is noted: patients older than 60 years, presence of atypical features (e.g., fatigue, fever, joint pain, macrocytosis, neutropenia) or before splenectomy in the patient whose diagnosis is not definitive. Testing for antiplatelet antibodies is generally not recommended. Antiplatelet antibodies have a sensitivity of 49% to 66%, a specificity of 78% to 92%, and a positive predictive value of 80% to 83%. A negative test result does not rule out the diagnosis.
In the asymptomatic patients with a platelet count of less than 30,000/mm3 or in the symptomatic patient with a platelet count higher than 30,000 but less than 50,000/mm3, treatment with steroids such as prednisone, 1 to 1.5 mg/kg/day, has an expected response rate of 50% to 75%.5,6 A response is usually seen after days of treatment. Experts differ on the length of time needed before labeling the patient steroid-unresponsive and changing therapy. Accordingly, a trial of 1 to 3 weeks of a corticosteroid is considered an adequate therapeutic trial.
Intravenous immunoglobulin (IVIG), 1 g/kg/day for 2 to 3 days, is used to treat major bleeding, platelet counts of less than 5,000/mm3 despite 3 days of steroids, or extensive and progressive purpura.6 It is also the initial agent in patients with platelet counts of less than 50,000/mm3 with life-threatening bleeding. The response rate for IVIG is 80%.6 Disadvantages include cost, the low rate of long-term response, and risks of anaphylaxis (especially in patients with IgA deficiency), renal failure, or pulmonary failure.
Rho(D) immune globulin (RhoGAM) for Rh-positive patients, 75 μg/kg, is as effective but less toxic than steroids. Significant adverse effects of this treatment include a hemolytic anemia that rarely results in more than a 2-g/dL drop in the hemoglobin level. It is, however, more expensive than prednisone and affords a similar long-term remission (5% to 30%).6
Splenectomy should be considered after 3 to 6 months if the patient continues to require 10 to 20 mg/day of prednisone to keep the platelet count higher than 30,000/mm3 or within 6 weeks of diagnosis in the patient with a platelet count of less than 10,000/mm3, despite treatment. Laparoscopic splenectomy is been increasingly used in high-volume centers and helps decrease the duration of hospitalization. Pneumococcal, meningococcal, and Haemophilus vaccination is indicated before splenectomy.
Urgent treatment for ITP patients with neurologic deficits or internal bleeding, or for emergency surgery, includes methylprednisolone, 30 mg/kg/day for 2 to 3 days, for a maximum of 1 g/day and/or IVIG, 1 g/kg/day for 2 to 3 days, combined with platelet transfusions. Vincristine, antifibrinolytic therapy, recombinant factor VIIa, or continuous platelet transfusions should also be considered.
Treatment is indicated only for those with a platelet count of less than 30,000/mm3. Splenectomy (with a 66% response rate) is indicated in patients who relapse and do not respond to treatment with steroids, IVIG, or Rho(D) immune globulin. Rho(D) immune globulin is traditionally less effective in patients with ITP refractory to treatment.6
Rituximab, a monoclonal antibody to CD20, has been used in patients with ITP with varying success. Disadvantages include cost, infusion reactions and lack on of long-term safety data. The role of rituximab therapy in ITP patients remains to be defined. It is currently being evaluated in the newly diagnosed and relapsed refractory patient.
A pentad of signs is classically described—thrombocytopenia (platelet counts usually less than 20,000/mm3), microangiopathic hemolytic anemia, fever, renal dysfunction, and neurologic signs. A clinical triad of thrombocytopenia, red blood cell fragments (schistocytosis), and an increased lactate dehydrogenase (LDH) level is enough to suggest the diagnosis.7 Examination of the peripheral blood smear in patients with thrombocytopenia of unclear cause is imperative to exclude this diagnosis (Fig. 1). If severe renal failure is a prominent feature of the syndrome, the hemolytic-uremic syndrome may be a more likely diagnosis. Although ADAMTS13 (a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor) levels can be measured, the diagnosis of TTP is a clinical one and results are often not available at the time of diagnosis.
Thrombotic microangiopathies are characterized by destructive thrombocytopenia, erythrocyte fragmentation, and tissue ischemia and necrosis, as evidenced by increased LDH levels. In nonacquired TTP, systemic clumping of platelets is caused by unusually large von Willebrand factor (vWF), often caused by a deficiency of the metalloproteinase ADAMTS13 that cleaves vWF into smaller multimers.7
TTP can be familial or acquired. Familial TTP manifests in infancy or childhood, and often remits and relapses. Acquired TTP manifests in adults or older children and often occurs as a single acute episode.
Drug-induced TTP often occurs weeks after exposure. Medications commonly associated with this diagnosis include ticlopidine, mitomycin C, cyclosporine, tacrolimus, quinine and, less frequently, clopidogrel. Whole-body irradiation and organ transplantation also may result in a clinical syndrome similar to that of TTP.7
The treatment of childhood TTP (often related to ADAMTS13 deficiency) involves the transfusion of platelet-poor fresh-frozen plasma (FFP), FFP treated with organic solvent, or cryoprecipitate-poor plasma (cryosupernatant) every 3 weeks. The treatment of adults or older children with acquired TTP is by daily plasma exchange until platelet counts and LDH levels normalize. 7 Patients not responding to these modalities might require the addition of steroids, consideration of splenectomy, or administration of vincristine. More recently, rituximab has been used in patients with refractory TTP, with varying efficacy. Platelets should not be transfused unless a life-threatening hemorrhage or intracranial bleed is present.
PTP is a transfusion reaction characterized by severe thrombocytopenia lasting days to weeks after transfusion of platelet-containing products. Platelet antigen 1a, Pl(A1) antigen, is required to confirm the diagnosis.
Patients become sensitized to platelet antigen, most frequently platelet antigen 1a—Pl(A1) antigen—from prior transfusion of platelet-containing products or from pregnancy. This explains the much higher incidence among women. Pl(A1) antigen is also the platelet antigen most commonly involved in the pathophysiology of neonatal alloimmune purpura, thrombocytopenia that occurs in the neonatal period in the offspring of patients with PTP.8
The treatment of choice is IVIG, 400 mg/kg/day for 5 days or 1 g/kg/day for 2 days for severe thrombocytopenia. Further transfusions should be washed or Pl(A1) antigen–negative.8
HIT can be of two types:
The remainder of this discussion will focus on type II HIT, because type I HIT is of no clinical consequence.
The pathophysiology involves antibody formation against the heparin-platelet factor 4 complex, with resultant thrombosis. Thrombosis is usually venous, in the form of deep venous thrombosis or pulmonary embolism), but can be arterial as well, in the form of myocardial infarction or stroke.10
HIT is rare with platelet counts of less than 20,000/mm3; the average platelet count nadir is approximately 60,000/mm3.10 HIT has an earlier onset with re-exposure to heparin. A high index of suspicion is required and HIT should be considered in hospitalized patients with nosocomial thrombocytopenia. In addition, thrombosis is often associated with HIT and is usually asymptomatic.10
The diagnosis is clinical, despite the availability of adjunctive laboratory tests. These include the serotonin release assay, which is expensive and not widely available, but has high sensitivity and specificity and still remains the gold standard, the heparin-induced platelet aggregation test (HIPA), with a low sensitivity but high specificity, and the platelet-factor IV assays, highly sensitive but with a 10% to 20% clinical discordance with other tests.10 These adjunctive tests are often used in combination.
Because they have been associated with lower rates of HIT (2.2% vs. 7.8% with unfractionated heparin), the use of low-molecular-weight heparin is believed to result in a decreased incidence of HIT. Prophylaxis with fondaparinux may also result in a lower incidence of HIT.
Treatment involves discontinuation of all heparins, including IV line flushes and avoidance of warfarin until the platelet count normalizes. This approach carries a 30-day risk of thrombosis (de novo deep venous thrombosis) of 53%. Strategies to decrease the high risk of thrombosis include the following:
Caution must be exercised with the use of argatroban, danaparoid, and lepirudin, because their effects cannot be reversed.
DIC is a systemic process that results in thrombosis and hemorrhage. Often, one presentation predominates and patients may have signs of bleeding or thrombosis.11 It is estimated to occur in 1% of hospitalized patients.
DIC represents a massive activation of the coagulation cascade that results in excessive production of thrombin, systemic intravascular fibrin deposition, and consumption of clotting factors and platelets. The initiating factor is the release of tissue factor caused by various mechanisms, including extensive endothelial injury and the monocyte response to endotoxin or various cytokines.
DIC can be acute, decompensated when the generation of clotting factor cannot keep up with the excessive consumption, or chronic, compensated when the clotting factors are generated at the same rate as they are consumed. Acute DIC occurs secondarily to various insults (Box 2) and its pathogenesis involves the massive generation of thrombin and consumption of coagulation factors.
|Box 2: Common Causes of Disseminated Intravascular Coagulation|
|Obstetric complications, including abruptio placentae, septic abortion, and intrauterine fetal death|
|Infections—viral, bacterial, rickettsial, fungal, and protozoal|
|Malignancy, including acute leukemias, but also solid organ malignancies|
|Intravascular hemolysis, including transfusion reactions, drug-induced hemolysis, and paroxysmal nocturnal hemoglobinuria|
|Vascular malformation and aneurysms|
|Massive tissue injury (includes trauma)|
|Hypoxia and hypoperfusion (e.g., pulmonary embolism, myocardial infarction, hypothermia)|
|Miscellaneous factors (snake bites, head trauma, anaphylaxis, heat strokes, graft-versus-host disease, acute pancreatitis, status epilepticus, acute iron toxicity)|
Acute DIC manifests with bleeding and oozing from multiple sites, catheter access or mucosal surfaces, often in a critically ill patient with multisystem organ failure. Chronic DIC is most often associated with malignancy, usually solid tumors, and results from continuous slow exposure of blood to small amounts of tissue factor without overwhelming the compensatory mechanisms that regenerate depleted factors. It most often manifests clinically with thrombosis rather than hemorrhage.
The diagnosis of acute DIC relies on the following: history and clinical setting, with particular attention to trauma, sepsis, malignancy, pregnancy, and miscarriages; moderate to severe thrombocytopenia; evidence of microangiopathic hemolysis on the peripheral smear (e.g., the presence of schistocytes); and suggestive laboratory test results. Clinically significant DIC is unlikely in the presence of nor-mal fibrin degradation products (FDPs) or d-dimers.11 Prolonged PT and aPTT can also be noted, as well as decreased fibrinogen levels; fibrinogen, however, is an acute-phase reactant and may be falsely normal. The thrombin time (TT) is prolonged, whereas antithrombin III (ATIII), protein C, and protein S levels are often depressed.
Chronic DIC may manifest with more subtle laboratory results—smear microangiopathy and an elevated d-dimer (or FDP) level may be the only laboratory finding.
Acute DIC in the setting of sepsis, trauma, or burns carries 40% to 80% mortality. Increasing age and severity of multiorgan failure represent worse prognostic factors.
Treatment is largely supportive, with platelet or FFP transfusions, or both, in bleeding patients and in those at high risk for bleeding. Cryoprecipitate transfusion in patients with a fibrinogen level lower than 100 mg/dL is often considered although its benefit is difficult to demonstrate.
Heparin was not shown to be beneficial in acute DIC in controlled trials, and its role is limited to the treatment of DIC associated with the retained products of gestation or with giant hemangiomas.11 Heparin has been used with varying efficacy in patients with DIC and disseminated malignancy.11
Emerging but not yet validated treatment for DIC includes protein C concentrates for patients with homozygous protein C deficiency, antithrombin, and activated protein C, which has demonstrated survival benefit in severe sepsis.
Qualitative platelet disorders are suggested by a prolonged bleeding time (abnormal platelet function screen) or clinical evidence of bleeding in the setting of a normal platelet count and coagulation studies. They are most commonly acquired, but can be inherited. A new platelet function test, PFA-100 (Dade-Behring, Deerfield, Ill), has a 96% sensitivity for detecting von Willebrand disease and aspirin-induced platelet defects.13 It has yet to find a place among routine coagulation laboratory tests.
The most common drug responsible is aspirin, which irreversibly inhibits cyclooxygenase for 5 to 7 days—hence, the need to hold aspirin for 5 days before elective surgery. Other common drugs include clopidogrel, ticlopidine, and glycoprotein IIb/IIIa inhibitors. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase reversibly. Ethanol use and aspirin therapy have synergistic effects. Table 1 lists drugs associated with platelet dysfunction. Treatment includes discontinuation of the offending drug and platelet transfusion in the setting of clinically significant bleeding.
|Interfering with Platelet Membrane||Inhibition of Prostaglandin Pathways||Inhibition of Platelet Phosphodiesterase||Unknown Mechanism of Action|
|Imipramine||Nonsteroidal anti-inflammatory drugs||Dipyridamole||Ethacrynic acid|
This imparts a predisposition to bleeding that is incompletely understood. Treatment involves correction of anemia, institution of hemodialysis, and the use of desmopressin14 (DDAVP; its use is discussed later, “Treatment of von Willebrand Disease”). Platelet transfusions do not correct the coagulopathy because the transfused platelets will assume the dysfunction of the uremic platelets.
Whether acute or chronic, hepatic disease is associated with platelet dysfunction that is multifactorial in origin. Increased FDP levels from activation of the fibrinolytic pathway compromise platelet function and impair release of platelet factor III from platelets because of cirrhosis or manifestations of hepatic dysfunction.
Acquired von Willebrand disease (vWD) is often described in patients with autoimmune disorders, lymphoproliferative disorders, or monoclonal gammopathies. It may also be drug induced (e.g., by dextran or valproic acid). The pathophysiology varies, from adherence of vWF to tumor cells to vWF degradation by proteolytic enzymes. Treatment involves a desmopressin trial, intermediate-purity factor VIII concentrates, high-dose IVIG, or recombinant factor VIIa, depending on availability and urgency.
Platelet dysfunction has also been associated with plasma cell dyscrasias and is believed to be related to coating of the platelet membrane by monoclonal proteins. Myelodysplastic and myeloproliferative syndromes may result in platelet dysfunction (e.g., through an acquired glycoprotein IIb/IIIa deficiency). The bleeding time is often prolonged but does not correlate with the bleeding tendency.
Other disorders associated with platelet dysfunction include cardiopulmonary bypass or valvular defects, autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), and severe iron or folate deficiency.
These include the common von Willebrand disease and the less common Glanzmann thrombasthenia and Bernard-Soulier disease. The latter two are beyond the scope of this chapter.
Von Willebrand disease is the most common inherited bleeding disorder. It affects about 1% of the population, although only a fraction come to medical attention, often because of the paucity of symptoms in the absence of significant hemostatic challenge but also because of failure to recognize abnormal bleeding. Laboratory testing for mild disease is often difficult to interpret, making its definitive incidence difficult to determine.
|Type of Von Willebrand Disease|
|Von Willebrand factor (vWF) antigen||↓||↓ or N||↓||↓ or N||N||↓↓↓|
|Ristocetin cofactor activity||↓||↓↓||↓↓||↓||N||↓↓↓|
|Factor VIII activity||↓↓||↓ or N||↓ or N||↓ or N||↓↓||↓↓↓|
|High-molecular-weight vWF multimers||N||↓↓||↓||N||N||↓↓↓|
|Ristocetin-induced platelet aggregation||↓ or N||↓||↑||↓||N||↓↓↓|
N, normal; ↓, mildly decreased; ↓↓, moderately decreased; ↓↓↓, markedly decreased; ↑ increased.
This accounts for approximately 70% of patients, has an autosomal dominant inheritance, and represents a quantitative deficiency of vWF. Bleeding can be mild to moderately severe.
This is further subdivided into the following subtypes:
This is a rare, autosomal recessive subtype, characterized by a marked decrease in vWF. It may result from different genetic defects in compound heterozygotes.
Treatment of vWD is difficult to monitor because of the lack of laboratory tests that correlate with bleeding. Hence, commonly monitored parameters include clinical bleeding, factor VIII levels, and ristocetin cofactor levels.
Desmopressin promotes the release of vWF from endothelial cells. It is effective for patients with type 1 disease, but has a varying effect for patients with type 2A disease. It is relatively contraindicated in patients with type 2B disease. It may also be helpful for patients with type 2M or 2N vWD, but is not helpful for patients with type 3 disease. Desmopressin can be given intra- venously or subcutaneously at 0.2 μg/kg (maximum dose, 20 mg), with a response noted as early as 30 minutes later, lasting 6 to 12 hours. The dose may be repeated in 12 hours and then daily. The intranasal preparation is given at a dose of 150 mg for patients weighing less than 50 kg and 300 mg for those weighing more than 50 kg. A trial infusion is needed to assess the efficacy of treatment and adequacy of prophylactic use. Adverse effects include facial flushing, headaches, hyponatremia with continuous use, and a potential for thrombotic events.
Intermediate purity factor VIII concentrates are used for patients who do not benefit from desmopressin and for those with serious bleeding or before major surgery. Intermediate-purity factor VIII concentrate is used to maintain factor VIII levels between 50% and 100% for 3 to 10 days. A dose of 20 to 30 IU/kg is typically used twice daily. Overzealous treatment results in high factor VIII levels, which is believed to increase the risk of thrombosis.
Aminocaproic acid, 50 mg/kg four times daily, and tranexamic acid, 25 mg/kg three times daily, have been used for mild bleeding episodes and for dental procedures. They carry a risk of thrombotic events, which is especially pronounced in older individuals and with long-term use.
Topical treatment for oral or nasal bleeding with Gelfoam or Surgicel soaked with thrombin has been used successfully. Topical therapy plays an important role in prophylaxis and treatment after dental procedures.
Recombinant factor VIIa has been used successfully in patients with type 3 vWD with alloantibodies. In addition, its use should be considered in patients with life-threatening bleeding in whom other measures have failed. Disadvantages include its high cost as well as increased risks of thrombotic events, which are more pronounced in older adults.