The hallmark of platelet underproduction is decreased marrow megakaryocytes (or, when available, a decreased peripheral blood reticulated platelet count).^4,5

Common causes include infections (including HIV); drugs (frequently chemotherapy or ethanol, but other medications in rare instances); radiotherapy; vitamin deficiency (folate or vitamin B₁₂); or marrow infiltration by tumor, storage disease, or marrow failure syndromes (such as myelodysplastic syndrome, acute or chronic leukemias).

Management involves treatment of the underlying condition and supportive platelet transfusions if needed. More recently, two recombinant thrombopoietin (TPO) made their way into the clinical arena for the treatment of chemotherapy-induced thrombocytopenia (recombinant human thrombopoietin rHuTPO and pegylated recombinant megakaryocyte growth and development factor PEG-rHuMGDF).⁶ A single dose of rHuTPO or PEG-rHuMGDF increases the platelet count after about 5 days and the peak effect is observed about 10-12 days later.^6,7 rHuTPO increased the nadir platelet count, reduced the duration of thrombocytopenia and resulted in a decrease in platelet transfusion for patients receiving dose intense chemotherapy for ovarian cancer.⁸

Hypersplenism from a variety of causes including liver disease or malignancy may result in platelet sequestration (Table 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.

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,⁹ partial splenic embolization¹⁰ or transjugular intrahepatic portosystemic shunting for congestive splenomegaly.¹¹

The hallmark is increased marrow megakaryocytes (or, when available, high reticulated platelet count).^4,5 Platelet destruction results from a variety of immune conditions including the following:

• Immune thrombocytopenic purpura
• Thrombotic microangiopathies
• Post-transfusion purpura (PTP)
• Heparin-induced thrombocytopenia (HIT)
• Disseminated intravascular coagulation (DIC).

The incidence of ITP in a Danish study was 100 cases per 1 million person-years, with half the cases occurring in the pediatric age group.^12,13

It can be of either 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) while childhood onset has equal gender distribution.¹²

ITP is subdivided into chronic or acute, with the latter being of 6 months or less in duration.¹³

Etiology:

ITP can be either primary or secondary. Causes of secondary ITP include systemic lupus erythematosus, antiphospholipid antibody syndrome, IgA deficiency, common variable hypogammaglobulinemia, lymphoproliferative disorders (chronic lymphocytic leukemia, lymphomas), viral (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).^13-15 Patients with drug induced ITP usually present within 1-2 weeks from the initiation of the offending drug with petechiae, and a platelet count less than 20,000/mm³. Recovery usually occurs 5-7 days after discontinuation of the offending agent but can occasionally be more prolonged.¹⁶

In this chapter, we will focus on primary ITP. Recommendations are derived from the consensus guideline of the American society of Hematology.¹⁷

Pathophysiology:

The pathophysiology of primary ITP involves the formation of antiplatelet antibodies, frequently directed at platelet glycoproteins IIb/IIIA, IIb/IX, Ia/IIa, V, or multiple platelet antigens.^13-15

Clinical Features:

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.^13-15,17

Diagnosis:

The CBC 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 only in patients older than 60 years; in the presence of atypical features (which include fatigue, fever, joint pain, macrocytosis, and neutropenia); or before performing splenectomy in the patient whose diagnosis is not secure. 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.^13-15,17

Treatment:

First presentation

• Steroids: In the asymptomatic patients with a platelet count less than 30,000/mm³ or in the symptomatic patient with a platelet count greater than 30,000/mm³ but less than 50,000/mm³, treatment with Prednisone at a dose of 1 to 1.5 mg/kg/day has an expected response rate of 50%-75%. A response is usually seen after days of treatment but the expert panel from the American society of hematology differ on the length of time needed before changing therapy from 1 week to 3 weeks.¹⁷
• Intravenous immunoglobulin (IVIG) at a dose of 1 g/kg/day for 2 to 3 days is used to treat major bleeding, platelets counts less than 5,000/mm³ despite 3 days of steroids, or extensive and progressive purpura. It is also the initial agents in patients with platelet counts less than 50,000/mm³ with life threatening bleeding. The response rate for IVIG is 80%. 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.^13,17
• Anti-D immune globulin (Rhogam®) for Rhesus-positive patients at a dose of 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 greater than 2g/dL drop in hemoglobin. It is, however, more expensive than prednisone and affords a similar long term remission (5% to 30%).^13,17
• Splenectomy should be considered after 3 to 6 months^13,17 if the patient continues to require 10 to 20 mg/day of prednisone to keep the platelet count greater than 30,000/mm³ or within 6 weeks of diagnosis in the patients with platelet counts less than 10,000/mm³ despite treatment.¹⁷
• Urgent treatment for ITP patients with neurologic deficits or internal bleeding, or for emergency surgery, includes methylprednisolone at a dose of 30 mg/kg/day for 2 to 3 days for a maximum of 1 gram per day and/or IVIG at a dose of 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.^13,17

First relapse

• Treatment is indicated only for platelet counts 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 anti-D immune globulin.^13,17 Anti-D immune globulin is traditionally less effective in patients with ITP refractory to treatment.

Pathophysiology:

Thrombotic microangopathies are characterized by destructive thrombocytopenia, erythrocyte fragmentation, and tissue ischemia and necrosis as evidenced by increased lactate dehydrogenase (LDH). In non- acquired thrombotic thrombocytopenic purpura (TTP), systemic clumping of platelets is caused by unusually large vWF, often due to a deficiency of a metalloproteinase (ADAMTS 13) that cleaves vWF into smaller multimers.¹⁸

Diagnosis:

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 increased LDH is enough to suggest the diagnosis. If severe renal failure is a prominent feature of the syndrome, then the hemolytic uremic syndrome may be a more likely diagnosis.¹⁸

Etiology and Precipitating Causes:

TTP can be familial or acquired. Familial TTP presents in infancy or childhood, and often remits and relapses. Acquired TTP presents in adults or older children and often occurs as a single acute episode.¹⁸

Drug-induced TTP often occurs weeks after the culprit exposure. Medications commonly associated with it include Ticlopidine (and less frequently with Clopidogrel) Mitomycin, Cyclosporine, Tacrolimus, and Quinine. Total-body irradiation and organ transplantation also may result in a clinical syndrome similar to TTP.¹⁹

Treatment:

The treatment of childhood TTP (often related to ADAMTS 13 deficiency) involves 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 with daily plasma exchange until platelet counts and LDH levels normalize. Patients not responding to the above-mentioned treatment might require the addition of steroids, consideration of splenectomy, or the use of Vincristine.

Rituximab is investigational for refractory TTP, and its current use is not routine. Platelets should not be transfused short of a life-threatening hemorrhage or intracranial bleed.¹⁸

Post-transfusion purpura (PTP)^20,21 is a transfusion reaction characterized by severe thrombocytopenia lasting days to weeks after transfusion of platelet containing products.

Pathophysiology:

Patients become sensitized to platelet antigen, most frequently platelet antigen 1a (HPA-1a), from prior transfusion of platelet-containing products or from pregnancy. This explains the much higher incidence among women. HPA-1a 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).^20,21

The treatment of choice is IVIG at a dose of 400 mg/kg/day for 5 days or 1 g/kg/day for 2 days for severe thrombocytopenia. Further transfusions should be washed or HPA-1a-negative.^20,21

Heparin-Induced Thrombocytopenia (HIT) can be of two types:

1. Type I HIT occurs in about 10% of patients receiving heparin, usually within 2 days of heparin initiation, and platelet counts return to normal despite continued heparin exposure. As opposed to type II HIT, thrombocytopenia is mild (usually greater than 100,000/mm³). It is nonimmune in origin and has no clinical consequences.²²
2. Type II HIT: the incidence varies from 0.3% to 3% in patients who have received more than 4 days of heparin (most commonly unfractionated heparin) and has no relation to the heparin dose. It rarely occurs beyond 2 weeks of exposure.²³ The remainder of the discussion will focus on type II HIT.

Pathophysiology:

The pathophysiology involves antibody formation against the heparin-platelet factor 4 complex, with resultant thrombosis.²⁴ 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 strokes).²⁵

Clinical Presentation:

HIT is rare with platelet counts less than 20,000/mm³; the average platelet count nadir is around 60,000/mm³. HIT has an earlier onset with re-exposure to heparin.¹⁷

Diagnosis:

The diagnosis is clinical despite the availability of laboratory tests. Helpful tests include the Serotonin release assay (which is expensive and not widely available, but has high sensitivity and specificity; it remains the gold standard); the heparin-induced platelet aggregation test (HIPA, with a low sensitivity but high specificity); and the platelet-factor 4 assays (highly sensitive but with a 10% to 20% clinical discordance with other tests).²⁶

Prevention:

The use of low-molecular-weight heparins, as they have been associated with lower rates of HIT (2.2% versus 7.8% with unfractionated heparin).²³

Treatment:

Treatment involves discontinuation of all heparins including intravenous line flushes and avoidance of warfarin until the platelet count normalizes. This approach carries a 30-day risk of thrombosis (de-novo DVT) of 53%.²⁷ Strategies to decrease the high risk of thrombosis include the following:

• Anticoagulation with danaparoid (a heparinoid with a long half-life and 10% cross-reactivity with heparin), which requires monitoring of factor Xa activity.²⁷
• Lepirudin, a renally cleared recombinant hirudin, can be used at a bolus dose of 0.1-0.4 mg/kg followed by a 0.1-0.15 mg/kg/hr infusion for a goal aPTT of 1.5 to 2.5 times normal.²⁷
• Argatroban, a direct thrombin inhibitor metabolized in the liver, can be used in patients with renal failure at a dose of 2 µg/kg/min for a goal aPTT of 1.5 to 3 times normal. It has a short half-life (the anticoagulant effect wears off after 3 hours with normal hepatic function), and prolongs both the PT and the aPTT in a dose-dependent fashion. In patients with hepatic insufficiency, the dose should be decreased to 0.5 µg/kg/min. ²⁷

Caution must be exercised with the use of the agents (Argatroban, Danaparoid, and Lepirudin) as their effects cannot be reversed.

Disseminated Intravascular Coagulation (DIC)^28-32 is a systemic process that results in both thrombosis and hemorrhage. It is estimated to occur in 1% of hospitalized patients.

Pathophysiology:

DIC represents a massive activation of the coagulation cascade, that results in excessive production of thrombin, systemic intravascular fibrin deposition, and clotting factors and platelet consumption. The initiating factor is the release of tissue factor from a variety of causes: extensive endothelial injury, the monocytes response to endotoxin exposure or to various cytokines.

Acute Versus Chronic:

It 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 a variety of insults (Table 2), and its pathogenesis involves massive generation of thrombin and consumption of coagulation factors.^28,30,32

Clinical Features:

Acute DIC presents as bleeding and oozing from multiple sites (catheter access or mucosal surfaces), often in a critically ill patient with multiple system organ failure.^28,30,32

Chronic DIC is most often associated with malignancy (solid tumors most commonly), and results from continuous slow exposure of blood to small amounts of tissue factor without overwhelming the compensatory mechanisms that regenerate depleted factors. It is most often manifest clinically with thrombosis rather than hemorrhage.^28,30,32

Diagnosis:

The diagnosis of acute DIC relies on the 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 (for example the presence schistocytes); and suggestive laboratory testing. Clinically significant DIC is unlikely in the presence of normal FDPs or D-dimers. Prolonged PT and aPTT can also be noted, as well as decreased fibrinogen (fibrinogen, however is an acute-phase reactant and may be falsely normal). Thrombin time is prolonged, antithrombin III levels, protein C, and protein S levels are often depressed.^28,30,32

Chronic DIC may present with more subtle laboratory findings: smear microangiopathy and elevated D-dimer (or FDPs) may be the only laboratory finding.^28,30,32

Treatment:

Acute DIC in the setting of sepsis, trauma or burns carries a 40% to 80% mortality. Increasing age and severity of multiorgan failure represent worse prognostic factors.

Treatment is largely supportive, with platelets and/or FFP transfusions in bleeding patients and in those at high risk for bleeding. Cryoprecipitate transfusion in patients with a fibrinogen level less than 100 mg/dL.^28,30,31

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 product of gestation or associated with giant hemangiomas.^28,30,31

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.^33,34

It has also been associated with plasma cell dyscrasias and is thought to be related to coating of the platelet membrane with paraproteins. Myelodysplastic and myeloproliferative syndromes may result in platelet dysfunction (for example through an acquired glycoprotein IIb/IIIa deficiency). The bleeding time is often prolonged but does not correlate with the bleeding tendency.^37,41

Miscellaneous disorders associated with platelet dysfunction include: cardiopulmonary bypass or valvular defects, autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, scleroderma), and severe iron or folate deficiency.³⁷

Von Willebrand Disease is the most common inherited bleeding disorder.^42-54 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.^42,44,45,53 Laboratory testing in mild disease is often difficult to interpret.

Pathophysiology and Types:

VWD is subdivided into three types based on clinical and laboratory features (Table 4).^44,45,47

Type 1
It accounts for 70% of patients, has an autosomal dominant inheritance, and represents a quantitative deficiency of vWF. Bleeding can be mild to moderately severe.^53,54

Type 2
It is further subdivided into the following:

• Type 2A: accounts for about 15% of patients, is transmitted in an autosomal dominant fashion, and involves a deficiency of the high-molecular-weight multimers of vWF.^53,54 Patients present with moderate to severe bleeding.
• Type 2B: accounts for approximately 5% of patients, is inherited in an autosomal dominant fashion, and involves a gain-of -function mutation that results from increased binding of vWF to platelet glycoprotein 1B and resultant decreased circulating vWF.^53,54 The hallmark of type 2B vWD is an enhanced aggregation of the patient's platelets in the presence of Ristocetin. Patients with type 2B often have mild thrombocytopenia. Bleeding is moderate to severe.
• Type 2M: is rare, autosomal dominant, and characterized by reduced binding of vWF to platelet glycoprotein 1B.^53,54
• Type 2N: This subtype is a rare, autosomal recessive disorder characterized by decreased binding of vWF to factor VIII, resulting in low factor VIII levels and bleeding patterns similar to that seen in the hemophilias.^53,54

Type 3
It is rare, autosomal recessive subtype, characterized by a marked decrease in vWF. It may result from different genetic defects in compound heterozygotes.^53,54

Treatment of vWD
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.^46,48-51

DDAVP
DDAVP promotes the release of vWF from endothelial cells. It is effective for patients with type 1 disease, has a varying effect for patients with type 2A disease, is relatively contraindicated in patients with type 2B disease. DDAVP may also be helpful for patients with type 2M or 2N, but is not helpful for patients with type 3.⁴³ DDAVP can be given intravenously or subcutaneously at 0.2 µg/kg (maximum dose, 20 µg) with a response noted as early as 30 minutes later and lasting 6 to 12 hours.⁴³ The dose may be repeated in 12 hours and then daily. The intranasal preparation is given at a dose of 150 µg for patients weighing less than 50 kg and 300 µg 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.⁴³

For serious bleeding or prior to 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.^48-51

ε-Aminocaproic acid (EACA) at a dose of 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.^48-51

Topical treatment for oral/nasal bleeding with Gelfoam or Surgicel soaked with thrombin has been used successfully.^48-51

Recombinant factor VIIa has been used successfully in patients who have type 3 vWD with alloantibodies.

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