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Disorders of platelet number and function 

Disorders of platelet number and function
Chapter:
Disorders of platelet number and function
Author(s):

Kathryn E. Webert

and John G. Kelton

DOI:
10.1093/med/9780199204854.003.220603
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Essentials

Platelets are released from megakaryocytes in the bone marrow and circulate for 5 to 10 days before being cleared by the cells of the reticuloendothelial system. They play a critical role in haemostasis, with key features being (1) adhesion—when the wall of a blood vessel is damaged, platelets adhere to exposed collagen and other components of the subendothelium via the glycoprotein Ib receptor and other adhesive receptors; followed by (2) activation—release of thrombin, adenosine diphosphate, and arachidonic acid, which is converted by a cascade of enzymes into platelet activating agents including thromboxane A2; and (3) aggregation—glycoprotein IIb/IIIa undergoes conformational changes, making it able to bind fibrinogen and resulting in the formation of the haemostatic plug

Thrombocytopenia

Thrombocytopenia is defined as a reduction in the number of circulating platelets to less than 150 × 109/litre. Bleeding is uncommon unless the platelet count falls below 10 to 20 × 109/litre, or unless there is abnormal platelet function.

Increased platelet destruction: autoimmune thrombocytopenia—mediated by antibodies that bind to individual platelet glycoproteins, most frequently glycoprotein IIb/IIIa. May be (1) Primary (idiopathic thrombocytopenic purpura, ITP)—a disorder of children and (typically) young or middle-aged women. May present in adults with incidentally discovered thrombocytopenia, a long history of easy bruising, or acute onset of petechiae, purpura, and bleeding. Many patients will not require specific treatment, but those with severe thrombocytopenia (platelets <10 × 109/litre) and/or significant haemostatic impairment are treated with corticosteroids, typically oral prednisone (1 mg/kg). Second-line treatments include high-dose intravenous immunoglobulin, splenectomy, and danazol. (2) Secondary—conditions that can cause immune thrombocytopenia include systemic lupus erythematosus, drug induced (most commonly heparin, quinidine, sulfonamides, valproic acid, and gold), chronic lymphocytic leukaemia, post-transfusion purpura, and infections (e.g. HIV, varicella, Epstein–Barr virus).

Increased platelet destruction: nonimmune thrombocytopenia—disorders associated with both thrombocytopenia and fragmentation haemolysis include (1) Thrombotic thrombocytopenic purpura—manifestations include thrombocytopenia, microangiopathic haemolytic anaemia, renal impairment, fever, and ischaemic neurological findings; may be related to a deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-1-like domains); treatment is with plasmapheresis. (2) Haemolytic uraemic syndrome—presents as renal failure, microangiopathic haemolytic anaemia, and thrombocytopenia. May be epidemic in association with a diarrhoeal illness caused by enterohaemorrhagic or verotoxigenic Escherichia coli serotype O157:H7 or Shigella dysenteriae serotype I; can also be hereditary or sporadic, sometimes in association with noninfectious conditions. Aside from supportive care, treatment is usually with plasmapheresis. (3) Disseminated intravascular coagulation—patients are usually very unwell and present with fulminant bleeding and organ dysfunction, most often in the context of sepsis; characterized by large amounts of thrombin that overwhelm the physiological inhibitors of coagulation; replacement therapy with fresh frozen plasma, cryoprecipitate, and platelets should be considered.

Decreased platelet production—may rarely be congenital, but most cases are acquired, with common or important causes being (1) toxins—drugs (e.g. chemotherapeutic agents, chloramphenicol, nonsteroidal anti-inflammatory drugs, antiepileptic medications, gold), alcohol; (2) nutritional deficiencies—folate or vitamin B12; (3) bone marrow infiltration; (4) myelodysplastic syndrome.

Disorders of platelet distribution and platelet sequestration—these include (1) splenomegaly and hypersplenism; (2) haemodilution—in patients who have received large volumes of crystalloid solutions or blood products; (3) extracorporeal circulation; (4) hypothermia.

Thrombocytosis

Thrombocytosis is defined as an increase in the number of circulating platelets to more than 600 × 109/litre.

Primary thrombocytosis (thrombocythaemia)—a chronic myeloproliferative disorder often caused by mutation in the JAK2 tyrosine kinase. Presentation may be with thrombosis or bleeding. Young, asymptomatic patients do not require treatment. Low-dose aspirin can prevent thrombosis and may relieve symptoms such as headache and erythromelagia, but it may unmask bleeding tendencies and hence should be avoided in patients with a history of bleeding. Hydroxyurea will lower the platelet count and usually reduces thrombohaemorrhagic complications.

Secondary thrombocytosis—causes include infections, malignancy, chronic inflammatory bowel disease, rheumatoid arthritis, iron deficiency, and hyposplenism.

Disorders of platelet function

Congenital disorders—these can affect platelet (1) adhesion and aggregation—e.g. Bernard–Soulier syndrome, caused by a deficiency or abnormality of platelet glycoprotein Ib/IX; (2) secretion; and (3) procoagulant activity.

Acquired disorders—most common causes of platelet dysfunction are (1) medications and toxins—e.g. aspirin, nonsteroidal anti-inflammatory agents, ticlopidine, clopidrogel, glycoprotein IIb/IIIa inhibitors; (2) systemic disorders—e.g. chronic renal failure; and (3) haematological diseases—e.g. chronic myeloproliferative disorders, myelodysplastic syndromes, dysproteinaemias.

Introduction

Platelets are the smallest of the circulating blood cells and their numbers in healthy individuals range from 150 × 109/litre to 450 × 109/litre. Platelets are released from the megakaryocytes in the bone marrow and circulate for 5 to 10 days before being cleared by the cells of the reticuloendothelial system. Disorders of platelet number and function are frequently encountered.

Platelets are discoid cells that average 4 µm in diameter. The external membrane is a glycocalyx surface covering a phospholipid bilayer. Penetrating the membrane and traversing the platelet is a tubular system termed the open canalicular system. This system is continuous with the surface membrane and acts as a conduit for the release and uptake of nutrients and biologically active compounds. The platelet cytoskeleton is composed of three filamentous systems consisting of microtubules, microfilaments, and intermediate filaments. These tubules maintain the platelet’s shape and participate in shape change, a complex process that occurs following platelet activation.

Platelets contain several organelles including α‎-granules, dense granules, lysosomes, peroxisomes, and mitochondria. The α‎-granules are the most numerous platelet granules (c.50 granules/platelet) and contain proteins synthesized by megakaryocytes, including β‎-thromboglobulin, platelet factor 4, thrombospondin, and von Willebrand factor (VWF). The α‎-granules also contain plasma-absorbed proteins such as fibrinogen, albumin, IgG, and certain coagulation factors, particularly factor V. On the α‎-granule membrane are a variety of proteins including P-selectin and glycoprotein IIb/IIIa. Dense granules are far fewer in number than α‎-granules (4–8/platelet) and are smaller. These electron-dense granules are important for platelet activation and contain ATP, serotonin, calcium, magnesium, pyrophosphate, and granulophysin. Their membranes also contain a number of platelet proteins including P-selectin, glycoprotein Ib, and glycoprotein IIb/IIIa. Lysosomal granules contain proteolytic enzymes.

Platelet surface structures

Penetrating the platelet membrane are platelet glycoproteins. Most of these glycoproteins can be classified as one of five supergene families: integrins, leucine-rich glycoproteins, immunoglobulin domain molecules, selectins, and quadraspanins. The integrin family is the most common with glycoprotein IIb/IIIa being the most abundant integrin. Glycoprotein IIb/IIIa, also known as α‎IIbβ‎3, is present in high numbers (40 000–50 000 surface copies per platelet) and is the key binding site for platelet aggregation. Glycoprotein Ib/IX complex is the second most abundant platelet glycoprotein with an average of 20 000 surface copies per platelet. Glycoprotein Ib is a binding site for VWF. A variety of other platelet glycoproteins are present in lower numbers such as glycoprotein Ia/IIa, the receptor for collagen. Finally, platelets carry 400 to 4000 copies of an IgG Fc receptor, which is important in heparin-induced thrombocytopenia.

Thrombopoiesis

Pluripotent stem cells produce precursors of the red and white cells and the platelets. The platelet precursor is the megakaryocyte. Megakaryocytes undergo repeated nuclear replication without cytoplasmic division. This produces very large cells with 4 to 12 times the nuclear material of other cells of the body. Platelets bud off the cytoplasm of the megakaryocytes and are released into the circulation. The mean platelet volume can be measured using a cell counter and is roughly correlated with the number of nuclei in the megakaryocyte. Thrombocytopenia usually leads to proliferation of megakaryocytes and the resultant platelets are large.

The primary regulator of megakaryopoiesis and platelet production is thrombopoietin. Thrombopoietin, an erythropoietin-like hormone, is primarily produced in the liver, with secondary sites including the kidney, bone marrow, brain, smooth muscle cells, and testes. The receptor for thrombopoietin, c-Mpl, is present on stem cells, megakaryocytes, and platelets. Binding of thrombopoietin to c-Mpl activates a variety of pathways resulting in the proliferation of megakaryocyte progenitors, an increased rate of megakaryocyte maturation, an increase in megakaryocyte nuclear mass and ploidy, and increased platelet release. Thrombopoietin is constitutively secreted and the circulating level of thrombopoietin is primarily determined by the platelet mass. Platelets bind the thrombopoietin, internalize it, and degrade it. Consequently, less is available to stimulate platelet production by megakaryocytes. When the platelet count falls, less thrombopoietin is bound to platelets resulting in increased circulating levels of thrombopoietin and increased platelet production. Platelet production is also regulated, to a lessor degree, by a number of other cytokines including interleukins 6 and 11.

The role of platelets in haemostasis

Platelets play a critical role in haemostasis. When the wall of the blood vessel is damaged, platelets adhere to exposed collagen and other components of the subendothelium. The key receptor is glycoprotein Ib linked to the vessel wall through VWF. Other adhesive receptors include glycoprotein Ia/IIa, which binds collagen. Adhesion to the vessel wall asctivates platelets and agonists such as thrombin or adenosine diphosphate are released from their granules. The prostaglandin pathway is also activated; arachidonic acid is released from the platelet membrane and converted by a cascade of enzymes into platelet activating agents including thromboxane A2. A rate-limiting step in this pathway is catalysed by the cyclooxygenase enzyme. Aspirin, an antiplatelet agent, irreversibly inactivates this enzyme. After platelet activation, glycoprotein IIb/IIIa undergoes conformational changes making it able to bind fibrinogen. This process is termed platelet aggregation and results in the formation of the haemostatic plug. Activated platelets also contribute to the clotting cascade by providing the phospholipid membrane surface needed for many reactions leading to thrombin generation, especially the activation of factor X by a complex of factors IXa and VIIIa (‘tenase’ complex) and the activation of prothrombin by a complex of factors Xa and Va (prothrombinase complex).

Disorders of platelet number

Thrombocytopenia

Thrombocytopenia is defined as a reduction in the number of circulating platelets to less than the laboratory’s normal reference range (typically <150 × 109/litre). Bleeding is uncommon unless the platelet count falls below 10 to 20 × 109/litre or unless there is abnormal platelet function.

Classification of thrombocytopenia

It is convenient to classify disorders of thrombocytopenia into problems of underproduction, increased destruction, and sequestration (Table 22.6.3.1). Since megakaryocytes originate from stem cells, it is rare to let sequestration is usually due to splenomegaly and can cause isolated thrombocytopenia, but often also causes mild leucopenia or anaemia.

Table 22.6.3.1 Classification of thrombocytopenia by aetiology

Aetiology of thrombocytopenia

Relative frequency

Decreased platelet production

Acquired

Marrow infiltration: metastatic cancer, haematological malignancies (leukaemia, lymphoma, myeloma), myelofibrosis, storage disorders (Gaucher’s disease etc.), granulomatous disorders (sarcoidosis)

+++

Marrow aplasia—aplastic anaemia, postchemotherapy or radiation

+++

Amegakaryocytic thrombocytopenia

++

Ineffective thrombopoiesis—myelodysplasia, secondary to toxins (alcohol), folate and vitamin B12 deficiency, paroxysmal nocturnal haemoglobinuria

+

Congenital

+

Wiskott–Aldrich syndrome and variants

Bernard–Soulier syndrome

R

May–Hegglin anomaly

R

Alport syndrome and variants

R

Other

R

Increased platelet destruction

Immune mechanisms

Autoimmune

ITP

+++++

Evan’s syndrome

++

Secondary to other disorders—lymphoproliferative disorders, systemic lupus erythematous, HIV infection, thyroid dysfunction, hypogammaglobulinemia, antiphospholipid antibody syndrome

+++

Alloimmune

Neonatal alloimmune thrombocytopenia

++

Post-transfusion purpura

+

Refractoriness to platelet transfusions

+++

Immune complex mediated

R

Drug-induced

++

Nonimmune mechanisms

DIC

++

TTP

++

HUS

++

Sepsis

++++

Malignant hypertension

++

Hypertensive disorders of pregnancy

+++

Hypersplenism

+++

Abnormal vascular surfaces

++

Decreased numbers of circulating platelets (sequestration)

Splenomegaly

++++

Extracorporeal circulation

++++

Dilutional disorders

++

Hypothermia

++

DIC, disseminated intravascular coagulation; HUS, haemolytic uraemic syndrome; TTP, thrombotic thrombocytopenic purpura.

+ to +++++ indicates the relative frequency. R indicates it is rare.

History and physical examination of the thrombocytopenic patient

The physician must explore the risk of the thrombocytopenia as well as determine the underlying cause. It is important to elicit the duration of the haemostatic impairment to determine if the patient has recently ingested an antiplatelet agent such as aspirin or alcohol, which interferes with platelet function and can trigger bleeding (see Chapter 22.6.2).

The history should be guided by the potential mechanism of thrombocytopenia. For example, if increased destruction is considered, then the patient should be questioned about drugs including prescription drugs, over-the-counter medications, herbal remedies, and illicit drugs. Secondary associations of thrombocytopenia, which include systemic lupus erythematosus (SLE), HIV infection, and lymphoproliferative disorders (Box 22.6.3.1), will lead to other questions. Finally, one should obtain information about any family members with a history of thrombocytopenia or bleeding disorders.

Physical evaluation focuses on evidence of haemostatic impairment and signs of an underlying cause of the thrombocytopenia. Many patients with thrombocytopenia are asymptomatic. Only at low platelet counts will one see petechiae, which are tiny, red collections of red cells found on dependent parts of the body and sites of trauma. Petechiae are relatively specific for thrombocyto penia. Large bruises or purpura can be observed on the limbs and trunk and have a lower specificity. The risk of bleeding increases progressively from asymptomatic patients, to patients with petechiae and purpura, to patients who have mucous membrane bleeding, which is typically manifest by blood blisters in the mouth. Blood blisters usually occur on the bite margins of the oral mucosa and on the tongue. They indicate that the patient is at significant risk for bleeding and treatment is urgently required. The physical examination should focus on the examination of the joints, lymph nodes, spleen, and liver since abnormalities indicate a secondary cause of the thrombocytopenia.

Laboratory evaluation of the thrombocytopenic patient

One of the most important tasks is first to review the peripheral blood film to exclude pseudothrombocytopenia. Pseudothrombocytopenia is a laboratory artefact that causes spontaneous platelet agglutination which can be identified by the presence of platelet clumps in the peripheral blood film. Automated determination of the platelet count will be inaccurate, as the machine will not recognize the larger platelet aggregates as platelets. Pseudothrombocytopenia commonly occurs because of agglutination of the patient’s platelets in ethylenediaminetetra acetic acid (EDTA). This effect occurs in 0.1% of blood samples and is caused by a clinically insignificant autoantibody which agglutinates platelets at low calcium concentrations. Often the artefact can be avoided by using an anticoagulant other than EDTA in which to collect the blood sample.

The haemoglobin concentration and white blood cell count should be determined. Cytopenias involving other cell lineages are suggestive of disorders involving the bone marrow such as myeloproliferative or myelodysplastic diseases. The platelet count helps to determine the patient’s risk of bleeding. Patients with mild thrombocytopenia (platelet count >50 × 109/litre) have a low risk of bleeding. Patients with severe thrombocytopenia (platelet count <20 × 109/litre) have a higher risk of bleeding and can experience spontaneous bleeding. The peripheral blood film may lead to the diagnosis of the condition causing the thrombocytopenia. Fragmented red cells or schistocytes may be seen in thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS), disseminated intravascular coagulation (DIC), and renal graft rejection. Leukoerythroblastic changes in the peripheral smear, such as teardrop-shaped red blood cells, nucleated red blood cells, and immature white cells suggest infiltration of the bone marrow. The presence of abnormal circulating cells such as lymphoblasts or myeloblasts suggests a malignant process. Typical changes on the peripheral smear such as megaloblastic red blood cells and hypersegmented neutrophils suggest vitamin B12 or folate deficiency. The finding of atypical lymphocytes should cause one to consider the diagnosis of a viral infection. Finally, the finding of giant platelets on the peripheral smear suggests the diagnosis of certain congenital thrombocytopenias. Examination of the bone marrow should be considered if the aetiology of the thrombocytopenia is uncertain after the initial evaluation. Additionally, a bone marrow examination is required when abnormalities are seen on the peripheral blood smear or when multiple blood cell lineages are affected. The finding of normal or increased numbers of megakaryocytes in the marrow supports the diagnosis of peripheral destruction or sequestration of the platelets. Other laboratory investigations that may be indicated include antinuclear antibody, rheumatoid factor, thyroid stimulating hormone, and testing for HIV infection.

Disorders of increased platelet destruction

Disorders of increased platelet destruction can be subdivided into two principal categories: immune and nonimmune. Nonimmune causes include DIC, and a variety of schistocytic or haemolytic anaemias such as TTP. For most thrombocytopenic disorders caused by nonimmune mechanisms, the underlying cause is apparent and the patient’s clinical presentation indicates the correct diagnosis (i.e. fever and clinical septicaemia suggest infectious causes of thrombocytopenia, fragmentation haemolysis suggests TTP or HUS).

Immune-mediated platelet disorders

Immune-mediated disorders can be caused by autoantibodies, e.g. idiopathic thrombocytopenic purpura (ITP); alloantibodies, exemplified by post-transfusion purpura; and immune complexes, as demonstrated in heparin-induced thrombocytopenia. Most immune mediated platelet disorders are caused by IgG antibodies that bind to the platelet membrane.

Autoimmune thrombocytopenia

Autoimmune thrombocytopenia is mediated by antibodies that bind to individual platelet glycoproteins, most frequently glycoprotein IIb/IIIa. The autoimmune thrombocytopenia is classified as primary if there are no underlying conditions and secondary if it is associated with a systemic disease.

Primary autoimmune thrombocytopenia (ITP)

Idiopathic thrombocytopenic purpura (ITP) is one of the most common autoimmune disorders. It is a disorder of both children and adults. In young children, frequently under the age of 5, the disease presents abruptly with dramatic evidence of a bleeding tendency. At least 80% of children will have a spontaneous remission of their disease. Girls and boys are affected equally. In contrast, 80% of adults who present with ITP will have a long-standing disease. The disorder is typically seen in young and middle-aged adult women. The natural history of ITP in adults in children is different; however, the risk of bleeding and general approach to therapy is similar.

Adults with ITP can present in one of three ways. Many will be asymptomatic and will have thrombocytopenia discovered incidentally. Others will give a history of easy bruising that may have occurred for many years and, frequently, worsened with ingestion of a substance which interferes with platelet function, such as aspirin or alcohol. Finally, patients may have an acute onset of petechiae, purpura, and bleeding. From mucous membranes as commonly occurs in affected children.

Treatment of adults with idiopathic thrombocytopenic purpura

The most important decision is whether the patient requires any treatment. If the patient has mild or moderate thrombocytopenia (platelet count >30–50 × 109/litre) and no history of haemostatic impairment, we would monitor this patient with periodic platelet counts every few weeks. These patients usually maintain a consistent platelet count that tends to drop only if the patient has an immune stimulus such as an infection. The decision is more difficult in patients with more severe thrombocytopenia (platelet count 20–30 × 109/litre) and who have modest signs of haemostatic impairment such as occasional bruising. We often do not treat these patients, but would alert the patient that the platelets should be raised before a haemostatic challenge such as a tooth extraction or surgery. Patients with severe thrombocytopenia (platelets <10 × 109/litre) usually require treatment, especially if they have clinical signs of haemostatic impairment. The first line of treatment is corticosteroids, typically oral prednisone (1 mg/kg). Corticosteroids are effective in two-thirds of patients, but have predictable side-effects (Cushing’s syndrome, hypertension, diabetes mellitus, osteoporosis, and mental changes). Corticosteroids should be given for as short an interval as possible, tapering the dose once the platelet count has reached haemostatically safe levels (>100 × 109/litre). Patients who have a relapse of their thrombocytopenia may require consideration of more definitive treatment such as splenectomy.

Reticuloendothelial blockade through high-dose intravenous immunoglobulins (1 g/kg delivered over 6 h on two consecutive days) or anti-D in a rhesus positive individual (75 µg/kg) usually results in a more rapid rise in the platelet count than corticosteroids and are indicated when platelets must be urgently raised. The principal disadvantage of these treatments is that they are more expensive than corticosteroids; however, they may have fewer side effects. There is a strong correlation between the response of a patient to high-dose intravenous immunoglobulins and response to a subsequent splenectomy. About 80% of patients will respond to reticuloendothelial blockade with the peak platelet count occurring within 7 days and lasting for 4 to 8 weeks.

Splenectomy

Splenectomy should be considered for patients who require ongoing medical management. Patients needing splenectomy should be vaccinated 2 weeks prior to the procedure with pneumococcal, meningococcal, and Haemophilus influenzae type B vaccines. The platelet count should be raised to safe levels prior to the procedure. Because of its reduced morbidity and significantly shortened hospital stay, laparoscopic splenectomy is the preferred approach. Splenectomy will result in a long-term remission or cure in about two-thirds of patients.

Second-line therapies

As many as one-third of patients will not respond to splenectomy and will require an alternative therapy. Danazol, an attenuated anabolic steroid, will induce a dose-dependent rise in platelet count in some refractory patients. The typical dose ranges from 200 to 1200 mg/day. Unfortunately, it has adverse effects including dose-dependent liver enzyme abnormalities and virilization. Vincristine or vinblastine have been used in refractory patients. However, if a rise in platelet count does occur, it is generally transient. Hence, the drug needs to be given repeatedly, which invariably causes dose-dependent neurotoxicity. Patients with refractory ITP who require ongoing therapy may need aggressive immunosuppression that includes oral chemotherapy such as azathioprine, intermittent high-dose intravenous immunoglobulins, or intermittent corticosteroids.

Emergency treatment of ITP

Patients with ITP who have severe bleeding require aggressive therapy including platelet transfusions, high-dose intravenous immunoglobulins, and high-dose corticosteroids, in addition to standard resuscitation including blood replacement if required.

Experimental therapies of ITP

Experimental therapies for ITP include romiplostim, eltrombopag, and rituximab. Eltrombopag and romiplostim are novel thrombopoietin-stimulating proteins. Clinical studies have demonstrated increased platelet counts in patients with ITP treated with these agents. Case reports and small clinical trials of rituximab, a chimeric monoclonal anti-CD20 antibody that targets B cells, have suggested a beneficial response in patients with ITP. Larger clinical trials are ongoing investigating the effectiveness of these medications.

ITP during pregnancy

ITP occurs in young women and frequently these young women will become pregnant. Most of these patients can successfully carry a child without excessive morbidity or mortality. Typically, the platelet count falls across the pregnancy and the mother may require treatment. We use high-dose intravenous immunoglobulins since corticosteroids may be associated with an increased risk of hypertensive disorders in pregnancy. About 10% of the infants born to these mothers will be thrombocytopenic, with the platelet nadir occurring several days after delivery. Very severe thrombocytopenia is uncommon (c.1%) and should suggest an alternative diagnosis such as alloimmune neonatal thrombocytopenia. Infant thrombocytopenia cannot be predicted by any maternal factor or serological test with the possible exception of a history of a previously affected infant. We manage these mothers with routine vaginal delivery unless there is an obstetrical indication for caesarean section.

Secondary immune thrombocytopenias

A variety of medical disorders cause secondary immune thrombocytopenia (Box 22.6.3.1). The treatment for secondary immune thrombocytopenia is similar to that of ITP.

Thrombocytopenia complicating SLE

Thrombocytopenia can occur in up to 25% of patients with SLE. The thrombocytopenia is usually caused by autoantibodies. Some patients will have concomitant platelet dysfunction characterized by increased bleeding and bruising. The treatment is similar to that for ITP.

A subset of patients with SLE or lupus-like disorders have antibodies which interfere with phospholipid-dependent coagulation reactions, commonly detected by an unexplained prolongation of the patient’s partial thromboplastin time. These antibodies are immunoglobulins with specificity for negatively charged phospholipids and are also called lupus anticoagulant antibodies. They tend to be heterogenous in their epitope specificity with most binding phospholipid protein complexes including β‎2-glycoprotein I. Another class of antibodies, the anticardiolipin antibodies, is detected by an enzyme-linked immunosorbent assay using cardiolipin as the antigen. Cardiolipin is the same antigen that is detected in the VDRL test for syphilis, which explains the false-positive VDRL test in these patients. The two classes of antibodies are distinct, but have overlapping specificities. Most anticardiolipin antibodies recognize an epitope on β‎2-glycoprotein I. The term ‘antiphospholipid antibodies’ applies to both sets of antibodies.

Antiphospholipid antibodies are associated with venous and arterial thrombosis. The antiphospholipid antibody syndrome includes any combination of arterial and venous thrombosis, recurrent fetal losses and thrombocytopenia plus a repeatedly positive test for these antibodies. Some of these patients also have a vascular rash termed livedo reticularis. Patients can have haematological abnormalities including mild thrombocytopenia, platelet dysfunction, autoimmune haemolytic anaemia, and leucopenia. As the thrombocytopenia is usually mild, treatment is rarely necessary. The thrombotic complications dominate this syndrome. Many patients require long-term anticoagulation therapy to prevent recurrent thrombotic events.

Thrombocytopenia secondary to lymphoproliferative disorders

Immune thrombocytopenia commonly complicates chronic lymphocytic leukaemia. This should be differentiated from thrombocytopenia of underproduction, which is seen in the late stage of chronic lymphocytic leukaemia. Immune thrombocytopenia is often seen in patients with Hodgkin’s disease and can predate or postdate the illness and is not a marker of disease activity.

Alloimmune thrombocytopenia

Alloimmune thrombocytopenia is caused by alloantibodies against platelet glycoproteins. There are two typical alloimmune thrombocytopenic disorders, alloimmune neonatal thrombocytopenia, and post-transfusional purpura.

Alloimmune neonatal thrombocytopenia

Alloimmune neonatal thrombocytopenia is mediated by alloantibodies in maternal plasma directed against fetal platelet glycoproteins inherited from the father. This disorder can cause severe and life-threatening fetal thrombocytopenia that can occur in utero. The most common alloantibody responsible for this disorder is targeted against a platelet glycoprotein called PLA1 (HPA-1a) located on platelet glycoprotein IIIa.

Post-transfusion purpura

In cases of post-transfusion purpura the patient, usually a woman, develops severe thrombocytopenia 5 to 12 days after receiving a transfusion of a blood product containing platelets. The thrombocytopenia is often very severe (platelet count <10 × 109/litre). Post-transfusion purpura occurs when a patient produces an alloantibody to a specific platelet antigen that she lacks, usually PLA1. The syndrome most commonly occurs in multiparous women because previous pregnancies lead to their sensitization. Patients, including men, who have previously been transfused are also at risk.

The diagnosis of post-transfusion purpura is made by the identification of a platelet-specific antibody in a patient with acute onset of thrombocytopenia 5 to 12 days after receiving a transfusion of a blood product. Although post-transfusion purpura is most commonly seen after transfusion of packed red blood cells, all blood products, including plasma, can cause the reaction. Post-transfusion purpura is self-limited with recovery occurring within 1 to 3 weeks. However, because the condition can be lethal, treatment with plasmapheresis or intravenous immunoglobulins should be considered. Platelet transfusions should be avoided except in cases of life-threatening haemorrhage. For uncertain reasons, the frequency of post-transfusion purpura is declining.

Drug-induced thrombocytopenia

Many drugs can cause thrombocytopenia. These medications most commonly implicated include heparin, quinidine, sulfonamides, valproic acid, and gold. However, virtually every medication has been associated with thrombocytopenia.

Patients with drug-induced thrombocytopenia typically have moderate to severe thrombocytopenia. Thrombocytopenia is usually seen 1 to 2 weeks after beginning a medication, but it may occur in patients who have been taking the medication for several years. The platelet destruction is usually IgG-mediated. The thrombocytopenia usually resolves within days of stopping the causative drug. In cases of severe thrombocytopenia, the drug should be discontinued and the patient treated with reticuloendothelial blockade using either intravenous immunoglobulins or intravenous anti-D immune globulin. Treatment with corticosteroids is less effective. In cases of life-threatening haemorrhage, platelet transfusions may be required. Patients should not take the drug causing the thrombocytopenia again as it will cause thrombocytopenia with subsequent exposure.

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia develops between 5 and 12 days after the initiation of heparin therapy but if the patient has been exposed to heparin within the last 3 months, it can occur earlier. Patients develop moderate thrombocytopenia (platelet counts 40–80 × 109/litre). Patients with heparin-induced thrombocytopenia frequently develop thrombotic complications, especially deep venous thrombosis and pulmonary embolism. Other clinical associations include arterial thrombosis, skin lesions, and uncommon thrombotic events such as adrenal gland thrombosis and haemorrhage.

Heparin-induced thrombocytopenia is caused by an IgG antibody, which recognizes a complex of heparin and platelet factor 4 (PF4). The PF4–heparin–IgG immune complexes bind to platelet crystallizable fragment receptors, causing platelet activation and microparticle formation resulting in activation of coagulation.

The risk of thrombocytopenia is to be related to the type, dose, and duration of heparin administration. For example, unfraction ated heparin is more immunogenic than low-molecular-weight heparin. Also, different patient populations have different risks of forming the heparin-induced thrombocytopenia IgG. For example, the risk of heparin-induced thrombocytopenia IgG is higher in orthopaedic patients than in medical patients.

The diagnosis of heparin-induced thrombocytopenia should be considered in all patients receiving heparin therapy who develop thrombocytopenia or thrombotic complications. Serological tests can be used to confirm the diagnosis of heparin-induced thrombocytopenia. Enzyme assays measure the binding of platelet antibodies to a complex of heparin and PF4. The gold standard tests are biological assays, such as the serotonin release assay.

Treatment of heparin-induced thrombocytopenia involves discontinuation of heparin. The patient should be treated with an agent that inhibits thrombin generation, such as hirudin or argatroban. Warfarin should not be used to treat acute heparin-induced thrombocytopenia because it can induce limb gangrene.

Gold-induced thrombocytopenia

Gold-induced thrombocytopenia occurs in as many as 3% of patients who receive therapeutic preparations of gold salts. There appears to be a genetic predisposition to the syndrome, with HLA DR3 occurring in up to 80% of affected patients. The thrombocytopenia usually occurs within the first several months of therapy and can range from mild to severe. Treatment involves stopping the gold agent drug and supportive treatment. The thrombocytopenia can persist for many months after the discontinuation of gold. This is probably due to gold-independent autoantibodies, but may be due to the prolonged release of gold from tissue stores. Rapid correction of the thrombocytopenia may be achieved with intravenous immunoglobulins; however, a relapse of the thrombocytopenia may occur in 2 to 4 weeks. Patients also respond to corticosteroids. Some patients with persistent thrombocytopenia may respond to splenectomy. There is less experience using a gold-chelating agent such as dimercaprol (BAL).

Nonimmune platelet disorders

Destructive thrombocytopenia and schistocytic haemolysis

Certain disorders are associated with both thrombocytopenia and schistocytic or fragmentation haemolysis. These disorders include TTP, HUS, and DIC.

TTP

This is a syndrome consisting of thrombocytopenia, microangiopathic haemolytic anaemia, renal impairment, fever, and ischaemic neurological findings. TTP is an uncommon disorder, but its recognition is important because it is usually fatal if not treated.

Most cases of TTP are likely related to a deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-1-like domains) that cleaves the large VWF multimers released by endothelial cells. This deficiency may be due to reduced blood levels or due to the presence of circulating inhibitory antibodies. Patients with the familial form of TTP–HUS have decreased ADAMTS13 activity caused by genetic abnormalities. The patients also have been found to have unusually large VWF multimers which have a greater ability to react with platelets.

Most patients who develop TTP are young to middle-aged, with slightly more women affected than men. The presentation of illness may be insidious or acute. Typically, the patient has a several day history of generalized malaise, fatigue, or focal ischaemic problems. The focal ischaemic events usually involve the central nervous system and can include sudden weakness, paraesthesiae, and confusion. Approximately 50% of patients will have a neurological event.

Most adult patients with TTP do not have an associated underlying condition. Nonetheless, the initial evaluation of a patient with TTP should exclude diseases associated with TTP (Box 22.6.3.2). TTP can develop spontaneously, but is often triggered by an infection, pregnancy, or an immune challenge.

All patients with TTP have destructive thrombocytopenia. The thrombocytopenia is the best indicator of disease activity. Additional laboratory investigations demonstrate abnormalities of microangiopathic haemolytic anaemia, such as anaemia, fragmented red blood cells, and increased reticulocyte count. Serum lactate dehydrogenase and bilirubin levels are elevated. Other abnormalities include elevated serum creatinine, proteinuria, and abnormal liver function tests. Investigators have identified the presence of abnormal VWF multimers in patients with TTP.

TTP is treated with plasmapheresis. This treatment has reduced the mortality from 80% to 20%. Plasma exchange of at least one to two volumes of plasma should be performed daily. Plasma should be replaced with cryosupernatant plasma or fresh frozen plasma. Some physicians believe that cryosupernatant plasma is more beneficial because it is depleted of VWF. Plasmapheresis should be continued until the platelet count and serum lactate dehydrogenase have normalized. This generally occurs after 3 to 10 exchanges. Plasma exchange is better than plasma infusion alone. However, when plasmapheresis is not immediately available, patients should be treated initially with plasma infusion. If the initial response to plasma exchange is poor, other therapies such as glucocorticoids may be added. Additionally, the volume of plasma exchange may be increased. Studies involving agents such as rituximab are ongoing and appear promising. Other treatments, such as antiplatelet agents, are of uncertain benefit. With discontinuation of plasma exchange, exacerbation of disease occurs in about a third of patients. This risk of relapse can be reduced by splenectomy.

HUS

This syndrome includes renal failure, microangiopathic haemolytic anaemia, and thrombocytopenia. Different types of HUS have been identified, including classic epidemic, sporadic, hereditary and sporadic in association with noninfectious conditions. Epidemic HUS is seen primarily in children and occurs in association with a diarrhoeal illness caused by enterohaemorrhagic or verotoxigenic Escherichia coli serotype O157:H7 or Shigella dysenteriae serotype I. HUS may be also associated with other bacterial, viral, and rickettsial infections. Patients have been reported to develop HUS after receiving immunizations.

Laboratory investigations demonstrate severe anaemia and thrombocytopenia. Examination of the peripheral smear shows fragmented red blood cells, burr cells, and spherocytes. Haemoglobinaemia and haemoglobinuria may be severe. Serum lactate dehydrogenase levels and other markers of red blood cell destruction are elevated. The serum creatinine is usually increased.

In children, the treatment of HUS focuses on providing supportive care with careful attention paid to fluid status and electrolyte levels. Plasma exchange should be considered in children with severe HUS. In adults, treatment of HUS generally includes plasmapheresis. Other therapies including antiplatelet agents, fibrinolytic therapy, and heparin therapy have not been shown to be beneficial, and are not recommended.

DIC

DIC is a disorder in which clotting occurs within the circulation. It is characterized by large amounts of thrombin that overwhelm the physiological inhibitors of coagulation. The thrombin causes platelet aggregation resulting in thrombocytopenia and fibrinogen cleavage into fibrin, which forms the microthrombi. The most common cause of DIC is sepsis, but DIC is associated with a large number of disorders including trauma and obstetric conditions (Box 22.6.3.3). The clinical presentation is variable, but patients with DIC are usually very unwell presenting with fulminant bleeding and organ dysfunction. Some patients have thrombotic events. Occasionally, DIC can be subclinical and detected only with laboratory tests. The diagnosis of DIC is supported by the laboratory finding of thrombocytopenia in association with fragmented red blood cells, decreased fibrinogen level, and elevated fibrinogen and fibrin degradation products such as D-dimers. Coagulation studies often show a prolonged international normalized ratio, partial thromboplastin time, and thrombin time. DIC is best managed by identifying and treating its cause. If the patient is bleeding, replacement therapy with fresh frozen plasma, cryoprecipitate, and platelets should be considered. Heparin therapy may be of benefit in patients with clinical evidence of ongoing microvascular thrombosis.

Sepsis and infection

Transient thrombocytopenia occurs with systemic infections. Thrombocytopenia occurs in 50 to 75% of patients with bacteraemia or fungal infections. It also occurs in association with viral infections, including HIV. The thrombocytopenia is generally mild to moderate and is not usually associated with symptoms of bleeding. The mechanism leading to the lowered platelet count is multifactorial including activation of platelets by bacterial products or mediators of inflammation; destruction due to immune mechanisms; or destruction due to chemokine-induced macrophage ingestion of platelets. Additionally, severe viral infections may lead to suppression of platelet production. Resolution of the platelet count occurs with eradication of the infection.

Thrombocytopenia associated with HIV is common, occurring in at least 20% of patients with symptomatic disease. Various mechanisms contribute to the thrombocytopenia. Some patients have immune-mediated destruction of platelets. Patients also have a defect in platelet production due to direct infection of megakaryocytes and the suppressive effects of medications. The platelet count can improve with antiretroviral therapy. Patients with severe thrombocytopenia should be treated similarly to patients with ITP including the performance of a splenectomy.

Haemophagocytic syndrome

This rare syndrome is caused by phagocytosis of haematological cells by macrophages. Adult patients can present with an acute illness consisting of fever, weight loss, hepatosplenomegaly, pancytopenia, and increased liver enzymes. Bone marrow aspiration is diagnostic and shows morphological evidence of phagocytosis of platelets, red blood cells, and granulocytes by macrophages. The haemophagocytic syndrome may be associated with infections, particularly with the Epstein–Barr virus, T-cell lymphoma, histiocytosis, or immune disorders such as SLE and Still’s disease. Treatment is directed at the underlying disorder.

Decreased platelet production

Platelet production is impaired by conditions affecting megakaryocyte progenitor cells, megakaryocytes, or the bone marrow stroma. It is rare to see a deficit in platelet production without abnormalities in the production of other cell lines as well. Decreased platelet production can occur when the bone marrow is aplastic, dysplastic, or infiltrated with other cells. Diagnosis of a defect in platelet production is usually made by evaluation of the bone marrow. Disorders causing decreased platelet production may be classified as congenital or acquired.

Congenital disorders causing decreased platelet production

Thrombocytopenia in infancy is usually due to increased platelet destruction and is only rarely due to decreased production. However, various congenital disorders may result in decreased platelet production. These disorders include congenital amegakaryocytic thrombocytopenia, thrombocytopenia with absent radii syndrome, Wiskott–Aldrich syndrome, May–Hegglin anomaly, Epstein’s syndrome, Fechtner’s syndrome, and Sebastian platelet syndrome. Bernard–Soulier syndrome is also associated with moderate thrombocytopenia.

Acquired disorders causing decreased platelet production

Toxins

Numerous drugs and toxins may cause bone marrow suppression and subsequent thrombocytopenia. Chemotherapy and irradiation cause direct destruction of megakaryocytes and other cells of the marrow. Other medications causing marrow aplasia are numerous and include chloramphenicol, nonsteroidal anti-inflammatory drugs, antiepileptic medications, and gold.

Alcohol thrombocytopenia

This is the most common haematological abnormality associated with alcohol abuse. The thrombocytopenia can be due to hypersplenism (described subsequently) or alcohol suppression of the marrow. Alcohol-induced marrow suppression can cause very severe thrombocytopenia requiring treatment by platelet transfusions. Elimination of alcohol intake will induce an increase of the platelet count within days to weeks. Associated haematological abnormalities include megaloblastic anaemia and ringed sideroblasts.

Nutritional deficiencies

Thrombocytopenia may occur with folate or vitamin B12 deficiency. The degree of thrombocytopenia is variable and may be severe. Associated haematological abnormalities include megaloblastic anaemia and hypersegmented neutrophils. Replacement of the deficient vitamin will result in recovery of the platelet count. Iron deficiency has also been associated with thrombocytopenia, although more frequently with thrombocytosis. Replacement of iron generally corrects the platelet count.

Infiltration of the bone marrow

The bone marrow may become infiltrated with nonhaematopoietic or nonstromal cells. Conditions that may lead to marrow infiltration include metastatic cancer, haematological malignancies (leukaemia, lymphoma, myeloma), myelofibrosis, storage disorders, and granulomatous disorders (sarcoidosis, tuberculosis).

Acquired amegakaryocytic thrombocytopenic purpura

Bone marrow aplasia is characterized by hypocellularity of the marrow. Aplasia involving more than one lineage of haematopoietic cells is called aplastic anaemia. When isolated decreased platelet production occurs, it is called amegakaryocytic thrombocytopenic purpura. This rare condition frequently progresses to aplastic anaemia. Bone marrow examination reveals absent or severely decreased numbers of megakaryocytes. The disorder may be secondary to various aetiologies including drugs, toxins, and infections, but most frequently it is idiopathic. Treatment varies with the suspected aetiology and typically is supportive, but can include intravenous IgG, corticosteroids, and immunosuppressive therapies.

Myelodysplastic syndromes

Myelodysplastic syndrome can present with isolated thrombocytopenia. Examination of the bone marrow usually demonstrates abnormal megakaryocyte morphology and cytogenetic analysis reveals chromosomal abnormalities.

Disorders of platelet distribution and platelet sequestration

Splenomegaly and hypersplenism

Decreased numbers of circulating platelets may be seen in patients with splenomegaly. Normally, one-third of the circulating platelets are pooled in the spleen. With splenomegaly the size of the pool of platelets sequestered in the spleen increases, decreasing the number of circulating platelets. Increased destruction of the platelets may also occur. The thrombocytopenia is usually moderate (platelets >40 × 109/litre). Bone marrow examination reveals normal numbers of megakaryocytes. Other laboratory abnormalities include leucocytosis with a normal differential and mild anaemia. Splenomegaly may be demonstrated by ultrasound or a liver–spleen scan. The diagnosis of hypersplenism can be confirmed by performing an autologous platelet survival test. This test will show a reduced recovery of transfused platelets (usually <30%) with a normal platelet survival. The thrombocytopenia is rarely severe enough to require treatment; however, splenectomy is curative.

Haemodilutional disorders

A low number of circulating platelets may also be seen in patients who have received large volumes of crystalloid solutions or blood products. This type of thrombocytopenia is commonly seen immediately after surgery and is generally transient. If treatment is required, the patient should receive platelet transfusions.

Extracorporeal circulation

Patients undergoing cardiopulmonary bypass commonly develop mild thrombocytopenia. The cause of the decreased platelet count is multifactorial; adherence of platelets to synthetic surfaces causes activation and damage to the platelets, haemodilution, and blood loss. The thrombocytopenia is usually mild. Generally, the platelet count recovers within 3 to 4 days to levels greater than the count preoperatively.

Hypothermia

Hypothermia is associated with transient thrombocytopenia. Decreased body temperature results in pooling of platelets in the peripheral circulation. Hypothermia may be seen in cases of environmental exposure, after prolonged surgery, and after transfusions of massive amounts of inadequately warmed blood products.

Thrombocytosis

Thrombocytosis is defined as a platelet count greater than 600 × 109/litre. An elevated platelet count may be primary (essential) or secondary to other disorders.

Thrombocythaemia

Primary thrombocytosis also known as thrombocythaemia is a chronic myeloproliferative disorder. Other chronic myeloproliferative disorders such as polycythaemia vera, myeloid metaplasia, and chronic myelogenous leukaemia can also cause an increase in platelet count.

Incidence and epidemiology

The incidence of thrombocythaemia is approximately two per 100 000 population per year. The average age at diagnosis is 60 to 80 years with men and women equally affected. Young women in their thirties may present with thrombocythaemia.

Aetiology and pathogenesis

Thrombocythaemia is probably a clonal process originating at the stem cell level leading to sustained proliferation of megakaryocytes with increased numbers of circulating platelets. A mutation in the JAK2 tyrosine kinase (JAK2V617F) is present in approximately 50% of patients with essential thrombocytosis. This mutation results in a constitutively active tyrosine kinase that is able to activate tyrosine kinase signalling when expressed with receptors including the erythropoietin receptor, the thrombopoietin receptor and the granulocyte colony-stimulating receptor. Thrombopoietin may also play a role in the pathogenesis of the disorder. Studies have shown reduction of c-Mpl protein and messenger RNA expression. This may reflect an intrinsic defect of c-Mpl transcription or decreased receptor expression that results in ineffective clearance of thrombopoietin.

Clinical findings

Two-thirds of patients have symptoms at the time of diagnosis, usually thrombosis or bleeding; however, thrombocythemia can occur in patients, typically young women, who are otherwise well. Thrombotic events are common, occurring in 20 to 30% of patients, particularly older people. The thrombosis involves the microvasculature and patients present with headache, transient ischaemic attacks or strokes, paraesthesiae of extremities, distal extremity gangrene, and erythromelagia (burning pain and redness of the toes or fingertips). Patients with essential thrombocythaemia have an increased risk of angina pectoris and myocardial infarction. Patients at greatest risk for thrombotic events are older and have a history of thrombosis. Major bleeding complications are rare, but bruising is common.

Laboratory findings

Patients have an unexplained elevation of their platelet count, typically above 800 × 109/litre. Examination of the peripheral smear can reveal megathrombocytes and leucocytosis with immature myeloid precursor cells. Mild eosinophilia and basophilia can occur. Bone marrow evaluation shows increased cellularity, marked megakaryocytic hyperplasia, and clustering of megakaryocytes. In addition the megakaryocytes often are morphologically bizarre with nuclear pleomorphism. Bone marrow karyotypes are usually normal. The Polycythaemia Vera Study Group has suggested criteria for the diagnosis of essential thrombocythaemia (Box 22.6.3.4). The JAK2V617F mutation is found in approximately 50% of patients.

From: Murphy S et al. (1997). Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol, 34, 29–39.

Management

Untreated, asymptomatic patients with thrombocythaemia can have a near normal life expectancy. Furthermore, the thrombotic risk in asymptomatic patients younger than 60 years of age with no history of thrombosis is not increased. Young, asymptomatic patients therefore do not require treatment, although aspirin may be given. Possible indications for treatment to lower platelet count include patients with a history of thrombotic events, patients with cardiovascular risk factors, elderly patients, and patients in whom platelet counts remain very high (>1000 × 109/litre).

Low-dose aspirin can be used to prevent thrombosis and it may relieve symptoms such as headache and erythromelagia. However, aspirin may unmask bleeding tendencies so it should be avoided in patients with a history of bleeding. Hydroxyurea will lower the platelet count and usually reduces thrombohaemorrhagic complications. Adverse affects include myelosuppression and possibly an increased risk of leukaemic transformation. Anagrelide can effectively lower the platelet count, but its efficacy at reducing complications has not been established. A randomized clinical trial comparing hydroxyurea plus low-dose aspirin with anagrelide plus low-dose aspirin found that both regimens gave equivalent long-term control of the platelet count; however, anagrelide was associated with an increased risk of arterial thrombosis, serious haemorrhage and transformation to myelofibrosis. Interferon-α‎ may also be used to lower platelet counts. Unfortunately, side effects including influenza-like symptoms, anorexia, and neuropsychiatric symptoms are severe enough to cause discontinuation of therapy in up to 25% of patients. Therefore, the standard of therapy for patients with essential thrombocytosis who are at high risk for thrombosis is generally considered to be hydroxyurea and low-dose aspirin.

Prognosis

The life expectancy of many patients with thrombocythaemia is near normal. However, there is a high rate of thrombotic events and 3 to 4% of patients develop leukaemia. This occurs predominantly in patients who have been treated with alkylating agents.

Secondary thrombocytosis

Essential thrombocythaemia must be differentiated from reactive or secondary thrombocytosis. Causes of secondary thrombocytosis include infections, malignancy, chronic inflammatory bowel disease, rheumatoid arthritis, iron deficiency, and hyposplenism. Reactive thrombocytosis is not associated with symptoms related to the elevated platelet count; it is usually not harmful and does not require treatment, although the underlying cause should be determined.

Disorders of platelet function

Congenital disorders of platelet function

Patients with congenital disorders of platelet function often present with a history of easy bruising, epistaxis, menorrhagia, and prolonged bleeding after surgery or dental procedures. Some of these patients may have family members with similar problems. The various platelet abnormalities may be classified functionally into disorders of platelet adhesion, aggregation, secretion, and procoagulant activity.

Disorders of platelet adhesion and aggregation

Platelet function disorders include Bernard–Soulier syndrome which is caused by a deficiency or abnormality of platelet glycoprotein Ib/IX, and Glanzmann’s thrombasthenia, caused by a deficiency of glycoprotein IIb/IIIa. Both are inherited in an autosomal recessive fashion and are very rare. The most common cause of abnormal platelet aggregation is likely a heterogeneous group of disorders characterized by abnormal platelet release of granule contents generally due to various disorders of signal transduction and internal metabolic pathways.

Disorders of platelet secretion

Disorders of platelet secretion occur when there are abnormalities of the platelet secretory pathways or if there is a deficiency of platelet granules. Grey platelet syndrome occurs when the α‎-granules are decreased or absent. Dense granule deficiency or platelet storage pool deficiency is due to a deficiency of dense granules. In alpha delta storage pool deficiency, both the α‎ and dense granules are deficient.

Disorders of platelet procoagulant activity

Platelets play an important role in haemostasis by providing a phospholipid membrane on which various coagulation reactions occur. In disorders such as Scott syndrome, abnormalities of the platelet membrane impair its procoagulant activity.

Treatment

There are no definitive therapies for any of the congenital disorders of platelet function. Administration of deamino-d-arginine vasopressin (DDAVP) induces the release of VWF from endothelial cells and may improve bleeding time and haemostasis. An effect is seen within 1 to 2 h and lasts for up to 12 h. Antifibrinolytic agents, such as aminocaproic acid, may improve haemostasis. Menorrhagia may be controlled by oral contraceptive medications and perhaps by antifibrinolytic medications. In cases of life-threatening bleeding, platelet transfusions may be necessary. However, platelet transfusions can cause immunization against the platelet receptors and should be avoided.

Acquired disorders of platelet function

The most common acquired causes of platelet dysfunction are medications and toxins, systemic disorders, and haematological diseases.

Drugs

There are numerous drugs that have been shown to affect platelet function (Box 22.6.3.5). Aspirin has been demonstrated to cause a significant increase in bleeding. Aspirin acts by irreversibly inhibiting platelet cyclooxygenase resulting in decreased formation of thromboxane A2, an agonist for platelet aggregation. Nonsteroidal anti-inflammatory agents also affect platelet function by reversibly inhibiting cyclooxygenase. Ticlopidine and clopidrogel inhibit platelet function by inhibiting the action of platelet ADP. Glycoprotein IIb/IIIa inhibitors block platelet aggregation by directly inhibiting the platelet receptor for fibrinogen, glycoprotein IIb/IIIa. β‎-lactam antibiotics may bind to and modify the platelet membrane resulting in abnormal platelet aggregation with ADP, adrenaline (epinephrine), and collagen. Nitrates inhibit platelet aggregation. Calcium channel blockers and β‎-blockers affect platelet aggregation by unknown mechanisms. Other drugs that may adversely affect platelet function include antiepileptic medications, tricyclic antidepressants, and phenothiazines.

Chronic renal failure

Patients with chronic renal failure or uraemia have platelet dysfunction including defects in adhesion, aggregation, secretion, and procoagulant activity. The bleeding time may be prolonged. The pathogenesis of the platelet dysfunction is unknown, but is probably secondary to toxins present in the uraemic plasma. Treatment of a bleeding uraemic patient includes prompt dialysis. DDAVP may improve haemostasis. Maintenance of a normal haematocrit may also decrease the bleeding tendency.

Cardiopulmonary bypass surgery

Excessive bleeding occurs in approximately 5 to 20% of patients undergoing cardiopulmonary bypass surgery. Studies have demonstrated decreased platelet aggregation, altered platelet surface membrane proteins, selective depletion of platelet α‎-granules, and evidence of in vivo platelet activation. An extrinsic platelet defect may occur resulting from thrombin inhibition by high doses of heparin. The aetiology of these abnormalities could be related to the hypothermia of the procedure and damage to the platelets as they pass through the pump system. The haemostatic abnormalities usually improve within hours after surgery.

Chronic myeloproliferative disorders and myelodysplastic syndromes

Disorders such as chronic myelogenous leukaemia, essential thrombocythaemia, polycythaemia vera, and myeloid metaplasia may be associated with abnormalities of platelet number and function. Abnormalities of platelet function include impaired aggregation with epinephrine, abnormal arachidonic acid metabolism, and storage pool defects. The bleeding tendency responds to treatment of the underlying disorder and correction of the associated thrombocytosis.

Dysproteinaemias

Patients with a paraproteinaemia, such as multiple myeloma or Waldenström’s macroglobulinaemia, can have abnormalities in both platelet number and function. Nonspecific binding of the paraproteins to the platelet membrane may interfere with membrane surface receptors. Treatment of the disorder causing the paraproteinaemia will usually correct the bleeding problem. Plasma exchange may be necessary in the acute phase of this condition.

Further reading

Arnold DM, et al. (2007). Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med, 146, 25–33.Find this resource:

Arnold DM et al. (2010). Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura. Blood, 115, 29–31.Find this resource:

George JN (2006). Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost, 4, 1664–72.Find this resource:

George JN (2006). Thrombotic thrombocytopenic purpura. N Engl J Med, 354, 1927–35.Find this resource:

Gill KK, Kelton JG (2000). Management of idiopathic thrombocytopenic purpura in pregnancy. Semin Hematol, 37, 275–89.Find this resource:

Lankford KV, Hillyer CD (2000). Thrombotic thrombocytopenic purpura: new insights in disease pathogenesis and therapy. Transfus Med Rev, 14, 244–57.Find this resource:

Li X, et al. (2007). Drug-induced thrombocytopenia: an updated systematic review. Drug Safety, 30, 185–6.Find this resource:

Nurden AT (1999). Inherited abnormalities of platelets. Thromb Haemost, 82, 468–80.Find this resource:

Provan D. (2010). International consensus report on the investigation and management of primary immune thrombocytopenia. Blood, 115,168–185.Find this resource:

Warkentin TE (2007). Drug-induced immune-mediated thrombocytopenia—from purpura to thrombosis. N Engl J Med, 356, 891–3.Find this resource: