Neutropenia and Thrombocytopenia PDF

Neutropenia Thrombocytopenia Ahmad Khalil, MD Hematologist Oncologist Lebanese University, FOMS Neutropenia Neutropenia Absolute neutropenia, characterized by neutrophil counts less than 1500–2000/μL It is a commonly encountered problem in medicine and can be due to a large number of...

Neutropenia Thrombocytopenia Ahmad Khalil, MD Hematologist Oncologist Lebanese University, FOMS Neutropenia Neutropenia Absolute neutropenia, characterized by neutrophil counts less than 1500–2000/μL It is a commonly encountered problem in medicine and can be due to a large number of disease entities Neutropenia Absolute neutropenia, characterized by neutrophil counts less than 1500–2000/μL It is a commonly encountered problem in medicine and can be due to a large number of disease entities Grading of Neutropenia Neutropenia (ANC) Absolute Neutrophils Count (cells/µL) Grade 1 1500 to < 2000 Grade 2 1000 to < 1500 Grade 3 500 to < 1000 Grade 4 < 500 Severity of Neutropenia Neutropenia (ANC) Absolute Neutrophils Count (cells/µL) Mild 1000 to < 1500 Moderate 500 to < 1000 Severe 200 to < 500 Very severe (profound) < 200 Types of Neutropenia Congenital neutropenia: severe form of neutropenia that is seen most often in babies or very young children, the most serious form of chronic congenital neutropenia is called Kostmann's syndrome. Idiopathic neutropenia: The term idiopathic means "of unknown cause." Idiopathi neutropenia affects children and adults. Cyclic neutropenia: This type of neutropenia usually occurs every 3 weeks and may last 3 to 5 days. It affects both children and adults, sometimes within the same family. Cyclic neutropenia happens when the rate of cell production in a person's bone marrow rises and falls. Autoimmune neutropenia: This is the most common cause of neutropenia in infants and young children. Occasionally, it is seen in adults aged 20-40 years (mostly women). The condition causes the body's immune system to fight and destroy its own neutrophils. Cyclic Neutropenia Cyclic Neutropenia Cyclic neutropenia is rare It is characterized by a lifetime history of neutrophil counts that decrease to zero or near zero for 3–5 days at a time every 3 weeks and then rebound Interestingly, the peripheral blood neutrophil counts and monocyte counts oscillate in opposite on this 3-week cycle. Etiology Classic, childhood-onset cyclic neutropenia results from heterozygous germline mutations in the gene ELANE (ELAstase, neutrophil expressed), formerly known as ELA2, which encodes for a single enzyme, neutrophil elastase (NE). NE is found in the primary azurophilic granules of neutrophils and monocytes. NE is an important factor promoting inflammation, has bactericidal effects, and shortens the inflammatory process There are approximately 100 cases in the literature, most of which are consistent with an autosomal dominant inheritance. However, sporadic adult cases also occur, and these are associated with neutrophil elastase mutations. There does not seem to be a racial predilection or gender bias in incidence. Neutrophil Elastase Synthesis Pathogenesis The neutrophil count in blood is stable in normal individuals, reflecting the fact that there is a large storage pool of granulocytes in the marrow. The marrow reserve exceeds the circulating pool of neutrophils by 5- to 10-fold. This large pool is necessary because it takes nearly 2 weeks for the full development of a neutrophil from an early stem cell within the bone marrow The average life span of a mature neutrophil in blood is less than 12 hours Daily measurements of neutrophil counts in the blood reveal striking variations in their number. Pathogenesis In cyclic neutropenia, the storage pool is not adequate Studies of neutrophil kinetics in affected patients reveal that the defect is in abnormal production, rather than abnormal disposition of neutrophils Pathogenesis In cyclic neutropenia, the storage pool is not adequate Studies of neutrophil kinetics in affected patients reveal that the defect is in abnormal production, rather than abnormal disposition of neutrophils Neutrophil production occurs in discrete waves even in normal individuals As neutrophils differentiate from an early progenitor cell, they produce neutrophil elastase, which is thought to inhibit the differentiation of myeloblasts in a negative feedback loop. This results in an oscillatory wave with peaks and troughs of neutrophil production. As neutrophil numbers increase in the marrow, a peak is obtained where enough neutrophil elastase causes a drop in neutrophil differentiation Then, as the number of neutrophils drops again to a nadir, the production of neutrophil elastase also declines, allowing the number of neutrophils to climb once again Pathogenesis In cyclic neutropenia, it is hypothesized that the mutant neutrophil elastase may have an excessive inhibitory effect, causing prolonged trough periods and inadequate storage pools to maintain a normal peripheral neutrophil count. However, once they are extruded from the marrow, the neutrophils appear to have a normal life span The myeloid progenitor for neutrophil can also produce monocytes. Therefore, during neutrophil nadirs, the myeloid progenitor cell can preferentially differentiate to the monocyte lineage, giving the opposing oscillatory waves of neutrophils and monocytes seen in these patients  Pathogenesis Feedback loop hypothesis to explain hematopoietic cycling. Neutrophil elastase (NE) is postulated to inhibit further differentiation by a myeloblast. Gray sinewave denotes neutrophil count oscillations. In this model, NE is produced by the terminally differentiating cohort of neutrophils and ultimately feeds back to inhibit further production of neutrophils, which results in loss of the inhibitory cycle at least for a while, until production of the neutrophils resumes, followed again by the inhibitory action of NE in a cyclic manner Pathogenesis The waves are remarkably constant in their periodicity. Almost every patient has a cycle between 19 and 22 days, and each patient’s cycle length is constant during his or her lifetime Platelet and reticulocyte counts also cycle with the same cycle length, but in contrast to the blood neutrophil count, clinically significant decreases are not observed. This is presumably because the blood life spans of these elements are so much longer than the life span of neutrophils. Because multiple cell lines are seen to cycle, it is believed that neutrophil elastase mutations accelerate the process of apoptosis (programmed cell death) in early progenitor cells, as well, unless they are “rescued” by G-CSF Pathogenesis Pathogenesis Clinically, administration of pharmacologic doses of G-CSF (filgrastim) to affected individuals has three interesting effects that partially overcome the condition. First, although cycling continues, mean neutrophil counts increase at each point in the cycle, such that patients are rarely neutropenic. Second, cycling periodicity decreases immediately from 21 days to 14 days. Third, other cell line fluctuations change in parallel However, the fact that cycling does not disappear demonstrates that there are other abnormalities yet to be discovered. Pathology The pathologic features of cyclic neutropenia are seen mostly in the laboratory. The peripheral blood smear appears normal except for the paucity of neutrophils during the nadirs of each cycle. Individual neutrophils appear normal. The bone marrow, however, shows striking differences depending on the day of the cycle on which it is examined. During the nadir of each cycle, there are increased numbers of early myeloid precursors such as promyelocytes and myelocytes, and mature neutrophils are rare. This picture is similar to that seen in acute leukemia, but 10 days later, as circulating neutrophil counts are rising, an entirely normal appearing marrow is typical. Clinical Manifestations In general, neutropenia from any cause places patients at risk for severe bacterial infections, generally from enteric organisms, because of the alteration in host defenses in the gastrointestinal tract. This is especially true when the neutropenia is due to administration of chemotherapeutic agents, because chemotherapy also affects the lining of the GI tract. Neutrophils, with their ability to engulf bacteria and deliver toxic enzymes and oxidizing free radicals to sites of infection, normally serve as the first line of host defenses against the bacteria that inhabit the gut. Such patients are also at risk for fungal infections if the neutropenia lasts more than several days; this is because it takes longer for fungi to reproduce and invade the bloodstream. Untreated infections of either type can be rapidly fatal, particularly if the neutrophil count is less than about 250/μL. Clinical Manifestations In cyclic neutropenia, then, recurrent infections are to be expected, and deaths from infections with intestinal organisms have been reported. Each cycle is characterized by malaise and fever coincident with the time neutrophil counts are falling. Cervical lymphadenopathy is almost always present as are oral ulcers. These symptoms usually last for about 5 days and then subside until the next cycle When infections occur, the site is usually predictable. Skin infections, specifically small superficial pyogenic abscesses ( furunculosis ) or bacterial invasion of the dermis or epidermis ( cellulitis ), are the most common and respond to antibiotic therapy with few sequelae Clinical Manifestations The next most common infection site is usually the gums, and chronic gingivitis is evident in about half of patients and it is also the most noticeably improved problem when patients receive therapy with filgrastim Other infections are unusual, but any neutropenic patient is at risk for infection anywhere In the few patients who have required abdominal surgery during their neutropenia, ulcers similar to those seen in the mouth have been noted Because the period of greatest susceptibility to infection is only a few days in each cycle, most patients grow and develop normally. Thrombocytopenia Platelet Disorders Causes of Thrombocytopenia: Drug-Associated Immune Thrombocytopenia Etiology Although there are many causes, the possibility of a drug-induced immune thrombocytopenia should always be considered In practice, the association between a given drug and thrombocytopenia is usually made clinically rather than with specific tests. Thrombocytopenia usually occurs at least 5–7 days after exposure to the drug, if given for the first time. The suspect drug is stopped and platelet counts rebound within a few days. Rechallenge with the drug, which is rarely done, almost always reproduces the thrombocytopenia Heparin is the most important cause of thrombocytopenia because of its frequent use in hospitalized patients Etiology Common drugs that may cause thrombocytopenia: Pathogenesis Although the phenomenon of drug-induced thrombocytopenia has been known for decades to be immune in nature The specific mechanisms have long been controversial. The association of antibodies with platelets leads to their destruction via the spleen. The spleen acts as the major “blood filter” and recognizes platelets bound to antibodies as abnormal and thus removes them. Spleen removal also occurs in autoimmune (idiopathic) thrombocytopenia, which is relatively common and difficult to distinguish clinically from drug-induced thrombocytopenia Pathogenesis There are various mechanisms underlying drug-induced immune thrombocytopenia. Quinine or NSAID induced thrombocytopenia involves the tight binding of antibody to normal platelets only in the presence of the sensitizing drug. The antibody usually targets epitopes on the glycoprotein IIb/IIIa or Ib/IX complexes, the major platelet receptors for fibrinogen and vWF, respectively. Penicillin and cephalosporin antibiotics are believed to lead to platelet destruction via hapten-dependent antibodies. The drug acts as a hapten, a small molecule that only elicits an immunologic response when it is bound to a large carrier molecule or protein. Pathogenesis There are various mechanisms underlying drug-induced immune thrombocytopenia. Quinine or NSAID induced thrombocytopenia involves the tight binding of antibody to normal platelets only in the presence of the sensitizing drug. The antibody usually targets epitopes on the glycoprotein IIb/IIIa or Ib/IX complexes, the major platelet receptors for fibrinogen and vWF, respectively. Penicillin and cephalosporin antibiotics are believed to lead to platelet destruction via hapten- dependent antibodies. The drug acts as a hapten, a small molecule that only elicits an immunologic response when it is bound to a large carrier molecule or protein. Pathogenesis Antithrombotic agents that block the binding of fibrinogen to gpIIb/IIIa receptors (abciximab, tirofiban, or eptifibatide) can cause an acute immune-mediated thrombocytopenia Patients develop severe thrombocytopenia within hours of the exposure. The mechanism involves either naturally occurring antibodies that recognize the murine component of abciximab or structural changes to the gpIIb/ IIIa receptor caused by the binding of tirofiban or eptifibatide. Some drugs (gold salts, procainamide, and possibly sulfonamides) can induce autoantibodies that are capable of binding to and destroying platelets even in the absence of the sensitizing drug Pathogenesis For heparin, there is clear evidence of binding to a platelet protein, platelet factor 4 (PF4). PF4 resides in the alpha granules of platelets and is released when they are activated. It binds back onto the platelet surface through a specific PF4 receptor molecule, further increasing platelet activation. It also binds with high affinity to heparin and to heparin-like glycosaminoglycan molecules present on the vascular endothelium. This non–immune-based adhesion to PF4 can lead to mild thrombocytopenia via promotion of platelet binding to fibrinogen and subsequent aggregation, known as heparin-induced thrombocytopenia ( HIT ) type I. This can happen in 30% of patients exposed to heparins without clinical sequelae Pathogenesis The combination of heparin with PF4 can also act as an antigenic stimulus that provokes the production of immunoglobulin G (IgG) directed against the combination. This immunologic response is known as heparin-induced thrombocytopenia ( HIT ) type II. About 10–20% of these patients with heparin- PF4 antibodies will develop a serious clinical syndrome, HIT(T) (heparin-induced thrombocytopenia [and thrombosis]), which paradoxically involves both Thrombocytopenia 5–10 days after drug exposure and a prothrombotic state via increased platelet activation. There is a 10-fold increased risk for HIT in patients receiving unfractionated heparin (UFH) compared with those receiving low-molecular-weight heparins. Cardiac or orthopedic surgery patients have a higher risk for clinical HIT (1–5%) than medical or obstetric patients (0.1–1%) when receiving UFH. Women have twice the risk for HIT as men. Pathogenesis Thrombocytopenia occurs in HIT type II after a series of steps. First, PF4 is released from platelets either by heparin itself or by other stimuli. Heparin then binds to PF4, forming an antigenic complex that results in the production of IgG antibodies that can bind directly to this compound. The new complex of IgG-heparin-PF4 binds to platelets through the platelet Fc receptor, via its IgG end. Platelets bound with this antibody complex are then destroyed by the spleen. Despite the resulting thrombocytopenia, HIT type II leads to a prothrombotic state via the additional binding of the heparin-PF4 portion to the PF4 receptor on platelets, promoting platelet cross-linking, activation, and aggregation Pathogenesis Thrombocytopenia occurs in HIT type II after a series of steps. First, PF4 is released from platelets either by heparin itself or by other stimuli. Heparin then binds to PF4, forming an antigenic complex that results in the production of IgG antibodies that can bind directly to this compound. The new complex of IgG-heparin-PF4 binds to platelets through the platelet Fc receptor, via its IgG end. Platelets bound with this antibody complex are then destroyed by the spleen. Despite the resulting thrombocytopenia, HIT type II leads to a prothrombotic state via the additional binding of the heparin-PF4 portion to the PF4 receptor on platelets, promoting platelet cross-linking, activation, and aggregation Pathogenesis Clinically, this decreases the numbers of circulating platelets, but it may also lead to creation of a thrombus at the site of activation. Thus, despite the fact that heparin is the most commonly used anticoagulant, in this case it may actually provoke coagulation. Furthermore, the activation of platelets via this mechanism leads to increased amounts of circulating PF4, which can bind to more heparin and continue the cycle. The excess PF4 can also bind to the endothelial surface via the heparin-like glycosaminoglycans and the antibodies to the heparin-PF4 construct could bind to the endothelial cells as well, which may lead to endothelial cell injury, further increasing the risk of local thrombosis by release of TF and ultimately thrombin. Pathogenesis Clinically, this decreases the numbers of circulating platelets, but it may also lead to creation of a thrombus at the site of activation. Thus, despite the fact that heparin is the most commonly used anticoagulant, in this case it may actually provoke coagulation. Furthermore, the activation of platelets via this mechanism leads to increased amounts of circulating PF4, which can bind to more heparin and continue the cycle. The excess PF4 can also bind to the endothelial surface via the heparin-like glycosaminoglycans and the antibodies to the heparin-PF4 construct could bind to the endothelial cells as well, which may lead to endothelial cell injury, further increasing the risk of local thrombosis by release of TF and ultimately thrombin. Pathogenesis Clinically, this decreases the numbers of circulating platelets, but it may also lead to creation of a thrombus at the site of activation. Thus, despite the fact that heparin is the most commonly used anticoagulant, in this case it may actually provoke coagulation. Furthermore, the activation of platelets via this mechanism leads to increased amounts of circulating PF4, which can bind to more heparin and continue the cycle. The excess PF4 can also bind to the endothelial surface via the heparin-like glycosaminoglycans and the antibodies to the heparin-PF4 construct could bind to the endothelial cells as well, which may lead to endothelial cell injury, further increasing the risk of local thrombosis by release of TF and ultimately thrombin. Pathogenesis of heparin-induced thrombocytopenia (HIT) Pathology The peripheral blood smear is not strikingly abnormal unless platelet counts are less than about 75,000/μL, and then it is usually abnormal only because relatively few platelets are seen. Platelet morphology, however, is usually normal, although large platelets can be seen. These large platelets are less mature and are a bone marrow compensation for a low peripheral platelet count, with platelet production from megakaryocytes being increased. Although drugs—heparin in particular— may cause platelet aggregation in vivo and in vitro, this is usual not apparent on review of the blood smear In patients who develop heparin-induced thrombocytopenia and thrombosis, thrombi are seen that are relatively rich in platelets when compared with “typical” thrombi seen in other situations. They are described as “white clots.” The thrombi may be either arterial or venous Pathology The bone marrow usually appears normal, although the megakaryocyte number may be relatively increased In a few cases of immune-mediated thrombocytopenia, however, there may be decreased numbers of megakaryocytes. There are many hypotheses as to why this may occur, but it most likely means that the antigenic combination of drug-platelet protein is also occurring on megakaryocytes This destruction would not involve the spleen, of course, but would require antibody-dependent cell killing. Clinical Manifestations The platelet count in immune-mediated thrombocytopenia can be extremely low (