Hematological System

14


Hematological System


Myelosuppression: Agranulocytosis and Thrombocytopenia


General Recommendations


Clinicians should recognize the risk for agranulocytosis in patients taking carbamazepine or clozapine, and more infrequently in those taking other SGAs or mirtazapine. Drug discontinuation is necessary in the setting of neutropenia.



Myelosuppression refers broadly to the failure of bone marrow to produce blood cells (red cells [anemia], white cells [agranulocytosis], and platelets [thrombocytopenia]). Aplastic anemia refers to a more serious form of myelosuppression. Neutropenia refers to an abnormally low number of neutrophils, and the absolute neutrophil count (ANC) is calculated from the percentage of neutrophils plus the percentage of bands (immature neutrophils). The ANC is typically defined on the basis of severity gradations that indicate the risk for infection as being mild (1,000–1,500/mm3), moderate (500–1,000/mm3), or severe (<500/mm3). A normal platelet count is 150,000 to 450,000 cells/μL of blood; clinically significant thrombocytopenia with risk for bleeding, requiring emergency intervention, is generally identified by a platelet count <50,000 cells/μL of blood. Myelosuppression can occur as rare adverse effects associated with a select number of psychotropic agents, as described in the following subsections.


Carbamazepine


Benign, transient leukopenia is a common phenomenon during initial treatment with carbamazepine. In the original Veterans Administration Multicenter Antiepileptic Drug Trial, leukocyte counts <5,000/mm3 were observed in approximately 30% of carbamazepine recipients during the first 6 months of treatment (Mattson et al. 1985). A pharmacoepidemiological study of 977 patients at McLean Hospital taking carbamazepine found a point prevalence of 2.1% (Tohen et al. 1995). Frank aplastic anemia is an exceedingly rare event with carbamazepine (), with an estimated occurrence of 1 in 200,000 exposures. Thrombocytopenia from carbamazepine, potentially related to immunologically mediated platelet destruction, typically occurs in conjunction with other systemic signs (e.g., rash, liver enzyme elevation). Some authorities advise obtaining a complete blood count (CBC) at baseline, then weekly for 2 months, and then once every 3 months. The myelosuppressive effects of carbamazepine are thought to result from toxicity caused by its epoxide metabolite (see Figure 2–1 in Chapter 2, “Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics”).


Divalproex


Mild, asymptomatic leukopenia occurs in rare instances with divalproex (0.4% point prevalence in the McLean Hospital pharmacoepidemiological study by Tohen et al. [1995]) and typically reverses upon dosage reductions or drug cessation. Thrombocytopenia has typically been defined on the basis of serum platelet counts <140,000×109 per liter. Initial case reports and case series in the late 1970s and early 1980s suggested that thrombocytopenia could be an immune-mediated reaction to divalproex caused by structural similarities between the drug and the cell membrane constituents. Later studies have suggested that the phenomenon reflects a dose-related toxicity rather than peripheral destruction or a dose-independent immunologically based event. Risk may be mediated by duration of exposure and may be higher in elderly patients and in women. Thrombocytopenia caused by divalproex typically remits after dosage reductions, without the need for drug discontinuation. No formal recommendation exists for surveillance monitoring of platelet counts during acute or ongoing therapy with divalproex, but periodic assessment (e.g., every 6–12 months) is advisable, particularly in older adults or patients taking >1,000 mg/day.


Second-Generation Antipsychotics


Clozapine is the most widely recognized SGA that carries a risk for developing agranulocytosis (~1%) (). The mechanism by which clozapine can suppress leukocyte counts is not well understood but is thought to involve an immunologically mediated cytotoxic effect of clozapine or its metabolites; however, research efforts have not demonstrated immunologically associated features such as eosinophilia. Clozapine-associated myelosuppression is most likely to occur within the first 6 months of treatment, although exceedingly rare single case reports have been published involving the development of clozapine-induced agranulocytosis after 17 months, 2.5 years, or even 11 years, lengthy time frames that represent the exception rather than the rule. Research efforts have not identified predictors of eventual agranulocytosis, although risk may increase somewhat with age and female sex. An earlier literature also suggested that rises in total white blood cell (WBC) counts by ~15% may sometimes precede agranulocytosis from clozapine.


Guidelines for WBC monitoring during clozapine therapy are presented in Table 14–1. In October 2015, the FDA began a centralized Risk Evaluation and Mitigation Strategy (REMS) program to oversee monitoring of hematological parameters and drug dispensing for all U.S. patients taking clozapine.


In July 2009, the FDA imposed a class effect on FGAs and SGAs, warning of an association with leukopenia/neutropenia and possible agranulocytosis. The clinical significance of the warning does not involve a need for widespread or routine monitoring of CBCs among patients taking SGAs, but rather an awareness that this drug class should be considered in the differential diagnosis of individuals who may present with low WBC counts. Antipsychotics should be discontinued in the setting of an ANC of <1,000/mm3, with subsequent close monitoring of WBC counts until recovery.


The risk for agranulocytosis may increase whenever a new antipsychotic agent is introduced and may be mediated in part by a longer duration of high-dose therapy.


Clinicians sometimes think of using lithium as a strategy to promote leukocytosis and boost WBC counts. At one time, it was thought that leukocytosis during lithium therapy merely reflected increased demargination of WBCs from blood vessel endothelial linings, rather than truly increasing the new production and differentiation of granulocytes from bone marrow. However, more recent efforts suggest that lithium may indeed foster a true myeloproliferative response (rather than demargination) by increasing granulocyte colony–stimulating factor and augmenting its effects (Focosi et al. 2009).








































TABLE 14–1.Monitoring of white blood cell counts during clozapine treatment


Event


Complete blood count (CBC) monitoring


0–6 months


Monitor weekly.


6–12 months


Monitor biweekly.


>12 months


Monitor monthly.


Substantial drop within 3 weeks (WBC≥3,000/mm3 or ANC≥1,500/mm3)


Repeat CBC. If WBC=3,000– 3,500/mm3 and ANC<2,000/mm3, monitor twice weekly.


WBC=3,000–3,500/mm3 or ANC=1,500–2,000/mm3


Monitor twice weekly until WBC>3,500/mm3 and ANC>2,000/mm3.


WBC=2,000–3,000/mm3 or ANC=1,000–1,500/mm3


Monitor CBC daily until WBC > 3,000/mm3 and ANC>1,000/mm3; then twice weekly until WBC > 3,500/mm3 and ANC>2,000/mm3; then weekly. May then rechallenge and monitor weekly for 1 year.


WBC<2,000/mm3 and ANC<1,000/mm3


Discontinue clozapine. Monitor CBC daily until WBC>3,000/mm3 and ANC>1,500/mm3; then twice weekly until WBC>3,500/mm3 and ANC>2,000/mm3; then weekly.


ANC≤500/mm3 (agranulocytosis)


Discontinue clozapine. Monitor CBC daily until WBC>3,000/mm3 and ANC>1,500/mm3; then twice weekly until WBC>3,500/mm3 and ANC>2,000/mm3; then weekly.


Note. ANC=absolute neutrophil count; WBC=white blood cell (count).


Although product information from clozapine’s manufacturer does not prohibit the reintroduction of clozapine after development of neutropenia, rechallenge is controversial and has not been systematically studied. Manu and colleagues (2012) identified 112 reported cases of clozapine rechallenge after neutropenia, occurring from 1 to 156 weeks after initial drug cessation. In about 30% of clozapine-rechallenged cases, the patient again developed neutropenia (about half the time resulting in even more severe agranulocytosis than had occurred previously), occurring at a mean of about 4 weeks after its reintroduction. After severe neutropenia (ANC<500/mm3), hematologically successful outcomes after clozapine rechallenge occurred in only 3 of 15 cases.


Granulocyte colony–stimulating factor (GCSF) itself is often used to treat neutropenia from myelodysplastic syndromes or myelosuppression caused by antineoplastic agents, although its use to counteract drug-induced agranulocytosis is less well established except in cases of severe bone marrow hypoplasia. Reports exist using the injectible GCSF compound filgrastim (dosed at >0.3 mg/week) to rechallenge patients with clozapine after their having developed agranulocytosis, although the efficacy of this strategy appears variable. Generally, psychotropic-induced agranulocytosis resolves after cessation of a causal agent, and new granulocytes arise within 21 days, obviating the need for further intervention other than supportive measures (as in the setting of fever or infection).


Other Agents


Thrombocytopenia has been described as a rare event with SSRIs, clonazepam, and diazepam. Agranulocytosis has been described as a rare, potentially immune-mediated occurrence during long-term treatment with chlordiazepoxide, diazepam, midazolam, and modafinil. Rare reports exist of pancytopenia, including aplastic anemia and pure red blood cell aplasia, occurring during treatment with lamotrigine. In premarketing studies of mirtazapine, agranulocytosis was observed in 2 of 2,796 patients, with one-third developing severe neutropenia, yielding a crude incidence of 1.1 per 1,000 exposed patients. All observed cases resolved after drug cessation. Mirtazapine should be stopped in patients who develop signs of an infection with an accompanying low WBC count.


Platelet Aggregation Disorders and Bleeding Risk


General Recommendations


Individuals with a history of gastrointestinal bleeding or other risk factors for bleeding (e.g., use of anticoagulants or NSAIDs, liver disease) may have a low but statistically significantly increased risk for bleeding during therapy with serotonergic antidepressants. The presence of clear, identifiable increased risk factors for bleeding may favor the use of nonserotonergic over serotonergic antidepressants when feasible, possible cotherapy with a proton pump inhibitor in individuals at particular risk for gastrointestinal bleeding, and the temporary discontinuation of serotonergic antidepressants before elective surgery on a case-by-case basis.



There is unresolved controversy surrounding the potential for bleeding disorders due to platelet serotonin dysfunction during therapy with serotonergic antidepressants. Some reports suggest a roughly 2-fold increased risk for upper gastrointestinal bleeding with SSRIs, particularly when combined with NSAIDs, anticoagulants including aspirin, or antiplatelet drugs (e.g., Andrade et al. 2010), whereas other studies have failed to replicate such concerns and dispute their validity. Short-term (rather than long-term) SSRI exposure also has been associated with intracranial and intracerebral hemorrhage as an extremely rare event (estimated as one additional case per 10,000 persons treated for a year (Hackam and Mrkobrada 2012). SSRI-induced thrombocytopenia also represents a separate mechanism by which some serotonergic antidepressants, such as citalopram, have reportedly been associated with bleeding disorders (Andersohn et al. 2010).


Clinicians should keep in mind that the differential diagnosis of iatrogenic abnormal bleeding extends beyond pharmacologically induced disruption of platelet aggregation and may include hepatic failure (e.g., diminished production of clotting factors, elevated prothrombin time), disseminated intravascular coagulopathy (which may rarely occur in the setting of serotonin syndrome), and inherited bleeding disorders (e.g., von Willebrand disease), among other factors.


Red Blood Cells


General Recommendations


Decreased red blood cell production is rarely iatrogenic and should prompt a comprehensive review of risk factors for anemia or suppression of other cell lines.



Although a number of psychotropic agents may cause fulminant aplastic anemia, relatively few have been associated solely with the suppression of red blood cell production (reticulocytopenia). Macrocytic anemia has been described in case reports following treatment with divalproex, oral contraceptives, sulfa antibiotics, and reverse transcriptase inhibitors, among other drugs. Drug-induced hemolytic anemias seldom are associated with psychotropic drugs (e.g., levodopa) and more often may result from antibiotics (e.g., cephalosporins or penicillins) or from NSAIDs. The evaluation and differential diagnosis of reticulocytopenia is extensive, and in addition to iron deficiency, may include liver or renal failure, myelodysplastic syndromes, nutritional deficiencies, toxicities (e.g., lead, arsenic), and endocrinopathies (e.g., hypothyroidism, hyperparathyroidism), among other causes. Table 14–2 identifies key considerations in the initial assessment of anemia.



























TABLE 14–2.Considerations in the assessment of anemia


Parameter


Relevance


Is patient’s anemia macrocytic or microcytic?


Most common causes of macrocytic anemias are alcoholism, malnutrition, or malabsorption disorders leading to vitamin B12 or folic acid deficiency. The most common cause of microcytic anemia is iron deficiency. Drug-induced hemolytic anemias are usually normocytic.


Is the reticulocyte count elevated?


A compensatory increase in reticulocytes would be expected due to blood loss, hypoxia, or hemolytic anemia.


Are there indications of jaundice (e.g., icteric sclerae)?


Jaundice may indicate a hemolytic process.


Are chronic inflammatory (e.g., rheumatoid arthritis) or neoplastic conditions present?


These conditions may indicate anemia of chronic disease.


 


_________________


The symbol ■ is used in this chapter to indicate that the FDA has issued a boxed warning for a prescription medication that may cause serious adverse effects.

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Sep 1, 2019 | Posted by in PSYCHOLOGY | Comments Off on Hematological System
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