Farxiga side effects: Common, rare, and serious
Medications And Their Potential To Cause Increase 'Hypochromic Microcytic Anemia'
Last Updated on Nov 16, 2023
This page lists all known medications that could potentially lead to 'Hypochromic microcytic anemia' as a side effect. It's important to note that mild side effects are quite common with medications. The medication(s) listed here may be used individually or as part of a broader combination therapy. The information provided is intended as a helpful resource; however, it should not replace professional medical advice. If you're concerned about 'Hypochromic microcytic anemia', it is advisable to consult a healthcare professional. In addition to 'Hypochromic microcytic anemia', there may be other similar symptoms or signs that better match your side effect. These have also been listed below for your convenience. If you find a symptom that more closely resembles your experience, you can use this information to identify potential medications that might be the cause. Find drugs that can cause other symptoms like 'Hypochromic microcytic anemia' ReferencesAdvertisement
What Is Polychromasia?
If your blood smear test results show multicolored red blood cells (RBCs), this may be a sign of polychromasia. Polychromasia can be caused by a variety of underlying blood disorders, including cancer.
Polychromasia is the presentation of multicolored red blood cells (RBCs) in a blood smear test. It's an indication of red blood cells being released prematurely from bone marrow during formation.
While polychromasia itself isn't a condition, various blood disorders may cause it. It's important to find the underlying cause so that you can receive treatment right away.
In this article, we discuss what polychromasia is, what blood disorders can cause it, and what the symptoms might be for those underlying conditions.
To understand what polychromasia is, it's helpful to know the concept behind a blood smear test, or a peripheral blood film.
Peripheral blood film
A peripheral blood film can be used to diagnose and monitor diseases that affect your blood cells.
During the test, a pathologist first smears a slide with a sample of your blood. Then they stain the slide to view the different types of cells within the sample.
The dye that's added to the blood sample in a peripheral blood film can help differentiate various cell types. For example, common cell colors can range from blue to deep purple and more.
Typically, red blood cells turn a salmon-pink color when stained.
However, with polychromasia, some stained red blood cells may appear blue, bluish-gray, or purple.
Why red blood cells turn blue
RBCs are formed in your bone marrow.
Polychromasia is caused when bone marrow prematurely releases immature RBCs called reticulocytes.
These reticulocytes appear on a blood film as a bluish color because they still contain RNA fragments, which aren't usually present on mature RBCs.
Conditions that affect RBC turnover are generally the root cause of polychromasia. These types of conditions can result in increased blood loss and the destruction of RBCs, which in turn can increase RBC production. This can cause reticulocytes to be released into the blood prematurely as the body compensates for the lack of RBCs.
If a doctor has noted that you have polychromasia, there are several underlying conditions that can likely be the cause.
Treating certain blood disorders, especially those related to bone marrow function, can also lead to polychromasia. In such cases, polychromasia becomes a treatment side effect rather than a sign of the disease.
The table below lists the most common conditions that can cause polychromasia. More information about each condition and how they affect RBC production follows the table.
Hemolytic anemia
Hemolytic anemia is a type of anemia that occurs when your body cannot produce RBCs as quickly as they're being destroyed.
Many conditions can cause RBC destruction and lead to hemolytic anemia. Some conditions, such as thalassemia, cause dysfunctional RBCs, which can also lead to hemolytic anemia.
Both types of conditions cause an increased turnover of RBCs and polychromasia.
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease that causes hemolytic anemia, blood clots, and bone marrow dysfunction.
With this disease, RBC turnover is most affected by hemolytic anemia. Bone marrow dysfunction may also cause the body to overcompensate and release RBCs early. Both can lead to polychromasia on blood smear results.
Certain cancers
Not all cancers affect RBC turnover. However, blood cancers can greatly affect the health of your blood cells.
Certain blood cancers, such as leukemia, start in the bone marrow and can greatly influence RBC production.
Additionally, when any type of cancer spreads within the body, it can cause further destruction of RBCs. These types of metastatic cancers are likely to show polychromasia during blood testing.
Radiation therapy
Radiation therapy is an important treatment option for cancer. However, almost all types of cancer treatment affect both cancer and healthy cells.
In some cases, radiation therapy can cause changes in the way blood cells look. This may lead to polychromasia when your blood is retested.
There are no symptoms directly associated with polychromasia. However, there are symptoms associated with the underlying conditions that cause polychromasia.
Symptoms of hemolytic anemia
Symptoms of paroxysmal nocturnal hemoglobinuria
Symptoms of blood cancers
If you have any of these symptoms, a medical professional will likely order some blood tests to determine if you have any of the associated underlying conditions.
At that time, they'll be able to detect polychromasia on a blood smear if it's present.
But it's important to keep in mind that polychromasia is not the only way to diagnose these conditions, so a doctor may not even mention it during a diagnosis.
What is the difference between polychromasia and hypochromic?
While polychromasia results in multicolored RBCs on a blood smear test, if your red blood cells appear lighter in color, it's called hypochromic.
RBCs that have a reduced red color may be a sign of microcytic, hypochromic anemia. This type of anemia can result from low blood iron levels.
A healthcare professional can help determine if your blood iron levels are low through blood tests.
What does it mean if you have immature red blood cells (RBCs)?
Your body makes RBCs in the bone marrow that are released into the bloodstream. They mature after about 1–2 days.
Sometimes, however, these immature blood cells, called reticulocytes, are released prematurely.
If you have increased levels of these reticulocytes, it may be a sign of anemia or bone marrow dysfunction.
Polychromasia can be a sign of a serious blood disorder, such as hemolytic anemia or blood cancer.
Polychromasia, as well as the specific blood disorders that cause it, can be diagnosed via a blood smear test.
There are no symptoms for polychromasia itself. However, the underlying conditions causing polychromasia can cause a variety of different symptoms.
If you have polychromasia, it's important to meet with a doctor to diagnose the underlying condition and discuss treatment options.
Compound Heterozygosity For KLF1 Mutations Is Associated With Microcytic Hypochromic Anemia And Increased Fetal Hemoglobin
Analysis of hemoglobinopathiesCorrelations between genotypes and phenotypes specific to hemoglobinopathies were analyzed according to the clinical presentation of the two patients with thalassemia intermedia. The patients had the hematological features of thalassemia, including microcytic hypochromic anemia, manifesting as increased HbF, elevated reticulocyte count, and slightly increased Hb Bart's level (Supplementary Figure S2). Abnormalities in peripheral erythrocytes and bone marrow erythroblasts were also detected (Figures 1a–c). A marked increase in γ-globin and a mild-to-moderate reduction in β-globin chains were observed by analyzing hemolysates from patients' peripheral blood (Figure 1d). However, mutations in the α-, β-, or γ-globin genes that could cause thalassemic phenotypes similar to those seen in the patients were excluded, prompting a screening of 64 genes involved in Hb regulation and inherited hemolytic anemia that could be responsible for the observed phenotypes.
Figure 1Phenotypic analyses of the patients in this study. (a) Peripheral blood smears from patients JK and GH show tear drop-shaped poikilocytes (black arrow), microcytosis and hypochromasia, fragmented erythrocytes (white arrow), and nucleated erythroblasts (asterisks). (b) Bone marrow smears show poikiloblast. (c) TEM analysis shows erythroblasts with heterochromatin clumps around the nuclear periphery. (d) Reversed-phase high-performance liquid chromatographic analysis of globin chains in JK, GH, and a healthy individual. Peaks and corresponding retention times for heme groups and different globin chains are indicated (red, patient; black, control). Data for α/β and α/β+γ ratios are shown above the chromatograms. (e) Flow cytometric analysis of CD44 expression in mature erythrocytes shows erythroid-specific CD44 deficiency in patients and reduced expression in their heterozygous parents. The mixed phenotype with low CD44 expression (arrow) likely arose from still-circulating transfused blood (50 days after the last transfusion).
Identification of KLF1 variantsNext-generation sequencing of 64 candidate genes revealed compound heterozygous KLF1 mutations in the patients, in addition to the known variant rs2072597 Chr19.Hg19:g.12885926 T>C of this gene. A frameshift mutation, c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)), and one of two missense mutations, c.892 G>C (p.(Ala298Pro)) and c.1012C>T (p.(Pro338Ser)), were confirmed by Sanger sequencing of the patients (Supplementary Figure S3), and healthy family members from the two unrelated Chinese families. A pedigree analysis showed a recessive pattern of inheritance for the disease in both families (Figure 2a). The two missense mutations in KLF1 were absent in control chromosomes from 400 normal individuals who were included in the analysis. KLF1 has been considered as a causative gene of CDA. We followed this clue to determine the relationship between this thalassemia-like syndrome and CDA. To exclude the possibility that other known CDA genes were responsible for the thalassemia-like syndrome in the two patients, the CDAN1, SEC23B, C15ORF41, and KIF23 genes were also screened for mutations, but none were detected by direct DNA sequence analysis (data not shown). Five known variants associated with elevated HbF were genotyped (Supplementary Table S2), but the outcomes could not explain the observed increases of 26.3% (Patient JK) and 33.2% (Patient GH) in HbF. Multiple alignment of KLF1 from various mammalian species showed conserved Ala and Pro at residues 298 and 338, respectively (Figure 2b). Three types of mutations were predicted to disrupt the ZF domain of KLF1: c.525_526insCGGCGCC p.(Gly176ArgfTer179) generated a truncated protein lacking the ZF domain; c.892G>C p.(Ala298Pro) in the first ZF domain; and c.1012C>T p.(Pro338Ser) located between the second and third ZF domains (Figure 2c). Comparative structural homology modeling of the c.892G>C p.(Ala298Pro) and c.1012C>T p.(Pro338Ser) mutations revealed how they affected the binding activity of the highly conserved ZF domain: an Ala-to-Pro substitution at position 298 perturbed the network of hydrogen bonds formed by S294, A298, and R301, and undermined the conformational stability of the ZF1 α-helix by restricting the flexibility of the loop. The substitution of Pro for Ser at position 338 changed the conformation of the TGERP-like linker between ZF2 and ZF3 by relaxing the secondary structure via disruption of the predicted hydrogen bonds between R337 to A347 (Figure 2d).
Figure 2Identification of disease-associated KLF1 mutations. (a) Pedigrees for two unrelated Chinese families and identified KLF1 mutations. Representative chromatograms show KLF1 sequences in probands' genomic DNA. Amino acids are indicated above each chromatogram, with base/amino-acid changes highlighted in red. (b) Sequence alignment of KLF1 proteins of various mammalian species shows a conserved Ala at residue 298 (upper red box) in the ZF1 domain and Pro at residue 338 (lower red box) in the TGERP-like linker between ZF2 and ZF3. (c) The KLF1 gene (NG_013087.1) and its products, consisting of three exons (green boxes, coding regions; white boxes, untranslated regions). The gene product consists of an N-terminal Pro-rich transactivation domain (green box) and three C-terminal C2H2 ZF domains. Base alterations and amino-acid substitutions corresponding to mutations are shown in red. (d) Upper panel: steady-state network of hydrogen bonds (broken red lines) formed by A298 (red), S294 (green), and R301 (purple) in WT KLF1 (left) and the unstable α-helix in the mutant A298P (right). Lower panel: predicted hydrogen bonding (broken red lines) of R337 (purple) to A347 (green) in WT KLF1 (left) and the loss of hydrogen bonds in the mutant P338S (right). DNA is shown in gray.
Unique phenotypic patient characteristicsTo further demonstrate the effects of KLF1 variants on various phenotypic changes of erythroid cells, apart from the morphological analysis of peripheral erythrocytes and bone marrow erythroblasts (Figures 1a and b). Clinical and laboratory data for affected and heterozygous members of the two Chinese families are provided in Table 1. The hematological parameters and Hb profiles of these patients were more complex than those of thalassemia patients. Examination of bone marrow smears revealed poikiloblast (Figure 1b) accompanied by erythroid hyperplasia (JK, 51.5% and GH, 61%). The TEM analysis showed an abnormal heterochromatin organization with heterochromatin clumps around the nuclear periphery (Figure 1c). The patients presented with moderate anemia combined with a wide spectrum of erythroid-specific defects, such as microcytosis/hypochromia with an In[Lu] blood type and reduced expression of CD44 protein. However, all eight adult carriers from the two Chinese families were asymptomatic, although they displayed a few specific benign phenotypes, including the In[Lu] blood type and moderately reduced expression of CD44 protein (Table 1 and Figure 1e). In summary, three main types of phenotypic abnormality were linked to this disorder: microcytic hypochromic anemia with a high reticulocyte count, decreased β/α ratio, and mildly increased Hb Bart's level; unusual benign changes in erythrocytes, including the InLu phenotype, abolition of the RBC membrane adhesion molecule CD44, moderately increased RBC protoporphyrin and high levels of ζ-globin chains; and morphological abnormalities, including poikiloblast and abnormal heterochromatin organization.
Table 1 Clinical and laboratory data for the two families Altered localization of mutant KLF1To study protein localization, we examined the expression subcellular localization of WT KLF1 and three KLF1 mutants using a GFP-tagged subcellular localization assay. The nuclear localization of the three mutants is not affected as seen in Figure 3a. Furthermore, it is not recognized by the protein quality control of the cell and degraded as seen in the western blot (Figure 3b). Interestingly, the c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)) mutation, which was similar in size to the WT KLF1 (only nine amino acids shorter), showed an additional feature, namely this mutant seems to produce aggregates in the nucleus, which may contribute to the phenotype by inducing stress in cells due to the accumulation of misfolded proteins. Hence, this protein aggregation, which probably escapes nonsense-mediated mRNA decay, may indeed contribute to the disease mechanism of this mutant.
Figure 3Effect of mutations on KLF1 function. (a) Subcellular localization of constructs encoding GFP-tagged wild-type KLF1 (WT) and the three mutants in HEK-293 and K-562 cells. Confocal images of GFP (green), DAPI nuclear staining (blue), and the merged signals are shown. (b) Expression of WT KLF1 and three mutants in K-562 cells, as determined by western blotting. (c–e) Effect of KLF1 mutations on the regulation of KLF1 target genes HBB, BCL11A, and CD44 in K-562 cells co-transfected with a HBB, BCL11A, or CD44 promoter-Luc construct, along with KLF1 constructs or an empty vector at concentrations of 0, 150, or 300 ng (0, 1, and 2, respectively). Data in (c–e) represent mean±s.D. Of three independent experiments.
Effect of KLF1 mutations on HBB, CD44, and BCL11A transcriptionIt was reasoned that abnormal erythroblast phenotypes resulted from the loss of KLF1 function. Thus, the transcriptional activity of KLF1 was investigated in HBB, CD44, and BCL11A, three KLF1 target genes associated with disease phenotypes.
In the KLF1-tagged promoter–reporter assay, KLF1 mutants reduce the transcription of HBB, CD44, and BCL11A in a simulated compound heterozygote for two of the mutations or a homozygote for each of the three mutations. The mutations did not interfere with the transcriptional activity of WT KLF1, and compound mutants had the same degree of reduction in reporter activity (26–61%) as single mutants. As expected, the c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)) mutant had the most prominent loss of transcriptional activity compared with the WT. However, when WT KLF1 was co-expressed with each of the three variants, the simulated heterozygotes were still able to activate the target gene promoters to varying degrees (Figures 3c–e): the transactivation decreased to only 85–94% for HBB and BCL11A, and up to 42–50% for CD44, respectively. This suggests that two mutant KLF1 alleles can differentially affect target genes to produce distinct phenotypes; for instance, the downregulation of HBB, BCL11A, and CD44 expression leads to an α/non-α chain imbalance, HPFH, and In[Lu] blood type, respectively.
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