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Benign Disorders of WBC: Neutropenia and Neutrophilia
Terms in this set (52)
The term 'benign WBC disorders' refers to
-non-malignant causes of either decreased or elevated WBCs.
-Therefore, for the purpose of this discussion, we will not include any malignant disorders
This term refers to a category white blood cells which have granules in the cytoplasm, and includes: neutrophils, basophils, and eosinophils
This term refers to a reduced granulocyte count
This term refers to a reduced neutrophil count, and typically is used when the absolute neutrophil count (ANC) < 1,500. The risk for infection increases once the ANC < 1,000, and the risk for severe life-threatening infection increases significantly if the ANC < 500.
This term refers to an increase in the absolute neutrophil count (ANC) > 7,500
This term refers to a complete absence of blood granulocytes, and is often used to indicate very severe neutropenia when the ANC < 500
Absolute Neutrophil Count (ANC)
[Total WBC x (% segmented neutrophils + % bands)
This term refers to a total WBC below the normal range, and generally that is defined as a total WBC < 4,300. For many institutions, the normal WBC range = 4.5K-11K.
This term refers to a decrease in the number of blood cells from all three cell lines: WBCs, RBCs, and platelets
Classes of Neutrophils
Class I: horseshoe shape; one lobe (band)
Class II: two nuclear lobes
Class III: three nuclear lobes
Class IV: four nuclear lobes
Class V: five or more nuclear lobes
younger vs older neutrophils
Arneth determined that younger neutrophils had one or two nuclear lobes, and older neutrophils had increasing number of lobes.
when infection was present, there was an increase in Class
I and II- representing an influx of less mature neutrophils being released by the body in response to the toxic state
Bone marrow 10-14 days
-Most of the body's neutrophil pool exists in the bone marrow
-As neutrophils mature, they develop the capacity to enter the bloodstream due to increased deformability and changes in adhesion proteins on surface membranes
-Stimulation of neutrophil release from the bone marrow with G-CSF
*, corticosteroids, or endotoxin administration can result in doubling or tripling of the blood neutrophil count within 3-5 hours.
Peripheral Blood 6-10 hrs
-In a healthy individual, ~ 5% of the body's total neutrophils are in the peripheral blood at any given time. The remaining neutrophils (~ 95% of the total body neutrophils) reside in the bone marrow, ready to be released in the event of bacterial infection or other trigger (e.g., G-CSF)
-Within the peripheral blood compartment, the neutrophils are equally divided between the circulating pool and the marginating pool*
Marginating pool can be swept into the circulation within minutes by:
a) endogenous or exogenous epinephrine
b) as a result of exercise
c) any cause of ↑ cardiac output
This response is known as demargination and is quickly reversible
The process whereby cells in the circulating pool enter the marginating pool
Neutrophils in the marginating pool leave the blood and enter the tissues by migrating between endothelial cells and penetrating the capillary basement membrane
Tissue phase 2-4 days
Neutrophils not actively involved in an inflammatory
response in the tissue will
-Sequestration of Neutrophils
-Margination of Neutrophils
is characterized by the combination of rheumatoid arthritis, splenomegaly and neutropenia
Sequestration of neutrophils: Portal HTN
When the spleen becomes "congested" due to portal hypertension, the blood flow is preferentially shunted toward the spleen resulting in splenic sequestration of the blood cells with resultant cytopenias.
Examples of disorders that may cause portal HTN include
a) Hepatic cirrhosis
b) Budd-Chiari syndrome
c) Splenic vein thrombosis
d) Portal vein thrombosis
Definition of Portal Hypertension (HTN)
-Portal HTN is a term used to define elevated pressure in the portal venous system.
-The portal vein supplies 70% of the hepatic blood supply; the hepatic artery supplies the remainder of the blood supply to the liver
causes of Portal vein thrombosis
Most common underlying cause is cirrhosis
-carcinoma of hepatobiliary system
Splenic vein thrombosis:
Isolated splenic vein thrombosis is rare and pancreatic disease is the most common cause (e.g., pancreatitis, malignancy)
-gastric varices frequently develop and may result in massive gastric hemorrhage.
Mesenteric vein thrombosis
-Pre-hepatic cause of portal HTN
10% of mesenteric ischemia cases are caused by mesenteric vein thrombosis.
Most common causes include hypercoagulable state, cancer, intra-abdominal infection or inflammation, cirrhosis, and surgery.
The most common cause of portal HTN. In Western countries, alcoholic and viral cirrhosis are leading causes of portal HTN.
Patients with cirrhosis have increased resistance to blood flow in the liver due primarily to fibrosis and regenerative nodules compressing the vessels.
There is also increased rate of blood flow to splanchnic circulation in cirrhosis; hyperdynamic circulation with 50% increased flow to GI tract, pancreas, and spleen in patients with cirrhosis due to increased levels of vasodilators (e.g., glucagon) in the blood and decreased vascular sensitivity to vasoconstriction.
Uncommon condition caused by thrombotic or non-thrombotic obstruction of hepatic venous outflow.
Clinical findings include abdominal pain, hepatomegaly, ascites
Acute/subacute, chronic, and fulminant forms of Budd-Chiari syndrome.
Chronic Budd-Chiari syndrome is most common presentation; clinical presentation with progressive ascites; 50% of patients will also have renal impairment; jaundice is absent.
Most often seen in association with hematologic disorders
Inferior vena cava (IVC) obstruction:
Malignancy such as renal cell carcinoma and other tumors close to the IVC may cause IVC thrombosis either by direct invasion of IVC by tumor or extrinsic compression of IVC.
Non-malignant causes of IVC thrombosis include congenital anomaly of IVC or extrinsic compression causing venous stasis and turbulent blood flow.
Patient presenting with bilateral lower extremity DVTs requires imaging of the IVC to evaluate for possible obstruction
Sequestration of neutrophils: Splenic trapping of neutrophils due to infection:
In cases of parasitic infections causing splenomegaly, such as acute malaria, splenic sequestration and accelerated destruction of neutrophils can cause a resultant neutropenia.
Sequestration of neutrophils: Felty's syndrome
-Recall that splenomegaly is associated with Felty's syndrome.
-As a result of the splenomegaly, there can be splenic trapping of neutrophils and accelerated destruction.
-These factors contribute to the multi-factorial neutropenia seen in Felty's syndrome
Margination of neutrophils
-Severe bacterial infections release endotoxin into the bloodstream causing margination, which results in the neutrophils remaining in the infected tissues and not returning to the bloodstream, especially in patients with already depleted bone marrow reserve due to prior chemotherapy, other drugs, or alcohol.
-If a patient with a severe bacterial infection has a low neutrophil count, this is a grave prognostic sign.*
Benign chronic neutropenia (BCN)
-begins within the first two years of life (also known as pediatric benign chronic neutropenia).
-Most children are asymptomatic.
-involves persons who are of African, Yemenite Jewish, or of Western European descent.
-total WBC and ANC may be as low as 50% of normal levels.
In stimulation tests, there is normal granulocyte reserve, suggesting that the low neutrophil count is related to the degree of neutrophil marrow release.
Life expectancy is normal, and these patients do not generally experience recurrent infections.
In certain situations, if there is excessive local or systemic complement activation, the result may be to stimulate the formation of neutrophil aggregates that are transiently sequestered in the pulmonary capillary bed, which can result in respiratory distress.
Dialysis patients may experience this type of neutropenia, which is thought to be stimulated by certain types of dialysis membrane.
Septic patients or patients undergoing cardiopulmonary bypass surgery may also experience complement-activated neutropenia.
Workup of new-onset neutropenia of unknown cause may include
-CBC with differential
-peripheral blood smear
-Antinuclear antibody (ANA), Rheumatoid factor (RF), and antineutrophil antibody testing (to rule out underlying autoimmune disease)
-Serum B12 and folate levels (to rule out meglaoblastic anemia)
Serial CBC with differential (ANC calculated serially in cyclic neutropenia)
-Assess spleen size (liver/spleen scan, CT scan, or ultrasound to rule out splenic sequestration)
-Obtain bone marrow aspirate and biopsy (to rule out underlying bone marrow disorders or malignancy)
-Epinephrine and prednisone mobilization tests (if suspect benign chronic neutropenia or pseudoneutropenia)- though in clinical practice, these tests are not routinely done
-Complete medication history is required (to rule out drug-induced neutropenia)
Clinical Presentation of the Febrile Neutropenic Patient S & S
Recall that since there is a very diminished number of neutrophils in the peripheral blood, the patient may not have sufficient neutrophils to make an inflammatory response such as an infiltrate on CXR, or pus in an abscess.
The only presenting symptoms may be fever and malaise.
In a neutropenic patient, any fever exceeding 100.4˚F (38˚C) is significant.
There may be other signs and symptoms of underlying infections such as shaking chills, skin breakdown (indicating a possible portal of entry for infection), hypotension, productive cough, urinary symptoms, among others
Diagnostic Evaluation of the Febrile Neutropenic Patient
Complete physical examination with close attention to any indwelling catheter sites, areas of skin breakdown/cellulitis, oral exam to assess for oral ulcers or abscesses, and perianal exam to visually inspect for any evidence of a perirectal abscess.
Note that the perirectal examination must be done very carefully. A digital rectal exam should NEVER be performed in a neutropenic patient, due to the concern that bacteria from the area could enter the bloodstream if any localized trauma to the area occurred as a result of the exam, or if skin breakdown was already present.
since findings suggesting a source of infection may be lacking due to the neutropenic state, you must
obtain cultures from any possible source of infection
Febrile Neutropenic Pt infection cultures should include
-Two sets of blood cultures
-Urine for urinalysis and culture
Empiric broad-spectrum antibiotic treatment
-should be initiated immediately after obtaining all necessary cultures.
-Delay in starting appropriate antibiotic coverage can be life-threatening for the febrile patient with significant neutropenia.
-Treatment of the Febrile Neutropenic Patient
Neutropenic Precuations and Treatment of the Neutropenic Febrile Patient
-Private room for the patient
-'Reverse isolation' for all caregivers of the patient, particularly if ill
-Avoid use of humidifiers or humidified oxygen, due to risk of bacterial contamination with standing water source
-Use sterile technique with venous access devices
-Avoid or minimize invasive techniques when possible
-No fresh flowers in patient room (due to risk of fungal contamination)
-No fresh fruits or raw vegetables (due to risk of exposure to gram-negative bacteria in these foods)
-Meticulous handwashing immediately before entering room and immediately after exiting from room
-Use soft swabs for oral care; avoid toothbrushing while neutropenic
-Stool softener (to prevent perirectal skin trauma during bowel movement)
Causes of Benign Neutrophilia
-Increased production of neutrophils
-Accelerated release of neutrophils from the bone marrow storage pool into the peripheral blood
-Shift from the marginating pool to the circulating pool of neutrophils (demarginiation)
-Reduced movement of neutrophils from the peripheral blood to the tissues
-A combination of these mechanisms
Increased bone marrow production of neutrophils may be due to
-Inflammatory conditions (vasculitis, gout)
-Drug-induced (ex. lithium)
Impaired movement of neutrophils from peripheral blood into tissues
*multifactorial process also includes release of neutrophils from bone marrow storage pool and demargination
What can cause a reduction in marginating pool with increase in circulating pool?
-Exercise-induced neutrophilia (causes demargination; as endogenous epinephrine shifts cells from marginating pool into circulating pool)
Increased peripheral distribution post-splenectomy
Since the spleen is no longer available as a reservoir for blood cells, there will be an increase in the number of circulating neutrophils in patients after the spleen has been removed.
Miscellaneous other causes of benign neutrophilia
-Hereditary neutrophilia (rare)
-Idiopathic neutrophilia (rare)
-Leukocyte adhesion deficiency (rare)
-Familial cold urticaria and leukocytosis (rare)
Benign Neutrophilia S & S
May be immediately apparent what underlying process is causing the neutrophilia and specific signs and symptoms would be associated with that condition.
Findings on exam that may be helpful include splenomegaly (consider myeloproliferative process)
Benign Neutrophilia Diagnostic Test
Peripheral blood smear
Leukocyte alkaline phosphatase (LAP) score
Benign Neutrophilia Peripheral blood smear
look for evidence of immature WBCs circulating in the peripheral blood, which may suggest leukemia.
Toxic granulations or Dohle bodies suggest serious underlying bacterial infection
Benign Neutrophilia Leukocyte alkaline phosphatase (LAP) score
should typically be elevated with a leukemoid reaction and low or absent in the setting of CML
Treatment of benign neutrophilia:
Except for the presence of an underlying myeloproliferative process, treatment of benign neutrophilia is generally not indicated.
The neutrophilia will generally resolve once the underlying inflammatory process resolves.
Hereditary and idiopathic neutrophilia are quite rare and follow a benign course.
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