Quiz Questions 3 Flashcards
(17 cards)
Monocytes, neutrophils, and eosinophils comprise the granulocytic phagocytes and are responsible for ingesting, killing, and digesting pathogens.
True or False
true
Phagocytic leukocytes are an essential component of the innate immune system that can rapidly respond to invading bacteria, fungi, and parasites. Phagocytes are responsible for ingesting, killing, and digesting pathogens. Neutrophils and eosinophils are granulocytic phagocytes that circulate in the blood stream until they sense chemotactic signals from infected tissue. The infected tissues produce chemokines and inflammatory cytokines leading to the expression adhesion molecules on the vascular endothelium which result in phagocyte attachment and subsequent migration into sites of infection. Monocytes circulate in the blood and in tissue are seen as macrophages. Mononuclear phagocytes primarily function as residual cells in tissue (e.g., liver, lung, spleen) where they play a role in surveillance and interact with lymphocytes to promote specific immune response.
An elevation of the white blood cell count secondary to neutrophils is referred to as neutrophilia and when present virtually always signifies the presence of a leukemia.
True or False
false
An elevated white blood cell count is typically defined as greater than 11,000 cells/ & microL. The normal percentage of neutrophils ranges from 45 – 78%. Therefore, an ANC greater than 8500 cell/ & microL liter would be considered neutrophilia. The causes of neutrophilia are numerous and revolve around two broad categories: reactive and malignant. The elevation of the neutrophil count very commonly signifies the presence of an infection, but rarely can be a sign of leukemia.
Patients with an absolute neutrophil count of 1000 – 1500 cells/ul are at a high risk of severe bacterial and fungal infections.
True or False
false
Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1500 cells/µL; it may be mild 1000 – 1500 cells/µl, moderate 500 – 1000 cells/µL, or severe 0 – 500 cells/µL. In general the risk for infection increases with the ANC less than a 1000 cells/µl; however the risk varies depending upon the cause. Most patients do not get into trouble with severe infections until the ANC is less than 200.
Patients with inherited disorders of granulocytic function typically present in infancy and childhood with recurrent, unusual, or recalcitrant bacterial and/or fungal infections. It typically is not difficult to determine that the clinical scenario is considerably out of the range of normal. The infections typically involve the skin, mucosa, lung, lymph nodes, deep tissue abscesses, or childhood periodontitis. These are rare conditions and represent 20% of primary immune deficiencies.
Functional disorders of phagocytes involve which of the following except:
- Abnormalities of phagocytic adhesion
- Abnormalities of the structure of lysosomes
- Diminished ability to make toxins to kill microbes
- Abnormal extrusion of the nucleus rendering the phagocytic function of the granulocyte diminished
Abnormal extrusion of the nucleus rendering the phagocytic function of the granulocyte diminished
Thrombopoietin (TPO) is a cytokine produced in the liver which regulates megakaryocytopoiesis (proliferation) and thrombopoiesis (maturation) of platelets. TPO binds to the Mpl receptor on the surface of megakaryocytes and platelets. Once bound to the Mpl receptor, TPO is internalized and degraded. This functions as a feedback loop (the less number platelets, the more TPO is found in the circulation; the more platelets, the less TPO is in the circulation). TPO has the effect of increasing the number, size and ploidy of megakaryoctyes, and increased the basal concentration of platelets in the peripheral blood by 4-6 fold when tested in normal volunteers.
True or False. A patient with ITP typically have a decrease in their platelet count, for this reason they have a high level of TPO since their body attempts to compensate for the thrombocytopenia by increasing platelet production.
false
ITP is disease in which autoantibodies are directed against GP IIb/IIIa and/or GP1b/IX and perhaps other targets on the platelet surface and megakaryocyte surface. As a consequence to this interaction platelet survival in the circulation may be decreased due to enhanced clearance by splenic macrophages and/or megakaryocytes may be decreased or become dysfunctional in the bone marrow are unable to proliferate normal or produce platelets. For these reasons, patients with ITP may have platelet production defect, a platelet survival defect or both. Because TPO, once bound to the MpL receptor on the megakaryoctye or platelet surface, is internalized and degraded, the rapid disappearance of platelets and/or megakaryocytes results in a decrease in TPO concentration in the serum. This is different than what is seen in patients who have platelet production defect due to a lack of megakaryocytes. Under these circumstances TPO concentration is expected to be increased the serum. There is a decreased number of Mpl receptors (because the megakaryoctye and platelet mass is primarily decreased), TPO is not removed from the circulation, TPO synthesis from the liver is increased (With acute onset thrombocytopenia, this usually occurs within 24 hours). TPO deficiency secondary to liver disease may be associated with thrombocytopenia both in the presence and absence of an enlarged spleen. This has been shown to be due to liver synthetic defect resulting in decreased TPO production and decreased proliferations and maturation of megakaryocytes and platelets.
TTP/HUS is a life-threatening disorder characterized by thrombocytopenia plus microangiopathic hemolytic anemia resulting from microvascular platelet/von Willebrand factor thrombi. Small vessel occlusion in various organs, notably the brain and kidney, is responsible for the clinical manifestations which include fluctuating neurologic abnormalities and a variable degree of renal insufficiency. TTP may occur on an idiopathic basis or in association with pregnancy, autoimmune conditions, infections, malignancy, stem-cell transplantation, and with exposure to certain medications. TTP can be associated with an abnormal proteolysis of von Willebrand factor and the presence of circulating ultra-large molecular weight multimers (ULvWF). The occurrence of these abnormalities are due a deficiency of ADAMTS-13 (A Disintegrin And Metalloprotease with Thrombospondin type I motifs) a plasma metalloprotease that processes vWF). Endothelial injury plays a critical role in perpetuating the disorder. Under physiologic conditions vWF is released from endothelial cells and platelets as ULvWF . Normally, ADAMTS-13 lysis the protein into smaller molecular weight multimers. The higher molecular weight forms have greater adhesive properties, and hence, a greater propensity to promote platelet-platelet and platelet-subendothelial interactions. Mutations in the ADAMTS-13 gene have been found to cause familial (chronic/relapsing) TTP. In the more common idiopathic TTP, deficiency of ADAMTS-13 has been associated with IgG inhibitors in most of the cases.
True or False. A patient is admitted to the hospital with a platelet count of 15,000/uL (normal 150,000/uL to 350,000/uL), elevated serum LDH, and acute renal failure, generalized ecchymoses and petehciae. He has a history of urinary burning and fever. The prothrombin time and activated partial thromboplastin time are both prolonged. Fibrinogen activity is depressed. Examination of the peripheral blood smear shows the presence of schistocytes and few platelets. His ADAMTS 13 level is 40% (normal >60%). The results of the ADAMTS 13 autoantibody (inhibitor) is pending. Based upon his clinical presentation and ADAMTS 13 levels, this patient has TTP.
false
The classic “pentad” findings, consisting of thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic changes, and renal dysfunction, are seen in only a minority of patients. Acceptable criteria for a provisional diagnosis include thrombocytopenia and microangiopathic hemolytic anemia in the absence of an alternative cause. Microangiopathic hemolysis is suggested by the presence of fragmented RBCs (shistocytes) on the blood smear in conjunction with elevated LDH levels. Neurological symptoms include episodes of focal weakness, visual disturbances, reduced mentation/decreased consciousness, headache, seizure, and coma. The evanescence of some of the early symptoms probably reflects reversibility of the microthrombi, which lodge in small vessels. Abdominal pain resulting from intestinal and/or pancreatic ischemia may also occur along with nausea, vomiting, and ileus. Even in cases without severe azotemia, renal involvement may be evident, including proteinuria and hematuria. Patients with TTP almost never have an associated coagulopathy with their disease. It is likely that this patient had an undiagnosed and untreated urinary tract infection and is now septic (this is supported by the history of burning on urination and fever). The presence of the prolonged PT and APTT and decreased fibrinogen is consistent with disseminated intravascular coagulation (DIC) which commonly occurs in patients with blood stream infections. Although the ADAMTS 13 is at concentration below normal, this can occur in patients with DIC because the ADAMTS 13 is lysed by the occurrence of excessive plasmin in the plasma as a result of the DIC. Schistocytes are result of the microangiopathic process which is a characteristic of both DIC and TTP. Although often difficult to discern a difference, the microvascular occlusions associated with DIC consists mostly of fibrin + platelets and those of TTP consist mostly of VWF + platelets. Being able to draw the appropriate distinction between these disease entities are important, since the treatment and consequences may be drastically different. TTP is best treated with plasmapheresis and plasma exchange. Whereas, DIC is often best treated with replacement of platelets, plasma components, and treatment of the underlying cause (in this case antibiotics).
Platelets are formed in the bone marrow by “budding” from megakaryocytes and circulate as 2-4 µ disks with a life span of 8-12 days. A number of different cytokines are involved, including stem cell factor (SCF), IL3, IL6, IL 11, and thrombopoietin (TPO). TPO has been identified as the most important lineage-specific growth and differentiation factor regulating platelet production. The average concentration of platelets in the blood is ~250,000 per µl with a range of between 150,000 and 400,000 per µl.
True or False. Under normal circumstances about 1/3 of the total platelet mass is temporarily retained in the spleen.
true
Platelets circulate through the spleen; their transit is normally delayed in the splenic sinusoids. This partially explains why the increment seen in the platelet count after platelet transfusion is less than might be expected. When the spleen enlarges, the area in which he platelets can be retained also tends to increase, for this reason more platelets tend to be retained resulting in thrombocytopenia. In this setting, the larger platelets tend to be filtered and retained longer than normal size platelets. This is reflected in the peripheral blood smear by a decrease or absence of large platelets. To some extent the degree of splenic enlargement is reflected by the severity of the thrombocytopenia. However, the platelet count rarely decreases to below 30,000/uL from splenomegaly alone. Common causes of splenomegaly and associated thrombocytopenia include: congestive splenomegaly from congestive heart failure, portal hypertension from cirrhosis of the liver, and infiltration of the spleen. It is important to note that patients with ITP (immune thrombocytopenic purpura) do not typically have an enlarged spleen. Patients with this disorder have a different mechanism of thrombocytopenia.
Platelets are non-nucleated delivery vehicles for specific proteins and small molecules needed to maintain normal hemostatic function. Their membrane surfaces have multiple invaginations, forming an “open canalicular system”. Actin-like proteins and microtubules, maintain their normal discoid shape. Platelets contain three types of secretory granules: alpha granules (contain high molecular weight proteins: VWF. Fibrinogen, thrombospondin, fibronectin, FV, PF4, PDGF), dense granules (contain low molecular weight substances: ADP, ATP, Ca++, serotonin), and lysosomes containing acid hydrolases. The granule contents are actively secreted by platelets during their activation. Von Willebrand’s factor (VWF), fibrinogen, thrombospondin, and fibronectin a bind platelets to each other and to the subendothelial matrix. Factor V (FV) binds to the platelet surface following its release wherein it becomes a receptor for activated Factor X, which, along with calcium ions forms the prothrombinase complex (critical for amplification of the coagulation pathway. Platelet derived growth factor (PDGF) is a fibroblast/smooth muscle mitogen that functions physiologically in wound healing, and pathologically in atherosclerosis. Platelet Factor 4 (PF4) is an “anti-heparin” that binds to heparin-like polysaccharides coating endothelial cells that line the inner aspect of blood vessels. Adenine nucleotides, calcium and serotonin are released from dense bodies. These substances participate in the recruitment of additional platelets into the hemostatic plug. Ca++ is necessary for coagulation to occur.
Platelet aggregation analysis is a laboratory test performed by measuring the transmission of light through a cuvette containing platelet rich plasma (PRP) before and after the addition of an aggregating agent. An increase in light transmission after the addition of the aggregating agent indicates that platelet aggregations has occurred and may indicate that a platelet “release reaction” has been successfully induced.
True or False. A patient is being cleared for surgery. She gives a vague history of easy bruising. She says that she is not taking any medications. Her prothrombin time, activated thromboplastin time, and CBC are normal. Platelet aggregations are performed with thrombin, collagen, epinephrine, ADP and arachidonic acid. The expected aggregation patterns occur with the exception of ADP and arachidonic acid which are both impaired. This patient appears to have an “aspirin-like” platelet defect.
true
Aspirin irreversibly inhibits the platelet enzyme cyclo-oxygenase which results in the blockade of the conversion of arachidonic acid and other intermediate molecules to thromboxane A2 for the life time of the platelet. Thromboxane A2 is essential for platelet aggregation. Therefore, the addition of arachidonic acid as a platelet aggregating agent does not result in the expected response (platelet aggregation). Although the patient’s platelet response to ADP is nonspecific, a characteristic of a release defect is that a secondary wave of aggregation does not occur. At modest ADP concentrations, platelets adhere together but may also revert to single platelets if the stimulus is insufficient. In the presence of a strong agonist, this is followed by a secondary increase in light transmission because of further platelet aggregation due to the “release reaction” stimulated by the initial ADP exposure. This “release” of the storage pool (specifically the dense granules) “dumps” endogenous ADP from the affected platelets which then enhances the aggregation of other platelets in the cuvette. It is likely that this patient has been recently exposed to aspirin or a non-steroidal anti-inflammatory drug (NSAID) (which also inhibits cyclo-oxygenase). This is a common problem. Aspirin is present in many non-prescription medicines and patients are often exposed to it without being aware. Also, patients often forget taking.
Thrombocytopenia is defined by platelet counts less than:
- 150,000
- 100,000
- 200,000
- 175,000
150,000
Which of the following is incorrect regarding acquired platelet dysfunction?
- Aspirin irreversibly acetylates platelets
- Antibiotic use does not affect platelet function or cause PT prolongation
- Medications like diclofenac, ibuprofen cause reversible cyclooxygenase inhibition
- Patients who develop renal failure Can have normal platelet function
- Cardiac by-pass surgery can be associated with excessive bleeding from several different causes including thrombocytopenia, heparin-induced platelet dysfunction, and excessive dumping of the platelet storage pool after the platelets are activated as they come in contact with the artificial surface of the by-pass pump.
Antibiotic use does not affect platelet function or cause PT prolongation
Several types of antibiotics can significantly alter platelet function and number resulting in either thrombocytopenia or platelet dysfunction or both.
- Aspirin irreversibly acetylates platelets
- Acetylation of components of the platelet is an irreversible event.
- Medications like diclofenac, ibuprofen cause reversible cyclooxygenase inhibition
- Unlike aspirin, these medications reversibly inhibit cyclooxygenases.
- Patients who develop renal failure Can have normal platelet function
- Typically patients with renal dysfunction have an acquired platelet function defect; however this is not universal.
- Cardiac by-pass surgery can be associated with excessive bleeding from several different causes including thrombocytopenia, heparin-induced platelet dysfunction, and excessive dumping of the platelet storage pool after the platelets are activated as they come in contact with the artificial surface of the by-pass pump.
- Patients undergoing cardiac y-pass surgery typically have platelet dysfunction associated with surgery, mediation and the by-pass pump.
Type I HIT is benign and usually occurs 1-2 days after heparin administration with drop in platelet count but recovers quickly.
True or False
true
Type I HIT (Heparin induced thrombocytopenia) is caused by the direct interaction of large negatively charged molecules of heparin with the platelet surface which causes platelets to activate and form intravascular clumps resulting in a decreased platelet count. Usually the thrombocytopenia resolves with either cessation of heparin or continuation of heparin. Type II HIT refers to a drop in the platelet count and or thrombosis (usually between 5 and 10 days of starting heparin) caused by antibodies directed against heparin-platelet factor 4 complexes which result in platelet and endothelial cell activation and excessive thrombin generation.
Complement potentiates the autoantibody induced clearance of the patient’s platelets in ITP.
True or False
true
In general, Abs specifically bound to cell-surface antigens not only mediate clearance from circulation by FC receptors in the reticulo-endothelial system, but also can serve to fix complement on cells. Plasma from ITP patients can fix complement to platelets in vitro. Platelets from ITP patients exhibit detectable complement, and the ability to fix complement is correlated with the presence of detectable antiplatelet Abs. Therefore, complement-mediated immunity, either by enhanced clearance or direct cell destruction, represents another mechanism by which platelet autoantibodies may lead to immune-mediated platelet destruction.
The following are all mechanisms for non-immune thrombocytopenia EXCEPT:
- Bone marrow infiltration with disorders like multiple myeloma, leukemia, lymphoma
- Sequestration in the can cause thrombocytopenia
- Disorders of platelet destruction causing thrombocytopenia result in megakaryocyte hypoplasia in the bone marrow
- Massive fluid / volume resuscitation results in dilutional thrombocytopenia.
Disorders of platelet destruction causing thrombocytopenia result in megakaryocyte hypoplasia in the bone marrow
Non-immune destruction of platelets usually results in megakaryocytic hyperplasia due to increased thrombopoietin (TPO) production and TPO associated stimulation of megakaryocyte proliferation.
- Bone marrow infiltration with disorders like multiple myeloma, leukemia, lymphoma
- Marrow infiltration is a common cause of non-immune thrombocytopenia.
- Sequestration in the can cause thrombocytopenia
- Sequestration of by the spleen normally retains 30% of the total circulating platelets. In patients with splenomegaly can result in a significantly decreased platelet count.
- Massive fluid / volume resuscitation results in dilutional thrombocytopenia.
- Massive hemorrhage with blood and fluid resuscitation may result in a fall in the platelet count. Generally, loss of at least 1-2 blood volumes occurs before a significant decrease in the platelet count is seen.
Which of the following features of chronic ITP is INCORRECT:
- Efficacy of steroids for first line treatment of Chronic ITP is around 30%
- Splenectomy is successful in treatment of about 80% of patients
- IVIG is also an options for chronic ITP but responses are not durable, requiring multiple infusions
- TPO (thrombopoietin) agonist drugs increase platelet count by stimulating megakaryocytes to produce platelets.
- TPO agonist drugs increase platelet count by stimulating megakaryocytes to produce platelets.
Efficacy of steroids for first line treatment of Chronic ITP is around 30%
The efficacy of corticosteroids for the first line of treatment is around 70-80%.
- Splenectomy is successful in treatment of about 80% of patients
- Splenectomy is successful in 70-80% of patients.
- IVIG is also an options for chronic ITP but responses are not durable, requiring multiple infusions
- IVIG is effective, but remission is not durable.
- TPO (thrombopoietin) agonist drugs increase platelet count by stimulating megakaryocytes to produce platelets.
- TPO agonists stimulate megakaryocytes to proliferate and produce more platelets.
Which of the following are clinical features of thrombotic thrombocytopenia purpuric are correct?
- Patients always present with altered mental status, thrombocytopenia, microangiopathy and renal failure
- Plasmapheresis has decreased mortality to around 50%
- Patients have an excess of a plasma metalloprotease that processes vWF (ADAMTS-13 - A Disintegrin And Metalloprotease with Thrombospondin type I motifs).
- Pathological hallmark consists of microvascular occlusion of terminal arteries and capillaries. Microvascular lesions contain predominantly fibrin deposition.
- Microangioathic hemolysis is suggested by the presence of fragmented RBCs (schistocytes) on the Blood smear in conjuction with low LDH levels.
- Neurologic symptoms tends to be short lived and renal failure is more prolonged in contrast to HUS (hemolytic-Uremic Syndrome) where neurological symptoms is more prolonged.
- None of the above
None of the above
- Patients always present with altered mental status, thrombocytopenia, microangiopathy and renal failure
- Not all patients with TTP present with all the elements of the “TTP – Pentad.”
- Plasmapheresis has decreased mortality to around 50%
- Plasmapheresis and plasma exchange has reduced mortality to about 10%.
- Patients have an excess of a plasma metalloprotease that processes vWF (ADAMTS-13 - A Disintegrin And Metalloprotease with Thrombospondin type I motifs).
- Patients the typical TTP have a reduction in ADAMTS13.
- Pathological hallmark consists of microvascular occlusion of terminal arteries and capillaries. Microvascular lesions contain predominantly fibrin deposition.
- Fibrin deposition is not a characteristic of the micorthrombi seen in TTP patients. Fibrin deposition implies that the process is more likely related to disseminated intravascular coagulation or some other prothrombotic coagulopathy.
- Microangioathic hemolysis is suggested by the presence of fragmented RBCs (schistocytes) on the Blood smear in conjuction with low LDH levels.
- Microangiopathic hemolysis generally is accompanied by an increase in serum LDH rather than a decrease in serum LDH.
- Neurologic symptoms tends to be short lived and renal failure is more prolonged in contrast to HUS (hemolytic-Uremic Syndrome) where neurological symptoms is more prolonged.
- Typical HUS is not usually characterized by neurological involvement.
Bernard Soulier Syndrome is characterized by:
- Defect in Gp IIb-IIIa
- Defect in Gp1b
- Alpha granule deficiency
- Increased binding of von Willebrand’s factor to the platelet surface
Defect in Gp1b
Patients with Bernard Soulier’s disease have large platelets which do not respond to the agglutinating effects of ristocetin while maintaining a normal response to other platelet aggregation agonists. The defect in the platelets is a reduction or loss of platelet Gp 1b-IX which serves as the receptor for von Willebrand’s factor.
- Defect in Gp IIb-IIIa
- Defective or absent Gp IIb/III is not a characteristic of Bernard-Soulier Syndrome.
- Alpha granule deficiency
- Alpha granule deficiency is a type of storage pool deficiency.
- Increased binding of von Willebrand’s factor to the platelet surface
- Increases bind of VW factor to the platelet surface is a characteristic of type 2B Von Willebrand’s Disease.
Glanzmann’s thrombasthenia is characterized by:
- Defect in Gp IIb-IIIa
- Defect in Gp 1b
- Alpha granule deficiency
- Deficiency of von Willebrand factor
Defect in Gp IIb-IIIa
Gp IIb/IIIa serves as the platelet receptor for fibrinogen. The conversion of fibrinogen to fibrin on the platelet surface is the final common pathway for platelet aggregation to be completed. Glanzmann’s thrombocytopenia is characterized by the presence of a low platelet count and abnormal aggregation response to all agonist except ristocetin (which does not cause true platelet aggregation, but rather causes a passive form of platelet agglutination). Alpha granule deficiency is a type of platelet storage pool defect and is not usually associated with a deficiency of any platelet surface glycoprotein. Von Willebrand’s disease is caused by either a deficiency or dysfunction of the von Willebrand’s protein.
- Defect in Gp 1b
- A defect in GP 1b is not a characteristic of Glanzmann’s thrombasthenia.
- Alpha granule deficiency
- Alpha granule deficiency is a type of platelet storage pool defect and is not usually associated with a deficiency of any platelet surface glycoprotein.
- Deficiency of von Willebrand factor
- Von Willebrand’s disease is caused by either a deficiency or dysfunction of the von Willebrand’s protein.
