Quiz Questions 4

Question 1

Normal hemostasis depends upon an interaction between the blood vessel wall, blood platelets, and coagulation factors which establishes the integrity of integrity of the circulatory system after a blood vessel has been injured. Once the blood vessel wall has been violated a series of complex steps occurs in sequence: reflex vasoconstriction (this limits blood loss), release of tissue factor (this activates the coagulation system), contact activation (in this process coagulation factor XII is changed to it’s activate form), and platelet adhesion (platelets stick to the injured site and form a primary hemostatic plug).

True or False. Tissue factor is a complex lipid material that has the capacity to activate factor VII and initiate a sequence of complex enzymatic events ultimately resulting in the production of thrombi and fibrin.

Answer 1

true

Factor VII is synthesized in the liver. Small amounts circulate in the plasma in both activated and non-activated forms. Tissue factor is a transmembrane receptor and activator of factor VII which is constitutively expressed by the cells surrounding blood vessels (this is the so-call “hemostatic envelope”). The endothelium physically separates this potent “activator” from its circulating ligand FVII/FVIIa and prevents inappropriate activation of the clotting cascade. Breakage of the endothelial barrier leads to exposure of extravascular TF and rapid activation of the clotting cascade. It is believed that this “hemostatic envelope” provides immediate access to tissue factor and the activation small amounts of factor VII at the site injury resulting in the formation of a small amount of fibrin. The potency of activated FVII appears to be enhanced greatly in the presence of TF. This FVIIa:TF complex can enzymatically convert factor X to activated factor X (FXa) and factor IX to activated factor IX (FIXa). FXa attaches itself to factor V on the platelet surface and converts a small amount of prothrombin to thrombin; whereas, FIXa associates with the platelet surface where it interacts with factor VIII. There is some evidence that FVIIa:TF complex serves to promote an “idling” mechanism which continuously provides low level activation of Factor X and may allow to an immediate prothrombotic response to injury. The evidence for this is the detection of activation peptides of both FX and FIX in plasma of healthy subjects and their absence in subjects with FVII deficiency. Recombinant forms of activated factor VII have been introduced for clinical use and have been useful in patients with significant bleeding disorders.

Question 2

Coagulation screening tests include the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time, Reptilase time, and platelet closure times. Each of these tests queries a different part of the blood clotting system and can provide the clinician with a reasonable indication of the type of bleeding defect which may be present.

The prothrombin time is done by adding phospholipid (derived from human, ox, or rabbit brain) to decalcified plasma. The phospholipid provides a platform (in the form of tissue factor) upon which coagulation occurs. This coagulation is initiated by the binding of FVIIa to the extrinsic tissue factor added to the patient’s plasma and then adding calcium which allows the coagulation process to proceed. For this reason, the prothrombin time is thought of as measuring the “extrinsic system” This concept is a useful artificial construct to explain a portion of the coagulation system. It is not physiologic, but nevertheless, does reflect to some extent what occurs “in vivo”. Once initiated, activated FVII activated factor X which in turn activates the zymogens of the common pathway. Prolongation of the prothrombin time occurs in patients who have deficiencies in the activities of factors VII, X, V, II and I.

The INR (international normalized ratio) is a method of adjusting the prothrombin time based upon the kind of phospholipids (tissue factor) added, since different tissue factors offer differing reactivates with FVII. This allows for cross comparisons of the test results between laboratories. It is important to note that the INR has been established only for patients who are being treated with warfare and offers no information in regard to bleeding risk in other situations.

The APTT (activated partial thromboplastin time) is done by adding tissue thromboplastin and a surface reactive agent (e.g. celite, ellagic acid, diatomaceous earth) to decalcified plasma. The tissue thromboplastin provides a lipid platform and the surface reactive agent provides a method of activating the so-called surface activated factors of the coagulation system. The surface activating factors include factor XII, high molecular weight kinninogen, and kallikrein. Once the plasma is recalcified, activated factor XII then activates FXI which in turn activates factor IX and this then converts factor X to factor Xa. It is important to point out the factor VIII behaves as a cofactor which enhances that interaction between activated factor IX and factor X. The APTT can be thought of as assessing the “intrinsic system”, since the glass surfaces have been noted to activate this system because it provides a large negatively charged surface which stimulates a conformational change in FXII which leads to its activation. Prolongation in the APTT may be the result of deficiencies in the activities of FXII, HMWK, Kallikrein, FXI, FIX, FVIII, FX, FV, FII, and FI. There are several things to remember about the APTT. First, relative to the prothrombin time, there is relatively little phospholipid involved in the test. This makes the APTT more sensitive to the presence of a lupus anticoagulant (a phospholipoprotien dependent inhibitor) than the prothrombin. Second, the APTT may be significantly prolonged and not reflect an increase in bleeding risk (the lupus anticoagulant typically is not associated with bleeding; deficiencies in the activities of FXII, HMWK, or kallikrein do not increase bleeding risk).

The thrombin time is performed by adding excess thrombin to patient plasma. The major substrate for thrombin is fibrinogen. Since thrombin is present in excess to fibrinogen, fibrinogen becomes the rate limiting substance in this enzymatic reaction. The thrombin time, therefore, is prolonged when the fibrinogen concentration in the plasma is low (and paradoxically when it is very high, but this is another story), when something interferes with the ability of thrombin to interact with fibrinogen (the presence of D-dimers and fibrinogen degradation products), or the presence of something which inhibits thrombin (antithrombin antibodies or heparin). It is important to remember that heparin inhibits that activity of thrombin via antithrombin mediation. If antithrombin (this used to be called antithrombin III) is not present heparin cannot inhibit thrombin activity.

The Reptilase time is performed by adding a specific snake venom called Reptilase to plasma. Reptilase enzymatically breaks down fibrinogen, but at different cleavage sites than thrombin. Reptilase is not dependent upon the presence of antithrombin and, for this reason, is not influenced by the presence of heparin in the plasma.

A patient comes to see you with a history of easy bruising for as long as she can remember. She has never had her teeth extracted, surgery or been pregnant. She is not taking medications. A physical examination reveals the presence of ecchymosis on her arms and legs. Her prothrombin time 25 seconds (normal

Answer 2

false

The fact that this patient has a prolonged prothrombin time and normal APTT localizes the defect to the “extrinsic pathway” alone. If both the “extrinsic” and “intrinsic” pathways were involved, you would expect the APTT to also be prolonged. Since the prothrombin time reflects the activities of FVII and the factors in the common pathway and the APTT reflects the activities of factors XII, XI, IX, VIII and the factors in the common pathway, the only possible explanation for this patient’s prolongation in the prothrombin time is a decreased in activity in Factor VII. The normal thrombin time and Reptilase exclude a deficiency in fibrinogen. The prothrombin time and APTT are generally not very sensitive to deficiencies I fibrinogen. Unless the fibrinogen deficiency is very severe, these two tests may remain normal. Both the thrombin time and Reptilase time may be prolonged with low fibrinogen and the presence of D-dimmers or fibrinogen degradation products, but only the thrombin time is prolonged in the presence of heparin. When the thrombin time is prolonged and the Reptilase time is normal, this almost always reflects that the patient is being exposed to heparin. Occasionally patients may be born with or acquire abnormal fibrinogen molecules which are not processed normally by either thrombin or Reptilase. This defect (referred to as dysfibrinogenemia) can be seen in patients with liver disease (this is where fibrinogen is synthesized) can be associated with either increased risk of bleeding or thrombosis, but is usually not clinically significant. In some patients with dysfibrinogenemia, the thrombin time may be prolonged and the Reptilase time may be much more prolonged (although this is variable).

Question 3

Disseminated intravascular coagulation (DIC) is a disorder that is always secondary to some underlying disease process (e.g., infection, trauma, obstetric complications, malignancy, and liver disease). It is characterized by the presence of excess thrombin generation and fibrinolysis and platelet consumption. Sometimes this process is quite severe with patients presenting with profound bleeding or more subtle in which patients tend to have evidence of chronic, recurrent thrombosis. The specific presentation depends upon the underlying disease and to the extent that the normal balance between fibrin formation and fibrinolysis has been perturbed. Excessive thrombin generation results in excess fibrin clot formation, thrombocytopenia (from platelet activation and agglutination), depletion of coagulation factors, and schistocytosis (from RBCs passing through fibrin containing small blood vessels). The natural inhibitors of the forwards reactions of coagulation may be profoundly deficient due to their consumption while unsuccessfully inhibiting the excess thrombin formed during DIC. For this reason patients with DIC typically have not only prolongations in the PT, APTT, and thrombin times (due to decreased fibrinogen and the presence of D-dimers and/or fibrinogen degradation products), but also marked depressions in protein C, protein S, and antithrombin activities.

You are asked to see a 60 year old female patient in the MICU because of profound, refractory thrombocytopenia (platelet count 4,000/uL). The rest of her CBC is normal. The peripheral blood smear shows a decreased number of platelets and schistocytes. Her PT and APTT is normal. She has worsening renal function (serum creatinine 3.5; normal

Answer 3

false

This patient has DIC. A characteristic of TTP is that it is not associated with a coagulopathy. The prolongation in the PT and APTT which is not corrected by administration of vitamin K should alert the clinician that something else is happening. It is not uncommon for patients in the ICU setting to develop a prolongations in the PT and APTT from vitamin k deficiency. This is usually due to the administration of antibiotics. For this reason, it is never unreasonable to administer vitamin K replacement when the cause of the prolonged PT and APTT is in doubt. DIC is always secondary to something else. In this case, the patient has no evidence of infection, no history of trauma or surgery, and had no obstetrical catastrophes. However, she did have history of a resected breast cancer. A subsequent bone marrow biopsy demonstrated the presence of metastatic breast cancer involving her bone marrow. Her ADAMTS13 activity was later returned as normal as was her ADAMTS13 autoantibody. Although a normal ADAMTS13 does not completely exclude TTP is makes it highly unlikely. ADAMTS13 is susceptible to degradation by plasmin. Plasmin activity is increased in DIC. For this reason, a low ADAMTS13 activity and low ADAMTS13 autoantibody titers would have been difficult assess due to the presence of DIC. Elevated D-dimers and/or fibrin(ogen) degradation products (FDPs) are non-specific findings. These can be elevated in patients with liver and renal impairment, post trauma or surgery, and in anything that causes inflammation, besides thrombosis or DIC. Sometimes when the diagnosis is DIC is in doubt it is worthwhile to check the serum fibrinogen or antithrombin levels over several days. In healthy individuals, fibrinogen circulates for about 10 days and antithrombin for 2.5 days. Since fibrinogen is consumed during fibrin clot formation and antithrombin forms complexes with thrombin and the complexes are then removed by the liver, both of these will be rapidly removed from the plasma in the presence of DIC. This patient is said to have refractory thrombocytopenia. This definition is problematic since apparent refractoriness may be secondary to poorly matched or non-matched platelet transfusion. In general, platelet refractoriness is considered to be present when the patient has demonstrated a lack of the expected increment in the platelet count (5000 platelets/uL for each unit of platelets transfused) after 2 to 3 infusions. It is important to note that platelet refractoriness may be caused by alloimmunization, severe immune thrombocytopenia, fever, infections, and DIC or other processes characterized by platelet consumption. The treatment of DIC is both supportive (replacement of missing plasma components and platelets; inhibiting the thrombin generation) and specific in that the underlying cause of the DIC needs be definitively addressed.

Question 4

The annual rates of venous thromboembolic events (VTE) in the U.S. are estimated to be 5,000,000 for deep venous thrombosis (DVT) and 500,000 for pulmonary embolism (PE). The estimated mortality rate associated with VTE in the U.S. is 50,000. The risk of unprovoked VTE (i.e., VTE with no apparent extraneous precipitating event such as surgery, trauma, immobilization) increases with age. Patients with multiple unprovoked episodes of thrombosis or an identifiable congenial or irreversible cause of thrombosis are considered to have hypercoagulable states. (i.e., they have a predisposition to having thrombotic events). Some of the defects, which have been associated with hypercoagulable states, include: antithrombin deficiency (This used to be called antithrombin III; however this designation has been abandoned. The term Antithrombin III now refers to a commercial replacement product used to treat patients with antithrombin deficiency), Protein C deficiency, Protein S deficiency, plasminogen deficiency, dysfibrinogenemia, factor V Leiden mutation, and prothrombin gene G20210A mutation, and the presence of an antiphospholipid antibody.

Antithrombin deficiency can be either congenital or acquired. Homozygosity for antithrombin deficiency is generally not compatible with life and is not seen in the adult population. Patients with heterozygosity for antithrombin deficiency may have variable amounts of antithrombin present in the plasma and predominantly present with venous rather than arterial thrombosis.

Among Caucasian patients with venous thrombosis the prevalence of antithrombin deficiency ranges from 5-15%. This is similar the prevalence of protein C or protein S deficiencies and in contrast to that of factor V Leiden mutation (12-40%), prothrombin gene mutation (6-18%), and an antiphospholipid antibody (≈5%). It is important to note that despite intensive evaluation the cause of unprovoked VTE remains unknown in between 20-70% of patient evaluated.

The primary role of antithrombin is to inhibit both activated factor X and thrombin. In this way, antithrombin reduces or prevents the key forward reactions of coagulation, which ultimately activates platelets and causes the conversion of fibrinogen to fibrin.

True or False. Antithrombin is normally made in the liver. With significant liver impairment, antithrombin production is decreased in the liver and synthesis of antithrombin is increased in non-hepatic tissue. For this reason, patients with end-stage liver disease are protected from thrombotic events.

Answer 4

false

Antithrombin is synthesized by the hepatocytes. Patients with liver impairment may have decreased synthesis of multiple proteins including albumin, fibrinogen, antithrombin, protein C, protein S, and most of the coagulation proteins. Characteristically patients with liver disease have increased levels of factor VIII, since this molecule is manufactured as sites extraneous to the liver and its synthesis is increased in the presence of inflammation. Patients with severe liver impairment have complex coagulation abnormalities secondary to decreased liver function. They have decreased production or the production of abnormal coagulation protein and decreased plasma clearance of fibrinolytic proteins that may predispose patients to bleeding. In addition, some patients with liver disease of have abnormalities in platelet numbers (decreased platelet numbers from an associated splenomegaly or defect in production from deficient thrombopoietin production) or platelet function defects (cause unclear), which increase bleeding risk The same patients may also have decreases in the key natural inhibitors of the forward reactions of coagulation (antithrombin, PC, PS), which increases the risk of venous thrombosis.

Question 5

Protein C and protein S are natural inhibitors of the forward reactions of coagulation that are manufactured by hepatocytes via a vitamin K dependent process. Protein C normally bound to a specific receptor on endothelial cells and platelets is converted to its active form by thrombin. Protein S occurs bound to its carrier protein called C4b binding and in a free form in the plasma. Free protein S acts as a cofactor to activated protein C enhancing protein C’ s ability to inhibit the activities of both activated factor V and activated factor VIII. There is some evidence that free protein S may also be a weak direct inhibitor of activated factors V and VIII. In this way, proteins C and S regulate the forward reactions of coagulation. Deficiencies of either protein S or protein S may predispose patients to venous thrombotic events. It is unclear whether deficiencies in these proteins predispose to arterial events.

Activated protein C inhibits the activated factor V binding enzymatically cleaving the molecule at a specific site. Factor V Leiden is a mutation that eliminates the normal cleavage site of the factor V molecule rendering it resistant to the inhibiting properties of activated protein and predisposing the patient venous thrombosis.

True or False. You are asked to evaluate a 20-year-old college female college student who has had multiple VTEs over the previous year. She states that prior to these events she was placed on oral contraceptives for irregular menses. Prior to beginning college she has an unexpected pregnancy complicated by a miscarriage. The patient has no other known predisposing factors except a vague family history of a grandparent with a blood clot in the lung. The activate partial thromboplastin time is normal. Among other tests for hypercoagulability (which are normal), the test for activated protein C resistance is reported to be shorter than expected. It is likely that this patient has a factor V Leiden mutation.

Answer 5

true

The activated protein C resistance (APCR) assay is performed by determining the ratio of the activated partial thromboplastin times of plasma with or without the addition of exogenous activated protein C. In patients with activated protein C resistance, the ratio should be shortened. In most cases an abnormal activated protein C resistance assay is a clear indication of the presence of a factor V Leiden mutation. Other causes of an abnormal activated protein C resistance assay include: pregnancy (possibly due to decreases in free protein S), antiphospholipid antibodies (thought do directly inhibit the activity of either protein C or protein S), estrogen containing oral contraceptives or hormonal replacement (through to decrease free protein S). It is important to note that whether acquired causes of activated protein C resistance predispose patients to thrombosis is unclear. However, there exists an increasing body of evidence that at least one of the mechanisms of venous thrombosis or stroke associated with estrogen use is related to acquired APCR. In addition, present data shows that the use of estrogen containing oral contraceptives by individuals with factor V Leiden mutations increase the relative risk of thrombosis from 7:1 to approximately 40:1. For this reason, any female using estrogen containing oral contraceptives experiencing an otherwise unprovoked thrombotic event should be evaluated for an underlying hypercoagulable state (especially for factor V Leiden mutation). Because of her history of miscarriage and her “vague family history” and otherwise normal hypercoagulable evaluation, it is likely that this patient’s APCR is due to factor Leiden mutation. This patient has apparently increased her risk of thrombotic complications by smoking. The use of oral contraceptives and smoking tobacco in the presence of APCR increases the risk of an incident thrombotic event to 80 fold greater than that seen in the general population. Performing a factor V Leiden genetic test that confirms the presence of the abnormal factor V protein in the patient’s plasma can do confirmation of the presence of factor V Leiden mutation. Other factor V mutations such as factor V Cambridge or HR2 are much less frequent than factor V Leiden and for this reason the exact risk of thrombosis from heterozygous states are uncertain. It does appear, however, that heterozygous factor V HR2 alone does not increase thrombotic risk. Both the Cambridge and HR2 mutations may worsen the thrombotic risk when they occur in the presence of heterozygous factor V Leiden mutation.

Question 6

Low Molecular weight Heparin contains small molecules of heparin. Which of the following is CORRECT?

• Act by inhibiting factor IXa rather than thrombin and require a factor Xa assay for monitoring
• Can be used safely in pregnancy
• The risk of HIT is around 11-12% compared to unfractionated heparin
• Can be safely used in patients with previous history of HIT

Answer 6

Can be used safely in pregnancy

Both unfractionated heparin and low molecular weight heparin is safe to use during pregnancy.

• Act by inhibiting factor IXa rather than thrombin and require a factor Xa assay for monitoring
• Factor IXa is not affected by the presence of low molecular weight heparin. The target for low molecular weight fragments of low molecular weight heparin is predominately factor Xa with less activity toward factor IIa (thrombin).
• The risk of HIT is around 11-12% compared to unfractionated heparin
• The risk of HIT varies according to the patient population and the type of heparin used. It is most common in patients undergoing orthopedic and cardiovascular surgery and least common in pregnancy. However, the risk does not reach 11-12% in these patients.
• Can be safely used in patients with previous history of HIT
• The risk of developing HIT with low molecular weight heparin is very low compared to is the risk associated with unfractionated heparin.

Question 7

Heparin induced thrombocytopenia (HIT) is a side effect of heparin use that occurs in about 5% of patients. HIT causes platelet counts to fall usually after about 5 days of heparin use. Which of the following is TRUE?

• Heparin should be continued
• Heparin should be continued and argatroban added
• Stop heparin and change to argatroban
• Continue heparin and check for lower extremity dopplers as there is a risk of thrombosis

Answer 7

Stop heparin and change to argatroban

Argatroban is a direct thrombin inhibitor and is very effective for the treatment of HIT.

• Heparin should be continued
• Heparin should always be stopped, since continued use may be catastrophic.
• Heparin should be continued and argatroban added
• Heparin should always be stopped, since continued use may be catastrophic even in the face of the addition of a direct thrombin inhibitor.
• Continue heparin and check for lower extremity dopplers as there is a risk of thrombosis
• Heparin should always be stopped. Seeking evidence of thrombosis is important in determining whether HIT is present.

Question 8

Unfractionated heparin has been around since 1916. It has been widely used in for anticoagulation. Two of the statements below are Incorrect - which ones are incorrect.

• Heparin does not cross the placenta and can safely be used in pregnancy.
• Unfractionated heparin (UFH) acts by binding to antithrombin potentiating its ability to inactivate thrombin, the active form of factor II in the clotting cascade.
• Due to the wide variety of APTT reagents in use, the therapeutic range of aPTT is only accurate if the therapeutic range corresponds to a heparin level of 0.2-0.4 antiXa units/mL in the hospital laboratory.
• The therapeutic range of Heparin is usually 1.5 to 2.5 times the control APTT value
• Infusional heparin is commonly used in immobilized patients for prophylaxis in the hospital.

Answer 8

Due to the wide variety of APTT reagents in use, the therapeutic range of aPTT is only accurate if the therapeutic range corresponds to a heparin level of 0.2-0.4 antiXa units/mL in the hospital laboratory.

The therapeutic range of antiXa units/mL for unfractionated heparin is 0.3 – 0.7 antiXa units/mL.

Infusional heparin is commonly used in immobilized patients for prophylaxis in the hospital.

Almost all patients receive either subcutaneous unfractionated heparin or subcutaneous low molecular weight heparin as prophylaxis while hospitalized.

• Heparin does not cross the placenta and can safely be used in pregnancy.
• Heparin can be used safely in pregnancy.
• Unfractionated heparin (UFH) acts by binding to antithrombin potentiating its ability to inactivate thrombin, the active form of factor II in the clotting cascade.
• Heparin binds to antithrombin and enhances its activity. Antithrombin is a natural inhibitor of thrombin.
• The therapeutic range of Heparin is usually 1.5 to 2.5 times the control APTT value
• The APTT is generally used to monitor heparin therapy. The usual APTT therapeutic range is 1.5 – 2 times the control APTT value.

Question 9

The following are all cancers that can be cured with chemotherapy EXCEPT:

• Non Small Cell Lung Cancer
• Germ Cell Cancer
• Choriocarcinoma
• Acute Leukemia

Answer 9

Non Small Cell Lung Cancer

Chemotherapy can be delivered alone or in conjunction with radiation therapy or surgery. Once non-small cell lung cancer (NSCLC) becomes disseminated chemotherapy is used for palliative purposes only. However, in patients with early stage disease the addition of chemotherapy to the other treatment modalities indicated previously may result in higher cure rate

• Germ Cell Cancer
• Germ cell cancer can be cured with combination chemotherapy which includes cis-platinum.
• Choriocarcinoma
• Choriocarcinoma is a highly curable cancer with chemotherapy alone.
• Acute Leukemia
• Acute leukemia can be cured by aggressive chemotherapy. In the case of acute promyelocytic leukemia differentiation therapy is highly effective.

Question 10

The role of adjuvant chemotherapy is to use chemotherapy as initial therapy for patients who present with localized disease that is viewed as surgically unresectable.

True or False

Answer 10

false

Adjuvant chemotherapy refers to the administration of chemotherapy after treatment with some other modality (e.g., surgery or radiation therapy). Effective adjuvant chemotherapy reduces the risk of recurrence and hence the cure rate. Neoadjuvant chemotherapy refers to chemotherapy administered prior to either surgery or radiation therapy with the intent of “debulking” or shrinking the tumor so that it may be easier resected or better included in a radiation port. Neoadjuvant chemotherapy may also decrease the risk of recurrence and increase the chances of achieving a cure.

Question 11

The following regarding cell cycle is correct EXCEPT:

• G2 phase - Interval during which the formation of specialized proteins in preparation for mitosis occurs.
• S Phase - Time during which DNA is synthesized
• M phase - Period of mitosis / Cell division
• G1 phase - This is the shortest phase and is time when RNA synthesis and cellular grown occurs

Answer 11

G1 phase - This is the shortest phase and is time when RNA synthesis and cellular grown occurs

G1 phase together with the S phase and G2 phase comprise the long growth period of the cell cycle called interphase that takes place before cell division in mitosis (M phase). During G1 phase, the cell grows in size and synthesizes mRNA and proteins that are required for DNA synthesis. Once the required proteins and growth are complete, the cell enters the next phase of the cell cycle, S phase. The duration of each phase, including the G1 phase, is different in many different types of cells. In human somatic cells, the cell cycle lasts about 18 hours, and the G1 phase takes up about 1/3 of that time

Question 12

Regarding Gompertzian model of growth and regression - the tumor growth fraction is not constant and rather decreases exponentially with time.

True or False

Answer 12

true

The Gompertzian growth curve is a model of tumor growth. Similar in appearance to the growth curve associated with bacterial colonies, it indicates that tumor growth is at first exponential in character but later equilibrates due to the fact that tumor cell proliferation and tumor cell death reach equilibrium. Under these circumstances, initially the tumor growth fraction (the number of tumor cells actively proliferating) is predominantly reflected by the curve. Later, as tumor cells begin to cease proliferation or die off the tumor growth fraction no longer dominates the curve and tumor growth slows or stops. This is important since while the tumor growth fraction is expanding, it is expected that many of the tumor cells will be actively dividing be sensitive to the effects of cell-cycle specific anticancer drugs. It is during this exponential portion of the Gompertzian curve that it would be expected that there would be the greatest risk of the occurrence of spontaneous mutations which might transform the character of the tumor.

Question 13

Dose limiting features of anthracyclines includes all of the following EXCEPT:

• Neutropenia
• Cardiotoxicity
• Paraesthesias
• Arrhythmias

Answer 13

Paraesthesias

Typically anthracyclines do not cause nerve damage.

• Neutropenia
• A decrease in the white blood count is common and is caused by bone marrow suppression.
• Cardiotoxicity
• Anthracyclines: Typically anthracyclines do not cause nerve damage. They, however, can cause both and idiosyncratic and dose-related cardiac toxicity which damages the heart muscle and may cause arrhythmias and heart failure. These drugs also damage cells found in rapidly growing tissues like hair follicles, mucosa surfaces, and in the hematopoietic stem cell. As result patients will experience mucositis, hair loss, and peripheral blood cytopenias.
• Arrhythmias
• Typically anthracyclines do not cause nerve damage. They, however, can cause both idiosyncratic and dose-related cardiac toxicity which damages the heart muscle and may cause arrhythmias and heart failure.

Question 14

All of the following are Alkylating agents apart from:

• Ifosfamide
• Cyclophosphamide
• Busulphan
• Idarubicin
• Melphalan

Answer 14

Idarubicin

Idarubicin or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA from unwinding by interfering with the enzyme topoisomerase I. It is an analog of daunorubicin, but the absence of a methoxy group increases its fat solubility and cellular uptake. It is currently combined with cytosine arabinoside and is considered by some clinicians as a first line treatment of acute myeloid leukemia.

• Ifosfamide
• Ifosfamide is an alkylating agent.
• Cyclophosphamide
• Cyclophosphamide is an alkylating agent.
• Busulphan
• Busulphan is an alkylating agent.
• Melphalan
• Melphalan is an alkylating agent.

Question 15

Regarding Etoposide, which of the following is true:

• Is used as first line treatment for acute myelocytic leukemia
• The oral bioavailability is about 50%, so oral dose is twice the IV dose
• Inhibits topoisomerase I and so resulting in DNA damage
• Dose reduction is not required in renal dysfunction

Answer 15

The oral bioavailability is about 50%, so oral dose is twice the IV dose

Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme (which aids in DNA unwinding), prevents re-ligation of the DNA strands, and by doing so causes DNA strands to break. Cancer cells rely on this enzyme more than healthy cells, since they divide more rapidly. Therefore, this causes errors in DNA synthesis and promotes apoptosis of the cancer cell. When given orally only about 50% of the drug is absorbed when compared to when it is given intravenously. The drug is partially excreted via the kidneys and, therefore, dosage reduction is required when renal impairment is present. This drug has minor activity against acute myelocytic leukemia and slightly more activity in acute lymphoblastic leukemia. Its major role in these settings is in patients with refractory disease or as part of conditioning for bone marrow transplantation.

• Is used as first line treatment for acute myelocytic leukemia
• First line therapy for acute myelocytic leukemia includes an anthracycline plus cytosine arabinoside
• Inhibits topoisomerase I and so resulting in DNA damage
• Etoposide is not a topo I inhibitor.
• Dose reduction is not required in renal dysfunction
• Dose reduction is not generally necessary with this drug because of renal dysfunction.

Question 16

Rituximab has been used in treatment of many different hematological malignancies and disorders. From the list below, identify a disorder that is NOT treated by Rituximab

• TTP
• Diffuse Large B cell Lymphoma – CD 20 negative
• ITP
• Diffuse large B cell lymphoma – CD 20 positive
• Post transplant lymphoproliferative disorder

Answer 16

Diffuse Large B cell Lymphoma – CD 20 negative

Rituximab is a monoclonal antibody which targets the B cell marker CD20 on the cell surface. In the absence of this target this antibody has no effect on the tumor.

• TTP
• Thrombotic thrombocytopenic purpura (TTP) appears to be an autoimmune disorder in which an antibody inhibits that activity of ADAMTS 13, an enzyme important for the normal processing of von Willebrand’s protein. Although the usual treatment for this disorder is steroids and plasmapheresis and plasma exchange, some patients respond to rituximab. Rituximab is thought to reduce antibody production and thus ease the inhibition of ADAMTS 13.
• ITP
• Immune thrombocytopenic purpura (ITP) is another autoimmune process characterized by decreased platelet survival. Although the usual treatment is steroids and IVIG and splenectomy, there is emerging evidence in small numbers of patients with ITP rituximab may result in long term remissions.
• Diffuse large B cell lymphoma – CD 20 positive
• Post-transplant lymphoproliferative disorder (PTLD) refers to a group of benign and malignant lymphoid disorders that are related to the anti-rejection therapy in patients who have received a stem cell or solid organ transplant. The majority of these disorders are either lymphoid hyperplasias or diffuse B cell lymphomas and are associated with Ebstein Barr virus infection. These tend to be responsive to either withdrawal of the anti-rejection medications, rituximab, antiviral agents or chemotherapy.