Hemostasis, Surgical Bleeding, and Transfusion

Question 1

Which of the following is NOT one of the four major physiologic events of hemostasis?

A. Fibrinolysis

B. Vasodilatation

C. Platelet plug formation

D. Fibrin production

Answer 1

Answer: B

Hemostasis is a complex process and its function is to limit blood loss from an injured vessel. Four major physiologic events participate in the hemostatic process: vascular constriction, platelet plug formation, fibrin formation, and fibrinolysis. Though each tend to be activated in order, the four processes are interrelated so that there is a continuum and multiple reinforcements.

(See Schwartz 10th ed., p. 85.)

Question 2

Which is required for platelet adherence to injured
endothelium?

A. Thromboxane A2

B. Glycoprotein (GP) Ilb/IIIa

C. Adenosine diphosphate (ADP)

D. Von Willebrand factor (vWF)

Answer 2

Answer: D

Platelets do not normally adhere to each other or to the vessel wall but can form a plug that aids in cessation of bleeding when vascular disruption occurs. Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere.

This process requires von Willebrand factor (vWF), a protein in the subendothelium that is lacking in patients with von Willebrand disease. vWF binds to glycoprotein (GP) I/IX/V on the platelet membrane. Following adhesion, platelets initiate a release reaction that recruits other platelets from the circulating blood to seal the disrupted vessel.

Up to this point, this process is known as primary hemostasis. Platelet aggregation is reversible and is not associated with secretion. Additionally, heparin does not interfere with this reaction and thus hemostasis can occur in the heparinized patient. Adenosine diphosphate (ADP) and serotonin are the principal mediators in platelet aggregation.

(See Schwartz 10th ed.,p. 85.)

Question 3

Which of the following clotting factors is the first factor
common to both intrinsic and extrinsic pathways?

A. Factor I (fibrinogen)

B. Factor IX (Christmas factor)

C. Factor X (Stuart-Prower factor)

D. Factor XI (plasma thromboplasma antecedent)

Answer 3

Answer: C

The intrinsic pathway begins with the activation of factor XII that subsequently activates factors XI, IX, and VII. In this pathway, each of the primary factors is “intrinsic” to the circulating plasma, whereby no surface is required to initiate the process. In the extrinsic pathway, tissue factor (TF) is released or exposed on the surface of the endothelium, binding to circulating factor VII, facilitating its activation to VIla.

Each of these pathways continues on to a common sequence that begins with the activation of factor X to Xa (in the presence of Villa). Subsequently, Xa (with the help of factor Va) converts factor II (prothrombin) to thrombin and then factor I (fibrinogen) to fibrin. Clot formation occurs after fibrin monomers are cross-linked to polymers with the assistance of factor XIII.

(See Schwartz 10th ed., p. 87.)

Question 4

Which congenital factor deficiency is associated with delayed bleeding after initial hemostasis?

A. Factor VII

B. Factor IX

C. Factor XI

D. Factor XIII

Answer 4

Answer: D

Congenital factor XIII (FXIII) deficiency, originally recognized by Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis.

The male-to-female ratio is 1:1. Although acquired FXIII deficiency has been described in association with hepatic failure, inflammatory bowel disease, and myeloid leukemia, the only significant association with bleeding in children is the inherited deficiency.

Bleeding is typically delayed because clots form normally but are susceptible to fibrinolysis. Umbilical stump bleeding is characteristic, and there is a high risk of intracranial bleeding.

Spontaneous abortion is usual in women with FXIII deficiency unless they receive replacement therapy. Replacement can be accomplished with fresh frozen plasma(FFP), cryoprecipitate, or a FXIII concentrate. Levels of 1 to 2% are usually adequate for hemostasis.

(See Schwartz 10th ed.,p. 89.)

Question 5

In a previously unexposed patient, when does the platelet count fall in heparin-induced thrombocytopenia (HIT)?

A. <24 hours

B. 24-28 hours

C. 3-4 days

D. 5-7 days

Answer 5

Answer: D

Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia (ITP). It is an immunological event in which antibodies against platelet factor-4 (PF4) formed during exposure to heparin, affecting platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis.

The platelet count typically begins to fall 5 to 7 days after heparin has been started, but if it is a re-exposure, the decrease in count may occur within 1 to 2 days.

(See Schwartz 10th ed., p. 90.)

Question 6

Which is NOT an acquired platelet hemostatic defect?

A. Massive blood transfusion following trauma

B. Acute renal failure

C. Disseminated intravascular coagulation (DIC)

D. Polycythemia vera

Answer 6

Answer: C

Impaired platelet function often accompanies thrombocytopenia but may also occur in the presence of a normal platelet count. The importance of this is obvious when one considers that 80% of overall strength is related to platelet function.

The life span of platelets ranges from 7 to 10 days, placing them at increased risk for impairment by medical disorders, prescription, and over-the-counter medications. Impairment of ADP-stimulated aggregation occurs with massive transfusion of blood products.

Uremia may be associated with increased bleeding time and impaired aggregation. Defective aggregation and platelet dysfunction is also seen in patients with
thrombocythemia, polycythemia vera, and myelofibrosis.

DIC is an acquired syndrome characterized by systemic activation of coagulation pathways that result in excessive thrombin generation and the diffuse formation of microthrombi.

(See Schwartz 10th ed., p. 92.)

Question 7

What is true about coagulopathy related to trauma?

A. Acute coagulopathy of trauma is mechanistically similar to DIC.

B. Coagulopathy can develop in trauma patients following acidosis, hypothermia, and dilution of coagulation factors, though coagulation is normal upon admission.

C. Acute coagulopathy of trauma is caused by shock and tissue injury.

D. Acute coagulopathy of trauma is mainly a dilutional
coagulopathy.

Answer 7

Answer: C

Traditional teaching regarding trauma-related coagulopathy
attributed its development to acidosis, hypothermia, and dilution of coagulation factors. Recent data, however, have shown that over one-third of injured patients has evidence of coagulopathy at the time of admission.

More importantly, patients arriving with coagulopathy are at a significantly higher risk
of mortality, especially in the first 24 hours after injury.

Acute Coagulopathy of trauma is not a simple dilutional coagulopathy but a complex problem with multiple mechanisms.

Whereas multiple contributing factors exist, the key initiators
to the process of ACoT are shock and tissue injury. ACoT is a separate and distinct process from DIC with its own specific components of hemostatic failure.

(See Schwartz 10th ed., p.93.)

Question 8

What is the best laboratory test for determine degree of
anticoagulation with dabigatran and rivaroxaban?

A. Prothrombin time/ international normalized ratio
(PT/INR)

B. Partial thromboplastin time (PTT)

C. Bleeding time

D. None of the above

Answer 8

Answer: D

Newer anticoagulants, such as dabigatran and rivaroxaban,
have no readily available method of detection of the degree of anticoagulation.

More concerning is the absence of any available reversal agent. Unlike warfarin, the nonreversible coagulopathy associated with dabigatran and rivaroxaban is of great concern to those providing emergent care to these patients.

(See Schwartz 10th ed., p. 94.)

Question 9

A fully heparinized patient develops a condition requiring emergency surgery. After stopping the heparin, what else should be done to prepare the patient?

A. Nothing, if the surgery can be delayed for 2 to 3 hours.

B. Immediate administration of protamine 5 mg for every
100 units of heparin most recently administered.

C. Immediate administration of FFP.

D. Transfusion of 10 units of platelets.

Answer 9

Answer: A

Certain surgical procedures should not be performed in concert with anticoagulation.

In particular, cases where even minor bleeding can cause great morbidity such as the central nervous system and the eye. Emergency operations are occasionally necessary in patients who have been heparinized.

The first step in these patients is to discontinue heparin. For
more rapid reversal, protamine sulfate is effective. However,
significant adverse reactions, especially in patients with severe fish allergies, may be encountered when administering protamine.

Symptoms include hypotension, flushing, bradycardia, nausea, and vomiting. Prolongation of the activated partial thromboplastin time (aPTT) after heparin neutralization with protamine may also be a result of the anticoagulant effect of protamine. In the elective surgical patient who is receiving coumarin-derivative therapy sufficient to effect anticoagulation, the drug can be discontinued several days before operation and the prothrombin concentration then checked (level greater than 50% is considered safe).

(See Schwartz 10th ed., p.94.)

Question 10

Primary ITP

A. Occurs more often in children than adults, but has a
similar clinical course.

B. Includes HIT as a subtype of drug-induced ITP.

C. Is also known as thrombotic thrombocytopenic purpura (TTP).

D. Is a disease of impaired platelet production, unknown
cause.

Answer 10

Answer: B

Primary immune thrombocytopenia is also known as idiopathic thrombocytopenic purpura (ITP).

In children it is usually acute in onset, short-lived, and typically follows a viral

illness. In contrast, ITP in adults is gradual in onset, chronic in nature, and has no identifiable cause. Because the circulating platelets in ITP are young and functional, bleeding is less for a given platelet count than when there is failure of platelet
production.

The pathophysiology of ITP is believed to involve both impaired platelet production and T cell-mediated platelet destruction.

Treatment of drug-induced ITP may simply entail withdrawal of the offending drug, but corticosteroids, gamma globulin, and anti-D immunoglobulin may hasten recovery of the count.

HIT is a form of drug-induced ITP. It is an immunological event during which antibodies against platelet factor-4 (PF4) formed during exposure to heparin affect platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis.

(See Schwartz 10th ed., P-90.)

Question 11

Which of the following is the most common intrinsic
platelet defect?

A. Thrombasthenia

B. Bernard-Soulier syndrome

C. Cyclooxygenase deficiency

D. Storage pool disease

Answer 11

Answer: D

The most common intrinsic platelet defect is known as storage pool disease. It may involve loss of dense granules (storage sites for adenosine 5’-diphosphate [ADP], adenosine triphosphate [ATP], Ca2*, and inorganic phosphate) and a-granules (storage sites for a large number of proteins, some of which arc specific to platelets [eg, PF4 and ß-thromboglobulin], while others are present in both platelet a-granules and plasma [eg, fibrinogen, vWF, and albumin]).

Dense granule deficiency is the most prevalent of these. It may be an isolated defect or occur with partial albinism in the Hermansky-Pudlak syndrome. Bleeding is variable; depending on how severe the granule defect
is. Bleeding is primarily caused by the decreased release of ADP from these platelets.

An isolated defect of the a-granules is known as gray platelet syndrome because of the appearance of the platelets on Wright’s stain. Bleeding is usually mild with this syndrome. A few patients have been reported who have decreased numbers of both dense and a-granules. These
patients have a more severe bleeding disorder. Patients with mild bleeding as a consequence of a form of storage pool disease may have decreased bleeding if given DDAVP.

It is likely that the high levels of vWF in the plasma after DDAVP somehow compensate for the intrinsic platelet defect. With more
severe bleeding, platelet transfusion is required.

Question 12

Which finding is not consistent with TTP?

A. Microangiopathic hemolytic anemia

B. Schistocytes on peripheral blood smear

C. Fever

D. Splenomegaly

Answer 12

Answer: D

In TTP, large vWF molecules interact with platelets, leading
to activation. These large molecules result from inhibition of a metalloproteinase enzyme, ADAMtS13, which cleaves the
large von Willebrand factor molecules. TTP is classically characterized by thrombocytopenia, microangiopathic hemolytic
anemia, fever, and renal and neurologic signs or symptoms.

The finding of schistocytes on a peripheral blood smear aids in the diagnosis.

Plasma exchange with replacement of FFP is the treatment for acute TTP. Additionally, rituximab, a monoclonal antibody against the CD20 protein on B lymphocytes has shown promise as an immunomodulatory therapy directed against patients with acquired TTP, of which the majority are autoimmune-mediated.

(Sec Schwartz 10th cd.,p. 91.)

Question 13

What is FALSE regarding coagulation during cardiopulmonary bypass (CPB)?

A. Contact with circuit tubing and membranes activates inflammatory cascades, and causes abnormal platelet and clotting factor function.

B. Coagulopathy is compounded by sheer stress.

C. Following bypass, platelets’ morphology and ability to aggregate are irreversibly altered.

D. Coagulopathy is compounded by hypothermia and hemodilution.

Answer 13

Answer: C

Under normal conditions, homeostasis of the coagulation system is maintained by complex interactions between the
endothelium, platelets, and coagulation factors.

In patients undergoing cardiopulmonary bypass (CPB), contact with circuit tubing and membranes results in abnormal platelet
and clotting factor activation, as well as activation of inflammatory cascades, that ultimately result in excessive fibrinolysis and a combination of both quantitative and qualitative platelet defects.

Platelets undergo reversible alterations in morphology and their ability to aggregate, which causes sequestration in the filter, partially degranulated platelets,
and platelet fragments.

This multifactorial coagulopathy is compounded by the effects of shear stress in the system, induced hypothermia, hemodilution, and anticoagulation.

(See Schwartz 10th cd.,p. 95.)

Question 14

Following a recent abdominal surgery, your patient is in the ICU with septic shock. Below what level of hemoglobin would a blood transfusion be indicated?

A. <12g/dL

B. <10g/dL

C. <8g/dL

D. <7g/dL

Answer 14

Answer: D

A 1988 National Institutes of Health Consensus Report challenged the dictum that a hemoglobin value of less than 10 g/dL or a hematocrit level less than 30% indicates a need for preoperative red blood cell (RBC) transfusion.

This was verified in a prospective randomized controlled trial in critically ill
patients that compared a restrictive transfusion threshold to a more liberal strategy and demonstrated that maintaining hemoglobin levels between 7 and 9 g/dL had no adverse effect on mortality. In fact, patients with APACHE II scores of <20 or patients <55 years actually had a lower mortality.

Despite these results, change in daily clinical practice has been slow. Critically ill patients still frequently receive transfusions, with the pre-transfusion hemoglobin approaching 9 mg/dL in a recent large observational study. This outdated approach unnecessarily exposes patients to increased risk and
little benefit.

Question 15

Less than 0.5% of transfusions result in a serious transfusion-related complication. What is the leading cause of transfusion-related deaths?

A. Transfusion-related acute lung injury

B. ABO hemolytic transfusion reactions

C. Bacterial contamination of platelets

D. Iatrogenic hepatitis C infection

Answer 15

Answer: A

Transfusion-related complications are primarily related to blood-induced proinflammatory responses.

Transfusion-related events are estimated to occur in approximately 10% of all transfusions, but only less than 0.5% are serious in nature.

Transfusion-related deaths, though rare, do occur and are
related primarily to transfusion-related acute lung injury (TRALI) (16-22%), ABO hemolytic transfusion reactions (12-15%), and bacterial contamination of platelets (11-18%).

(See Schwartz 10th ed., p. 100.)

Question 16

Allergic reactions do not occur with

A. Packed RBCs

B. FFP

C. Cryoprecipitate

D. None of the above

Answer 16

Answer: D

Allergic reactions are relatively frequent, occurring in about 1% of all transfusions. Reactions are usually mild and consist of rash, urticaria, and flushing. In rare instances, anaphylactic shock develops.

Allergic reactions are caused by the transfusion of antibodies from hypersensitive donors or the
transfusion of antigens to which the recipient is hypersensitive.

Allergic reactions can occur after the administration of any blood product but are commonly associated with FFP and platelets. Treatment and prophylaxis consists of the administration of antihistamines.

In more serious cases, epinephrine or steroids maybe indicated.

(See Schwartz 10th ed., p. 100.)

Question 17

What is the risk of Hepatitis C and HIV-1 transmission
with blood transfusion?

A. 1:10,000,000

B. 1:1,000,000

C. 1:500,000

D. 1:100,000

Answer 17

Answer: B

Transmission of hepatitis C and HIV-1 has been dramatically minimized by the introduction of better antibody and nucleic acid screening for these pathogens.

The residual risk among allogeneic donations is now estimated to be less than
1 per 1,000,000 donations and hepatitis B approximately 1 per
300,000 donations.

(See Schwartz 10th cd., p. 102.)

Question 18

What is NOT a cause of bleeding due to massive
transfusion?

A. Dilutional coagulopathy

B. Hypofibrinogenemia

C. Hypothermia

D. 2,3-DPG toxicity

Answer 18

Answer: D

Massive blood transfusion is a well-known cause of thrombocytopenia. Bleeding following massive transfusion can occur due to hypothermia, dilutional coagulopathy, platelet dysfunction, fibrinolysis, or hypofibrinogenemia.

Another cause of hemostatic failure related to the administration of blood is a
hemolytic transfusion reaction. The first sign of a transfusion reaction may be diffuse bleeding.

The pathogenesis of this bleeding is thought to be related to the release of ADP from hemolyzed RBCs, resulting in diffuse platelet aggregation, after which the platelet clumps are removed out of the circulation.

(See Schwartz 10th cd.,p. 104.)

Question 19

The most common cause for a transfusion reaction is

A. Air embolism

B. Contaminated blood

C. Human error

D. Unusual circulating antibodies

Answer 19

Answer: G

Although contaminated or outdated blood may cause a reaction, the most common cause is human error—blood drawn for typing from the wrong patient, blood incorrectly crossmatched in the laboratory, blood units mislabeled in the laboratory, blood administered to the wrong patient.

Most blood banking programs have instituted elaborate checks and balances to minimize these errors.

(See Schwartz 10th ed., p. 101.)

Question 20

Frozen plasma prepared from freshly donated blood is necessary when a patient requires

A. Fibrinogen

B. Prothrombin

C. Antihemophilic factor

D. Christmas factor

E. Hageman factor

Answer 20

Answer: C

Frozen plasma is required for the transfusion of antihemophilic factor (factor VIII) or proaccelerin (factor V). The other factors are present in banked preparations.

(See Schwartz 10th ed.,p. 99.)

Question 21

The most common clinical manifestation of a hemolytic
transfusion reaction is

A. Flank pain

B. Jaundice

C. Oliguria

D. A shaking chill

Answer 21

Answer: C

All of the manifestations listed can occur with a hemolytic
transfusion reaction. In a large scries, oliguria (58%) and
hemoglobinuria (56%) were the most common findings. (See Schwartz 10th ed., p. 101.)

Question 22

What type of bacterial sepsis can lead to thrombocytopenia and hemorrhagic disorder?

A. Gram-negative

B. Gram-positive

C. A & B

D. Encapsulated bacteria

Answer 22

Answer: A

Lastly, severe hemorrhagic disorders due to thrombocytopenia have occurred as a result of gram-negative sepsis. The
pathogenesis of endotoxin-induced thrombocytopenia has been suggested that a labile factor V is necessary for this interaction.

(Sec Schwartz 10th ed., p.104.)

Question 23

After tissue injury, the first step in coagulation is

A. Binding of factor XII to subendothelial collagen

B. Cleavage of factor XI to active factor IX

C. Complexing of factor IX with factor VIII in the presence of ionized calcium conversion of prothrombin to thrombin

D. Formation of fibrin from fibrinogen

Answer 23

Answer: A

All the listed steps arc part of the cascade involved in establishing a firm clot. The process begins with binding of Hageman factor (factor XII) to subendothelial collagen and ends with the conversion of fibrinogen to fibrin. The fibrin forms an insoluble addition that stabilizes the platelet plug.

(Sec Schwartz 10th ed., p. 87.)

Question 24

What are the uses of thromboelastography (TEG)?

A. Predicting need for lifesaving interventions after
arrival for trauma

B. Predicting 24-hour and 30-day mortality following
trauma

C. Predicting early transfusion of RBC, plasma, platelets, and cryoprecipitate

D. All of the above

Answer 24

Answer: D

Thromboelastography (TEG) is the only test measuring all
dynamic steps of clot formation until eventual clot lysis or retraction. TEG has also been shown to identify, patients who arc likely to develop thromboembolic complications postinjury and postoperatively.

Recent trauma data have shown TEG to be useful in predicting early transfusion of RBCs, plasma, platelets, and
cryoprecipitate. TEG can also predict the need for lifesaving
interventions shortly after arrival and to predict 24-hour and 30-day mortality.

Lastly, TEG can be useful to guide administration of tranexamic acid to injured patients with hyperfibrinolysis.

(Sec Schwartz 10th cd., p. 103.)

Question 25

Bank blood is appropriate for replacing each of the following EXCEPT

A. Factor I (fibrinogen)

B. Factor II (prothrombin)

C. Factor VII (proconvertin)

D. Factor VIII (antihemophilic factor)

Answer 25

Answer: D

Factor VIII is labile, and 60 to 80% of activity is gone 1 week after collection. The other factors listed arc stable in banked blood.

(Sec Schwartz 10th ed., p. 99.)

Question 26

Which of the following is an antifibrinolytic agent used in regular clinical practice?

A. Unfractionated heparin (UFH)

B. Tranexamic acid (TXA)

C. Protamine sulfate

D. Tissue plasminogen activator (tPA)

E. Plasminogen activator inhibitor-1 (PAI-1)

Answer 26

ANSWER: B

COMMENTS: This question aims to delineate the processes of clot formation and breakdown, or coagulation and fibrinolysis.

Fibrinolysis is the process of active clot breakdown. The fibrinolytic system is regulated by activators and inhibitors of its principal protease plasminogen, the inactive form of active plasmin. Plasminogen activity becomes deranged in certain states such as major trauma and sepsis, both of which lead to hyperfibrinolysis, or excessive breakdown of newly formed clot, leading to excessive blood loss.

This state has a similar presentation to, but is clinically and therapeutically distinct from, coagulopathy, which is a derangement in the ability to primarily form a clot.

UFH is a glycosaminoglycan used in clinical practice to promote the activity of the anticoagulant protein antithrombin III against thrombin and factor Xa. Its principal use is in therapeutic anticoagulation and venous thromboembolism (VTE) prophylaxis.

Protamine sulfate is a protein that binds heparin and neutralizes its anticoagulant activity, often used to reverse supratherapeutic doses of UFH. Neither UFH nor protamine sulfate has a significant direct impact on fibrinolysis.

tPA is a profibrinolytic agent sometimes used in the clinical management of acute vascular occlusion. It promotes intravascular clot breakdown, and its effect would be the opposite of what is desired in a hyperfibrinolytic state.

PAI-1 is an endogenous antifibrinolytic protein that is not currently used in clinical practice.

TXA is an exogenous lysine analogue that competitively inhibits the conversion of plasminogen into active plasmin; thus it is antifibrinolytic. In trauma patients with hemodynamically significant hemorrhage, administration of TXA (1-g IV bolus followed by 1-g IV infusion over 8 h) within 3 h of injury has been shown to decrease the overall mortality and mortality secondary to bleeding without an increase in vascular occlusive events.

There was no benefit from the administration of TXA beyond 3h postinjury.

Question 27

Placement of an inferior vena cava (IVC) filter in patients with proximal lower extremity deep-vein thrombosis (DVT) is indicated in each of the following scenarios except:

A. Known large esophageal varices

B. Pulmonary embolus despite therapeutic anticoagulation

C. High-risk sonographic appearance of the proximal DVT

D. Recurrent unprovoked DVT

E. Severe congestive heart failure

Answer 27

ANSWER: D

COMMENTS: Mesh filters placed percutaneously in the infrarenal IVC can prevent lower extremity venous thromboses from embolizing to the lungs.

Use and complications of these filters have increased substantially over the last decade.

While older model filters are permanent, more recently developed filters may be safely removed or left in place.

Once a patient is safely anticoagulated, it is recommended that retrievable filters be removed.

As a practical matter, retrieval rates in temporary filters are historically low and long-term filter placement is associated with complications such as filter migration, caval thrombosis, and IVC perforation.

Indications for IVC filter placement include a proximal lower extremity DVT plus (1) any absolute contraindication to anticoagulation (A), (2) pulmonary embolism (PE) that occurs while a patient is therapeutically anticoagulated (B), (3) high-risk sonographic appearance of the thrombus such as a free-floating leading edge or iliocaval DVT (relative indication), and (4) low cardiopulmonary reserve (relative indication), in which case PE could be hemodynamically catastrophic.

IVC filter placement in patients without acute DVT, but a high risk of developing provoked DVT with absolute contraindications to anticoagulation, such as brain or spinal cord trauma, is a topic of active debate.

In patients who may safely and effectively undergo conventional anticoagulation, IVC filter placement is of no benefit.

The first-line treatment of an unprovoked proximal vein (popliteal, femoral, or iliac) DVT is anticoagulation for 3 to 12 months unless otherwise contraindicated.

Specific anticoagulation regimens vary by institution and clinical setting.

Recurrent provoked DVT is treated with longer-term anticoagulation but is not an indication for IVC filter placement.

Question 28

Dosing for therapeutic anticoagulation of which of the following modalities is least affected by renal impairment?

A. Warfarin

B. Low-molecular-weight heparin

C. UFH

D. Rivaroxaban (Xarelto)

E. Dabigatran (Pradaxa)

Answer 28

ANSWER: C

COMMENTS: Kidney disease in itself is a risk factor for both thrombotic and adverse bleeding events.

Uremic patients demonstrate impaired platelet adhesion and aggregation that present as increased risk of clinical bleeding and laboratory elevation of bleeding time.

These abnormalities are frequently correctable with the administration of desmopressin (DDAVP), which acts to increase the release of factor VIII:von Willebrand factor (vWF) from endothelial cells.

Therapeutic anticoagulation in patients with chronic or acute kidney disease requires particular consideration.

Rivaroxaban, dabigatran, and low-molecular-weight heparin demonstrate impaired clearance in both acute and chronic kidney disease. Use of these medications even for prophylactic anticoagulation in patients with severe renal disease is associated with bleeding complications, and while not absolutely contraindicated, alternative methods should be considered.

Warfarin is cleared primarily by the cytochrome P450 system, which causes therapeutic liability secondary to hepatic dysfunction or drug–drug interactions. However, indirect effects of kidney failure consistently increase warfarin sensitivity and require dose titration and frequent monitoring.

UFH is cleared mainly by the reticuloendothelial system except at high doses when unbound molecules are renally cleared. This generally does not require dose adjustments, but monitoring with serial activated partial thromboplastin time (aPTT) is indicated as in patients without renal dysfunction.

Question 29

Which of the following statements about resuscitation for
hemorrhagic shock is true?

A. Blood products should be used as the initial resuscitative fluid in hemodynamically unstable patients.

B. A balanced transfusion ratio (1:1:1) between packed red blood cells (PRBCs), fresh-frozen plasma (FFP), and platelets (PLTs) reduces the severity of coagulopathy in hemorrhagic shock.

C. Patients with circulating factor levels 50% of the normal will show clinically impaired hemostasis.

D. Addition of TXA to massive transfusion protocols comes with an increased risk of thrombotic complications.

E. Albumin-containing solutions have a proven mortality benefit over crystalloid fluids in the resuscitation of hypovolemic shock.

Answer 29

ANSWER: B

COMMENTS: Previous theories of intravenous fluid resuscitation relied heavily upon crystalloid fluids to bolster blood volume and pressure.

However, recent studies such as the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) and Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) have changed this practice.

These studies were grounded in findings from battlefield transfusion studies showing decreased mortality in patients transfused with whole blood when components such as PRBCs and FFP were unavailable.

The theory is that aggressive resuscitation with crystalloid fluids exacerbates the consumptive coagulopathy of trauma (clotting factors are used up in achieving systemic hemostasis) with an iatrogenic dilutional coagulopathy. Thus crystalloid-resuscitated patients initially responded hemodynamically but were coagulopathic and continued to bleed.

The PROMMTT trial first showed that patients who received higher ratios of platelets and plasma to FFPs had reduced all-cause mortality in the first 24 h following injury.

These results were sustained at 30 days postinjury. The PROPPR trial refined these findings and showed superior outcomes with a 1:1:1 ratio of PRBC:FFP:PLT compared with a 1:1:2 ratio. The data trended toward significance in 24-h and 30-day mortality but was underpowered.

Question 30

A unit of blood could be transfused most rapidly through which of the following vascular access catheters?

A. A 7-Fr, 16-cm, triple-lumen catheter in the right internal jugular vein (lumens: 16, 18, 18 gauge)

B. A 7-Fr, 30-cm, triple-lumen catheter in the right internal jugular vein (lumens: 16, 18, 18 gauge)

C. An 18-gauge catheter peripherally inserted into the cephalic vein at the wrist

D. A 16-gauge, 3-cm peripheral IV in the right antecubital fossa

E. An 18-gauge, 3-cm peripheral IV in the right antecubital
fossa

Answer 30

ANSWER: D

COMMENTS: Steady flow through a vascular catheter (and any rigid tube including blood vessels as well for that matter) is gov- erned by the Hagen-Poiseuille equation,
Q = (πΔPr4)/8 μL,
where Q = flow rate,
P = the driving pressure gradient,
r = radius of the tube (catheter),
μ = viscosity of the fluid in question (PRBCs), and
L = length of the tube (catheter).

Radius of the catheter is the most important determinant of the flow rate, as it is raised to a power of four.

In two catheters with identical radii, flow rates will be higher in the shorter of the two. Therefore when rapid transfusion is needed, faster flows can be obtained with larger-bore, shorter catheters, meaning that central lines are inferior to large-bore peripheral IVs for initial resuscitation.

Question 31

Transfusion of a unit of PRBCs into a hemodynamically stable patient with hemoglobin 7.5 g/dL does which of the following?

A. Increases systemic oxygen delivery (DO2)

B. Increases tissue extraction of oxygen

C. Increases systemic oxygen uptake (VO2)

D. Increases arterial O2 saturation (Sao2)

E. Decreases venous O2 saturation (Svo2)

Answer 31

ANSWER: A

COMMENTS: Multiple well-designed studies have shown that overuse of RBC transfusions in the critical care setting leads to poor outcomes. The findings of these studies can be summed up as “a risk to multiple organ systems without a physiologic benefit.”

Increasing circulating hemoglobin concentration through PRBC transfusion serves to increase systemic oxygen delivery (DO2), which is determined by cardiac output and arterial oxygen concentration.

This does not, however, lead to an increase in VO2. Animal and human studies have shown that the increase in oxygen delivery with RBC transfusions is accompanied by a proportional decrease in tissue oxygen extraction, leading to no net change in systemic oxygen utilization.

These studies were the basic science grounding for the 1999 Trial of Transfusion Requirements in Critical Care (TRICC) trial, which showed decreased mortality in the euvolemic intensive care unit (ICU) patients who were treated with a restrictive transfusion threshold [hemoglobin (Hb) < 7] compared with those treated with a liberal transfusion threshold (Hb < 10).

Question 32

Impaired platelet aggregation in uremia is responsive to all of
the following except:

A. Hemodialysis

B. Cryoprecipitate

C. DDAVP

D. Platelet transfusion

E. Desmopressin

Answer 32

ANSWER: D

COMMENTS: The uremic patient will have clinically and biochemically evident impaired platelet adhesion.

In the lab, this presents as an increased bleeding time. This occurs as a result of increased circulating levels of prostacyclin and altered binding to exposed vWF on the vascular endothelium.

This generally becomes clinically evident in patients with a creatinine level above 6.7 mg/dL. At this level, upper gastrointestinal (GI) bleeding is a major cause of mortality.

Hemodialysis can correct uremic bleeding in many patients. Beyond that, the vasopressin analogue desmopressin (DDAVP) acts to stimulate the release of circulating vWF and corrects impaired adhesion.

If bleeding persists, cryoprecipitate can be utilized as it contains vWF, thus directly increasing circulating levels.

Transfusion of platelets is not appropriate unless absolute counts are critically low, as the transfused platelets will show the same poor aggregative qualities as those already in circulation.

Question 33

Which of the following is most indicative of heparin-induced thrombocytopenia (HIT) in a patient undergoing an elective procedure without a past medical history?

A. Platelet counts falling by 50% by postoperative day 7 to a nadir of 100K

B. Platelet counts falling over 90% by postoperative day 7 toanadirof5K

C. Platelet counts falling by 50% by postoperative day 3 to a nadir of 40K

D. Low levels of serotonin release in response to therapeutic heparin exposure in laboratory assays

E. Negative enzyme-linked immunosorbent assay (ELISA) for antiplatelet factor 4 immunoglobulins

Answer 33

ANSWER: A

COMMENTS: The temporal course and magnitude of thrombocytopenia are essential to evaluation for HIT.

Falling platelet counts in the first 3 days following a patient’s initial exposure to heparin generally resolve spontaneously without discontinuation of heparin and are not clinically significant.

True HIT is immune mediated. Thus clinical and laboratory manifestations usually occur for a minimum of 4 days after initial exposure.

Given the nature of immune reactions, this time frame is invalid if the patient has been exposed to heparin at any time in the 3 months prior to his or her most recent exposure.

Absolute counts generally do not fall below 20,000 and are usually between 50 and 150,000 in true HIT. Thus other etiologies should be considered if thrombocytopenia is severe.

Despite low platelet counts, HIT is a hypercoagulable state secondary to deranged platelet degranulation and frequently presents with thrombosis, more commonly in the venous system.

HIT is not a dose-dependent reaction—patients with heparin- locked peripheral IVs have essentially the same risk as those on an UFH drip. Thus at the first suspicion of HIT, all heparin-containing medications should be discontinued and the appropriate serum assays sent.

A serotonin release assay will show exaggerated release in response to physiologic doses of heparin and a diminished response at supratherapeutic concentrations.

Serum ELISA for antiplatelet factor 4 antibodies will be positive. The risk of developing HIT is lower with low-molec- ular-weight heparins than with UFH. Once the diagnosis is confirmed, patients should be started on therapeutic levels of direct thrombin inhibitors such as argatroban to prevent additional thrombosis.

Question 34

Which of the following is not a proven etiology of dissemi-
nated intravascular coagulation (DIC)?

A. Gram-negative sepsis

B. Trauma

C. Retained products of conception

D. Malignancy

E. Supratherapeutic UFH drip

Answer 34

ANSWER: E

COMMENTS: DIC is a chain reaction. An initial inflammatory or traumatic insult leads to systemic activation of the coagulation system, which in turn leads to increased systemic inflammation, and so on.

Patients will present clinically with bleeding from mucosal surfaces and IV access sites secondary to a consumptive coagulopathy.

In addition, systemic microvascular thrombosis often causes multisystem organ dysfunction. Lab studies will show elevated international normalized ratio, prolonged aPTT, low fibrinogen, and elevated D-dimer.

Of the answer choices, all but a supratherapeutic heparin drip include an instigating inflammatory response that drives the coagulation– inflammatory cycle that creates DIC.

When patients with these conditions become coagulopathic, DIC should be suspected.

Unfortunately, no specific treatment has been shown to correct DIC.

Procoagulants such as clotting factor concentrates “feed the fire” so to speak and further drive the coagulation–inflammatory cycle.

Management of suspected DIC is limited to source control and supportive care.

Question 35

Which of the following is false regarding the factor V Leiden
mutation?

A. Both heterozygous and homozygous mutations are associated with increased rates of VTE.

B. Carriers with provoked DVTs are generally managed with the same therapeutic regimen as noncarriers.

C. The hypercoagulable state associated with the mutation is readily detectable on standard clinical coagulation assays as a shortened prothrombin time (PT).

D. Although the structural mutation is on factor V, it impacts the functional activity of activated protein C.

E. Roughly 5% of the American population is heterozygous, with the highest prevalence in Caucasians.

Answer 35

ANSWER: C

COMMENTS: Factor V Leiden is a mutation that alters the cleavage target of activated protein C.

Protein C is activated by thrombin with its cofactor thrombomodulin and proceeds to cleave and inactivate the procoagulant factor V.

Patients with the mutation resist cleavage and show increased thrombin generation and clotting compared with the general population. In normal hemostasis, the concept of autoregulation dictates that anticoagulant proteins such as protein C are activated in conjunction with procoagulants to prevent runaway clotting and end the process of hemostasis.

Patients with the factor V Leiden mutation are deficient in this crucial anticoagulant pathway and thus are prone to thrombosis.

The condition is most prevalent in Caucasians, and both heterozygotes and homozygotes are at increased risk for venous thrombosis.

Odds ratios calculated from retrospective studies are 4.9 and 20.0 for any VTE in heterozygotes and homozygotes, respectively.

Although carriers are at a higher risk than the general population, DVT and PE are generally not treated differently in the acute setting or for long term in these patients.

Question 36

Heparin acts principally through which mechanism?

A. Indirect inhibition of factors II and X through antithrombin III activation

B. Direct inhibition of thrombin

C. Direct degradation of cross-linked fibrin clots

D. Inhibition of platelet aggregation

E. Inhibition of platelet adhesion to exposed tissue collagen during primary hemostasis

Answer 36

ANSWER: A

COMMENTS: Heparin is a polysaccharide molecule that is both produced endogenously and administered either subcutaneously or intravenously.

Its principal mechanism of action is to serve as a scaffold between the anticoagulant protein antithrombin III and its targets, thrombin and factor X.

In the presence of heparin, antithrombin III acts to inactivate its targets at a rate roughly three orders of magnitude higher than it does in the absence of heparin.

Single-nucleotide polymorphisms in the heparin-binding domain of antithrombin III have been identified in the general population and help explain the clinical observation that patients require various amounts of heparin to achieve therapeutic anticoagulation.

Direct thrombin inhibitors such as argatroban inhibit thrombin activity outside of the antithrombin pathway—for this reason, traditional dose monitoring techniques such as aPTT are ineffective.

Both direct thrombin inhibitors and heparin serve to prevent the formation of blood clots. Fibrinolytic agents such as tPA and urokinase lead to plasmin-mediated degradation of existing fibrin clots. While heparin can, in fact, alter platelet function through minor pathways, this is not its principal mechanism of action.

Clopidogrel acts to irreversibly inhibit platelet aggregation through inhibition of adenosine diphosphate (ADP) binding to its surface receptor.

Aspirin irreversibly inhibits cyclooxygenase 1 (COX-1), preventing platelet generation of prothrombotic thromboxane A2.

Question 37

Gelatin sponge (Gelfoam), oxidized cellulose (Surgicel), fibrin sealants (Tisseel, Evicel), and topical thrombin all have what in common?

A. They are grossly resorbable.

B. They have intrinsic hemostatic activity.

C. They are derived from human tissue.

D. They should be used for definitive control of anastomotic bleeding.

E. They directly generate fibrin clots.

Answer 37

ANSWER: A

COMMENTS: Topical hemostatic agents are useful adjuncts in the cessation of tissue surface bleeding. They are derived from human, plant, or animal tissue and may or may not have intrinsic hemostatic activity.

The agents that are intrinsically hemostatic (Tisseel, Evicel, and topical thrombin) directly lead to generation of fibrin clots on the surfaces to which they are applied.

Others (Gelfoam, Surgicel) have an indirect mechanism and provide a scaffold for hemostasis on a cut tissue edge.

In any case, anastomotic or pulsatile bleeding should be definitively controlled with suture ligation or other means.

Question 38

Which of the following is most clearly diagnostic for lower extremity DVT in an ICU patient?

A. Venous duplex study with incompressibility and sluggish flow through the external iliac vein

B. Venous duplex study with incompressibility and sluggish flow through the great saphenous vein below the knee

C. Computed tomography (CT) of the lower extremities with a thrombus in the external iliac

D. Elevated circulating D-dimer

E. Unilateral leg swelling

Answer 38

ANSWER: A

COMMENTS: Hospitalized patients, particularly those in the ICU, are predisposed to venous thromboembolic events.

Risk factors include recent surgery or trauma (particularly to the central nervous system), active or occult malignancy, acute illness, prior VTE, mechanical ventilation, and immobility.

Many times patients lie with silent DVTs that first present as symptomatic pulmonary emboli.

Early detection and appropriate intervention are essential to prevent such events.

Virtually all patients with the risk factors listed above will have an elevated circulating D-dimer, as any active fibrinolysis will raise the level of circulating fibrin split products.

Thus the specificity and positive predictive value of this test are unacceptably low in the postsurgical and critical care setting.

Duplex ultrasound looks at the compressibility of a vein and flow.

Incompressibility and sluggish flow indicate thrombosis.

Clinically relevant DVTs that carry the risk of PE are limited to thromboses of the deep veins above the knee. CT scans of the lower extremities may raise suspicion for a DVT; however, the follow-up duplex result makes the diagnosis.

Question 39

The following groups of patients have a biochemically evident hypercoagulable state along with increased incidence of clinically relevant VTE except:

A. Patients with sickle cell anemia

B. Children with essential hypertension

C. Patients with solid-organ malignancy

D. Diabetics

E. Smokers

Answer 39

ANSWER: B

COMMENTS: The incidence of VTE is low in children compared with that in adults. This is attributable to distinct dynamics of the hemostatic and fibrinolytic systems in children and adults.

Most recent studies point to two principal differences: increased efficiency of the fibrinolytic system in children and lower circulating levels of fibrinogen.

Put simply, these differences lead to equally effective hemostasis without thrombosis in children compared with adults.

For this reason, VTE prophylaxis is not recommended in childhood. The hemostatic system in children has been described as a juvenile protective factor against VTE, and further research is warranted into pathways that would make the hemostatic system in adults behave more like it does in children.

Every other answer choice listed describes a patient group at increased risk for VTE compared with the general population.

Question 40

In patients with acute DVT, treatment with novel anticoagulants compared with vitamin K antagonists such as Coumadin showed:

A. Higher incidence of DVT recurrence

B. Lower incidence of PE

C. Higher incidence of significant bleeding complications

D. Lower incidence of significant bleeding complications

E. Lower incidence of all-cause mortality

Answer 40

ANSWER: D

COMMENTS: Novel anticoagulants such as dabigatran (Pradaxa) and rivaroxaban (Xarelto) are the cause of significant anxiety in the surgical world due to the lack of effective reversal agents.

However, the broad view of anticoagulation with these agents helps explain their popularity. At this point, multiple studies have shown that a broad group of novel anticoagulants, including rivaroxaban, dabigatran, apixaban, and edoxaban, are associated with similar rates of recurrent VTE, fatal PE, and overall mortality compared with traditional vitamin K antagonists such as warfarin, along with a significantly lower incidence of major bleeding.

Bleeding in patients receiving warfarin was attributed to labile pharmacodynamics, leading to supratherapeutic anticoagulation.

Currently, anticoagulation with Coumadin is familiar to surgeons and the most easily reversible modality, but data from the medical world and consumer preference (most of these drugs do not require routine dose monitoring) suggest that these agents will become progressively more popular.

Further research into reversal agents for novel anticoagulants is absolutely essential, and surgeons should stay abreast of developments on this front.

Question 41

Which of the following coagulation assays is used clinically to detect a hyperfibrinolytic state?

A. PT

B. aPTT

C. Bleeding time

D. Thromboelastography

E. Activated clotting time

Answer 41

ANSWER: D

COMMENTS: Traditional coagulation assays such as PT and aPTT were designed for accurate dosing of anticoagulant medications.

While they give some insight into patients’ global coagulation status, they were not intended for this purpose and did not approach the complete picture of a patient’s propensity to bleed or clot.

Thromboelastography is an old test that has recently been put to new clinical use in trauma patients. It is capable of detecting a hyperfibrinolytic state and the bleeding propensity through the percent lysis parameter or a variation of it.

This information is useful in determining the appropriateness of antifibrinolytic therapy and correlates well with injury severity scores and the magnitude of the systemic inflammatory response.

No test used in clinical practice can detect a hypercoagulable state and thrombosis risk with good sensitivity.

Question 42

Which of the following does not assist in hemostasis of
massively bleeding trauma patients?

A. Permissive hypotension

B. Crystalloid resuscitation

C. Active warming

D. Recombinant factor VII

E. Balanced transfusion ratio (platelets:FFP:PRBC)

Answer 42

ANSWER: B

COMMENTS: In massively bleeding patients, three important factors are perfusion of vital organs, control of bleeding, and regulation of the propensity to bleed.

Trauma patients, particularly those with blunt trauma, have an intrinsic coagulopathy that can worsen with misguided resuscitation.

The traditional practice of aggressive crystalloid resuscitation achieves the first goal at the expense of the other two. This is because infusion of large amounts of intravascular fluid decreases circulating concentrations of clotting factors, leading to dilutional coagulopathy, and excessive perfusion pressure leads to clot dislocation.

In patients with hemorrhagic shock, fluid-based resuscitation with a mean arterial pressure (MAP) goal of 50 mmHg decreases bleeding and increases long-term survival compared with patients who received fluids with a MAP goal of 65.

Severe derangements in body temperature alter the dynamics of the hemostatic system and can cause coagulopathy. Recombinant factor VII has been shown to decrease hemorrhagic mortality in specific subsets of patients in the setting of trauma.

Both whole-blood transfusions and balanced transfusion ratios have been shown to decrease blood product requirements and attenuate coagulopathy in hemorrhagic shock.

Question 43

The overall incidence, in terms of events per units transfused, of transfusion-related acute lung injury (TRALI) is closest to:

A. 1in10

B. 1 in 100

C. 1 in 1000

D. 1 in 10,000

E. 1 in 100,000

Answer 43

ANSWER: D

COMMENTS: While uncommon, TRALI is the leading cause of transfusion-related deaths.

In order to have a proper index of clinical suspicion, physicians ordering transfusions should be familiar with the relative rates of complications.

Broadly, 1 in 100 patients will experience urticaria; 1 in 1000 will develop anaphylaxis; and 1 in 10,000 will experience TRALI. Hepatitis B virus is transmitted in less than 1 in 200,000 units transfused and is by far the most frequently transmitted viral pathogen in blood products.

TRALI usually appears within the first hour after a transfusion begins. It presents with fever, respiratory distress, and, eventually, diffuse infiltrates seen on chest films. On the first suspicion of TRALI, the transfusion should be stopped and supportive care initicated.

Broadly, TRALI is treated in a similar fashion to ARDS.

Question 44

A patient with previously unrecognized gram-negative sepsis begins to bleed from peripheral IV catheter sites and is noted to have prolonged PT and aPTT along with a fibrinogen of 120 mg/dL. The most effective treatment for this patient’s coagulopathy is:

A. IV antibiotics and fluid resuscitation

B. PRBC transfusion

C. Desmopressin

D. FFP

E. All of the above

Answer 44

ANSWER: A

COMMENTS: In DIC, the mainstays of treatment are supportive care and control of the inflammatory instigator.

This patient has gram-negative sepsis, a known cause of DIC, and should be treated for that first and foremost. If the infection is not controlled, the coagulopathy will run rampant and the patient will bleed despite efforts to correct the coagulopathy, which is a secondary outcome of the underlying sepsis.

If patients become critically deficient in platelets (<10,000/μL per microliter), they should be given supplemental platelets; however, the response will almost always be less than expected, secondary to ongoing consumption.

Fibrinogen levels should be monitored and replenished with cryoprecipitate if they fall below 100 mg/dL.

Question 45

Which of the following is false about fibrinogen?

A. Circulating levels are on average higher in children than in adults.

B. It is a scaffold for infiltration of inflammatory cells into a healing wound.

C. Circulating levels decrease in direct proportion to the total blood loss in hemorrhage.

D. Pure fibrinogen may be delivered to bleeding patients as a reconstituted solution.

E. It is a negative acute-phase reactant.

Answer 45

ANSWER: E

COMMENTS: Platelets are the brick and fibrinogen is the mortar of hemostasis. In acute bleeding, fibrinogen is generally the first factor to become critically depleted through volume loss, consumption, and dilutional mechanisms.

Circulating levels are generally twice as high in adults as they are in children.

Outside of its hemostatic function, fibrin is intrinsically inflammatory.

Targets on its gamma chain attract inflammatory cells to sites of injury and are an essential part of the healing process in multiple organ systems.

Recent trials show that lyophilized fibrinogen has great promise as a hemostatic agent.

These powdered formulations are much better suited to long-term storage and do not require thawing and warming as blood products do.

The acute-phase response induces the up- or downregulation of over 1000 hepatic genes in response to interleukin (IL)-6, tumor necrosis factor, and IL-1 beta released from the site of injury.

Most clotting factors are positive acute-phase reactants, meaning that production rises in times of stress. Other proteins, including albumin, are negative acute-phase reactants.

Question 46

With regard to normal hemostasis, which of the following statements is true?

A. Vascular disruption is followed by vasoconstriction mediated by vasoactive substances released by activated platelets.

B. Platelet adhesion is mediated by fibrin monomers.

C. The intact endothelial surface supports platelet adhesion and thrombus formation.

D. Heparin inhibits ADP-stimulated platelet aggregation.

E. A prolonged bleeding time may be due to thrombocyto- penia, a qualitative platelet defect, or reduced amounts of vWF.

Answer 46

ANSWER: E

COMMENTS: Blood fluidity is maintained by the action of inhibitors of blood coagulation and by the nonthrombogenic vascular surface.

Three physiologic reactions mediate initial hemo- stasis following vascular injury: (1) the vascular response (vasoconstriction) to injury; (2) platelet activation, adherence, and aggregation; and (3) generation of thrombin with subsequent conversion of fibrinogen into fibrin.

Injury exposes subendothelial components and induces vasoconstriction independent of platelet participation (answer A), which results in decreased blood flow but an increase in local shear force.

Within seconds, platelets are activated by the increase in shear force and adhere to exposed subendothelial collagen by a mechanism dependent on the participation of vWF (answer B).

Adhesion stimulates the release of platelet ADP, thereby mediating the recruitment of additional platelets.

Fibrinogen binds to activated platelet receptors, and platelet aggregation follows to create a primary hemo- static plug (answer B; adhesion and aggregation are distinct processes).

The intact endothelium is antithrombotic (answer C). Formation of the plug requires calcium and magnesium and is not affected by heparin (answer D).

Bleeding time measurements reflect the time that it takes to form this platelet plug.

A reduction in platelet number or function, loss of vascular integrity, or a reduction in the amount or function of vWF may prolong the bleeding time.

Question 47

With regard to drug effects and platelet function, which of the following statements is true?

A. Vasodilators such as prostaglandin E1 (PGE1), prostacyclin (PGI2), theophylline, and dipyridamole elevate cyclic adenosine monophosphate (cAMP) levels and block platelet aggregation.

B. Aspirin and indomethacin interfere with platelet release of ADP and inhibit aggregation.

C. Furosemide competitively inhibits PGE2.

D. The effect of aspirin is reversible in 2 to 3 days.

E. Aspirin will decrease platelet counts, but bleeding time is unchanged.

Answer 47

ANSWER: A

COMMENTS: Aspirin, indomethacin, and most other nonsteroidal antiinflammatory drugs (NSAIDs) are inhibitors of prostaglandin synthesis. They block the formation of PGG2 and PGH2 from platelet arachidonic acid and, as a result, inhibit platelet aggregation.

PGI2, PGE1, and thromboxane A2 stimulate cAMP production, whereas dipyridamole and theophylline derivatives block its degradation.

Aspirin inhibits thromboxane production, acetylates fibrinogen, interferes with fibrin formation, and makes fibrin susceptible to accelerated fibrinolysis.

The effect of aspirin begins within 2 h, is irreversible, and lasts the 7- to 9-day life span of affected platelets.

The clinical result is increased bruising and bleeding and increased risk of surgical bleeding. Platelet counts are normal, but the bleeding time is prolonged.

Furosemide competi- tively inhibits ADP-induced platelet aggregation and reduces the response of platelets to PGG2.

Furosemide may also cause thrombocytopenia. A wide variety of drugs inhibit platelet function.

Question 48

With regard to measurement of bleeding times, which of the
following statements is true?

A. Spontaneous bleeding may occur with platelet counts higher than 15,000/μL.

B. Platelet counts higher than 150,000/μL exclude the possibility of a primary hemostatic disorder.

C. Bleeding time is a predictor of surgical bleeding.

D. Platelet counts higher than 50,000/μL are usually associated with a normal bleeding time and adequate surgical hemostasis.

E. Normal bleeding time excludes von Willebrand disease as a potential factor affecting surgical hemostasis.

Answer 48

ANSWER: D
COMMENTS: The bleeding time is a crude measure of platelet function, number of platelets, or both.

The normal value is 3 to 9 min and implies normal platelet function and counts greater than 50,000/μL.

Spontaneous bleeding rarely occurs when the platelet count is greater than 10,000/μL.

The bleeding time is prolonged in patients with normal platelet counts in whom qualitative abnor- malities are present as a primary platelet disorder or one secondary to drugs, uremia, or liver disease or in those who have thrombas- thenia or a variety of other defects in platelet function. Patients with defective platelets or capillaries; those with von Willebrand disease; and those with a history of recent ingestion of aspirin, NSAIDs, antibiotics (penicillins and cephalosporins), and a wide variety of miscellaneous drugs also have prolonged bleeding times. False-negative (normal) bleeding times are frequently due to the technical difficulty of performing the test and its lack of sensitivity. For example, only 60% of patients with von Willebrand disease have a prolonged bleeding time. Other tests of platelet function include assessment of platelet aggregation in response to a variety of agonists.

Question 49

With regard to classic hemophilia (hemophilia A), which of the following statements is true?

A. The incidence in the general population is 1 in 1000.

B. A given patient’s baseline factor VIII or IX level may fluctuate with stress.

C. Muscle compartment bleeding is the most common orthopedic problem.

D. Factor VIII replacement therapy is required before any elective surgery.

E. Therapy with cryoprecipitate plasma is free of risk for hepatitis.

Answer 49

ANSWER: D

COMMENTS: The incidence of classic hemophilia, the most common form of hemophilia, is 1 in 5000 males.

Bleeding in patients with hemophilia usually appears during early childhood.

Hemarthrosis is the most
common orthopedic problem. Epistaxis, hematuria, and intracranial bleeding may occur. Equinus contracture, Volkmann’s con- tracture of the forearm, and flexion contracture of the elbows or knees are sequelae of these bleeding episodes.

Retroperitoneal or intramural intestinal bleeding may produce abdominal symptoms. The level of factor VIII or IX in plasma (which tends to remain stable throughout life) determines the tendency to bleed.

Spontaneous bleeding is frequent in patients with severe disease, defined as less than 1% (of normal) factor VIII or IX activity.

Bleeding typically occurs with trauma in patients with moderately severe disease, defined as 1%–5% factor activity. In patients with mild hemophilia A or B, defined as 6%–25% factor activity, bleeding typically occurs only with major trauma or surgery.

The factor VIII or IX level must be raised to at least 30% to achieve hemostasis and to control minor hemorrhage.

A level of approximately 50% is required to control joint and muscle bleeding, whereas a level of 80%–100% is necessary to treat life-threatening hemorrhage (central nervous system, retroperitoneal, or retropharyn- geal bleeding) and to prepare patients for elective surgery.

After elective surgery, levels of 25% should be maintained for at least 2 weeks. Transmission of hepatitis or human immunodeficiency virus, the development of neutralizing antibodies, and qualitative platelet dysfunction are possible complications of factor replacement therapy.

Appropriate replacement includes infusions of factor VIII and factor IX. These products are available in both recombinant and highly purified concentrates that are virally inactivated.

Cryoprecipitate is not an optimal replacement therapy for factor VIII and vWF, does not contain factor IX, and is associated with a risk of viral transmission.

Question 50

A 12-year-old boy with known factor VIII deficiency has a painful, swollen, immobile right knee. The clinician suspects hemarthrosis. Therapeutic options include which of the following?

A. Immediate aspiration and compression dressings to prevent cartilage necrosis

B. Compression dressings and immobilization to prevent further bleeding

C. Immediate aspiration after appropriate factor VIII replacement therapy

D. Initial trial of factor VIII therapy, compression dressings, cold packs, and rest followed by active range-of-motion exercises

E. None of the above

Answer 50

ANSWER: D

COMMENTS: Treatment of hemarthrosis is aimed at preventing chronic synovitis and degenerative arthritis.

Early, intensive factor VIII therapy is critical for limiting the extent of hemorrhage.

Factor VIII replacement therapy is most effective when initiated before swelling of the joint capsule.

Frequently, replacement therapy is initiated before the onset of any objective physical findings, when the patient perceives only subtle signs of joint hemorrhage.

Factor VIII therapy, joint rest, compression dressing, and cold packs constitute the usual initial therapy.

Aspiration is to be avoided. The goal of treatment of hemarthrosis is maintenance of range of motion.

Active range-of-motion exercises should begin 24 h after factor VIII therapy.

Compression and cold packs should be continued for 3 to 5 days.

Question 51

With regard to von Willebrand disease, which of the following statements is true?

A. It is more common than hemophilia.

B. It is best treated with cryoprecipitate plasma.

C. Factor VIII levels are constant over time in a given patient.

D. Bleeding after elective surgery is rare.

E. All types of von Willebrand diseases can be effectively
treated with desmopressin

Answer 51

ANSWER: A

COMMENTS: von Willebrand disease is the most common congenital bleeding disorder, with 1% of the population being affected.

The prevalence of patients with symptomatic bleeding is approximately 1 in 1000.

Most patients have mild disease unless challenged by trauma or surgery.

von Willebrand disease is associated with a variable deficiency of both vWF and factor VIII. A platelet defect is also present in most patients.

The severity of coagulation abnormalities varies from patient to patient and from time to time for a given patient. In all but 1%–2% of patients, the bleeding manifestations are milder than in classic hemophilia patients.

In the same group of patients with type 3 von Willebrand disease, bleeding is more severe than in hemophilia patients.

Bleeding is treated with desmopressin (DDAVP), which induces the release of vWF from storage sites in endothelial cells and platelets.

The effect of DDAVP is rapid, with maximal procoagulant effects being reached in 1 to 2 h. The effects dissipate quickly (within 12 to 24 h) thus necessitating repeated dosing.

When more than two or three doses of DDAVP are given, the effects may diminish or are absent.

DDAVP is most effective for type 1 disease and is not effective for type 3 disease.

Because of a risk for thrombocytopenia, DDAVP is specifically contraindicated in type 2B disease but may be effective in other forms of type 2 disease.

In type 3 and most type 2 von Willebrand diseases, specific vWF replacement product should be administered.

Question 52

With regard to polycythemia vera, which of the following
statements is not true?

A. Spontaneous thrombosis is a complication of polycythemia vera.

B. Spontaneous hemorrhage is a possible complication of polycythemia vera.

C. The reason for bleeding is a deficit in platelet function.

D. A hematocrit of less than 48% and a platelet count of less than 400,000/μL are desirable before an elective operation is performed on a patient with polycythemia vera.

E. Postoperative complication rates may be as high as 60%.

Answer 52

ANSWER: E

COMMENTS: Patients with untreated polycythemia vera are at a high risk for postoperative bleeding or thrombosis. The complication rate is highest with uncontrolled erythrocytosis.

Increased viscosity and platelet count, along with a tendency toward stasis, may explain the spontaneous thrombosis seen in patients with polycythemia vera.

Patients most likely to bleed are those with platelet counts greater than 1.5 million/μL.

Polycythemia vera may cause a qualitative defect in platelet function. When possible, surgery should be delayed until the hematocrit and platelet count can be medically reduced.

Phlebotomy may help in acute situations.

Com- plication rates as high as 46% have been reported in patients with polycythemia vera undergoing surgery.

Spontaneous hemorrhage, thrombosis, a combination of hemorrhage and thrombosis, and infection are the major complications.

Question 53

In cirrhotic patients who are actively bleeding, the coagulopathy of end-stage liver disease can be differentiated from DIC most readily by estimation of which of the following factors?

A. Factor II

B. Factor IX

C. Factor VII

D. Factor VIII:C

E. Factor X

Answer 53

ANSWER: D

COMMENTS: Of all of the coagulation factors listed, only factor VIII:C is not produced by hepatocytes.

It is produced by reticulo- endothelial cells, and its levels are typically increased in the presence of cirrhosis.

Reductions in factor VIII:C are observed in patients with DIC because it is consumed along with the other coagulation factors.

Question 54

Sequence of the Intrinsic pathway?

Answer 54

Prekallikrein + HMW kininogen + factor XII + exposed collagen - activates factor XI - activates factor IX, combines with factor VIII - activates factor X, combines with factor V -t converts prothrombin (factor II) into thrombin. Thrombin converts fibrinogen into fibrin.

Question 55

Sequence of the extrinsic pathway of ooagulation:

Answer 55

Factor VII + tissue factor -t activates factor X, combines with factor V -t converts prothrombin into thrombin. Thrombin converts fibrinogen into fibrin.

Question 56

Which factor is the convergence point and common to both the extrinsic and intrinsic pathways of coagulation?

Answer 56

Factor X

Question 57

What does the prothrombin complex consist of?

Answer 57

Factor V.

X, platelet factor 3, and prothrombin catalyze the formation of thrombin

Question 58

What function does thrombin have?

Answer 58

Activates factors V and VIII, activates platelets, and converts fibrinogen into fibrin and fibrin split products

Question 59

Which factor has the shortest half-life?

Answer 59

Factor VII

Question 60

What factor can be used to differentiate a consumptive coagulopathy from hepatocellular disease?

Answer 60

Factor VIII:C; consumptive coagulopathy will have reduced levels of all factors, and hepatocellular disease will have reduced levels of all factors except factor VIII

Question 61

Which factors are known as the labile factors (activity lost in stored blood)?

Answer 61

Factors V and VIII

Question 62

What function does factor XIII have?

Answer 62

Cross-links fibrin

Question 63

What does protein C do?

Answer 63

Degrades fibrinogen and factors V and VIII (vitamin K dependent)

What does protein S do?

Acts as protein C cofactor (vitamin K dependent)

What does Von Willebrand factor (vWF) do?

Links collagen to the Gplb receptor on platelets

What is the function of antithrombin III?

Binds heparin, inhibits factors IX, X. XI, and thrombin

Where does tissue plasminogen activator come from, and what does it do?

Released from endothelium, and it converts plasminogen into plasmin

What does plasmin do?

Degrades fibrinogen, fibrin, and factors V and VIII

What is the natural inhibitor of plasmin called, and where does it come from?

Alpha-2 antiplasmin; comes from the endothelium

What are the vitamin K-dependent factors?

Factors II, VII, IX, and X and proteins C and S

What function does tissue factor pathway inhibitor have?

Inhibits factor X

PT measures the function of these factors:

Factors II, V, VII, and X and fibrinogen

What 2 factors are not measured by the PTT?

Factors VIl and XIII

PTT measures the function of these factors:

Factors II, V, VIII, IX, X. XI, and XII and fibrinogen

What is the normal value for bleeding time, and what does it imply?

Normal bleeding time ranges from 3 to 9 minutes and implies platelet counts >50,000/mL and normal platelet function

What test aids in detecting circulating anticoagulants, qualitative abnormalities of fibrin, inlu’bition of fibrin polymerization, and measures the clotting time of plasma?

Thrombin time

Patients bleeding after a large number of blood transfusions should be considered to have:

Dilutional thrombocytopenia (vs. hemolytic transfusion reaction)

What factors are common to both PT and PTT

Factors II, V, and X and fibrinogen

How many hours must elapse after the last dose of IV heparin before the PT can be reliably measured?

Minimum of 5 hours

Sequence of physiologic reactions that mediate hemostasis following vascular injury:

1. Vasoconstriction
2. Platelet activation/adherence/aggregation
3. Thrombin generation

What is Virchow triad?

Stasis, endothelial injury, and hypercoagulability

What is the most common cause of acquired hypercoagulability?

Smoking

What is the most common inherited hypercoagulable state?

Factor V Leiden

What is the treatment for hyperhomocysteinemia?
Vitamin B-12 and folate

Name the prothrombin gene defect causing spontaneous venous thrombosis:

Prothrombin gene defect G20210A

What is the normal life span of a platelet?

7 to 10 days

Formation of a platelet plug requires these 2 electrolytes:

Calcium and magnesium