Hemostasis, Surgical Bleeding,
BASIC SCIENCE QUESTIONS
1. What percentage of platelets can be sequestered in the spleen?
Platelets are anucleate fragments of megakaryocytes. The normal circulating number of platelets ranges between 150,000 and 400,000/μL. Up to 30% of circulating platelets may be sequestered in the spleen. (See Schwartz 9th ed., p 68.)
2. Which of the following is required for platelet adherence to exposed areas of an injured vessel?
B. von Willebrand factor
C. Glycoprotein IX
D. Prostaglandin GI2
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’s factor (vWF), a protein in the subendothelium that is lacking in patients with von Willebrand’s disease. The vWF binds to glycoprotein I/IX/V on the platelet membrane. After 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.
Prothrombin initiates the common phase of the coagulation cascade, which occurs after primary hemostasis.
Prostaglandin GI is a vasodilator and inhibits platelet aggregation. (See Schwartz 9th ed., p 68.)
3. Which of the following drugs irreversibly inhibits platelet COX (cyclo-oxygenase)?
Arachidonic acid released from the platelet membranes is converted by COX to prostaglandin G2(PGG2) and then to prostaglandin H2(PGH2), which, in turn, is converted to TXA2. TXA2 has potent vasoconstriction and platelet aggregation effects. Arachidonic acid may also be shuttled to adjacent endothelial cells and converted to prostacyclin (PGI2), which is a vasodilator and acts to inhibit platelet aggregation. Platelet COX is irreversibly inhibited by aspirin and reversibly blocked by NSAIDs but is not affected by COX-2 inhibitors.
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) and reversibly affects platelet COX.
Both aspirin and clopidogrel irreversibly inhibit platelet function, clopidogrel through selective irreversible inhibition of ADP-induced platelet aggregation and aspirin through irreversible acetylation of platelet prostaglandin synthase.
Celebrex is a COX-2 inhibitor and therefore does not affect platelet COX. (See Schwartz 9th ed., p 68.)
4. An abnormal aPTT (partial thromboplastin time) is associated with an abnormality in which portion of the clotting mechanism?
A. Platelet aggregation
B. Intrinsic pathway
C. Extrinsic pathway
D. Coagulation (clot formation)
One convenient feature of depicting the coagulation cascade with two merging arms is that commonly used laboratory tests segregate abnormalities of clotting to one of the two arms (Table 4-1). An elevated activated partial thromboplastin time (aPTT) is associated with abnormal function of the intrinsic arm of the cascade, whereas an elevated prothrombin time (PT) is associated with the extrinsic arm. (See Schwartz 9th ed., p 69.)
TABLE 4-1 Coagulation factors tested by the PT and the aPTT
5. Patients with factor V Leiden are predisposed to thrombosis because they have a genetic mutation in factor V which
A. Leads to inadequate production of factor V
B. Leads to overproduction of factor V
C. Leads to an inability to inactivate factor V
D. Leads to an inability to activate factor V
A third major mechanism of inhibition of thrombin formation is the protein C system. On its formation, thrombin binds to thrombomodulin and activates protein C to activated protein C (APC), which then forms a complex with its cofactor, protein S, on a phospholipid surface. The APC–protein S complex cleaves factors Va and VIIIa so they are no longer able to participate in the formation of tissue factor–VIIa or prothrombinase complexes. Of interest is an inherited form of factor V that carries a genetic mutation, called factor V Leiden, that is resistant to cleavage by APC and thus remains active (procoagulant). Patients with factor V Leiden are predisposed to venous thromboembolic events. (See Schwartz 9th ed., p 70.)
1. A patient with hemophilia has a factor level of 8%. This is considered to be
A. Mild hemophilia
B. Moderately severe hemophilia
C. Severe hemophilia
D. Extremely severe hemophilia
Hemophilia A and hemophilia B are inherited as sex-linked recessive disorders with males being affected almost exclusively. The clinical severity of hemophilia A and hemophilia B depends on the measurable level of factor VIII or factor IX in the patient’s plasma. Plasma factor levels 1% of normal are considered severe disease, factor levels between 1 and 5% moderately severe, and levels of 5 to 30% mild disease. Patients with severe hemophilia have severe spontaneous bleeds, frequently into joints, which leads to crippling arthropathies. Intramuscular hematomas, retroperitoneal hematomas, and GI, genitourinary, and retropharyngeal bleeding are added clinical sequelae seen with severe disease. Intracranial bleeding and bleeding from the tongue or lingual frenulum may be life-threatening with severe disease. Patients with moderately severe hemophilia have less spontaneous bleeding but are likely to bleed severely after trauma or surgery. Those with mild disease do not bleed spontaneously and frequently have only minor bleeding after major trauma or surgery. Because platelet function is normal in individuals with hemophilia, patients may not bleed immediately after an injury or minor surgery because they have a normal response with platelet activation and formation of a platelet plug. At times, the diagnosis of hemophilia is not made in these patients until after their first minor procedure (e.g., tooth extraction or tonsillectomy). (See Schwartz 9th ed., p 71.)
2. Which of the following is the best choice to prepare a patient with type 1 von Willebrand’s disease for surgery?
A. Recombinant (pure) factor XIII
B. von Willebrand factor
C. Factor XIII
von Willebrand’s disease (vWD), the most common congenital bleeding disorder, is characterized by low levels of factor VIII. It is an autosomal dominant disorder, and the primary defect is a low level of vWF, a large glycoprotein responsible for carrying factor VIII and platelet adhesion. The latter is important for normal platelet adhesion to exposed subendothelium and for aggregation under high-shear conditions. Patients with vWD have bleeding that is characteristic of platelet disorders (i.e., easy bruising and mucosal bleeding). Menorrhagia is common in women. vWD is classified into three types. Type I is a partial quantitative deficiency, type II is a qualitative defect, and type III is total deficiency. One treatment for vWD is an intermediate-purity factor VIII concentrate such as Humate-P that contains vWF as well as factor VIII. The second treatment strategy is desmopressin acetate, which raises endogenous vWF levels by triggering release of the factor from endothelial cells. Desmopressin acetate is used once a day because time is needed for synthesis of new stores of vWF within the endothelial cells. Historically, patients with type I disease have been found to respond well to desmopressin acetate. Type II patients may respond, depending on the particular defect. Type III patients are usually unresponsive. (See Schwartz 9th ed., p 71.)
3. Hemophilia C is caused by a deficiency of
A. Factor VIII
B. Factor IX
C. Factor X
D. Factor XI
Factor XI deficiency, an autosomal recessive inherited condition sometimes referred to as hemophilia C, is more prevalent in the Ashkenazi Jewish population. Spontaneous bleeding is rare, but bleeding may occur after surgery, trauma, or invasive procedures. Patients with factor XI deficiency who present with bleeding or for whom surgery is planned and who are known to have bled previously are treated with fresh-frozen plasma (FFP). Each milliliter of plasma contains 1 unit of factor XI activity, so the volume needed depends on the patient’s baseline level, the desired level, and the plasma volume. Recombinant factor VIIa treatment has been used successfully in children with severe factor XI deficiency who require major operations such as open heart surgery. Desmopressin acetate also may be useful in the prevention of surgical bleeding in these patients. (See Schwartz 9th ed., pp 71-72.)
4. Factor XIII deficiency most commonly presents as
A. Severe intraoperative bleeding
B. Delayed bleeding after injury or surgery
C. Spontaneous hemarthrosis
D. Spontaneous gastrointestinal bleeding
Congenital factor XIII deficiency, originally recognized by François Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis. The male:female ratio is 1:1. Although acquired factor XIII 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 typically is 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 factor XIII deficiency unless they receive replacement therapy. Replacement can be accomplished with FFP, cryoprecipitate, or a factor XIII concentrate. Levels of 1 to 2% are usually adequate for hemostasis. (See Schwartz 9th ed., p 72.)
5. Bleeding in patients with thrombasthenia is treated with
A. Factor V
B. Factor VII
C. Fresh frozen plasma transfusion
D. Platelet transfusion
Thrombasthenia or Glanzmann thrombasthenia is a rare genetic platelet disorder, inherited in an autosomal recessive pattern, in which the platelet glycoprotein IIb/IIIa complex is either lacking or present but dysfunctional. This defect leads to faulty platelet aggregation and subsequent bleeding. The disorder was first described by Dr. Eduard Glanzmann in 1918. Bleeding in thrombasthenic patients must be treated with platelet transfusions. (See Schwartz 9th ed., p 72.)
6. Bleeding in patients with the Bernard-Soulier syndrome is treated with
A. Factor V
B. Factor VII
C. Fresh frozen plasma transfusion
D. Platelet transfusion
The Bernard-Soulier syndrome, caused by a defect in the glycoprotein Ib/IX/V receptor for vWF, is necessary for platelet adhesion to the subendothelium. Transfusion of normal platelets is required to treat bleeding in these patients. (See Schwartz 9th ed., p 72.)
7. A patient with partial albinism and a bleeding disorder most likely has
A. von Willebrand’s disease
B. Hemophilia C
C. Dense granule deficiency
D. Factor XIII deficiency
The most common intrinsic platelet defect is storage pool disease. It involves loss of dense granules [storage sites for ADP, adenosine triphosphate (ATP), Ca2+, and inorganic phosphate] and α-granules. 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 the severity of the granule defect. Bleeding is caused by the decreased release of ADP from these platelets…. Patients with mild bleeding as a consequence of a form of storage pool disease can be treated with desmopressin acetate. It is likely that the high levels of vWF in the plasma after desmopressin acetate administration somehow compensate for the intrinsic platelet defect. With more severe bleeding, platelet transfusion is required. (See Schwartz 9th ed., p 72.)
8. First line therapy in an adult with idiopathic thrombocytopenia purpura includes
C. IV immunoglobulin
First line therapy for ITP in adults is corticosteroids and IV immunoglobulin. Splenectomy is second line therapy. Desmopressin is not used in the treatment of ITP. (See Schwartz 9th ed., pp 72-73, andTable 4-2.)
TABLE 4-2 Management of idiopathic thrombocytopenic purpura (ITP) in adults
a. Corticosteroids: The majority of patients respond, but only a few long term.
b. IV immunoglobulin: Indicated with clinical bleeding, along with platelet transfusion, and when condition is steroid unresponsive. Response is rapid but transient.
c. Anti-D immunoglobulin: Active only in Rh-positive patients before splenectomy. Response is transient.
a. Splenectomy: Open or laparoscopic. Criteria include severe thrombocytopenia, high risk of bleeding, and continued need for steroids. Treatment failure may be due to retained accessory splenic tissue.
a. Patients for whom first- and second-line therapies fail are considered to have chronic ITP. The objective in this subset of patients is to maintain the platelet count >20–30×109/L and to minimize side effects of medications.
b. Rituximab, an anti-CD20 monoclonal antibody: Acts by eliminating B cells.
c. Alternative medications producing mixed results and a limited response: Danazol, cyclosporine A, dapsone, azathioprine, and vinca alkaloids.
d. Thrombopoietic agents: A new class of drugs for patients with impaired production of platelets rather than accelerated destruction of platelets. Second-generation drugs still in clinical trials include AMG531 and eltrombopag.
9. The diagnosis of heparin-induced thrombocytopenia is made by
A. >20% fall in platelet count
B. Positive serotonin release assay
C. Platelets 25,000 with clinical bleeding
D. Prolonged aPTT
Heparin-induced thrombocytopenia (HIT) is a form of drug induced immune thrombocytopenia. It is an immunologic disorder in which antibodies against PF4 formed during exposure to heparin affect 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. HIT should be suspected if the platelet count falls to 100,000/μL or if it drops by 50% from baseline in a patient receiving heparin. Although HIT is more common with full-dose unfractionated heparin (1 to 3%), it also can occur with prophylactic doses or with low molecular weight heparins. Interestingly, approximately 17% of patients receiving unfractionated heparin and 8% of those receiving low molecular weight heparin develop antibodies against PF4, yet a much smaller percentage develop thrombocytopenia and even fewer clinical HIT. In addition to the mild to moderate thrombocytopenia, this disorder is characterized by a high incidence of thrombosis, which may be arterial or venous. Importantly, the absence of thrombocytopenia in these patients does not preclude the diagnosis of HIT.
The diagnosis of HIT may be made by using either a serotonin release assay or an enzyme-linked immunosorbent assay (ELISA). The serotonin release assay is highly specific but not sensitive, so that a positive test result supports the diagnosis but a negative result does not exclude HIT. On the other hand, the ELISA has a low specificity, so although a positive ELISA result confirms the presence of anti–heparin-PF4, it does not help in the diagnosis of clinical HIT. A negative ELISA result, however, essentially rules out HIT. (See Schwartz 9th ed., p 73.)
10. In addition to stopping the heparin, a patient with heparin-induced thrombocytopenia (HIT) should be treated with
B. Low molecular weight heparin
The initial treatment of suspected HIT is to stop heparin and begin an alternative anticoagulant. Stopping heparin without adding another anticoagulant is not adequate to prevent thrombosis in this setting. Alternative anticoagulants are primarily thrombin inhibitors. Those available in the United States are lepirudin, argatroban, and bivalirudin. In Canada and Europe, danaparoid also is available. Danaparoid is a heparinoid that has approximately 20% cross reactivity with HIT antibodies in vitro but a much lower cross reactivity in vivo. Because of warfarin’s early induction of a hypercoagulable state, only once full anticoagulation with an alternative agent has been accomplished and the platelet count has begun to recover should warfarin be instituted. (See Schwartz 9th ed., p 73.)
11. The most effective treatment for bleeding secondary to thrombotic thrombocytopenic purpura is
A. Platelet transfusion
C. Emergency splenectomy
In thrombotic thrombocytopenic purpura (TTP), large vWF molecules interact with platelets, which leads to activation. These large molecules result from inhibition of a metalloproteinase enzyme, ADAMTS13, which cleaves the large vWF 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. The most effective treatment for TTP is plasmapheresis, although plasma infusion also has been attempted. A recent study comparing these two modalities reported a higher relapse rate and a higher mortality with plasma infusions. Platelet transfusions are contraindicated. Additionally, rituximab, a monoclonal antibody against the CD20 protein on B lymphocytes, has shown promise as an immunomodulatory therapy directed against acquired TTP, which in the majority of cases is autoimmune mediated. (See Schwartz 9th ed., p 73.)
12. In a 70-kg patient, transfusion of 1 unit of platelets should raise the circulating platelet count by approximately
One unit of platelet concentrate contains approximately 5.5 × 1010 platelets and would be expected to increase the circulating platelet count by approximately 10,000/μL in the average 70-kg person. (See Schwartz 9th ed., p 74.)
13. Which of the following is a common initiating event for disseminated intravascular coagulation (DIC)?
A. Spider bite
B. Depressed skull fracture
C. Type A influenza
D. Amniotic fluid embolization
The presence of an underlying condition that predisposes a patient to DIC is required for the diagnosis. Specific injuries include central nervous system injuries with embolization of brain matter, fractures with embolization of bone marrow, and amniotic fluid embolization. Embolized materials are potent thromboplastins that activate the DIC cascade. Additional causes include malignancy, organ injury (such as severe pancreatitis), liver failure, certain vascular abnormalities (such as large aneurysms), snakebites, illicit drugs, transfusion reactions, transplant rejection, and sepsis. DIC frequently accompanies sepsis and may be associated with multiple organ failure. (See Schwartz 9th ed., p 74.)
14. A patient with a prolonged aPTT and deep venous thrombosis should be evaluated for which of the following conditions?
A. Heparin-induced thrombocytopenia
B. Thrombotic thrombocytopenic purpura
C. Antiphospholipid syndrome
D. Protein C deficiency
Among the most common acquired disorder of coagulation inhibition is the antiphospholipid syndrome (APLS), in which the lupus anticoagulant and anticardiolipin antibodies are present. These antibodies may be associated with either venous or arterial thrombosis, or both. In fact, patients who show recurrent thrombosis should be evaluated for APLS. The presence of antiphospholipid antibodies is very common in patients with systemic lupus erythematosus but also may be seen in association with rheumatoid arthritis and Sjögren’s syndrome. There are also individuals who have no autoimmune disorders but develop transient antibodies in response to infections or who develop drug-induced APLS. The hallmark of APLS is a prolonged aPTT in vitro but an increased risk of thrombosis in vivo. (See Schwartz 9th ed., p 75.)
15. Which of the following would increase the effect of warfarin and require a decrease in the dose given for anticoagulation?
D. Oral contraceptive pills
Cephalosporins are among the agents that can increase the effect of warfarin. (See Schwartz 9th ed., p 76, and Table 4-3.)
TABLE 4-3 Medications that can alter warfarin dosing
16. A patient on chronic warfarin therapy presents with acute appendicitis. INR is 1.4. Which of the following is the most appropriate management?
A. Proceed immediately with surgery without stopping the warfarin
B. Stop the warfarin, give fresh frozen plasma, and proceed with surgery
C. Stop the warfarin and proceed with surgery in 8-12 hours
D. Stop the warfarin and proceed with surgery in 24-36 hours
Surgical intervention may prove necessary in patients receiving anticoagulation therapy. Increasing experience suggests that surgical treatment can be undertaken without discontinuing the anticoagulant program, depending on the procedure being performed. Furthermore, the risk of thrombotic complications may be increased when anticoagulation therapy is discontinued abruptly. When the aPTT is 1.3 times the control value in a patient receiving heparin or when the INR is 1.5 in a patient taking warfarin, reversal of anticoagulation therapy may not be necessary. However, meticulous surgical technique is mandatory, and the patient must be observed closely throughout the postoperative period. (See Schwartz 9th ed., p 76.)
17. Which of the following devices is most advantageous for hemostasis during a thyroidectomy?
A. Monopolar electrocautery
B. Bipolar electrocautery
C. Harmonic scalpel
D. Argon coagulator
The Harmonic scalpel is an instrument that cuts and coagulates tissue via vibration at 55 kHz. The device converts electrical energy into mechanical motion. The motion of the blade causes collagen molecules within the tissue to become denatured, forming a coagulum. No significant electrical current flows through the patient. The instrument has proved advantageous in performing thyroidectomy, hemorrhoidectomy, and transsection of the short gastric veins during splenectomy, and in transecting hepatic parenchyma.
Heat achieves hemostasis by denaturation of protein that results in coagulation of large areas of tissue. With cautery, heat is transmitted from the instrument by conduction directly to the tissue. When electrocautery is used, heating occurs by induction from an alternating current source. (See Schwartz 9th ed., p 77.)
18. Which topical anticoagulating agent is best for use in patients with a coagulopathy?
B. Fibrin sealant
C. Thrombostat (topical thrombin)
Thrombin-derivative products direct the conversion of fibrinogen to fibrin, aiding in clot formation. Thrombin takes advantage of natural physiologic processes, thereby avoiding foreign body or inflammatory reactions, and the wound bed is not disturbed.
Fibrin sealants are prepared from cryoprecipitate (homologous or synthetic) and have the advantage of not promoting inflammation or tissue necrosis. The sealant is administered using a dual syringe compartment system. In one compartment is fibrinogen, factor XIII, fibronectin, and fibrinolysis inhibitors. The second compartment contains thrombin and calcium chloride. The use of fibrin glue is particularly helpful in patients who have received heparin or who have deficiencies in coagulation (e.g., hemophilia or von Willebrand’s disease).
Purified gelatin solution can be prepared into several vehicles, including powders, sponges or foams, and sheets or films. Gelatin is hygroscopic, absorbing many times its weight in water or liquid. It is effectively metabolized and degraded by proteinases in the wound bed over a period of 4 to 6 weeks. Gelfoam provides effective hemostasis for operative fields with diffuse small-vessel oozing. Thrombin may be applied to this vehicle to boost hemostasis. Gelatin is relatively inexpensive, readily available, pliable, and easy to handle. Although relatively inert, the implanted gelatin can serve as a nidus for infection. (See Schwartz 9th ed., p 77, and Table 4-4.)
TABLE 4-4 Common hemostatic agents
19. What percent of the population is Rh negative?
Rh-negative recipients should receive transfusions only of Rh-negative blood. However, this group represents only 15% of the population. Therefore, the administration of Rh-positive blood is acceptable if Rh-negative blood is not available. However, Rh-positive blood should not be transfused to Rh-negative females who are of childbearing age. (See Schwartz 9th ed., p 78.)
20. What is the maximum number of units of blood that can be autologously donated for elective surgery as long as the patient’s hemoglobin is >11 gm?
A. A single donation can be made 2-3 weeks before surgery
B. 2 donations can be made 2 and 4 weeks before surgery
C. 3 donations can be made, 1 week apart, starting 4 weeks before surgery
D. 5 donations can be made, 3-4 days apart, starting 6 weeks before surgery
The use of autologous transfusion is growing. Up to 5 units can be collected for subsequent use during elective procedures. Patients can donate blood if their hemoglobin concentration exceeds 11 g/dL or if the hematocrit is >34%. The first procurement is performed 40 days before the planned operation and the last one is performed 3 days before the operation. Donations can be scheduled at intervals of 3 to 4 days. Administration of recombinant human erythropoietin accelerates generation of red blood cells and allows for more frequent harvesting of blood. (See Schwartz 9th ed., p 78.)
21. When should cryoprecipitate be given to a patient needing a massive transfusion of packed RBCs?
A. 1 unit of cryoprecipitate should be given for each unit of PRBCs
B. 10 units of cryoprecipitate should be given for each unit of PRBCs
C. After 6 units of PRBCs, cryoprecipitate should be given if the serum fibrinogen level is 100 mg/dl
D. Never, fresh frozen plasma will provide the necessary factors
(See Schwartz 9th ed., p 80, and Table 4-5.)
TABLE 4-5 Component therapy administration during massive transfusion
22. Which of the following best assesses clot strength?
A. Clinical history
B. Thrombin levels
C. Ivy bleeding time
D. Thromboelastogram (TEG)
TEG measures the viscoelastic properties of blood as it is induced to clot in a low-shear environment (resembling sluggish venous flow). The patterns of change in shear elasticity allow the kinetics of clot formation and growth as well as the strength and stability of the formed clot to be determined. The strength and stability data provide information about the ability of the clot to perform the work of hemostasis, whereas the kinetic data determine the adequacy of quantitative factors available for clot formation.
The usefulness of TEG has been sufficiently documented in general surgery, cardiac surgery, urologic surgery, obstetrics, pediatrics, and liver transplantation. It is the only test measuring all dynamic steps of clot formation until eventual clot lysis or retraction. Its role in evaluating coagulopathic patients is still being investigated. (See Schwartz 9th ed., p 84.)