Hemostasis & Thrombosis Pathology & Pharmacology- 2 Flashcards
Answer C
This patient with glomerulonephritis, photosensitive skin rash, and arthralgia has systemic lupus erythematosus (SLE). Many patients with SLE have circulating antiphospholipid antibodies (ie, lupus anticoagulant [LA], anticardiolipin antibody [aCL], anti-beta-2 glycoprotein I antibody).
Antiphospholipid antibodies interfere with common serologic tests: LA cross-reacts with phospholipid reagents in the activated PTT test, and aCL binds cardiolipin, the predominant antigen used in the rapid plasma reagin (RPR) and VDRL tests. Therefore, patients with circulating antiphospholipid antibodies have paradoxical PTT prolongation and false-positive RPR/VDRL results. Bleeding time and PT, which are coagulation tests unaffected by antiphospholipid antibodies, are normal.
Patients with antiphospholipid antibodies (with or without the concomitant diagnosis of SLE) are at risk for antiphospholipid antibody syndrome (APS), a hypercoagulable disorder characterized by venous (eg, deep vein thrombosis) or arterial (eg, ischemic stroke) thrombosis. The presence of antiphospholipid antibodies promotes thromboembolism due to activation of phospholipid-dependent coagulation pathways.
Patients with APS have increased obstetric morbidity, including recurrent pregnancy loss, preterm delivery due to preeclampsia or placental insufficiency, and stillbirth. The underlying mechanism is likely thrombosis of placental vessels, which decreases perfusion to the fetus.
(Choices A and B) Hemophilias (eg, inherited deficiency of factor VIII, IX, or XI) can cause prolonged activated PTT but normal PT; these patients may have heavy menstrual bleeding and/or painful hemarthroses (bleeding into a joint). However, in the setting of SLE, this patient’s abnormal coagulation test results are more consistent with interference by antiphospholipid antibodies than an inherited coagulopathy.
(Choice D) Sclerodactyly can occur with other autoimmune diseases such as scleroderma or CREST (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia) syndrome. However, it is does not typically occur with SLE.
(Choice E) Tabes dorsalis is a manifestation of tertiary syphilis that results in sensory ataxia. Because this patient has a negative specific treponemal test (Treponema pallidum enzyme immunoassay [TP-EIA]), her positive RPR test result is likely a false-positive, and therefore she is not at risk for tabes dorsalis.
Educational objective:
Many patients with systemic lupus erythematosus have antiphospholipid antibodies, which can cause paradoxical PTT prolongation and false-positive RPR/VDRL results; antiphospholipid antibody syndrome is characterized by arterial or venous thrombosis and increased obstetric morbidity (eg, recurrent pregnancy loss).
Answer A
Nonambulatory hospitalized patients are at increased risk for developing lower extremity deep venous thrombosis (DVT), which can lead to pulmonary embolism. In patients undergoing elective surgery without prophylaxis against DVT, the risk can be even higher, particularly with certain orthopedic procedures such as hip and knee replacement. In such cases, DVT prophylaxis is usually initiated within hours of wound closure.
Unfractionated and low molecular weight heparins (LMWHs) are commonly used for DVT prevention in inpatient settings. Administration of heparin (a negatively charged chemical naturally present in mast cells) increases the effect of the naturally occurring anticoagulant antithrombin III (AT III). Unfractionated heparin binds to AT III via a pentasaccharide in the heparin chain. This results in a conformational change of AT III, which subsequently inhibits factor Xa and neutralizes thrombin, promoting anticoagulation. AT III activated by LMWH (which has better bioavailability and does not need laboratory monitoring when given therapeutically) acts predominantly on factor Xa, not thrombin.
(Choice B) Direct thrombin inhibitors directly inhibit thrombin-mediated fibrin formation. Lepirudin and argatroban (parenteral) are primarily used for management of heparin-induced thrombocytopenia. Dabigatran (oral) is used for DVT prevention and treatment and for stroke prevention in atrial fibrillation.
(Choice C) Clopidogrel and ticlopidine inhibit ADP-mediated platelet aggregation. They are useful following percutaneous coronary intervention and for treatment of unstable angina and non-ST segment elevation myocardial infarction.
(Choice D) Use of drugs that convert inactive plasminogen to plasmin leads to fibrinolysis and clot lysis; such medications are given for clot lysis in acute myocardial infarction, pulmonary embolism, and arterial thrombosis.
(Choice E) Aspirin irreversibly acetylates platelet cyclooxygenase-I, leading to decreased formation of thromboxane A2. Aspirin is used for primary and secondary prevention of myocardial infarction and stroke.
Educational objective:
Heparin is commonly used for the prevention of deep venous thrombosis in nonambulatory patients or those undergoing elective surgery, especially hip and knee surgery. Heparin increases the effect of the naturally occurring anticoagulant antithrombin III.
Answer C
This is a young patient with recurrent deep venous thromboses, features indicative of a hypercoagulable state. Inherited causes of hypercoagulability must be considered in all patients under age 50 who present with thromboses in the absence of any obvious explanation for an acquired prothrombotic state.
The patient’s plasma is resistant to the normally antithrombotic effects of activated protein C. Thus, the most likely diagnosis is a mutation in the factor V gene, which renders factor Va resistant to inactivation by activated protein C. A specific factor V mutation, known as the Leiden mutation, and mutations in the prothrombin gene are the most common inherited causes of hypercoagulability. Activated protein C resistance (factor V Leiden mutation) is detected in approximately 20% (range 12–40%) of patients with abnormal venous thromboses.
(Choice A) Antiphospholipid antibody syndrome is a common immune cause of hypercoagulability. This condition is defined by the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies) plus one or more of the following: venous thromboembolism, arterial thromboembolism, or frequent fetal loss. Unlike the patient in the vignette, patients with antiphospholipid antibody syndrome typically have a prolonged baseline aPTT. Lupus anticoagulants are the most common cause of aPTT prolongation.
(Choice B) Folic acid deficiency can cause hyperhomocysteinemia, which is a prothrombotic state. However, activated protein C resistance is not seen with this condition.
(Choice D) Endovascular infections and/or systemic inflammatory states may affect vascular endothelial cells in a way that favors thrombosis. However, infection and inflammatory mediators do not directly promote activated protein C resistance in the aPTT coagulation test.
(Choice E) A paraneoplastic syndrome of hypercoagulability may be seen in some patients with cancer, especially patients with adenocarcinomas of the pancreas, colon, or lung. The mechanism of cancer-induced hypercoagulability is thought to involve release of procoagulant tumor products. Vascular stasis due to obstruction of blood flow by the tumor, patient immobility, hepatic involvement and dysfunction, sepsis, and advanced age may also contribute to the tendency toward thrombosis in cancer patients. None of these mechanisms/factors directly promotes activated protein C resistance in the aPTT coagulation test.
Educational Objective:
Inherited causes of hypercoagulability should be considered in patients younger than age 50 who present with thrombosis and no obvious explanation for an acquired prothrombotic state. The factor V Leiden mutation, which causes factor Va resistance to inactivation by activated protein C, may account for approximately 20% of cases of atypical venous thrombosis.
Answer E
Rivaroxaban is a direct oral anticoagulant (DOAC) that binds to and inhibits factor Xa, thereby preventing conversion of prothrombin to thrombin. DOACs are generally preferred over vitamin K antagonists (VKAs) such as warfarin for most conditions requiring prolonged anticoagulation due to less variability in therapeutic effect.
The therapeutic effect of VKAs is affected by changes to dietary intake of vitamin K, disruption to vitamin K– producing intestinal flora (eg, antibiotics), and a wide range of medications that inhibit or induce cytochrome P450 2C9; therefore, patients given VKAs require coagulation monitoring (eg, with INR) to ensure adequate anticoagulation. In contrast, the therapeutic effect of DOACs is not typically altered by environmental or medication changes; therefore, laboratory monitoring is not required. DOACs may also have a lower risk of intracranial bleeding, the most serious risk of anticoagulation, when compared to VKAs.
(Choice A) Rates of patient compliance are roughly equivalent for DOACs and VKAs.
(Choices B and C) Heparin can cause thrombocytopenia due to either heparin-induced thrombocytopenia type I (nonimmune mediated) or type 2 (immune mediated). VKAs target vitamin K–dependent clotting factors (not platelets), so they do not typically cause thrombocytopenia. VKAs and DOACs have roughly the same efficacy.
(Choice D) A loading dose is required with heparin. Some DOACs (eg, rivaroxaban) also require a higher dose for the first few weeks prior to initiating a lower maintenance dose. VKAs do not require a loading dose.
Educational objective:
Direct oral anticoagulants (DOACs) such as rivaroxaban are often preferred over vitamin K antagonists (VKAs) such as warfarin in the treatment of conditions that require anticoagulation due to less variability in therapeutic drug effect; in contrast to VKAs, the efficacy of DOACs is unaffected by dietary changes and most medications. Therefore, patients given DOACs do not require laboratory monitoring.
Answer A
This patient’s intracranial hemorrhage was likely treated with andexanet alfa, a biologic agent that shares homology with factor Xa but has no proteolytic effect. It is administered to patients who have life-threatening bleeding while on a factor Xa inhibitor (eg, rivaroxaban, apixaban). The similarity of andexanet to factor Xa allows it to function as a decoy that binds to factor Xa inhibitors. This restores intravascular coagulation by increasing the availability of endogenous factor Xa, which converts prothrombin to thrombin and generates fibrin clots. Andexanet is reserved for life-threatening bleeding because it is associated with a significant risk of thrombosis.
(Choice B) Aspirin inhibits cyclooxygenase, which prevents platelet aggregation by blocking the generation of thromboxane A2. There is no reversal agent for aspirin widely available. Aspirin does not target factor Xa.
(Choice C) Dabigatran is a direct oral anticoagulant (DOAC) that inhibits circulating and clot-bound thrombin. It is reversed by idarucizumab, a monoclonal antibody fragment that binds to and inhibits dabigatran. Although dabigatran is a DOAC, it targets thrombin rather than factor Xa.
(Choice D) Ticagrelor blocks the P2Y12 adenosine diphosphate receptor on the surface of platelets, which prevents platelet aggregation. Its activity is not mediated by factor Xa.
(Choice E) Warfarin is a vitamin-K antagonist that prevents the generation of vitamin–K dependent clotting factors by blocking epoxide reductase in the liver. It is reversed by the administration of vitamin K.
Educational objective:
Andexanet alfa is a factor Xa decoy that has no proteolytic effect. It is administered to patients on factor Xa inhibitors (eg, rivaroxaban, apixaban) who have life-threatening bleeding in order to reverse the anticoagulation effect.
Answer A
Warfarin is a vitamin K antagonist that blocks epoxide reductase in the liver, leading to impaired vitamin K recycling. This depletes the reduced form of vitamin K, which is required for gamma carboxylation of vitamin K–dependent clotting factors (II, VII, IX, and X). In the absence of gamma carboxylation, vitamin K–dependent clotting factors cannot bind calcium or phospholipid membranes to induce coagulation.
Because warfarin inhibits gamma carboxylation of new vitamin K–dependent clotting factors, therapeutic efficacy is delayed until preexisting clotting factors in the plasma are consumed. Although INR tends to slowly increase in the first few days of administration due to the short half-life of factor VII (4-6 hours), full therapeutic effect does not typically occur for 3 days due to the long half-life of factor II.
Warfarin also inhibits gamma carboxylation of the proteins C and S. Because these proteins exert an anticoagulant effect, the initiation of warfarin can be associated with an initial procoagulant state. However, once preexisting vitamin K–dependent clotting factors are consumed, an anticoagulant effect is established.
(Choice B) Anti-platelet factor 4/heparin antibodies cause heparin-induced thrombocytopenia, which typically arise 5-10 days after heparin initiation. This condition is marked by thrombocytopenia and a high risk of arterial and venous thrombosis, but would not result in a delay in therapeutic INR following warfarin administration.
(Choice C) Total body vitamin K is sufficient for several weeks; it does not contribute to a delay in warfarin efficacy. However, increased intake of foods rich in vitamin K (eg, green leafy vegetables) can lead to subtherapeutic INR due to increased vitamin K availability in the liver.
(Choice D) Warfarin is metabolized by the hepatic cytochrome P450 2C9 enzyme. Because many other medications induce or inhibit this enzyme, warfarin is susceptible to a wide range of drug interactions. However, the delay in achieving therapeutic INR is primarily due to the presence of preexisting clotting factors.
(Choice E) Warfarin reaches maximal plasma concentration approximately 90 minutes after administration. The delay in efficacy is due to the presence of preexisting clotting factors.
Educational objective:
Warfarin blocks epoxide reductase, which lowers the reduced form of vitamin K in the liver; this prevents gamma carboxylation of vitamin K–dependent clotting factors (II, VII, IX, and X). Because warfarin only blocks the generation of new clotting factors, therapeutic effect is delayed 3-5 days until preexisting clotting factors are consumed.
Answer A
Excessive bleeding is common in patients with significant renal dysfunction due in part to the accumulation of uremic toxins in the circulation. These toxins impair platelet aggregation and adhesion, resulting in a qualitative platelet disorder characterized by prolonged bleeding time with normal platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT). Uremic bleeding can be improved with dialysis as it removes the toxins and partially reverses the bleeding abnormality.
(Choice B) von Willebrand factor (vWF) acts as a bridge between glycoprotein 1b receptors and subendothelial collagen, allowing platelets to bind to damaged vessels. vWF deficiency results in platelet dysfunction with a prolonged bleeding time and normal platelet count. Since vWF also protects factor VIII from degradation, vWF deficiency can result in decreased factor VIII and prolonged aPTT.
(Choice C) Isolated aPTT prolongation is seen with hemophilia A, an X-linked disorder caused by factor VIII deficiency. Heparin use also prolongs the aPTT via antithrombin-associated inhibition of factors II and X (PT is usually normal due to the addition of heparin neutralizers in the PT reagent).
(Choice D) Disseminated intravascular coagulation is a consumptive coagulopathy associated with decreased platelet count and increased bleeding time, aPTT, and PT.
(Choice E) Warfarin inhibits vitamin K-dependent clotting factors (II, VII, IX, and X). Warfarin prolongs both PT and aPTT, but PT is increased much more than aPTT. Platelet count and bleeding time are normal.
Education objective:
Abnormal bleeding in patients with uremia is due to a qualitative platelet disorder that causes prolonged bleeding time with normal platelet count, prothrombin time, and activated partial thromboplastin time.
Answer B
This patient with cystic fibrosis (CF) has bruising, epistaxis, and a prolonged PT, findings consistent with vitamin K deficiency. Patients with CF are at increased risk due to a predisposition to pancreatic insufficiency, in which viscous exocrine secretions block pancreatic ducts. Reduced secretion of pancreatic enzymes leads to fat malabsorption and deficiency of fat-soluble vitamins (ie, A, D, E, K).
Vitamin K normally acts as an important cofactor in the hepatic activation of coagulation factors II, VII, IX, and X, as well as proteins C and S. Vitamin K deficiency results in low levels of activated vitamin K–dependent coagulation factors, and prolonged PT is caused by deficiency of activated factor VII. Activated PTT (aPTT) is typically normal, as seen in this patient, although it can be prolonged with severe vitamin K deficiency (due to the effect on factor II).
Vitamin K deficiency presents with easy bruising and mucosal bleeding (eg, epistaxis). Treatment is vitamin K administration, and patients with CF also should receive pancreatic enzyme replacement therapy to improve fat-soluble vitamin absorption.
(Choice A) Factor V is not dependent on vitamin K for activation. Factor V deficiency is rare and leads to prolonged PT and aPTT.
(Choice C) Hemophilia A is an X-linked recessive disorder caused by factor VIII deficiency. As part of the intrinsic pathway, factor VIII deficiency results in prolongation of aPTT with normal PT.
(Choice D) Factor XII (ie, Hageman factor) is part of the intrinsic coagulation pathway and is not vitamin K dependent. Patients with inherited factor XII deficiency are typically asymptomatic but have prolonged aPTT.
(Choice E) Fibrinogen normally assists in coagulation via the final common pathway through fibrin clot formation and platelet binding. Fibrinogen is not dependent on vitamin K for activation. Coagulation disorders involving fibrinogen include severe liver disease and disseminated intravascular coagulation, which are associated with prolonged PT and aPTT.
Educational objective:
Patients with cystic fibrosis are at risk for fat-soluble vitamin (ie, A, D, E, K) deficiency due to fat malabsorption from pancreatic insufficiency. Vitamin K is an important cofactor in the activation of coagulation factors II, VII, IX, and X. Vitamin K deficiency leads to easy bruising, mucosal bleeding, and prolonged PT.
Answer E
This patient’s clinical findings (fever, headache, neck stiffness, rash) and cerebrospinal fluid analysis (elevated protein, low glucose, leukocytosis, gram-negative diplococci) are indicative of meningococcal meningitis; he subsequently developed septic shock (severe hypotension) while in the emergency department. His bleeding from venous puncture sites is highly suggestive of disseminated intravascular coagulation (DIC), a consumptive coagulopathy associated with sepsis, malignancy, trauma, and obstetric complications.
In DIC due to gram-negative sepsis, the coagulation cascade is activated by bacterial endotoxins, leading to widespread fibrin deposition and the consumption of coagulation factors and platelets, with eventual bleeding. Deposition of fibrin strands in small vessels can cause shearing of circulating erythrocytes, resulting in schistocytes (fragmented erythrocytes) on peripheral smear. Laboratory values in DIC typically show decreased platelet count and fibrinogen level and prolonged PT and PTT (indicating a consumption of coagulation factors).
(Choice A) Atypical lymphocytes are reactive lymphocytes with abundant, pale-blue cytoplasm and large nuclei. They are often seen in viral infections, particularly infectious mononucleosis.
(Choice B) Howell-Jolly bodies are round, dark, purple/red inclusions within erythrocytes. These represent nuclear fragments that are typically removed by the spleen; they can be seen in patients with splenectomy or reduced splenic function (eg, sickle cell).
(Choice C) Hypersegmented neutrophils are characterized by nuclei with ≥6 lobes. They are a feature of megaloblastic anemia (vitamin B12 or folate deficiency).
(Choice D) Reactive thrombocytosis is common in infection due to cytokine-mediated megakaryocyte proliferation and the release of platelets into the peripheral bloodstream. In contrast, patients with DIC have thrombocytopenia due to platelet consumption.
(Choice F) Severe pancytopenia is often seen in patients with aplastic anemia, which is characterized by destruction of hematopoietic stem cells and profoundly hypocellular bone marrow. Although patients with severe pancytopenia are at risk for bleeding, oozing from venipuncture sites in the setting of sepsis almost always indicates DIC.
Educational objective:
Disseminated intravascular coagulation is a common complication of gram-negative bacterial sepsis due to activation of the coagulation cascade by bacterial endotoxins, which leads to the formation of microthrombi. Peripheral smear shows fragmented erythrocytes (schistocytes) and thrombocytopenia. Laboratory tests show decreased fibrinogen levels and prolonged PT and PTT.
Answer E
This patient with extreme hyperthermia and seizures has exertional heat stroke, a life-threatening multisystem disorder caused by inadequate body heat dissipation. Severe hyperthermia increases tissue oxygen demand and metabolic rate and shunts blood away from the central organs (eg, brain, kidneys, liver, GI tract) to the skin to dissipate heat. This can lead to tissue ischemia/necrosis and the release of procoagulant proteins (eg, tissue factor), which can trigger disseminated intravascular coagulation (DIC).
DIC is marked by the excessive activation of the extrinsic (tissue factor) coagulation cascade, leading to the generation of thrombin and cross-linked fibrin clots. **Fibrinolysis is then activated **to clear the intravascular thrombi; plasminogen is converted to plasmin, which cuts the cross-linked fibrin-fibers and generates fibrin-degradation products (eg, elevated D-dimer). Other anticoagulant proteins (eg, protein C, protein S) are also rapidly consumed.
Patients with acute DIC usually have bleeding (eg, oozing from venipuncture sites) and end organ damage (eg, confusion, lung injury, renal insufficiency); laboratory studies are diagnostic and show thrombocytopenia (due to consumption of platelets) and prolonged PT/PTT (due to consumption of coagulation factors).
Educational objective:
Disseminated intravascular coagulation is marked by widespread activation of the coagulation cascade, leading to excessive thrombin production and formation of microthrombi. Subsequent conversion of plasminogen to plasmin results in increased fibrinolysis to clear the thrombi. Laboratory studies show a consumption of clotting factors (prolonged PT/PTT) and platelets (thrombocytopenia) and signs of excessive fibrinolysis (eg, elevated D-dimer).
Answer C
This patient presents with findings consistent with acute coronary syndrome, with ongoing injury as evidenced by the positive troponin. An important component of therapy involves not only treating the existing clot but also preventing its propagation. The coagulation cascade amplifies the generation of thrombin, which activates platelets to form a plug and also helps convert fibrinogen to fibrin to reinforce the platelet plug. Antithrombin can inhibit both Factor Xa in the coagulation cascade and also thrombin.
Both unfractionated heparin and low molecular weight heparin (LMWH) contain a pentasaccharide sequence that binds to antithrombin and causes a conformational change that increases its ability to inactivate Factor Xa. However, heparin must bind to both antithrombin and thrombin together to form a ternary complex to inactivate thrombin. Only unfractionated heparin (not LMWH) has a pentasaccharide chain long enough (>18 saccharide units) to bind to both antithrombin and thrombin. As a result, unfractionated heparin has equal activity against Factor Xa and thrombin, while LMWH has greater activity against Factor Xa than thrombin.
(Choice A) Enoxaparin is a low molecular weight heparin that has fewer of the required long saccharide units that bind to thrombin and less antithrombotic activity compared to unfractionated heparin.
(Choice B) Fondaparinux is a synthetic pentasaccharide Factor Xa inhibitor. It has none of the required long saccharide units that bind to thrombin and much lower antithrombin activity compared to unfractionated heparin.
Educational objective:
Both unfractionated heparin and LMWH can bind to antithrombin to increase its activity against Factor Xa. Only unfractionated heparin is able to bind to both antithrombin and thrombin to allow antithrombin to inactivate thrombin.
Answer A
This patient with multiple injuries following a severe motor vehicle accident developed respiratory distress, reduced renal output, and oozing from the catheter and venipuncture sites. This presentation raises strong suspicion for disseminated intravascular coagulation (DIC), a consumptive coagulopathy associated with trauma, sepsis, malignancy, and obstetrical complications.
In DIC due to trauma, the coagulation cascade is triggered by damage to the vascular endothelium (exposes tissue factor) and tissues (releases procoagulant proteins and phospholipids). This leads to the generation of fibrin- and platelet-rich microvascular thrombi, which consumes platelets, coagulation factors (eg, low factor VII), and fibrinogen. Fibrinolysis and anticoagulant proteins then dissolve the clots, which depletes protein C, protein S, and antithrombin.
Most patients with acute DIC develop bleeding complications such as oozing from catheters/venipuncture sites, ecchymosis, and petechiae. End organ damage to the kidneys (eg, renal insufficiency) and lungs (eg, pulmonary hemorrhage) is common. Many patients also have microangiopathic hemolytic anemia (eg, schistocytes) due to shearing of red blood cells by intravascular thrombi.
Educational objective:
Acute disseminated intravascular coagulation is a consumptive coagulopathy linked to severe trauma. Widespread formation of microvascular thrombi leads to consumption of platelets, coagulation factors, and fibrinogen. Subsequent activation of anticoagulant proteins leads to low protein C/S; fibrinolysis elevates D-dimer. Most patients have bleeding complications (eg, oozing from venipuncture/catheter sites) and end organ damage to the lungs or kidneys.
Answer C
Unfractionated heparin (UFH) and low-molecular weight heparins (LMWHs) are commonly used anticoagulants in the hospital setting. Heparin increases the effect of the naturally occurring anticoagulant antithrombin III (ATIII). Activated partial thromboplastin time (aPTT) is measured to monitor the therapeutic effect of heparin. Bleeding and heparin-induced thrombocytopenia are serious complications of heparin therapy. Bleeding due to heparin toxicity is treated with protamine sulfate, a specific antagonist. Protamine sulfate is a peptide that binds to heparin, forming a complex that has no anticoagulant activity. Although protamine is often used in the management of LMWH toxicity, it does not completely reverse the anti-Xa activity of LMWH.
Vitamin K is used for reversal of warfarin overdose but requires new synthesis of coagulation factors. As a result, its full effect takes time to manifest. For this reason, in the setting of acute life-threatening bleeding due to warfarin, fresh frozen plasma (FFP) (contains all blood proteins and clotting factors) should be given. However, FFP is not useful for heparin overdose as it contains ATIII, which can further potentiate the effects of heparin. Prothrombin complex concentrates (PCCs), which contain the vitamin K-dependent factors II, VII, IX, and X, can be used to treat bleeding due to warfarin (not heparin) overdose (Choices A, D, and F).
(Choices B and E) Platelet function is not affected by warfarin therapy. Aminocaproic acid and tranexamic acid inhibit fibrinolysis by inhibiting plasminogen activation.
Educational objective:
Protamine sulfate binds to heparin, causing chemical inactivation. Vitamin K and fresh frozen plasma can be used to reverse warfarin effects.
Answer A
This patient with chest pain, ST depressions, and mild troponin elevation appears to be experiencing a myocardial infarction. Enoxaparin is a form of low-molecular-weight heparin (LMWH) that, like heparin, functions by binding antithrombin III (AT III) via a pentasaccharide sequence. Once activated, AT III binds to factor Xa and stops factor Xa from converting prothrombin to thrombin. Less thrombin is produced, resulting in an anticoagulant effect.
Unfractionated heparin has more molecules than LMWH, allowing it to bind factor Xa and thrombin; it is more effective than LMWH in inactivating thrombin.
(Choices B and C) Tissue plasminogen activator (t-PA) converts plasminogen to plasmin. Plasmin functions to break down fibrin, resulting in thrombolysis. Because t-PA can only bind plasminogen strongly in the presence of fibrin, its thrombolytic action is clot specific.
(Choice D) Protein C and protein S are endogenous antithrombotic molecules that are also vitamin K-dependent. Due to their shorter half-lives in the circulation, these molecules are depleted first during initiation of warfarin therapy, causing a transient procoagulant state. For this reason, patients are typically treated with heparin or LMWH during initiation of warfarin therapy.
(Choice E) Prothrombin (factor II) is a vitamin K-dependent clotting factor. This factor, along with factors VII, IX, and X, is depleted by warfarin. LMWHs inhibit prothrombin production (through factor X inhibition), but they do not directly bind prothrombin.
Educational objective:
Enoxaparin is a low-molecular-weight heparin (LMWH) that functions like heparin in that it binds and activates antithrombin III (AT III). Activated AT III binds to factor Xa and stops factor Xa from converting prothrombin to thrombin. Due to its fewer number of molecules, LMWH acts primarily on factor Xa, not thrombin.
Answer D
This patient has palpitations, an irregular pulse, and ECG findings consistent with atrial fibrillation. Treatment with a rate control medication (eg, metoprolol) reduces atrioventricular conduction and limits ventricular tachycardia, which helps prevent symptoms (eg, palpitations, dizziness) and risk of cardiomyopathy. However, rate control agents do not inhibit uncoordinated atrial contraction, so patients remain at risk for atrial thrombus and embolic stroke. As a result, most patients are also initiated on anticoagulation.
Direct factor Xa inhibitors (eg, apixaban) are often used for stroke prevention in atrial fibrillation as they are administered orally and do not require monitoring of drug levels (unlike warfarin). This class of medications blocks the active site of factor Xa, which prevents it from converting prothrombin to thrombin. Direct factor Xa inhibitors are denoted by names that end in “Xa-ban.”
(Choice A) The conversion of factor X to factor Xa is the beginning the final common pathway of the coagulation cascade and is triggered by factor VIIIa (intrinsic pathway) and tissue factor (extrinsic pathway). Factor Xa inhibitors block conversion of prothrombin to thrombin, not factor X to factor Xa.
(Choice B) Factor Xa inhibitors reduce the conversion of fibrinogen to fibrin. However, this is a downstream (not direct) effect that occurs as a result of decreased thrombin levels.
(Choice C) Tissue plasminogen activator is a fibrinolytic enzyme that increases the conversion of plasminogen to plasmin. It is primarily used to lyse ongoing clots in patients with acute ischemic strokes.
(Choice E) Warfarin inhibits vitamin K epoxide reductase, which decreases the reduced form of vitamin K and limits gamma-carboxylation of vitamin K–dependent coagulation factors (II, VII, IX, X).
Educational objective:
Direct factor Xa inhibitors (eg, apixaban) are anticoagulants that block the active site of factor Xa, which leads to reduced conversion of prothrombin to thrombin. This class of medications is administered orally and requires no drug level monitoring.
Answer C
This pregnant patient with new bleeding from the gums and catheter sites likely has disseminated intravascular coagulation (DIC), a life-threatening complication that can occur with postpartum hemorrhage, abruptio placentae, or amniotic fluid embolism. This patient has DIC due to abruptio placentae (ie, placental bleeding between the uterine wall and placenta), which results in premature placental separation, fetal hypoxia, and in severe cases, fetal demise. Patients with abruptio placentae typically have vaginal bleeding, uterine rigidity and/or tenderness, and contractions. Maternal hypertension (eg, preeclampsia) and tobacco use are risk factors.
Severe placental abruption (eg, retroplacental hematoma) causes decidual damage and ischemia, thereby triggering tissue factor release into the maternal circulation. Tissue factor, a procoagulant, then activates the extrinsic pathway of the coagulation cascade to cause excessive thrombin generation with formation of circulating platelet-fibrin microthrombi. As clotting factors and platelets are rapidly consumed, a consumptive coagulopathy (eg, thrombocytopenia, prolonged PT & aPTT) develops that results in profound bleeding, classically from mucosal surfaces and intravenous line sites.
(Choice A) Amniotic fluid embolism (AFE) introduces fetal antigens and tissue factor from the amniotic fluid into the maternal circulation, triggering a massive immune response and increased release of procoagulant factors that can lead to DIC. However, AFE typically causes maternal circulatory collapse with severe hypotension, making this diagnosis less likely in this patient.
(Choice B) An ascending polymicrobial infection of the endometrial lining (eg, postpartum endometritis) can cause uterine tenderness, vaginal bleeding, and sepsis, thereby precipitating DIC. However, patients typically also have fever and hypotension.
(Choice D) Acute fatty liver of pregnancy, characterized by microvesicular fatty infiltration of hepatocytes, can impair maternal hepatic function, reducing production of clotting factors and impairing clearance of fibrin degradation products, which may result in DIC. However, patients typically have elevated liver transaminases.
(Choice E) Complete uterine rupture through the endometrium, myometrium, and serosa can cause vaginal bleeding, abdominal pain, and fetal compromise. However, patients usually have had a prior uterine surgery and present with palpable fetal parts protruding through the disrupted uterine wall rather than a firm, tense uterus.
Educational objective:
Disseminated intravascular coagulation (DIC) can occur with abruptio placentae due to release of tissue factor, a procoagulant that activates the coagulation cascade, from the damaged decidua into the maternal circulation. DIC classically presents with thrombocytopenia and bleeding from mucosal surfaces (eg, gums) and intravenous line sites.
Answer C
This patient with Crohn disease has epistaxis, bruising, and prolonged PT and PTT that are corrected with an intravenous medication. This presentation is consistent with vitamin K deficiency. Intestinal diseases associated with malabsorption (eg, inflammatory bowel disease [IBD]) are a risk factor for vitamin K deficiency. Infectious complications of IBD may also require frequent antibiotics, another possible contributing factor.
Vitamin K is a cofactor for gamma-glutamyl carboxylase, an enzyme required for the activation of coagulation factors II (prothrombin), VII, IX, and X. These factors are produced in the liver as inactive forms. The carboxylase enzyme converts glutamic acid residues to gamma-carboxyglutamic acid in the hepatocyte endoplasmic reticulum (ie, posttranslational carboxylation). Carboxylation allows the coagulation proteins to bind calcium ions in the blood and subsequently adhere to the platelet’s negatively charged phospholipid bilayer, resulting in efficient coagulation.
Vitamin K deficiency leads to decreased coagulation factor activity, which predisposes to bruising and mucosal bleeding. Patients have prolonged PT and, in severe cases, PTT. Vitamin K replacement allows for carboxylation of vitamin K–dependent coagulation factors and reverses the coagulopathy.
(Choice A) Some chemotherapeutic medications alter gene expression by affecting epigenetic modifications (eg, DNA methylation). Azacitidine, used to treat myelodysplastic syndrome, inhibits DNA methyltransferase, leading to hypomethylation and increased expression of tumor suppressor genes.
(Choice B) RNA processing (posttranscriptional modification) includes 5′ capping, polyadenylation, and splicing. Targeting splicing machinery is a new approach for treating several neoplastic/genetic diseases; for example, eteplirsen may be used to treat Duchenne muscular dystrophy.
(Choice D) Certain chemotherapeutic agents (eg, dactinomycin, doxorubicin) interfere with transcription by intercalating in DNA, therefore preventing RNA synthesis.
(Choice E) Asparaginase, used in the treatment of acute lymphoblastic leukemia/lymphoma, interferes with protein translation within the leukemic cells by reducing the amount of asparagine available.
Educational objective:
Vitamin K is a cofactor for gamma-glutamyl carboxylase, an enzyme that activates coagulation factors II, VII, IX, and X via posttranslational gamma carboxylation. Intestinal diseases associated with malabsorption (eg, inflammatory bowel disease) are a risk factor for vitamin K deficiency, which typically presents with mucosal bleeding, bruising, and prolonged PT and PTT (if severe).
Answer E
This patient who is thin and disoriented has ecchymoses and gingival bleeding with normal platelets and coagulation factors. These findings are suggestive of vitamin C (ascorbic acid) deficiency (scurvy), which typically occurs due to insufficient intake (eg, chronic alcohol use, malnourishment, restrictive diets). This patient’s disorientation and thin body habitus are concerning for possible malnutrition and/or chronic substance use.
Vitamin C is a water-soluble vitamin that functions as a cofactor in collagen synthesis. Impaired collagen synthesis results in cutaneous signs of scurvy, including phrynoderma (perifollicular hyperkeratosis), coiled hair, and poor wound healing. Fragility of vasculature due to poor connective tissue strength can lead to hemorrhagic complications involving the mucosa (eg, gingival bleeding), skin (eg, ecchymoses, petechiae), and musculoskeletal system (eg, subperiosteal/intramuscular hemarthrosis causing limp/arthralgias).
Patients with scurvy frequently have anemia, which may be normocytic due to blood loss within tissues or microcytic due to associated poor iron intake or absorption. However, coagulation studies (PT, PTT) are normal (although exposed endothelial collagen normally activates the intrinsic clotting cascade, the in vitro PTT test uses alternate activating substances [eg, kaolin] and is not affected by defective collagen).
(Choice A) Endothelial cell dysfunction in von Willebrand disease can lead to bleeding symptoms but would cause a prolonged PTT. In addition, this patient’s thin habitus, disorientation, and anemia make vitamin C deficiency more likely than an inherited bleeding disorder.
(Choice B) Deficiency in vitamin K, a fat-soluble vitamin, can lead to easy bruising and mucosal bleeding, but PT would be prolonged.
(Choice C) Defective clotting factor production in liver disease can lead to easy bleeding, but prolongation of PT (and sometimes PTT) is expected.
(Choice D) Platelet dysfunction in chronic kidney disease can cause easy bruising and mucosal bleeding with a normal platelet count and coagulation studies. However, this patient’s normal creatinine level is inconsistent with declining kidney function, and azotemia alone (eg, due to dehydration) is not associated with platelet dysfunction.
(Choice F) Zinc deficiency can present with an erosive dermatitis involving the perioral region, but gingival bleeding or easy bruising would be unexpected.
Educational objective:
Deficiency of vitamin C, a water-soluble vitamin, results in impaired collagen production. Manifestations include cutaneous findings of coiled hair and perifollicular keratosis, in addition to hemorrhagic complications such as gingival bleeding and easy bruising. PT, PTT, and platelet count are normal.
