Hemostasis & Thrombosis Pathology & Pharmacology- 1 Flashcards
Answer I
This patient with pleuritic chest pain, dyspnea, tachypnea, tachycardia, and hypoxia most likely experienced a recurrent pulmonary embolism (PE) in the setting of a subtherapeutic INR level, reflecting decreased warfarin efficacy. Warfarin is an oral anticoagulant that inhibits activation of vitamin K–dependent clotting factors, particularly factor VII. As a result, warfarin administration leads to prolongation of the prothrombin time (PT) and INR (ratio of a patient’s PT compared to a normal control). In patients with atrial fibrillation, deep venous thrombosis, or PE who are taking warfarin for anticoagulation, the dose is usually adjusted to achieve a target therapeutic INR range (generally 2.0-3.0).
Precise dosing of warfarin can be difficult due to its many interactions with other drugs that affect cytochrome P-450 activity, plasma protein binding, and/or gastrointestinal absorption. Warfarin elimination occurs primarily through hepatic metabolism by cytochrome P-450 enzymes. Drugs that increase P-450 activity, such as phenytoin, phenobarbital, and rifampin, increase warfarin elimination and decrease its anticoagulant activity (reflected as a subtherapeutic INR <2.0). Cholestyramine binds warfarin (and other drugs) in the intestine, thereby decreasing warfarin’s therapeutic effect.
(Choices A, C, and F) When used concurrently with warfarin, aspirin and other nonsteroidal anti-inflammatory drugs such as indomethacin increase the risk of bleeding due to antiplatelet effects and gastrointestinal ulceration. These drugs can also displace warfarin from plasma protein binding sites (increasing the concentration of free warfarin). Acetaminophen can interfere with vitamin K metabolism and enhance the effect of warfarin.
(Choices B, D, and G) Both cimetidine and amiodarone inhibit the metabolism of warfarin, which can result in an increased PT/INR and bleeding risk. The interaction between amiodarone and warfarin is important because some patients with atrial fibrillation may be prescribed both medications. The commonly used antibiotics metronidazole and trimethoprim-sulfamethoxazole also inhibit warfarin metabolism.
(Choices E and H) Benzodiazepines and opiates usually do not interact significantly with warfarin.
Educational objective:
Rifampin, phenobarbital, and phenytoin are potent enhancers of the cytochrome P-450 pathway; concurrent use of warfarin with these medications results in decreased efficacy of warfarin. In contrast, cimetidine, amiodarone, and trimethoprim-sulfamethoxazole inhibit warfarin metabolism, increasing the risk of bleeding.
Answer E
This patient’s ECG (irregularly irregular rhythm with absent P waves) suggests atrial fibrillation (AF), which alters cardiac flow dynamics, making thrombus formation more common. If this thrombus detaches from the atrial wall, there is a risk of stroke. The oral anticoagulant warfarin (Coumadin) reduces thrombus formation risk by inhibiting the activation of vitamin K-dependent clotting factors II, VII, IX, and X (vitamin K antagonist). This leads to decreased levels of these factors, particularly factor VII, and therefore prolongs the prothrombin time (PT). Another useful laboratory value is the International Normalized Ratio (INR), a ratio of the patient’s PT to a control (usual INR target for AF: 2.0-3.0). Examples of indications include AF, deep venous thrombosis, and pulmonary thromboembolism. Outpatients who take warfarin typically have their INR checked every few weeks (more frequently initially).
The most common side effect is excessive anticoagulation leading to bleeding (which can require vitamin K and fresh frozen plasma if rapid reversal is needed). Skin necrosis can occur during the first few days of treatment due to a transient hypercoagulable state (reduction in protein C anticoagulant activity before affecting other factors’ procoagulant activity); for this reason, heparin is typically administered temporarily at the start of warfarin therapy (“heparin bridge”). Warfarin should not be used during pregnancy because it is teratogenic and can cause fetal bleeding.
(Choice A) Activated partial thromboplastin time (aPTT) is used to monitor unfractionated heparin, which primarily affects the intrinsic coagulation pathway.
(Choice B) Bleeding time is used for the assessment of platelet function. Increased bleeding time can be seen with thrombocytopenia, von Willebrand disease, defects of platelet aggregation, disseminated intravascular coagulation (DIC), and aspirin therapy.
(Choices C and D) The combination of a decreased fibrinogen level and the presence of fibrin split products (such as D-dimer) is characteristic of DIC.
Educational objective:
Warfarin is an oral anticoagulant that inhibits the carboxylation of vitamin K-dependent coagulation factors II, VII, IX, and X. It is used in atrial fibrillation, deep venous thrombosis, and pulmonary thromboembolism. Prothrombin time (PT)/International Normalized Ratio (INR) should be monitored regularly during treatment with warfarin. Activated partial thromboplastin time (aPTT) is used for monitoring unfractionated heparin.
Answer C
This patient has deep venous thrombosis, which is typically treated with anticoagulation therapy for >3 months to prevent recurrent thrombosis. Initial treatment is often with heparin agents (eg, unfractionated heparin, low-molecular-weight heparin, fondaparinux), followed by bridging to an oral anticoagulant (most commonly warfarin). Additional treatment options include direct factor Xa inhibitors (eg, apixaban, rivaroxaban) and direct thrombin inhibitors (eg, dabigatran).
In general, medications that affect the extrinsic pathway prolong the prothrombin time (PT), whereas inhibition of the intrinsic pathway mainly prolongs the activated partial thromboplastin time (aPTT). The thrombin time (TT) is prolonged with medications that directly or indirectly inhibit thrombin. Because factor Xa is located at the junction of the intrinsic and extrinsic pathways, direct factor Xa inhibitors prolong both **aPTT and PT **with no effect on TT.
(Choice A) Cyclooxygenase inhibitors (eg, aspirin) directly inhibit platelet activity and have little overall effect on aPTT, PT, or TT.
(Choice B) Direct factor VIIa inhibitors are currently in development and work by inhibiting the extrinsic pathway of the coagulation cascade. Therefore, they would prolong PT with no effect on aPTT or TT.
(Choice D) Direct thrombin inhibitors (eg, dabigatran) prevent the formation of thrombin (factor IIa), resulting in prolongation of aPTT, PT, and TT.
(Choice E) Unfractionated heparin binds to antithrombin and causes inactivation of several coagulation factors, most significantly thrombin and factor Xa. As a result, aPTT and TT will be prolonged. Although the PT should theoretically be prolonged by the action of heparin on the final common pathway, in practice, the PT reagent contains heparin neutralizers that minimize this effect.
Educational objective:
Direct factor Xa inhibitors (eg, apixaban, rivaroxaban) increase the prothrombin and activated partial thromboplastin times but do not affect the thrombin time. Unfractionated heparin and direct thrombin inhibitors (eg, dabigatran) prolong the thrombin time.
Answer B
This patient has right lower extremity proximal deep venous thrombosis (DVT), with his recent long flight from Japan being a possible risk factor. Many patients with DVT receive long-term anticoagulation with warfarin. Alternates include direct **factor Xa **inhibitors (eg, rivaroXaban, apiXaban), which bind to the active site of factor Xa and prevent thrombin formation. These drugs can be administered orally as monotherapy and do not require laboratory monitoring. They are used for venous thromboembolism treatment as well as for stroke prophylaxis in patients with atrial fibrillation (who are at risk for embolic stroke).
(Choice A) Factor VIII replacement (not inhibition) is the mainstay of hemophilia A treatment.
(Choice C) Eptifibatide inhibits platelet aggregation and thrombosis by blocking the glycoprotein IIb/IIIa receptor, which is the binding site for fibrinogen. This drug is typically used in acute coronary syndrome and in patients undergoing percutaneous coronary intervention.
(Choice D) Ticagrelor binds the adenosine diphosphate (ADP) P2Y12 receptor on platelets, which prevents platelet aggregation by blocking ADP-mediated activation of the glycoprotein IIb/IIIa receptor complex. This drug is also used in acute coronary syndrome and in patients undergoing percutaneous coronary intervention.
(Choice E) Dabigatran is an oral direct thrombin inhibitor that inactivates both circulating and clot-associated thrombin. It is also used for treatment of thromboembolic disease and stroke prophylaxis in atrial fibrillation.
Educational objective:
Rivaroxaban is an oral anticoagulant that directly inhibits factor Xa. It is used in venous thromboembolism and atrial fibrillation.
Answer E
The major clinical manifestations of factor V Leiden include deep vein thrombosis (DVT), cerebral vein thrombosis, and recurrent pregnancy loss. Because pulmonary thromboembolism occurs in approximately 50% of all individuals with untreated DVTs, the young woman presented here is at significant risk of developing a pulmonary thromboembolism at some point in her lifetime.
Factor V Leiden is a common cause of inherited thrombophilia. Heterozygote carriers of factor V Leiden have five to ten times the risk of developing a thrombosis, while homozygote carriers of factor V Leiden have fifty to one hundred times the risk of developing a thrombosis.
Factor V Leiden causes thrombophilia through two pathophysiological mechanisms. In normal hemostasis, activated protein C (APC) restricts clot formation by proteolytically inactivating factors Va and VIIIa. Factor Va Leiden has reduced susceptibility to cleavage by APC, however. Because factor Va is a cofactor in the conversion of prothrombin to thrombin, persistently circulating factor Va Leiden results in increased thrombin production. Additionally, factor V Leiden is unable to support APC anticoagulant activity. This combination of increased coagulation and decreased anticoagulation produces the hypercoagulable state seen in those with factor V Leiden.
(Choice A) Petechiae and ecchymoses are more consistent with qualitative or quantitative platelet abnormalities than factor V Leiden.
(Choice B) Recurrent hemarthroses are suggestive of hemophilia (factor VIII or IX deficiency), not factor V Leiden.
(Choice C) Renal artery stenosis is primarily caused by atherosclerosis and fibromuscular disease, not thrombosis. Moreover, factor V Leiden is associated with an increased risk of deep venous (not arterial) thrombosis.
(Choice D) Major causes of splenic infarction include sickle cell anemia, infectious endocarditis, and myeloproliferative disorders. Moreover, the factor V Leiden mutation is associated with deep venous (not arterial) thrombosis.
Educational Objective:
Heterozygote carriers of a mutation in factor V Leiden, which is modified to resist activated protein C, have a hypercoagulable state that predisposes to deep vein thromboses (the source of most pulmonary emboli).
Answer C
This patient’s costovertebral angle tenderness, dysuria, and leukocytosis are indicative of acute pyelonephritis complicated by septic shock (hypotension, tachycardia). Her laboratory results show a consumptive coagulopathy (thrombocytopenia, prolonged PT/PTT, low fibrinogen), which, along with bleeding from the central catheter site, are likely due to disseminated intravascular coagulation (DIC).
DIC is a common complication of sepsis (particularly with gram-negative organisms) because lipopolysaccharide is a procoagulant that triggers the coagulation cascade. This leads to the formation of fibrin- and platelet-rich thrombi in the vasculature, which consumes platelets (thrombocytopenia), coagulation factors (prolonged PT/PTT), and fibrinogen. Fibrinolysis is then triggered to degrade the clots, which elevates D-dimer (a fibrin degradation product) and depletes protein C, protein S, and antithrombin. The thrombi also often shear red blood cells, leading to microangiopathic hemolytic anemia (MAHA).
Most patients with acute DIC have signs of bleeding, such as oozing from vascular catheters, mucocutaneous bleeding, ecchymosis, or petechiae. End organ damage (eg, renal insufficiency, pulmonary hemorrhage) is also common.
(Choice A) Anticardiolipin antibody is antiphospholipid antibody often seen in patients with lupus erythematosus. It can cause antiphospholipid antibody syndrome, which is marked by thromboembolism and fetal loss (not bleeding). Although patients often have prolonged PTT (because the antiphospholipid interferes with the PTT test), PT is normal.
(Choice B) Thrombotic thrombocytopenic purpura (TTP) is caused by reduced activity of von Willebrand factor–cleaving protein ADAMTS13, leading to the accumulation of ultra-large von Willebrand factor multimers that trap platelets and generate platelet-rich thrombi in the microvasculature. Although patients usually develop thrombocytopenia, MAHA, fever, confusion, and organ damage (eg, acute renal failure), the coagulation cascade is unaffected; therefore, PT/PTT and fibrinolysis (fibrinogen level) are normal, and bleeding does not occur.
(Choice D) Immune (idiopathic) thrombocytopenic purpura (ITP) is marked by autoantibodies to platelets/megakaryocytes; thrombocytopenia is the only peripheral blood abnormality. Coagulation studies (eg, PT, PTT) and fibrinogen levels are normal. Spontaneous bleeding is very uncommon unless the platelet count is <10,000/mm3.
(Choice E) The liver generates thrombopoietin and the majority of clotting factors. Therefore, patients with significantly impaired hepatic function (eg, cirrhosis) sometimes have mild thrombocytopenia and prolonged coagulation studies. However, fibrinogen level is usually normal and this patient has no other signs of advanced hepatic dysfunction (eg, ascites, jaundice).
Educational objective:
Disseminated intravascular coagulation commonly occurs in the setting of sepsis and is characterized by widespread activation of the coagulation cascade with formation of microthrombi. Laboratory results reveal prolonged PT/PTT, thrombocytopenia, and low fibrinogen (ie, a consumptive coagulopathy), and patients usually have signs of bleeding (eg, oozing from venipuncture sites).
Answer D
Pregnancy increases the risk of venous thromboembolism (VTE) due to anatomic changes (eg, uterine compression of the inferior vena cava and iliac veins) and physiologic hypercoagulability (eg, increased production of clotting factors, decreased protein S levels, protein C resistance). Heparins are ideal anticoagulants for most pregnant women as they do not cross the placenta and the risk of fetal bleeding and teratogenicity is low:
Low-molecular-weight heparin (LMWH) (eg, enoxaparin, dalteparin) is preferred as it has a relatively long half-life (4.5 hours) and does not require routine laboratory monitoring. However, it is renally cleared and cannot be used in patients with severe renal insufficiency (creatinine clearance <30 mL/min).
Unfractionated heparin has a short half-life (1-2 hours) and requires frequent lab draws (ie, PTT) due to its more varied anticoagulant effect. However, it may be used in patients with renal insufficiency. It is also used in place of LMWH at term (37 weeks gestation) as it can be discontinued at the onset of labor to minimize hemorrhagic risk.
(Choices A and C) Direct thrombin inhibitors (eg, dabigatran) and factor Xa inhibitors (eg, apixaban) are not recommended in pregnant women. Both have been associated with fetal toxicity in animal studies.
(Choices B and E) Clopidogrel and aspirin have no role in acute VTE treatment. Clopidogrel, which blocks the platelet adenosine diphosphate receptor and limits platelet aggregation, is used in treatment of coronary artery disease, acute coronary syndrome, and prevention of recurrent ischemic stroke. Low-dose aspirin is prescribed to certain pregnant patients at risk of preeclampsia.
(Choice F) Recombinant tissue plasminogen activator is used for clot lysis. It has a high risk of major bleeding and is typically reserved for those with massive deep vein thrombosis at risk of limb ischemia or life-threatening pulmonary embolism with hypotension. Anticoagulation alone is preferred for VTE in hemodynamically stable patients.
(Choice G) Warfarin crosses the placenta, increasing risks of teratogenicity and fetal hemorrhage, and is typically avoided in pregnancy.
Educational objective:
Heparins are ideal anticoagulants for most patients with thromboembolic disease in pregnancy as they do not cross the placenta and therefore the risk of fetal bleeding or teratogenicity is low. Low molecular weight heparin (eg, enoxaparin) is the preferred therapy, with patients transitioned to unfractionated heparin at term.
Answer A
This patient’s hemarthroses and excessive bleeding following tooth extraction are suggestive of a coagulopathy (ie, clotting factor deficiency). Coagulopathies generally present with deep-tissue bleeding into joints, muscles, and subcutaneous tissue. In contrast, platelet defects typically manifest with mucocutaneous bleeding (eg, epistaxis, petechiae). The patient’s laboratory results show a normal bleeding time, normal activated partial thromboplastin time (aPTT), and a prolonged prothrombin time (PT). The normal bleeding time indicates adequate platelet function, and the normal aPTT indicates an intact intrinsic coagulation system. However, the prolonged PT indicates a defect in the extrinsic coagulation pathway. Therefore, the patient is most likely deficient in factor VII.
(Choice B) Factor VIII deficiency results in classic X-linked hemophilia A. Coagulation studies will show a normal bleeding time, normal PT, and prolonged aPTT.
(Choice C) Factor XI deficiency results in a rare autosomal recessive disorder called hemophilia C. Spontaneous bleeding is rare in this condition, but affected patients are at increased risk for bleeding following surgery or trauma. Coagulation studies will show a prolonged aPTT and normal PT.
(Choice D) Hageman factor (factor XII) deficiency is an autosomal recessive disorder that does not typically cause clinically significant bleeding despite aPTT prolongation.
(Choice E) von Willebrand factor (vWF) functions as both a carrier molecule for factor VIII (protecting it from being degraded) and as a mediator of platelet adhesion to the endothelium. It presents with prolonged bleeding time and normal/prolonged aPTT.
Educational objective:
A normal bleeding time indicates adequate platelet hemostatic function. A normal activated partial thromboplastin time (aPTT) indicates an intact intrinsic coagulation system. Prolonged prothrombin time in the setting of normal aPTT indicates a defect in the extrinsic coagulation system at a step that is not shared with the intrinsic system.
A 72-year-old man comes to the emergency department due to severe chest tightness and dyspnea that started 20 minutes ago at a family dinner. He has never experienced similar symptoms before. The patient’s medical conditions include hypertension, hyperlipidemia, type 2 diabetes mellitus, and prostate cancer. He takes multiple medications and has no drug allergies. The patient smoked a pack of cigarettes daily for 30 years but stopped smoking 10 years ago. Chest CT scan with contrast is shown in the image below.
Which of the following factors most likely contributed to this patient’s current condition?
A. Atherosclerosis
B. Fluid overload
C. Hypercoagulability
D. Intimal tear
E. Noninfectious vasculitis
F. Pulmonary bleb rupture
G. Pulmonary metastasis
Answer C
This patient is experiencing sudden-onset chest tightness and dyspnea, and CT scan of the chest shows a saddle pulmonary embolism (PE) straddling the bifurcation of the main pulmonary artery. The main pulmonary artery, usually comparable in diameter to the ascending aorta, is significantly dilated due to the proximal increase in hydrostatic pressure from the PE. Saddle PE can result in sudden cardiac death or severe hypotension, but many patients can be hemodynamically stable on presentation.
Venous thromboembolism (VTE) (ie, PE or deep venous thrombosis) results from the Virchow triad of endothelial injury, venous stasis, and a hypercoagulable state. Malignancy (eg, prostate cancer) induces a hypercoagulable state and is a strong risk factor for VTE. Active smoking is also a risk factor as it contributes to endothelial injury and a hypercoagulable state. Age plays a role as well, as older individuals tend to be more sedentary and are more prone to venous stasis.
(Choice A) Atherosclerosis primarily affects the higher pressure arteries in the systemic circulation (eg, aorta, popliteal arteries, carotid arteries) and the coronary arteries. Significant atherosclerosis in the relatively low-pressure pulmonary arteries is rare.
(Choice B) Fluid overload causes pulmonary edema, typically appearing as alveolar ground glass opacities on CT scan. This patient’s lungs appear clear of airspace disease.
(Choice D) An intimal tear can lead to aortic dissection, which classically manifests as severe chest pain radiating to the back. Pulmonary artery dissection is extremely rare.
(Choice E) Pulmonary vasculitis (eg, granulomatosis with polyangiitis) could cause dyspnea and chest tightness but would demonstrate an interstitial pattern on CT scan, sometimes leading to pulmonary hemorrhage.
(Choice F) Rupture of pulmonary blebs (thin-walled, air-filled subpleural structures) leads to pneumothorax.
(Choice G) For pulmonary metastasis to cause significant dyspnea, multiple lesions would likely be present. There is no evidence of lung masses on this patient’s CT scan.
Educational objective:
Saddle pulmonary embolism straddles the bifurcation of the main pulmonary artery. Venous thromboembolism (ie, pulmonary embolism or deep vein thrombosis) arises due to the Virchow triad of endothelial injury, venous stasis, and a hypercoagulable state. Malignancy causes a hypercoagulable state and is a strong risk factor for venous thromboembolism.
Answer A
This patient with severe aortic stenosis (AS) has symptomatic anemia (dyspnea, fatigue) with low mean corpuscular volume likely due to chronic bleeding from colonic angiodysplasias. Colonic, mucosal, and cutaneous bleeding is common in patients with severe AS due to acquired von Willebrand syndrome.
Von Willebrand factor (vWF) is a multimeric glycoprotein generated by endothelial cells and platelets. It plays 3 important roles in hemostasis:
vWF binds to sites of endothelial injury and serves as a scaffold for platelet aggregation.
vWF promotes platelet aggregation at sites of high shearing pressure (often seen in areas of endothelial injury).
vWF acts as a carrier protein for factor VIII, which dramatically reduces the metabolism of factor VIII.
The activity of vWF is greatest when it is in large, multimeric forms. However, large multimers of vWF are also most susceptible to unfolding in areas of high shear forces, exposing a cleavage site that makes them more vulnerable to destruction by the ADAMTS13 metalloproteinase. Because patients with severe AS typically have high shearing forces across the damaged valve, they have increased cleavage of vWF multimers, which eventually leads to vWF deficiency. Valve repair can reverse the bleeding diathesis.
(Choice B) The activity of ADAMTS13 is elevated in patients with severe AS because vWF multimers become unfolded by the high shear stress, leading them to be more susceptible to metalloproteinase destruction. Decreased activity of ADAMTS13 is seen in thrombotic thrombocytopenic purpura, which is marked by microvascular thrombosis.
(Choice C) Decreased hepatic synthesis of clotting factors can cause coagulopathy in patients with cirrhosis. Factor VIII levels are frequently low in patients with severe AS, which is due to increased destruction of vWF, not reduced hepatic synthesis.
(Choice D) Acquired antiphospholipid antibody syndrome is seen primarily in those with systemic lupus erythematosus or other rheumatologic conditions. It is marked by arterial or venous thrombosis or pregnancy complications; bleeding diathesis is uncommon.
(Choice E) Uremia reduces platelet adhesiveness and platelet aggregation, leading to an increased risk for bleeding. This patient has AS, not kidney disease.
Educational objective:
Patients with severe aortic stenosis are at high risk for mucocutaneous and colonic bleeding due to acquired von Willebrand deficiency. The von Willebrand factor multimers become unfolded by the high shear stress, leading to increased destruction by the ADAMTS13 metalloproteinase.
Answer E
This patient has warfarin-induced skin necrosis, a rare but important complication of warfarin initiation. It is thought to be due to a transient hypercoagulable state that can occur during the first few days of warfarin therapy.
The overall anticoagulant effect of warfarin is due primarily to its inhibition of the vitamin K-dependent gamma-carboxylation of clotting factors II, VII, IX, and X (“vitamin K-dependent clotting factors”). However, warfarin also decreases carboxylation of proteins C and S, which normally exert an anticoagulant effect (through proteolysis and deactivation of factors V and VIII). **Protein C **has a short half-life, so its anticoagulant activity is reduced quickly when warfarin therapy is initiated, by about 50% within the first day. During this time, the vitamin K-dependent clotting factors II, IX, and X continue to exert a procoagulant effect as they have longer half-lives (factor VII has a short half-life similar to protein C).
This difference in half-lives translates into a transient hypercoagulable state:
Decreased protein C (anticoagulant) activity → procoagulant effect
Persistent clotting factor II, IX, and X activity → procoagulant effect
Thrombosis and clot can interrupt blood flow to the skin and lead to skin necrosis. For this reason, overlapping coadministration of heparin (“heparin bridge”) is commonly used when warfarin is initiated. The risk of warfarin-induced skin necrosis is increased in patients with a preexisting protein C deficiency, as well as in those started on a large loading dose of warfarin.
(Choice A) Warfarin affects coagulation factor carboxylation, not synthesis.
(Choice B) Factor VII inhibition by warfarin has an anticoagulant effect.
(Choice C) Warfarin does not have a major direct effect on factor XI activity that would cause skin necrosis.
(Choices D and F) Fibrinogen and prothrombin activity may be impacted downstream, but this is not the primary process affected by warfarin.
Educational objective:
Warfarin inhibits proteins C and S (natural anticoagulants present in blood), which can lead to skin necrosis, particularly in patients with protein C or S deficiency. This complication is usually seen in the first few days of warfarin therapy.
Answer C
This patient with membranous nephropathy, flank pain, hematuria, and left varicocele likely has renal vein thrombosis (RVT) as a result of nephrotic syndrome. Due to increased glomerular capillary wall permeability in nephrotic syndrome, many important substances are lost in the urine, causing a number of complications. Loss of anticoagulant factors, especially antithrombin III, leads to a hypercoagulable state, of which RVT can be a manifestation. Patients with RVT can develop sudden-onset abdominal or flank pain and gross hematuria with elevated lactate dehydrogenase as a result of renal infarction.
Left-sided varicoceles are relatively common in healthy pubertal men as the aorta and superior mesenteric artery can compress the left renal vein (“nutcracker effect”), resulting in increased intravascular pressure in the left gonadal vein with retrograde blood flow and varicocele formation. However, a new-onset left varicocele associated with ipsilateral flank pain and hematuria should raise suspicion for RVT causing impaired left gonadal venous drainage.
(Choice A) Albumin is also lost in massive quantities in urine in nephrotic syndrome, leading to hypoproteinemia, decreased intravascular oncotic pressure, and fluid shifts into the interstitium. Albuminuria explains the patient’s edema (improved from his previous visit) but not his acute flank pain, hematuria, and left-sided varicocele, which are more likely due to thrombosis. Protein loss also results in a negative nitrogen balance.
(Choice B) Alpha-1 antitrypsin deficiency is an inherited condition that results in early emphysema and liver cirrhosis.
(Choice D) Serum ceruloplasmin is decreased in Wilson disease (hepatolenticular degeneration), which is clinically characterized by liver disease, motor abnormalities, and psychiatric symptoms. Ceruloplasmin has no role in the pathogenesis of nephrotic syndrome.
(Choice E) The loss of immunoglobulins and low-molecular-weight components of complement (such as factor B) makes patients with nephrotic syndrome vulnerable to infections, especially pneumococcal infections.
(Choice F) Lipiduria is common in nephrotic syndrome as a result of increased lipoprotein synthesis by the liver and increased glomerular capillary wall permeability, leading to lipid loss in the urine in the form of free fat and oval fat bodies (with characteristic Maltese cross appearance under polarized light). However, lipiduria does not contribute to the hypercoagulable state.
Educational objective:
Nephrotic syndrome is a hypercoagulable state. Sudden-onset abdominal or flank pain, hematuria, and left-sided varicoceles suggest renal vein thrombosis, a well-known complication of nephrotic syndrome. Loss of anticoagulant factors, especially antithrombin III, is responsible for the thrombotic and thromboembolic complications of nephrotic syndrome.
A 50-year-old woman comes to the emergency department due to a large, painful skin lesion. She does not remember sustaining any trauma. She was recently diagnosed with atrial fibrillation and started on treatment with warfarin. The patient noticed the lesion about a day and a half after starting the medication. Temperature is 36.7 C (98 F), blood pressure is 130/82 mm Hg, and pulse is 88/min and irregularly irregular. Physical examination findings are shown in the image below.
The remainder of the skin examination is normal. Which of the following is the most likely cause of this patient’s skin lesion?
A. Allergic drug reaction
B. Antithrombin deficiency
C. Autoimmune phenomena
D. Protein C deficiency
E. Vitamin K deficiency
Answer D
This patient was started on warfarin to prevent thromboembolism secondary to atrial fibrillation. The sharply demarcated purpuric lesion likely represents warfarin-induced skin necrosis, a rare complication that results from an excessive decrease in protein C activity; patients with underlying protein C deficiency are at increased risk.
Protein C and S are innate anticoagulants that are vitamin K dependent, as are procoagulant factors II, VII, IX, and X. Warfarin inhibits epoxide reductase (responsible for regenerating vitamin K), which leads to decreased levels of these proteins. Factor VII and protein C are depleted first due to their shorter half-life. The early loss of protein C activity relative to procoagulant factor activity leads to a transient hypercoagulable state that persists until the other procoagulant factors are sufficiently inhibited. In patients with protein C deficiency, this procoagulant state is exaggerated, promoting microvasculature occlusion and hemorrhagic skin necrosis. Underlying protein S deficiency also increases the risk of warfarin-induced skin necrosis, though not to the same extent.
Treatment of warfarin-induced skin necrosis includes discontinuing warfarin and administering fresh frozen plasma or protein C concentrate. The condition may be prevented by the coadministration of heparin during the first several days of warfarin therapy.
(Choice A) Allergic drug reactions are immune-mediated hypersensitivity reactions that can have variable cutaneous findings ranging from diffuse erythematous eruptions to extensive blistering and exfoliation (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis); this patient’s recent warfarin use and localized skin findings are more suggestive of warfarin-induced skin necrosis.
(Choice B) Antithrombin deficiency can be inherited (autosomal dominant) or acquired (eg, cirrhosis, nephrotic syndrome) and presents with venous thromboembolism (eg, deep vein thrombosis, pulmonary embolism) and resistance to heparin. Warfarin does not affect antithrombin activity.
(Choice C) Heparin-induced thrombocytopenia is an autoimmune phenomenon that causes arterial and venous thrombosis. It can produce skin findings similar to this patient’s but would generally be associated with thrombocytopenia and recent heparin use.
(Choice E) Vitamin K deficiency most often occurs in patients with fat malabsorption or those taking broad-spectrum antibiotics. The deficiency increases the inhibitory effect of warfarin on all vitamin K-dependent proteins (both anticoagulant and procoagulant), so it does not alter the relative coagulability balance to encourage warfarin-induced skin necrosis.
Education objective:
Patients started on warfarin develop a transient hypercoagulable state due to the short half-life of protein C. This hypercoagulability is further exaggerated by preexisting protein C deficiency and can result in thrombotic occlusion of the microvasculature with skin necrosis.
Answer D
Warfarin is the most commonly used agent for long-term anticoagulation in the setting of venous thromboses and pulmonary thromboembolism. Warfarin inhibits the vitamin K dependent g-carboxylation of the glutamic acid residues of clotting factors II, VII, IX and X, causing production of dysfunctional coagulation proteins.
The therapeutic effect of warfarin is monitored by measuring the prothrombin time (PT). The international normalized ratio (INR) is a standardized PT. The target INR for therapeutic warfarin anticoagulation is 2-3. Bleeding is a common complication of warfarin therapy and the risk is increased with INRs above 3.0. Treatment of life-threatening bleeding requires rapid reversal using fresh frozen plasma. Vitamin K can help to reverse warfarin action, but the effects take time.
(Choice B) Protamine is used for heparin reversal. It acts by binding and chemically inactivating heparin.
(Choice C) Aminocaproic acid is an antifibrinolytic agent that inhibits plasminogen activators and, to a lesser degree, antiplasmin activity. Aminocaproic acid helps achieve hemostasis when fibrinolysis is the cause of bleeding.
(Choice E) Whereas fresh frozen plasma contains all of the coagulation factors, cryoprecipitate contains only cold-soluble proteins (Factor VIII, fibrinogen, von Willebrand factor, and vitronectin).
(Choice F) Desmopressin is a synthetic analogue of anti-diuretic hormone (ADH) used in the treatment of diabetes insipidus. At high doses, desmopressin increases factor VIII activity in patients with hemophilia A and von Willebrand disease. High-dose desmopressin can help control bleeding associated with these disorders.
Educational Objective:
Both vitamin K and fresh frozen plasma are used for reversing warfarin-induced anticoagulation. Fresh frozen plasma rapidly reverses warfarin’s effects whereas vitamin K requires time for clotting factor re-synthesis.
Answer B
Warfarin is a vitamin K antagonist that inhibits epoxide reductase in the liver, thereby preventing gamma carboxylation of vitamin K–dependent clotting factors (II, VII, IX, X). This creates an anticoagulant state that is reflected on laboratory assessment as a prolonged INR. Because the effect of warfarin is significantly altered by certain foods and medications, patients on long-term warfarin are at risk for subtherapeutic or supratherapeutic INR due to any of the following:
Change in dietary vitamin K intake: Increase in dietary vitamin K increases the availability of vitamin K in the liver, which counters the inhibitory effect of warfarin on epoxide reductase. Therefore, patients on warfarin are advised to eat a consistent amount of vitamin K–containing foods (eg, leafy greens, brussels sprouts).
Disruption to intestinal flora: Intestinal flora produce vitamin K as a byproduct of metabolism. Therefore, antibiotics that target gram-negative bacteria such as metronidazole, macrolides, and fluroquinolones can cause supratherapeutic INR due to destruction of vitamin K–producing bacteria in the gut. In this patient, the administration of an antibiotic (eg, ciprofloxacin) for pyelonephritis likely destroyed gram-negative bacteria in her gut, thereby reducing vitamin K production and causing a supratherapeutic INR.
Alteration to cytochrome P450 2C9 activity: Several medications induce or inhibit cytochrome P450 2C9, which alters the speed of warfarin metabolism. For instance, phenytoin, carbamazepine, and rifampin increase cytochrome P450 2C9 activity, which can result in a subtherapeutic INR (Choice D). In contrast, metronidazole, fluconazole, and amiodarone inhibit cytochrome P450 2C9 activity, which can result in a supratherapeutic INR.
(Choice A) Aspirin exerts an anticoagulation effect by inhibiting the release of thromboxane A2 by platelets, which subsequently reduces platelet aggregation. This can lead to prolonged bleeding time but does not increase INR.
(Choice C) Anticlotting factor antibodies can occasionally occur due to recent pregnancy, malignancy, or rheumatologic disease. Most cases involve inhibition of factor VIII, which leads to a bleeding diathesis and prolonged aPTT (not INR, which reflects PT). This patient with a recent infection treated with antibiotics is more likely to have supratherapeutic INR due to disruption of vitamin K production by intestinal flora.
(Choice E) Increased dietary vitamin K leads to a subtherapeutic INR due to increased vitamin K availability in the liver.
Educational objective:
Patients on warfarin who take antibiotics that target gram-negative microorganisms (eg, metronidazole, macrolides, fluroquinolones) can develop supratherapeutic INR due to disruption of vitamin K–producing intestinal flora.
Answer B
This patient has liver dysfunction due to alcohol use disorder. The liver synthesizes many proteins, including clotting factors. Chronic alcohol use leads to progressive hepatic fibrosis/cirrhosis, resulting in acquired coagulopathy.
Clotting factors II, VII, IX, and X are produced initially by the liver in an inactive form and then activated by vitamin K-dependent carboxylation. Factor VII, part of the extrinsic pathway, has the shortest half-life of all coagulation factors. Prothrombin time (PT) assesses the extrinsic and common pathways of coagulation and is the first to become abnormal in liver disease. This patient’s PT prolongation is likely due to factor VII deficiency in the setting of cirrhosis. Because clotting factor synthesis is impaired, PT may not improve with vitamin K supplementation as there are insufficient quantities of clotting factors to undergo vitamin K-dependent carboxylation/activation.
The liver also synthesizes albumin, and hypoalbuminemia results in ascites and peripheral edema. In addition, severe cirrhosis causes high-output heart failure due to chronic splanchnic vasodilation and development of mesenteric and intrahepatic arteriovenous shunts.
(Choice A) Dietary vitamin K deficiency impairs activation of factors II, VII, IX, and X. Risk factors include severe malnourishment (eg, alcohol use disorder) and long-term antibiotic use (alters vitamin K-producing gut flora). In vitamin K deficiency, supplementation would likely improve PT.
(Choice C) In contrast to other coagulation factors, factor VIII is synthesized by endothelial cells. As part of the intrinsic pathway, factor VIII deficiency results in prolonged activated partial thromboplastin time (PTT) with a normal PT. Hemophilia A is an X-linked recessive disorder of factor VIII deficiency.
(Choice D) Cirrhosis is associated with intrinsic platelet dysfunction and thrombocytopenia due to decreased hepatic synthesis of thrombopoietin and increased splenic platelet sequestration (secondary to hypersplenism). Platelet dysfunction and significant thrombocytopenia (eg, platelets <50,000/mm3) lead to mucocutaneous bleeding/petechiae and prolonged bleeding time but do not affect PT.
(Choice E) Von Willebrand disease causes defects in platelet adhesion and coagulation (due to associated factor VIII deficiency). PTT may be normal or prolonged based on the level of factor VIII deficiency, and platelet aggregation to ristocetin will be abnormal.
Education objective:
Vitamin K-dependent coagulation factors (II, VII, IX, and X) are synthesized in the liver. Factor VII has the shortest half-life of the coagulation factors. Failure of the prothrombin time to correct with vitamin K supplementation indicates factor VII deficiency, which is often due to underlying liver disease.
Answer A
Heparin is the most important cause of thrombocytopenia in hospitalized patients. Occurrence of heparin-induced thrombocytopenia (HIT) is much more common with the use of unfractionated heparin compared to low molecular weight heparin. HIT more commonly leads to paradoxical thrombosis rather than bleeding. HIT is a serious disorder caused by antibodies to heparin and platelet factor IV.
Direct thrombin inhibitors (hirudin, lepirudin and argatroban) do not require antithrombin-III for their action and are drugs of choice in the treatment of HIT. Patients with HIT need ongoing anticoagulation due to the presence of, or possibility of thrombosis. Upon clinical suspicion of HIT, the most important initial step in treatment is to stop all forms of heparin.
(Choice B) Warfarin inhibits vitamin K dependent γ-carboxylation of glutamic acid residues of clotting factors II, VII, IX and X.
(Choices C, D and E) Platelet plug formation involves three critical steps: adhesion, aggregation and release (see diagram). Drugs that inhibit platelet aggregation work by different mechanisms.
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 strokes.
Ticlopidine and clopidogrel inhibit ADP mediated platelet aggregation. They are useful following percutaneous coronary intervention (PCI), and for treatment of unstable angina and non-Q wave myocardial infarction.
Dipyridamole and cilostazol inhibit platelet aggregation by inhibiting phosphodiesterase activity and increasing cAMP.
Glycoprotein IIb/IIIa inhibitors inhibit binding of platelet glycoprotein IIb/IIIa with fibrinogen and fibronectin. The glycoprotein IIb/IIIa inhibitors abciximab, eptifibatide and tirofiban are approved for use following percutaneous intervention (PCI) in acute coronary syndrome.
Educational objective:
Heparin-induced thrombocytopenia (HIT) is treated with direct thrombin inhibitors (DTIs) such as argatroban. Both high molecular weight heparin and LMWH should be avoided in these patients.
Answer E
Heparin is an endogenous anticoagulant that exerts its effect indirectly by binding to antithrombin III (AT), a serine protease inhibitor that irreversibly neutralizes clotting factors. Heparin binding alters the shape of AT, which converts it from a slow to rapid inactivator of clotting factors and increases its activity >1,000 fold.
Although AT neutralizes a number of clotting factors in the intrinsic pathway, its anticoagulant effect primarily stems from the inactivation of factor Xa and thrombin. Therefore, patients who receive heparin products typically have the following coagulation changes:
Prolonged thrombin time: Thrombin inactivation is strongest with unfractionated heparin infusion because the length of heparin chains in this formulation are longer, which inactivates thrombin more rapidly. Although low-molecular-weight heparin formulations contain shorter chain heparin molecules, they also inactivate thrombin but to a lesser extent.
Decreased activity of factor Xa: All forms of heparin (eg, unfractionated, low molecular weight, fondaparinux) have strong activity against factor Xa. Antifactor Xa activity is usually monitored to determine when adequate anticoagulation is achieved.
Prolonged partial thromboplastin time (PTT): Heparin primarily inhibits the intrinsic and final common clotting pathway; therefore, PTT is prolonged.
Unlike heparin medications, which exert their anticoagulation effects broadly through the activation of AT, direct oral anticoagulants inhibit a single enzyme in the coagulation cascade, such as thrombin (eg, dabigatran) or factor Xa (eg, rivaroxaban).
Educational objective:
Heparin is an indirect anticoagulant that alters the shape of antithrombin (AT) III, thereby converting it from a slow to rapid inactivator of clotting factors. Because AT primarily neutralizes factor Xa and thrombin, patients on heparin have decreased factor Xa activity and prolonged thrombin time/partial thromboplastin time. In contrast, direct oral anticoagulants specifically target a single enzyme in the coagulation cascade, such as thrombin (eg, dabigatran) or factor Xa (eg, rivaroxaban).
