Anticoagulants, Antiplatelet Agents, and Thrombolytics

Dipyridamole and Cilostazol

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Bivalirudin and Desirudin

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A 72-year-old man comes to the office complaining of leg pain. The man is well known to you, as he has a long history of vascular disease, including two previous myocardial infarctions and a carotid endarterectomy following a stroke 2 years ago. Since his stroke the man has regained his ability to walk, after completing a long rehabilitation program. Now when he walks even half a block, however, he suffers dull, crampy pain in his left calf. The pain improves with rest and has never woken him from sleep, but it is making it nearly impossible for him to complete his regular daily activities or to complete his heart healthy exercise routine. Current medications include baby aspirin, clopidogrel, metoprolol, simvastatin, and lisinopril. Physical examination reveals diminished left-sided posterior tibialis and dorsalis pedis pulses. Further, the left foot appears shiny and hairless and, when elevated, displays an increase in pallor. An ankle-brachial index reveals: Left lower extremity 0.5 Right lower extremity 0.9 The man is not interested in surgery and mainly wishes to be able to walk further than he currently can. The medical treatment most likely to improve his symptoms is (A) adding cilostazol (B) adding pentoxifylline (C) increasing the dose of aspirin (D) stopping clopidogrel (E) stopping metoprolol

(A) adding cilostazol Cilostazol is a phosphodiesterase inhibitor that causes arterial vasodilatation and inhibits platelets. It is a useful treatment for claudication symptoms, particularly when used in conjunction with lifestyle modifications (structured exercise program and smoking cessation) and other medications, such as aspirin, clopidogrel, a statin, and an ACE inhibitor, all of which have been shown beneficial in the treatment of peripheral vascular disease. Pentoxifylline (choice B) may provide a slight improvement in claudication symptoms but has been shown to be less effective than cilostazol in head-to-head trials. There has never been shown any benefit to increasing the dose of aspirin (choice C) from 81 mg a day (a baby aspirin) to 325 mg a day. Presumably, 81 mg is an adequate dose to inhibit platelets.

What effect do Thrombolytics have on -Bleeding time -PT -PTT

-Bleeding time: No Effect (no change in platelet count) -PT: Increase -PTT: Increase

Fondaparinux

-add slides about pentasaccharide seq -finish talking about HIT 1 vs 2 -

Which of the following is true regarding skin necrosis after warfarin therapy 1. Skin lesions occur weeks to months after the start of therapy 2. Pretibial area is the most common area for the skin necrosis 3. Lesions usually occur only when INR exceeds 3.5 4. Patients need to be heparanized to treat the skin necrosis 5. Patients with lupus anticoagulant OR antithrombin III deficiency are predisposed

4. Patients need to be heparanized to treat the skin necrosis

A 63-year-old man is aiming to improve his health by eating a well balanced diet, walking daily, and quitting smoking following a 45-year smoking history. While on his daily walks he notices a strong cramping pain in his calves that consistently appears after a mile of walking. He sees his physician and a diagnosis of peripheral artery disease with intermittent claudication is made. To improve his symptoms, cilostazol is prescribed. What is the mechanism of action of this medication? 1. Irreversible cyclooxygenase inhibitor 2. Glycoprotein IIB/IIIA inhibitor 3. Thromboxane synthase inhibitor 4. Adenosine diphosphate receptor inhibitor 5. Phosphodiesterase inhibitor

5. Phosphodiesterase inhibitor Cilostazol is a phosphodiesterase III inhibitor that leads to arterial vasodilation and decreased platelet aggregation. It is a first-line medication for the treatment of claudication caused by peripheral artery disease (PAD).

A 66-year-old woman is evaluated for pain and cramping of her right leg while vacuuming and shopping. She has no nocturnal pain. She is a long-time smoker (140 pack-year history) and has well-controlled hypertension and mild congestive heart failure. Her medications are lisinopril, hydrochlorothiazide, and atenolol. On examination, the blood pressure is 146/68 mm Hg and pulse rate is 74/min and regular. Cardiac examination reveals an S4. The lungs are clear. There is a right femoral artery bruit with absent right foot pulses but no pedal edema. Which of the following interventions would be most effective for limb preservation in this patient? A Smoking cessation B Discontinuation of atenolol C Initiation of warfarin D Initiation of cilostazol E Exercise training

A Smoking cessation Key Points ** Smoking cessation is the single most effective intervention for patients with peripheral vascular disease.* * β blockade does not promote clinical claudication. ** Cilostazol is relatively contraindicated in patients with congestive heart failure.* Smoking cessation is the most important intervention in patients with peripheral vascular disease and may reduce the progression of disease. Although β blockade may inhibit peripheral vasodilation and thereby be detrimental to peripheral blood flow, clinical studies demonstrate no adverse effect on peripheral vascular disease. Warfarin is relatively contraindicated due to increased bleeding risk without added benefit over aspirin. Cilostazol, a phosphodiesterase inhibitor, suppresses platelet aggregation and is a direct arterial vasodilator. Cilostazol is associated with increased maximal and pain-free walking distances, but there is no evidence that it improves limb salvage rates. . Although exercise training is beneficial in improving symptoms, its long-term benefits are inferior to smoking cessation

A 68-year old man comes to the emergency department because of chest pain for 30 minutes. An ECG shows a regular rate and rhythm and inverted T waves. While Laberatory studies are being done he gies oxygen and aspirin. Aspirin is most appropriate in the treatment of this patient because of inhibition of which of the following enzymes? A) Cyclooxygenase B) Lipoxygenase C) Phospholipase A2 D) Prostacyclin (PGI2) synthase E) Thromboxane A2 synthase

A) Cyclooxygenase

Which one of the following antiplatelet drugs is most commonly associated with thrombocytopenia? A. Abciximab. B. Cilostazol. C. Clopidogrel. D. Ticlopidine

A. Abciximab. Abciximab causes immune thrombocytopenia in about 1% of patients. Severe thrombocytopenia and other signs and symptoms of thrombotic thrombocytopenic purpura develop in approximately 1 of every 2500 patients treated with the platelet inhibitor ticlopidine and a much smaller fraction of those given the closely related drug clopidogrel, usually after 1 to 2 weeks of treatment. Reports of thrombocytopenia occurring in association with cilostazol have been limited to case reports.

All of the ADP receptor inhibitors are ___________ (reversible/irreversible) inhibitors of the ADP receptor except for ____________

All are irreversible except for Ticagrelor which is reversible *Note that it is the only one ending in a r

What are the three Glycoprotein IIb/IIIa receptor inhibitors?

Abciximab Epitifibatide Tiofiban Mnemonic: EpitiFIBatide and tioFIBan both prevent aggregation by inhibiting the binding of FIBrinogen to GP2B3A receptors

Name two drugs that can be used in the treatment of acute bleeding due to thrombolytic use Describe their MOAs

Aminocaproic Acid and Tranexamic acid Aminocaproic Acid -*Lysine* analogue -Inhibits lysine proteases like plasmin and other fibrinolytic enzymes Tranexamic Acid -displaces plasminogen from fibrin and inhibits the proteolytic activity of plasmin Both may be of use in treating *Hereditary Angioedema*

warfarin acute pancreatitis warfarin and heparin and spinal surgery contraindication? therapeautic INR goal of wafarin rapid reversal = fresh frozen plasma, vitamin k otherwise? reducing the dose of warfarin in pateints with polymporphism of VKORC1?? Warfarin and hyperthyroidism???

Anticoagulation is contraindicated in patients with recent neurosurgery or eye surgery. Consider using an IVC filter (greenfield filter) to prevent further embolism in these patients

Aspirin inhibits platelet activation and aggregation through what mechanism?

Aspirin inhibits TXA2 synthesis by acetylation of a serine residue on COX-1; resulting in irreversible inhibition of the enzyme COX-1 converts Arachidonic acid to prostaglandin H2 , the precursor to TXA2

A 65-year-old male with a previous history of a stroke is treated with ticlopidine as prophylaxis for preventing further stroke. What is the mechanism of action of ticlopidine? A. Inhibition of platelet thromboxane production B. Antagonism of ADP receptor C. Antagonism of glycoprotein IIb/IIIa D. Inhibition of the synthesis of vitamin Kâ€"dependent coagulation factors E. Activation of plasminogen to plasmin

B. Antagonism of ADP receptor Ticlopidine inhibits platelet aggregation and the release of platelet granule constituents. It does this by inhibiting the binding of ADP to its platelet receptor. Platelet membrane function is altered irreversibly by inhibition of ADP-induced activation of the platelet glycoprotein GPIIb/IIIa complex, resulting in decreased fibrinogen binding. Decreased platelet aggregation stems from the inability of activated platelets to recruit circulating platelets. Clopidogrel is relatively newer than ticlopidine. It appears to be as effective as ticlopidine and has fewer side effects.

A 50-year-old is started on warfarin therapy for new-onset atrial fibrillation. Thirty-six hours later, he develops a painful lesion on his arm. The lesion is shown below. Which of the following is the most likely cause of this lesion? A. Vitamin K deficiency B. Protein C deficiency C. Antithrombin III deficiency D. Autoimmune phenomena E. Allergic drug reaction

B. Protein C deficiency

A 65-year-old woman was hospitalized for pulmonary embolus and eventually discharged on warfarin (Coumadin) with a therapeutic INR. During the next 2 weeks as an outpatient, she was started back on her previous ACE inhibitor antihypertensive, given temazepam for insomnia, treated with ciprofloxacin for a urinary tract infection, started on over-the-counter famotidine (Pepcid) for GI symptoms, and told to stop the OTC naproxen she was taking. Follow-up INR was 5.0. Which of the following drugs most likely potentiated the effects of warfarin and led to the high INR? A) ACE inhibitor B) Temazepam C) Ciprofloxacin D) Famotidine E) Naproxen discontinuation

C) Ciprofloxacin Many medications can potentiate warfarin (Coumadin), including the fluoroquinolone, ciprofloxacin, and various other broad-spectrum antibiotics. Ciprofloxacin potentiates the effect of warfarin by two mechanisms 1) By eliminating the vit. K producing GI bacterial flora, can potentiate the effects of warfarin 2) Ciprofloxacin is an inhibitor of the cytochrome P450 system and therefore potentiates the effect of warfarin, because it is metabolized by cytp450

What are the four ADP (P2Y12) receptor inhibitors?

Clopidogrel Prasugrel Ticagrelor Ticlopidine

Which clotting factors are affected by Warfarin? Which two have the shortest half lives?

Clotting factors II, VII, IX, X, protein C, protein S are the vitamin K-dependent Factors and are affected by Warfarin Factor VII and Protein C have the shortest half life (3-6 hrs and 8 hrs respectively)

Foods high in Vitamin K can _____________ (increase/decrease) the effect of warfarin. Give four examples of foods that are high in Vitamin K

Decrease Brussel sprouts, green tea, spinach, and other green leafy vegetables (broccoli, asparagus, kale)

An 81-year-old woman is admitted to the hospital because of a massive pulmonary embolism from a deep venous thrombosis. Her platelet count is 160,000/mm3. Appropriate pharmacotherapy is started. One week later, her platelet count is 55,000/mm3. The thrombocytopenia was most likely caused by a drug with which one of the following mechanisms of action? A) Activates tissue plasminogen B) Interferes with the carboxylation of coagulation factors C) Irreversibly inactivates cyclooxygenase D) Potentiates the action of antithrombin III E) Selectively inhibits factor Xa

D) Potentiates the action of antithrombin III

A 57-year-old male visits your office with complaints of exertional thigh and leg pain and decreased sexual performance. His dorsalis pedis pulses are weak in both feet. Evaluation shows moderate peripheral arterial disease of both lower extremities. This patient experiences symptomatic improvement from a drug that dilates arteries and inhibits platelet aggregation. Which of the following drugs is most likely described in this scenario? A. Heparin B. Argatroban C. Warfarin D. Abciximab E. Cilostazol

E. Cilostazol Dipyridamole and cilostazol are phosphodiesterase inhibitors used in patients with intermittent claudication. In addition to inhibition of platelet aggregation, cilostazol is also a direct arterial vasodilator. Several molecules, including thrombin, ADP, and thromboxane A2, activate platelets by acting on cell surface receptors. Interference with post receptor signaling can alter platelet functions. Agents that increase platelet cyclic AMP decrease platelet aggregation by preventing platelet shape change and granule release. Cilostazol, in addition to inhibition of platelet aggregation, also is a direct arterial vasodilator

Clinical uses of Glycoprotein IIb/IIIa receptor inhibitors?

Given IV along with heparin and aspirin Abciximab is used in combination with aspirin and heparin in patients undergoing percutaneous coronary intervention (PCI).

Co-administration of which anticoagulant can reduce the risk of skin/tissue necrosis and venous thromboembolism due to Warfarin therapy?

Heparin Co-administration of heparin can help "bridge" a patient past the transient hypercoagulation phenomena associated with the first few days of warfarin therapypr

Describe the mechanism of action of Heparin

Heparin binds to antithrombin III and catalyzes its activity in inactivating thrombin(factor IIa) and factor Xa When bound to heparin, ATIII undergoes a conformational change that makes its serine protease binding site more accessible. In the absence of heparin, antithrombin interacts very slowly with factor IIa and Xa (the rate of inactivation can be increased by 1000 due to heparin binding)

Which notable endocrine disorder can increase the effects of warfarin and what is the mechanism by which this occurs?

Hyperthyroidism as well as certain hepatic disorders enhance the effects of warfarin by increasing the turnover rate of clotting factors.

Streptokinase vs Alteplase (tPA)

Streptokinase -acts on both bound and free plasminogen (NOT CLOT SPECIFIC), depleting circulating plasminogen and factors 5 and 8 -ANTIGENIC: strep antibodies may decrease activity Alteplase -Clot Specific; Acts mainly on fibrin-bound plasminogen -not antigenic

What is the mechanism of action of protamine sulfate as an antidote to heparin toxicity?

Protamine sulfate is a positively-charged peptide that binds to and sequesters negatively-charged heparin (or LMWH). The protamine sulfate-heparin complex has no anticoagulant activity and is subsequently eliminated.

What are the respective treatments for warfarin overdose in the following situations: - Rapid reversal? - Non-rapid reversal?

Rapid reversal: fresh-frozen plasma or 4-factor prothrombin complex concentrate (PCC, Kcentra), if available Non-rapid reversal: vitamin K1 (phytonadione)

What are two significant side effects associated with ADP (P2Y12) receptor inhibitors?

TTP and Neutropenia Neutropenia is most associated Ticlopidine TTP is associated all of the four except Ticagrelor

Warfarin is administered to a 56-year-old man following placement of a prosthetic cardiac valve. The warfarin dosage is adjusted to maintain an INR of 2.5. Subsequently, trimethoprim-sulfamethoxazole therapy is begun for a recurring urinary tract infection. In addition to monitoring prothrombin time, which of the following actions should the physician take to maintain adequate anticoagulation? A. Begin therapy with vitamin K B. Increase the dosage of warfarin C. Make no alterations in the dosage of warfarin D. Decrease the dosage of warfarin E. Stop the warfarin and change to low-dose aspirin

Trimethoprim-sulfamethoxazole is a sulfa-based drug. Sulfonamides are known inhibitors of the P-450 enzymatic system, and warfarin is primarily metabolized by CYP450:2C9. Trimethoprim-sulfamethoxazole would be expected to increase the serum levels of warfarin and push the INR to super-therapeutic levels with the increased risk of bleeding. Therefore, it would be recommended to decrease the dosage of warfarin (choice D).

How do you reverse the effects of heparin?

When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. 1 mg/100 units of heparin administered (excess given may exacerbate bleeding as protamine sulfate is a weak anticoagulant)

A 65-year-old woman is admitted to the hospital on Friday night with an episode of squeezing, substernal chest pain that occurred while the patient was watching her favorite TV show. The pain lasted for twenty minutes and was not relieved by nitroglycerin. A dobutamine stress echocardiogram was done a month ago by her private physician, which showed posterior and lateral wall motion abnormalities. Her past medical history is significant for diabetes mellitus. On arrival at the hospital, an EKG shows ST-segment depression in the lateral leads. She is started on aspirin, nitrates, beta-blockers, and intravenous unfractionated heparin. Three sets of cardiac enzymes are negative. A complete blood count shows a white cell count of 7,800/mm3, a hematocrit of 37%, and a platelet count of 180,000/mm3. The medications are continued, and she is transferred from the cardiac care unit on Sunday evening with plans for a coronary angiography the next day. On Monday, the patient complains of pain in the right leg. The physical examination is unremarkable, except for moderate right-calf tenderness. The venous Duplex shows thrombosis of the right popliteal vein. Another complete blood count shows: WBC 9,900/mm3, hematocrit 38.8%; and platelets 45,000/mm3. The prothrombin time (PT) is 13.6 seconds, INR 1.0, and partial thromboplastin time (PTT) 68 seconds. What is your next step in the management of this patient? (A) Continue unfractionated heparin and start coumadin after the angiogram (B) Switch unfractionated heparin to low-molecular-weight heparin (C) Immediately stop heparin and remove heparin-coated catheters (D) Corticosteroids (E) Switch unfractionated heparin to lepirudin

(E) Switch unfractionated heparin to lepirudin This patient is suffering from heparin-induced thrombocytopenia (HIT) and also a deep venous thrombosis, which is most likely the result of this disorder. One to 3% of patients who receive unfractionated heparin will develop antibodies against platelets. All forms of heparin must be stopped when HIT occurs. You cannot just switch to low-molecular-weight heparin. Although low-molecular-weight heparin carries a much smaller risk of developing thrombocytopenia, 70% of the antibodies that develop will cross-react with low-molecular-weight heparin. Again, all heparins must be stopped because 30% of those with HIT will develop some form of thrombosis. Seventy-five percent of the time, the thrombi are venous, and only 25% are arterial. This patient has a thrombosis and therefore needs an alternate type of anticoagulation. Coumadin will not be effective rapidly enough, and the patient is also scheduled for angiography the following day. Lepirudin is an analog of hirudin. These drugs are natural anticoagulants that inhibit thrombin and are derived from leeches. They do not cross-react with HIT-induced antibodies. Lepirudin can be monitored with the PTT. Danaparoid is a heparinoid that is no longer marketed in the United States.

Warfarin

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Thrombolytics

* *Indicated for EARLY MI/CVA, or severe PE *MOA: catalyzes conversion of plasminogen to plasmin *Plasmin cleaves fibrin clots * *Adverse effects: bleeding and intracerebral hemorrhage **Streptokinase may cause hypersensitivity* **Treat toxicity with Aminocaproic acid or Tranexamic acid *

Heparin Induced Thrombocytopenia (Type 2)

*Caused by antibodies formed against heparin-PF4 complexes *Typically manifests initially as thrombocytopenia 5-10 days following exposure to a heparin product *More common with unfractionated heparin *Associated with significant risk of thrombosis (venous > arterial) * *Tx: Immediate discontinuation of heparin; Administration of Lepirudin or Bivalirudin (direct thrombin inhibitors)

Heparin

*Fast-Acting Anti-Coagulant *MOA: binds to antithrombin III and catalyzes its activity (x1000) in inactivating thrombin(factor IIa) and factor Xa *Clinical use: Prophylaxis and initial treatment of DVT and PEs. Treatment of Arterial thrombosis (Acute coronary syndromes and stokes) *Side Effects: Bleeding, Thrombocytopenia (HIT) *ContraIndications: Active Bleeding, bleeding disorders, conditions worsened by anti-coagulation (e.g. Aortic dissection), history of HIT type II. *Safe during pregnancy because it does not cross the placenta *Metabolism: IV/SC. Eliminated by RES system. Half-life 60-90 mins *Heparin effects is clinically measured by aPTT. *Protamine is used to bind and neutralize heparin, rapidly reversing the anticogualation in case of toxicity *Low Molecular Weight Heparins (Enoxaparin) act on Factor Xa, have better bioavailability, 2-4 times longer half-life, given SC and do not require lab monitoring, but not easily reversible *Due to the low molecular weight, they are less likely to cause opsonization of platelets and there is less risk of HIT

Heparin Induced Thrombocytopenia (Type 1)

*HIT- Type I is caused by heparin mediated platelet aggregation, ~10% of cases, mild and self limiting.

Describe the pathophysiology of Type 2 Heparin Induced Thrombocytopenia (HIT)

*Heparin induces the release of PF4 (Platelet Factor 4), a positively charged molecule from the alpha granules of platelets *PF4 binds to heparin due to charge differences (heparin is neg charged) *IgG antibodies bind to the PF4/heparin complex with their Fab receptor and the Fc portion activates other platelets (via FcR), which triggers the release of alpha granules and even more PF4, creating a positive feedback look. *The activation of platelets results in the paradoxical finding of thrombosis in HIT *The thrombocytopenia is a result of platelet consumption and removal by macrophages in the reticuloendothelial system

Unfractioned Heparin vs Low Molecular Weight Heparin

*LMWH is about 1/3 the size of UH *UH equally enhances AT effects on Factor Xa and thrombin (IIa) *LMWH effects more selectively on Factor Xa than on thrombin (IIa) *UH is given IV/SC *LMWH is given SC *UH: binds non specifically to plasma proteins => unpredictable dose response *LMWH: less binding to plasma proteins => more predictable dose response) *LMWH does not require intense lab monitoring as UH does (exception = renal failure or pregnant pts) *LMWH is metabolized by RES *1/2 life of UH: 1.5 hours *1/2 life of LMWH: 3-12 hours *HIT is more likely with UH *LMWH have better bioavailability and a quicker onset of coagulation *UH toxicity can be readily reversed with protamine sulfate *LMWH toxicity is not readily reversed *LMWH may be associated with improved cardiac outcomes

Name 6 patients in which the use of Thrombolytics is contraindicated

*Recent major surgery *Bleeding disorder *Anticoagulant use *Severe hypotension *History of intracranial bleeding *Active bleeding

Warfarin induced tissue/skin necrosis

*Usually occurs three to five days after drug therapy is begun **High initial dose (loading dose) increases the risk of development* *Inherited deficiency of Protein C increases the risk *Higher incidence in middle aged obese women *Common sites: breasts, thighs, buttocks (areas with subcutaneous fat) *Mechanism: In Warfarin's initial stages of action, inhibition of protein C and Factor VII is stronger than inhibition of the other vitamin K-dependent coagulation factors because their half lives are much shorter. Protein C is an innate anticoagulant, and as warfarin further decreases protein C levels, it leads to paradoxical activation of coagulation, resulting in a hypercoagulable state. It can lead to massive thrombosis with necrosis and gangrene of limbs. **Co-administration of heparin reduces the risk of skin/tissue necrosis and venous thromboembolism* *Tx: Discontinue Warfarin; Rapid reversal via FFP

A 67-year-old man is evaluated for palpitations, heat intolerance, and a 2.4-kg (5-lb) weight loss over 1 month. The patient has a history of dilated cardiomyopathy and congestive heart failure, and his medications include warfarin, digoxin, lisinopril, and carvedilol. On physical examination, the pulse is 82/min and regular, the thyroid gland is twice normal size, and he has a moderate resting tremor. Laboratory testing shows free T4 3.1 ng/dL (39.7 pmol/L) and serum thyroid-stimulating hormone <0.01 µU/mL (0.01 mU/L). Which of the following changes in his therapeutic regimen should be made while he remains thyrotoxic? A Decrease both warfarin and digoxin doses B Increase both warfarin and digoxin doses C Increase warfarin dose, decrease digoxin dose D Decrease warfarin dose, increase digoxin dose E No change in warfarin or digoxin dose

D Decrease warfarin dose, increase digoxin dose Thyroid hormone increases the metabolism of warfarin but increases the turnover of clotting proteins even more, resulting in a decreased dose requirement of warfarin. Thyrotoxicosis leads to a decreased warfarin dose requirement. The effect of thyrotoxicosis on warfarin dosing may seem counterintuitive. Although thyroid hormone increases the metabolism of warfarin, it increases the turnover of clotting proteins even more, resulting in a decreased dose requirement. Digoxin metabolism is increased during thyrotoxicosis, so a dose increase can be anticipated. Anticoagulated patients developing thyrotoxicosis require close monitoring of anticoagulation parameters and frequently require adjustment of the warfarin dose both upon initial diagnosis of thyrotoxicosis and during the course of its correction.

A 57-year-old man has been hospitalized for 2 days for treatment of unstable angina pectoris. He is currently receiving intravenous heparin and undergoing evaluation for coronary artery bypass grafting. His blood pressure is 160/90 mm Hg, pulse is 88/min, and respirations are 16/min. Laboratory studies show: Platelet count 90,000/mm3 Prothrombin time 12 sec (INR=1.1) Partial thromboplastin time 35 sec Which of the following is the most likely cause of these findings? A) Excessive platelet destruction B) Factor VIII deficiency C) Inadequate platelet production D) Uncontrolled activation of coagulation and fibrinolytic cascades E) Vitamin K deficiency

D) A) Excessive platelet destruction Most sources say that Thrombocytopenia in HIT is largely due to the clearance of activated platelets and antibody-coated platelets by the reticulo-endothelial system . A couple sources have said that the thrombocyopenia is rather due to the activation of the platelets leading to thrombosis, which consumes the platelets

A 26-year-old primigravid woman at 12 weeks' gestation comes to the physician because of pain and swelling in her right thigh. She first noted the onset of the pain 2 days ago, and since then it has grown worse. An ultrasound study performed on her lower-extremity venous system reveals evidence of a proximal thrombus in the right leg. She is started on low-molecular-weight heparin injections. Which of the following is an advantage of low-molecular-weight heparin compared with unfractionated heparin? A. Low-molecular-weight heparin has a shorter half-life B. Low-molecular-weight heparin is cheaper C. Low-molecular-weight heparin is less likely to cause birth defects D. Low-molecular-weight heparin is less likely to cause thrombocytopenia E. Low-molecular-weight heparin is less likely to cross the placenta

D. Low-molecular-weight heparin is less likely to cause thrombocytopenia Low-molecular-weight heparin has been shown to be an excellent anticoagulant because it has a longer half-life and a more predictable dose-response relationship compared with unfractionated heparin, which allows once- or twice-daily dosing without the need for frequent laboratory monitoring of the prothrombin time and activated partial thromboplastin time. Low-molecular-weight heparin is also less likely to cause thrombocytopenia and hemorrhagic complications than unfractionated heparin.

A 67-year-old man comes to the emergency department complaining of stuttering chest pain and shortness of breath. He has had similar episodes of pain, which usually occur with exertion, but none have lasted this long and in the past they have always resolved with rest. The patient has numerous cardiac risk factors, including a history of anginal chest pain, a 50-pack-year tobacco history, a family history of coronary heart disease, and dyslipidemia. A workup for acute coronary syndrome in the emergency room includes a set of cardiac enzymes, which are within normal limits, and an electrocardiogram, which shows T-wave inversions and 1-mm ST segment depression in an inferior distribution. The decision is made to anticoagulate the patient while coronary catheterization is being arranged. In choosing between low molecular-weight heparin and unfractionated heparin, which of the following is an argument in favor of unfractionated heparin? A. Ease of administration B. Improved cardiac outcomes C. Lower overall hospital costs D. Quicker onset of anticoagulation E. Reversibility of anticoagulation

E. Reversibility of anticoagulation In general, studies comparing low molecular-weight heparin and unfractionated heparin in acute coronary syndrome favor low molecular-weight heparin. However, one of the advantages of unfractionated compared with low molecular-weight heparin is that the unfractionated can be fully reversed with protamine. Low molecular-weight heparin is generally given as a subcutaneous twice-daily injection for the treatment of acute coronary syndromes. It is easier to administer (choice A) than unfractionated heparin, which requires a continuous infusion. Unfractionated heparin, compared with low molecular-weight formulations, has not been associated with improved outcomes (choice B). Indeed, while a mortality benefit has yet to be proven, studies have indicated that low molecular-weight heparin may be associated with improved cardiac outcomes. Unfractionated heparin is a less expensive medication than low molecular-weight heparin. However, when the administrative costs are factored in, such as the laboratory and nursing costs associated with frequent monitoring of the partial thromboplastin time, unfractionated heparin is associated with higher overall hospital costs (choice C). Low molecular-weight heparin has more predictable dosing effects and is associated with a quicker onset of anticoagulation (choice D) than is unfractionated heparin

A 70-year-old man comes to the urgent care clinic complaining of massive bruising and bleeding from his gums when he brushes his teeth. He is known to have a history of atrial fibrillation, which is treated with metoprolol and warfarin. He has been stable on his current dose of warfarin, so it is surprising that he is now suffering from increased bleeding. None of his other medications have recently been changed, and he denies using any NSAID or other recent use of over-the-counter medications. The patient reports that he is taking his warfarin as prescribed, and has been recently trying to live a healthy life.Upon further questioning, he reports trying to exercise more often, taking daily vitamins, and eating more vegetables. His new diet includes a lot of vegetables, such as spinach, Brussels sprouts, and broccoli, as well as copious amounts of green tea for its anticancer effects. A prothrombin time is ordered, but will not be available for another hour. Which of the following dietary changes is most likely responsible for this patient's increased bleeding? A. Brussels sprouts B. Green tea C. Spinach D. Unrelated to diet E. Vitamins

E. Vitamins Vitamins, particularly vitamin E, can increase the risk of bleeding in patients taking warfarin. Patients taking warfarin need to be educated on the risks of drug interactions from over-the-counter drugs, particularly analgesics and the risk of drug interactions from other prescription medications; and should also be cautioned not to radically change their diets. Dietary change, which may alter the amount of vitamin K consumed, can reduce the efficacy of warfarin. Foods high in vitamin K include Brussels sprouts (choice A), green tea (choice B), and spinach (choice C), as well as organ meat, alfalfa, asparagus, broccoli, cabbage, cauliflower, kale, turnip greens, and watercress.

A 5-year-old male with no previous medical history is brought to the ER by his mother because he accidentally ingested a large dose of rat poison. He is conscious but appears quite agitated. On physical exam, he is found to have a blood pressure of 110/70 and a heart rate of 90. Labs are significant for an elevated PT but a normal PTT. The patient should be immediately treated with A. atropine B. flumazenil C. N-acetylcysteine D. protamine E. vitamin K

E. vitamin K The correct answer is E. As you might have guessed from his elevated PT level, the active ingredient in rat poison is warfarin. It acts as an anticoagulant by interfering with the normal hepatic synthesis of the vitamin K-dependent clotting factors II, VII, IX, and X. The most important adverse effect of warfarin is bleeding. The action of warfarin can be reversed with vitamin K. Atropine (choice A) is used as an antidote for anticholinesterase toxicity (e.g., ingestion of organophosphates). Flumazenil (choice B) is used as an antidote for benzodiazepine toxicity (e.g., Valium). N-acetylcysteine (choice C) is used as an antidote for acetaminophen toxicity. Protamine (choice D) is used as an antidote for heparin overdose. Note that heparin enhances the activity of antithrombin III, producing its anticoagulant effect. Heparin toxicity would have resulted in an elevated PTT.

A 72-year-old man has stable angina pectoris, ischemia, and stenosis of an artery that perfuses a large segment of the myocardium that lacks collateral vessels. He is scheduled to undergo percutaneous transluminal coronary angioplasty to revascularize the myocardium. Which of the following is a cyclic peptide platelet glycoprotein IIb/IIIa inhibitor that could be given to this patient to prevent platelet aggregation during percutaneous transluminal coronary angioplasty? a) Abciximab b) Aspirin c) Cilostazol d) Dipyridamole e) Eptifibatide

e) Eptifibatide The three GP IIb/IIIa inhibitors are Abciximab, Eptifibatide, and Tirofiban Abciximab is a monoclonal antibody Eptifibatide is a cyclic peptide that binds to GP IIb/IIIa at the site that interacts with the arginine-glycine-aspartic acid sequence of fibrinogen Tirofiban is not a peptide, but it blocks the same site as eptifibatide