Case Presentation by Dr. Katie Ohlendorf
History of Present Illness:
The patient is a 78 year old female with no prior CVA. The patient was last seen well by her son yesterday evening. Today, the patient was supposed to go to her grandson’s birthday party. She did not show up and her son has been trying to call the patient for the prior 3 hours without response. EMS was called to the patients home. Here, she was found with slurred speech, left sided gaze and left sided hemiparesis.
The patient is following commands. She is difficult to understand secondary to severe dysarthria. She denies dyspnea or chest pain. She cannot tell us when her neurological symptoms started.
Review of Systems:
Per HPI – unable to obtain further secondary to patients severe dysarthria.
Past Medical History:
Hypertension, palpitations, rheumatic fever, pneumonia, and breast cancer.
Past Surgical History:
Lumpectomy, hysterectomy, cardiac ablation, and cardiac valve replacement.
Coumadin, multivitamins, metoprolol, docusate, vitamin D3, calcium carbonate, Arimidex, and alendronate.
Negative for alcohol and smoking. The patient presents with her son.
Examination of Organ Systems and Body Areas:
VITAL SIGNS: Blood pressure 184/80, pulse 101, respirations 18, temperature 37.5 temporal, and pulse ox on room air 99%.
GENERAL: The patient is awake and alert. Does not appear to be in acute cardiopulmonary distress.
HEENT: Pupils equal, round andreactive, although gazing to the right. No conjunctival injection or subconjunctival hemorrhage. Unable to assess her hearing. No hemotympanum. Droop to her left face. No pus or redness in the posterior pharynx. Intact gag reflex.
NECK: Supple without adenopathy.
RESPIRATORY: Symmetrical breath sounds. No rales, rhonchi or wheezes.
CARDIAC: Regular rate and rhythm without murmur, rub or gallop. Patient has a valvular click from prosthetic aortic valve.
GASTROINTESTINAL: Soft, nontender. Active bowel sounds. No organomegaly, hernias or masses. Bowel sounds present in all quadrants.
MUSCULOSKELETAL: Hemipareses, left side.
NEUROLOGIC: Patient awake and alert. Dysarthric speech. Hearing unable to be assessed. Right sided gaze preference. Left sided facial droop. Intact gag reflex. Left sided hemiparesis with 0/5 muscle strength with left upper and left lower extremity. 5/5 muscle strength with right upper and right lower extremity. Receptive wise, she processes her questions fairly well.
SKIN: No rash.
1) How would you manage a warfarin induced coagulopathy if…
- a. The INR is between 3.5 to 5 without significant bleeding
- b. The INR is between 5-9 without significant bleeding
- c. The INR is > 9 without significant bleeding
- d. The patient has an elevated INR and life threatening bleeding
2) How do you manage a heparin induced coagulopathy in a patient with…
- e. Minor bleeding
- f. Major bleeding
3) How do you manage a patient on Pradaxa with significant bleeding?
I. Administer 10 mg of vitamin K with a slow IV push and 10 – 15 ml/kg of FFP
II. Hold next 1 – 2 doses and consider oral vitamin K 1 – 2.5 mg
III. Consider hemodialysis, PCC and rFVIIa
IV. Stop heparin administration
V. Hold next 1 – 2 doses and administer oral vitamin K 2.5 – 5 mg
VI. Lower or admit next dose of warfarin
VII. Protamine 1 mg per 100 units of total amount of IV heparin administered within the past 3 hours
1) a. VI.
2) a. IV.
There are several anticoagulants on the market today. Anticoagulants are used in the management of many conditions – they may stop further thrombosis reduce the risk of a thromboembolic event, or help prevent thrombi from forming. One of the biggest risks of using these agents is hemorrhage and life threatening bleeding. We will discuss the pharmacology and the complications and management of the various anticoagulants available today.
Warfarin is the most common oral anticoagulant encountered in the emergency department. It works by blocking the activation of vitamin K and therefore interferes with the vitamin K dependent clotting factors II, VII, IX and X. This provides the antithrombotic effect via the extrinsic coagulation pathway (“The EX patriot went to WARfarin”). Warfarin also has a pro-thrombotic effect via inhibition of proteins C and S. During maintenance therapy, the antithrombotic effect outweighs the pro-thrombotic effect.
The pro-thrombotic effect is greatest when starting and discontinuing warfarin therapy. Therefore, when starting warfarin therapy it is necessary to bridge with a parental anticoagulant (such as heparin) until the international normalized ratio (INR) reaches the therapeutic range. It is also necessary to gradually taper warfarin when discontinuing this medication. This is due to the differences in the half-lives of the clotting factors and proteins C and S. The clotting factor half-lives vary from 7 hours (factor VII) to 60 hours (factor II), whereas the antithrombotic proteins have shorter half-lives of 8 hours.
Dosing of warfarin is guided by measuring the INR. Normal therapeutic range is 2-3. The INR of 2.5 to 3.5 is goal for those with mechanical heart valves and those who have antiphospholipid antibody syndrome. The risk of bleeding increases with the increasing INR.
To manage a warfarin coagulopathy you must consider the INR, the patient status, and whether or not they have significant bleeding. To reverse a warfarin coagulopathy the first step is to hold warfarin, the next to administer vitamin K, and the final is to administer fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) or recombinant Factor VIIa (rFVIIa).
For asymptomatic patients the first step is to hold the next dose to two doses of warfarin. If the patient is at a high risk of bleeding with an INR of 5-9, consider PO vitamin K administration. If the INR is > 9 and no significant bleeding then administer 2.5 to 5 mg of PO vitamin K.
Oral vitamin K will decrease the INR in approximately 16 hours (longer if INR > 10). Oral vitamin K will decrease the INR faster than subcutaneous vitamin K if the INR is < 10. IV vitamin K may also be used. This is associated with risk of anaphylaxis and is not used in the routine reversal of anticoagulation. IV vitamin K also carries a risk of over correction and is reserved for those with life threatening bleeds or those who ingested a rodenticide. The peak effect from vitamin K is seen in 1-2 days.
FFP is used if there is life threatening bleeding present. It is the fastest way to reverse the anticoagulant effects of warfarin, and is considered safe. Administer FFP at a dose of 10-15 mL/kg (typically 3-4 units).
Rapid (and complete) reversal of warfarin may be achieved by PCC or rFVIIa. PCC contains factors II, VII, IX and X and works in under 30 minutes. The dose is 25-50 units/kg. rFVIIa dose is 5 mcg/kg (typical dose is one 1200 mcg vial). May repeat the dose if INR remains elevated.
Heparin and Low Molecular Weight Heparin
Unfractionated heparin (UFH) activates antithrombin III (AT III), leading to the inhibition of Factor Xa and thrombin. Heparin has a very short half life (30-150 minutes) and must be given arenterally. It has a relatively unpredictable anticoagulation effect and requires frequent monitoring of the activated partial thromboplastin time (aPTT). Goals with therapy are usually an aPTT 1.5 to 2.5 times the normal range. Heparin may affect the PT and INR, but this is not used to guide therapy.
If bleeding develops while a patient is on UFH, you must first stop the heparin administration. The aPTT may lag behind the actual anticoagulation dosing; therefore you cannot rely on the aPTT to predict whether your patient has a serious bleed.
Protamine is used to reverse UFH in severe bleeding. One milligram IV protamine neutralizes 100 units of UFH administered in the prior 3 hours. Protamine has a risk of anaphylaxis. It should be given slowly over 1 to 3 minutes and not exceed 50 mg in a 10 minute period. Protamine has a very short half life (7 minutes) therefore may require more than one dose.
Low molecular weight heparin (LMWH) also work by binding AT III and deactivation of Factor Xa. LMWH’s include enoxaparin (Lovenox), dilteparin and tinzaparin. The half life is longer than UFH and therefore allows for once or twice a day dosing.
LMWH usually cause less bleeding than UFH. Protamine will not completely reverse the anticoagulant effect of LMWH, only reversing 60% of function. rFVIIa has been reported to stop severe bleeding with use of LMWH.
Fondaparinux (Arixtra)is a synthetic drug that is a selective Factor Xa inhibitor. The use of protamine does NOT reverse fondaparinux. Hemodialysis (HD) will reduce the level by 20%. rFVIIa may be used to reverse serious bleeds.
Dibigatran is a competitive, direct thrombin inhibitor. This prevents development of a thrombus via direct clotting factor inhibition (not depletion). It is approved for use in atrial fibrillation to help prevent thromboembolism.
Laboratory testing may help determine if dibigatran is contributing to the bleeding event. aPTT is insensitive to the effects of dibigatran. If the aPTT is normal this suggests little anticoagulant activity present, but even mild elevations in aPTT can be associated with significant bleeding. Thrombin time (TT) is less helpful in overdose, but a normal TT excludes the presence of significant dibigatran levels. Ecarin clotting time (ECT) has a linear relationship with dibigatran levels, although this test is not available at all facilities.
There is no reversal agent for dibigatran. In an acute overdose, activated charcoal may help in absorbing dibigatran. Because dibigatran is a direct thrombin inhibitor, administration of clotting factors (FFP, PCC) is unlikely to be helpful in reversal of coagulation. They may be administered only as a last resort when supportive measures fail to control the bleed. If a patient develops life threatening bleeding while on dibigratan, consider hemodialysis (primarily excreted in urine, HD will remove approximately 60% of the drug) and the use of rFVIIa and PCC.
Rivaroxaban is a direct Factor Xa inhibitor. It is approved for the prevention of stroke and thromboembolism in patients with atrial fibrillation and prevention of thrombus in those who are undergoing knee or hip replacement surgery.
Laboratory testing will show a dose dependent effect on PT and aPTT, however this is not a reliable test. Similarly the INR is not sensitive to the effects of rivaroxaban. There are new laboratory testing under development to help determine the level of anticoagulation achieved with rivaroxaban.
There are no reversal agents available. If a patient has minor bleeding either discontinue therapy or delay the next dose. If there is moderate to severe bleeding, initiate supportive treatment (blood, IVF, cardiac monitoring)and try to control the site of the bleeding. Oral charcoal may be administered if rivaroxaban was administered within the prior 2 hours. Unlike dibigatran, rivaroxaban is NOT dialyzable. If severe/life threatening bleeding PCC may be tried.
Great resource on anticoagulant reversal: