ORAL ANTI-COAGULANTS

Friends venous thromboembolism in pregnancy, is one of those topics which we donot study in detail during undergraduation. So, I am giving in brief, all the important points you need to remember :

Venous thromboembolism in pregnnacy :

• Venous thromboembolism is the leading cause of maternal deaths in developed countries.
• Pregnancy increases the risk of thromboembolism 6 times as all components of virchow’s triad are increased.° A. Deep vein thrombosis :
• Left sided DVT is more common than Right sided DVT.
• Clinical features : swelling / redness / pain and calf muscle tenderness and oedema.
• Investigations

–    Recommended method during pregnancy : Doppler ultrasound

–    Gold standard (in conditions other than pregnancy) : venography

• Mangement : Therapeutic

The treatment should be started on clinical grounds if confirmatory tests are not available. Drug of choice – Heparin (as it doesnot cross the placenta)

Initially intravenous Heparin is given with the aim to prolong APTT (activated partial thromboplastic time) by 1.5 to 2 times the control followed by subcutaneous Heparin.

• Monitoring is done by APTT and platelet count (as Heparin causes Thrombocytopenia).
• Oral anticoagulants like Warfarin cross the placenta and cause teratogenesis therefore should be avoided in pregnancy.
• Treatment is continued for 6 weeks following which prophylactic subcutaneous heparin is given throughout pregnancy.
• Heparin is stopped just before delivery.
• Regional anaesthesia should be avoided at the time of delivery in patients on heparin due to the risk of hematoma formation.
• Heparin is restarted about 6 – 8 hours after delivery as the puerperium is the time of greatest risk for VTE.
• Warfarin is commenced simultaneously and thereafter monitoring is done by prothrombin time (PT).
• Once the prothrombin time INR is between 2 and 3, heparin can be discontinued.
• Usually warfarin is continued for 6                  to 18 weeks and is safe for breast feeding mothers.

Thromboprophylaxis :

Thromboprophylaxis is considered for women who are at increased risk of thromboembolism (TE).

Risk category                  Risk factors

High risk                          Recurrent TE

Previous TE with thrombophilia Previous TE with family history TE in current pregnancy

Low risk                           One episode of previous TE without thrombophiiia or family history
Thrombophilia without previous thrombosis

Additional risk                     Cesarean section, obesity, grand multiparity, age above 35, pre-eclampsia, prolonged immobilization etc.

• High risk patients need antepartum heparin, intrapartum heparin and postpartum prophylaxis for 6 weeks.
• Low risk patient require intrapartum and postpartum low dose prophylaxis for 6 weeks.

Well, now that you have a detailed knowledge of thromboembolism, lets have a look at the question.

It says : a female with previous history of embolism becomes pregnant,what medical management should be given to her‑

Option ‘a^. i.e. Compulsory prophylaxis with warfarin at 10 weeks.

• It is absolutely wrong as warfarin is not given during pregnancy.

Option ‘b Le to take warfarin after delivery – According to William obs. 22/e, p 1077 table 47-3, 23/e, p 1028 – table 47.6

• In case of prior VTE associated with a non recurring risk factor and no known thrombophilia‑

During pregnancy : Only surveillance is required as per American college of chest physicians.

Prophylaxis with low molecular weight heparin is required as per American college of obs & gynaecology (which also explains option ‘d is partly correct).

Postpartum : warfarin is given for 6 weeks.

So, option ‘b’ is absolutely correct i.e. warfarin should be given in the post partum period for six weeks.

The patient in the question is receiving rifampicin it enhance the metabolism of warfarin, as rifampicin is a microsomal enzyme inducer.

Increased metabolism of warfarin results in insufficient prolongation of prothrombin time.

Most effective next step in management is to increase the dose of warfarin.

Since such an option is not mentioned, next suitable approach would be to use low molecular weight heparin as an anticoagulant.

Ref: Essentials of Medical Pharmacology By KD Tripathi, 5th Edition, Pages 563, 700

Dabigatran etexilate is an oral thrombin inhibitor and rivaroxaban is an oral factor Xa inhibitor.

Dabigatran etexilate is used as an alternative to warfarin for stroke prevention in patients with atrial fibrillation.

Argatroban is a parenteral direct thrombin inhibitor. Alfimeprase is a fibrinolytic agent.

Absolute contraindications of warfarin:

• Previous CNS bleeding
• Recent neurosurgery
• Active frank bleeding
• Early pregnancy and delivery

Relative contraindications:

• Active peptic ulcer disease
• Chronic alcoholism
• Bleeding diathesis
• Severe hypertension

Severity and type of liver disease may influence warfarin pharmacokinetics. Severe cholestatic liver disease reduces CYP2C content, while severe cirrhotic liver without cholestasis does not.

Ref: Inpatient Anticoagulation By Margaret C. Fang, 2011, Page 34; Primary Care Medicine Recommendations By Allan H. Goroll, Albert G. Mulley, Jr., 2001, Page 224; Goodman and Gillman’s 11th edition, Page 955-956.

Warfarin inhibits vitamin K-dependent coagulation factor synthesis. These include factors II, VII, IX, and X, as well as protein C and S.

Warfarin acts to increase the prothrombin time.

Factors XI and XII are not vitamin K-dependent factors. Therefore, warfarin does not inhibit their synthesis.

Warfarin is an oral anticoagulant.

It acts by inhibiting vitamin K dependent coagulation factors.

Warfarin crosses the placenta readily and can cause a hemorrhagic disorder in the fetus.

Furthermore, fetal proteins with -carboxyglutamate residues found in bone and blood may be affected by warfarin; the drug can cause a serious birth defect characterized by abnormal bone formation.

Thus, warfarin should never be administered during pregnancy.

The t1/2 varies (25-60 hours), with a mean of 40 hours; the duration of action of warfarin is 2-5 days.

Ref: Zehnder J.L. (2012). Chapter 34. Drugs Used in Disorders of Coagulation. In B.G. Katzung, S.B. Masters, A.J. Trevor (Eds), Basic & Clinical Pharmacology, 12e.

• Barbiturates
• Rifampicin
• Griseofulvin
• Carbamazepine

For most indications, warfarin is administered in doses that produce a target INR of 2.0- 3.0. An exception is patients with mechanical heart valves, where a target INR of 2.5-3.5 is recommended. Studies in atrial fibrillation demonstrate an increased risk of cardio embolic stroke when the INR falls to 4.

Warfarin interferes with the synthesis of the vitamin K-dependent clotting proteins, which include prothrombin (factor II) and factors VII, IX, and X.

Like all anticoagulants, the major side effect of warfarin is bleeding. A rare complication is skin necrosis. Warfarin crosses the placenta and can cause fetal abnormalities. Consequently, warfarin should not be used during pregnancy.

Dabigatran etexilate, an oral thrombin inhibitor, and rivaroxaban, an oral factor Xa inhibitor are new oral anticoagulants.

Rivaroxaban is the first orally active Factor Xa inhibitor. Useful in Heparin induced thrombocytopenia and thrombosis syndrome.

Anticoagulants are the treatment of choice in patients with atrial fibrillation and prior stroke or transient ischemic attack (TIA). Vitamin K antagonists such as warfarin have long been the mainstay of therapy, but a new set of anticoagulants has emerged as a reasonable alternative that may indeed prove to have better efficacy and a reduced risk of hemorrhage.

Apixaban is one such oral direct factor Xa inhibitor; it was recently shown to be likely more effective compared with warfarin in the Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) trial.

Ans. is ‘a’ i.e., Inhibition of Vitamin K epoxide reductase

o During y- carboxylation of the coagulant factor II, VII, IX and X in the liver, active vitamin K (Vit K hydroquinone) is oxidized to an epoxide (vit K epoxide).

o Vit K epoxide must be reduced to vit K hydroquinone to become active once again (vit K cycle).

o Vit K epoxide is reduced to vit K hydroquinone by vit K reductase.

Ans. is ‘d’ i.e., Dose is increased in liver disease

Effect of liver disease on warfarin

o In liver diseases the dose of oral anticoagulats needs to be decreased because in liver disease the hepatic

synthesis of clotting factors is reduced.

o Thus there is already a deficiency of clotting factors (i.e. there is preexisting anticoagulant state). o Administration of warfarin is this state increases the risk of bleeding.

about other options

o Warfarin is an indirectly acting anticoagulant, i.e. it inhibits vitamin K which in turn inhibits coagulation factors.

o T1/2 of warfarin is 36 hrs.

o Warfarin can cross placenta and cause fetal warfarin syndrome. Therefore it is contraindicated pregnancy. Patient is switched to heparin from warfarin during pregnancy.

Ans. is ‘a’ i.e., Vitamin K

o Dicumarol (an oral anticoagulant) acts by inhibiting Vitamin K dependent clotting factors.

 Ans. is ‘a’ i.e., Protein C deficiency

o Warfarin – induced skin necrosis occurs in patients with undiagnosed protein C deficiency.

Ans. is ‘c’ i.e., Contraindicated in hepatic failure

o Liver disease requires dose reduction, but is not a contraindication.

Effect of liver disease on warfarin

o In liver diseases the dose of oral anticoagulats needs to be decreased because in liver disease the hepatic synthesis of clotting factors is reduced.

o Thus there is already a deficiency of clotting factors (i.e. there is preexisting anticoagulant state). o Administration of warfarin is this state increases the risk of bleeding.

About other options

o Warfarin is an indirectly acting anticoagulant, i.e. it inhibits vitamin K which in turn inhibits coagulation factors. o T1/2 of warfarin is 36 hrs.

o Warfarin can cross placenta and cause fetal warfarin syndrome. Therefore it is contraindicated pregnancy. Patient is switched to heparin from warfarin during pregnancy.

Ans. is ‘c’ i.e., Fresh frozen plasma

o Urgent reversal of warfarin therapy is required when immediate hemostatic competance is necessary because of serious life threatening bleeding or when 1NR > 20.

Ans. is ‘c’ i.e., Phytonadione

Vit K_i (Phytonadione) is the preparation of choice for overdose of oral anticoagulants (Dicumarol).

Remember

• Specific antidote for oral anticoagulants –> Vit K1
• Specific antidote for heparin Protamine
• Specific antidote for fibrinolytics (e.g. streptokinase) —–> antifibrinolytics (epsilone amino-caproic acid, Tranaexaemic acid, Aprotinin).

Ans. is ‘b’ i.e., 36 weeks

In pregnancy warfarin should be replaced by heparin prior to conception and continued throughout the first trimester (In early pregnancy , warfarin damages organogenesis in fetus).

After the first trimester heparin should he replaced by warfarin and continued upto term (continued exposure to heparin cause osteoporosis).

Warfarin should be discontinued near term and heparin can be substituted at this stage (warfarin exacerbates neonatal hypoprothrombinemia and its control is too imprecise to be safe in labour where as heparin can be discontiuned just before labour and its anticoagulant effect wears off in about 6 hrs).

Ans. is ‘b’ i.e., Phytonadione

o Warfarin shows a number of drug interactions and requires dose adjustment :‑

1)       Enzyme inducers (phenobarbitone, rifampicin, phenytoin, griseofulvin etc) and oral contraceptives (increase clotting factors) decrease the effect and hence require increase in dose of warfarin.

2)    Drugs that increase the effect of warfarin and require dose reduction are enzyme inhibitors (cimetidine, erythromycin, cotrimoxazole, disulfiram, isoniazid, metronidazole, azoles, allopurinol), cephalosporins (cefamendole, cefoperazone, moxalactam), phenylbutazone, amiodarone, sulfinpyrazone, acute alcohol intake, loop diuretics and valproate.

Ans. is ‘c’ i.e., Rifampicin

Ans. is ‘ d ‘ i.e., Griseofulvin

Ans. is ‘a’ i.e., Increase the dose of warfarin

Ans. is ‘b’ i.e., Erythromycin

Ans. is ‘d’ i.e., Benzodiazepenes

Ans. B: Increased metabolism of warfarin

Barbiturates increase the metabolism of oral anticoagulants, resulting in reduced anticoagulation effects. If co-administration is unavoidable, monitoring of INR and adjustment of anticoagulant dose is needed. An increase in anticoagulant dose (approximately 30-60%) may be needed when adding a barbiturate.

Withdrawal of barbiturates will result in reduced anticoagulant requirement over several weeks; a reduction in the anticoagulant dose may be needed to prevent bleeding complications

Ans. C i.e. Heparin

Reversal of warfarin effect

The effects of warfarin can be reversed with vitamin K, or, when rapid reversal is needed (such as in case of severe bleeding), with prothrombin complex concentrate—which contains only the factors inhibited by warfarin—or fresh frozen plasma (depending upon the clinical indication) in addition to intravenous vitamin K.

For patients with-an international normalized ratio (INR) between 4.5 and 10.0, a small dose (about 1000 mcg = one milligram) of oral vitamin K is sufficient.

• When warfarin is being given and INR is in therapeutic range, simple discontinuation of the drug for five days is usually enough to reverse the effect and cause INR to drop below 1.5.

Ans. A: Factor III

Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors as well as the regulatory factors protein C, protein S, and protein Z.

They interfere with regeneration of the active hydroquinone form of vitamin K which carries out the final step of gamma carboxylating glutamate residues of prothrombin and factors VII, IX and X.

Other proteins not involved in blood clotting, such as osteocalcin, or matrix Gla protein, may also be affected.

Ans. D: Chronic Alcoholism

Other broad-spectrum antibiotics can reduce the amount of the normal bacterial flora in the bowel, which make significant quantities of vitamin K, thus potentiating the effect of warfarin. In addition, food that contains large quantities of vitamin K will reduce the warfarin effect. Thyroid activity also appears to influence warfarin dosing requirements; hypothyroidism (decreased thyroid function) makes people less responsive to warfarin treatment, while hyperthyroidism (overactive thyroid) boosts the anticoagulant effect.

Liver diseases, chronic alcoholism may enhance effect as synthesis of clotting factor may be deficient.

Ans. A: INR

Ans. B: Give oral Vitamin K1

Vitamin K1 is the specific antidote for warfarin

Treatment of bleeding due to oral anticoagulants consists of:

Withhold the anticoagulant

• Give fresh blood transfusion; supplies clotting factors and replenishes ost blood. Alternatively fresh frozen plasma may be used as a source of clotting factors
• Give vit K1 (phytonadione)-specific antidote, but it takes 6-24 hours for the clotting factors to be resynthesized and released in blood after vit K administration.

Ans. is ‘d’ i.e., Propylthiouracil

INTERACTIONS OF ORAL ANTICOAGULANT

The list of drugs and other factors that may affect the action of oral anticoagulant is prodigious and expanding. Any substance or condition may affect oral anticoagulants if it alters

1. The uptake or metabolism of the oral anticoagulant or vitamin K.

2.The synthesis, function or clearance of any factor or cell involved in hemostasis or fibrinolysis.

3. The integrity of any epithelial surface.

Ans. is ‘c’ i.e., Inhibiting Vitamin K dependent carboxylation

Warfarin inhibits vitamin K dependent carboxylation of clotting factors by inhibiting the enzyme Vitamin K epoxide reductase.

Oral anticogulants

• They act indirectly by interfering with the synthesis of vit K dependent clotting factors in liver.
• They interfere with regeneration of the active hydroquinone form of vit K, which is required for the final step gamma carboxylating glutamate residues ofprothrombin (factor II) and factor VII, IX and X. This carboxylation is essential for the ability of the clotting factors to bind Ca⁺² and to get bound to phospholipid surface, necessary for coagulation sequence to proceed.

Mechanism of action

• During y – carboxylation of the coagulant factor II, VII, LX and X in the liver, active vitamin K (Vit K hydroquinone) is oxidized to an epoxide (vit K epoxide).
• Vit K epoxide must be reduced to vit K hydroquinone to become active once again (vit K cycle).
• Vit K epoxide is reduced to vit K hydroquinone by vit K reductase.
• This vit K reductase is inhibited by oral anticoagulants.

Ans. is ‘c’ i.e., Fresh frozen plasma

Ans. is ‘c’ i.e., VII

Ans. is ‘b’ i.e., 4 to 5 days

• Warfarin may increase peri- operative bleeding, except for minor procedures such as cataract surgery without bulbar blocks. No consensus exists on the optimal perioperative management of patients receiving warfarin.
• The usual recommendation is to withhold warfarin starting 4 to 5 days preoperatively (if the INR is between 2^.0 and 3^.0) to allow the INR to decrease to less than 1^.5, which is a level considered safe for surgical procedures and neuraxial blockade.
• If the INR is greater than 3^.0, it is usually necessary to withhold warfarin longer than 4 to 5 days.
• If the INR is measured the day before the surgical procedure and remains higher than 1^.8, a small dose of vitamin K (1 to 5 mg administrated orally or subcutaneously) can reverse anticoagulation.
• Vitamin K has an effect within 6 to 10 hours after oral or subcutaneous administration (more predictable with oral administration), and it peaks within 24 hours to 48 hours. Administration of higher doses may lead to warfarin resistance when therapy is initiated again.

Ans. is ‘c’ i.e., Rivaroxaban 

• Rivaroxaban – it is an orally active direct inhibitor of activated factor Xa which has become available for prophylaxis and treatment of DVT.
• Alteplase – given by i.v. infusion due to short half life of 4 – 8 min and often requires heparin coadministration.
• Argatroban – direct thrombin inhibitor; given by i.v. infusion; used in place of lepirudin for short term indications in patients with heparin induced thrombocytopenia.
• Fondaparinux – 100% bioavailability with subcutaneous injection

Ans. is ‘b’ i.e., Cimetidine

Ans. is ‘a’ i.e., Inhibition of Vitamin K epoxide reductase