Drug Class 14: Thrombolytics/Fibrolytics, Anti-coagulants and other hemostatic agents

Drug Class 14: Thrombolytics and other hemostatic agents (Protamine, Tranexamic acid, Vitamin K)

Part 1———————————————————————————————–Thrombolytics—————————————————————————————————————————-

What are thrombolytics?

-Drugs that activate the natural anticlotting system, conversion of plasminogen to plasmin. Activation of this system breaks down fibrin threads and dissolves any formed clot. Effective only if pt. has plasminogen in the plasma.

14.1 Mechanism of action:

-They convert plasminogen to plasmin, which catalyses the breakdown of fibrin.

14.2 Clinical Indications

(a) Acute STEMI (ST-segment elevation myocardial infarction)

(b) Acute massive VTE (venous thromboembolism)/DVT in patients who are hemodynamically unstable

(c) Peripheral arterial thromboemolism

(d) Thrombosed IV cannulae, central venous catheters and hemodialysis shunts

14.3 Precautions

1. Risk of bleeding

CONTRAINDICATED in severe active bleeding disorders or disease states with an increased risk of bleeding e.g. severe uncontrolled hypertension, severe hepatic disease, bleeding orders, severe thrombocytopenia.

-Other drugs that can affect the clotting process may increase the risk of bleeding.

*Low dose aspirin (up to 150mg daily) or heparin may be used where indicated.

2. Spinal injection or puncture

-Seek specialist advice before considering intra-thecal or epidural analgesia or anesthesia or lumbar puncture

-Risk of epidural hematoma, which may cause paralysis

3. Pregnancy

-Only minimal amounts of streptokinase cross the placenta.

Streptokinase specific antibodies are found in fetal blood.

Alteplase: CAT B-AUS

Reteplase, Tenecteplase and Streptokinase: CAT C-AUS

4. Breastfeeding

-No data unavailable but unlikely to be absorbed by infant

14.4 Adverse effects/Side effects


1. Bleeding, including bleeding at injection sites

2. Intracranial bleeding

3. Internal bleeding (e.g. Gastrointestinal, genitourinary)

4. Transient Hypotension


-Allergic reactions including fever, chills, rash, nausea, headache, bronchospasm, anaphylaxis, vasculitis, nephritis


-Cholesterol embolism

14.5 Practice points

-Avoid Intra-muscular injections and other invasive procedures during thrombolytic treatment.

-In the case of severe bleeding not controlled by local pressure, stop infusion of thrombolytic, fibrinogen, platelets, coagulation factors, tranexamic acid may be used (or protamine if herparin has been used).

-In acte MI, give aspirin in antiplatelet dose at least until discharge.

14.6 Types of thrombolytics

1. Alteplase (rt-PA) [Fibrin specific]

-Plasminogen activators produced by recombinant DNA technology.

-More fibrin specific than streptokinase because they activate plasminogen associated with thrombi in preference to circulating plasminogen.

  • Clinical Indications: (a) Acute STEMI (b) Massive pulmonary embolism (c) Acute ischemic stroke

2. Reteplase [Fibrin specific]

-Plasminogen activators produced by recombinant DNA technology.

-More fibrin specific than streptokinase because they activate plasminogen associated with thrombi in preference to circulating plasminogen.

  • Clinical Indications: Acute STEMI
  • Administration advice: No other medication, including heparin, should be injected through the line reserved for reteplase because of the risk of precipitation. 

3. Tenecteplase [Fibrin specific]

-Plasminogen activators produced by recombinant DNA technology.

-More fibrin specific than streptokinase because they activate plasminogen associated with thrombi in preference to circulating plasminogen.

  • Clinical Indications: Acute STEMI

4. Streptokinase (Contraindicated if previously exposured)

-Streptokinase: Produced by beta-hemolytic streptococci.

-Production of anti-bodies towards streptokinase occurs after streptokinase treatment or streptococcal infection.

-Streptokinase is likely to be ineffective if given between 5 days and 1 months or more after previous streptokinase treatment or acute severe streptococcal infection (e.g. glomerulonephritis, rheumatic fever, pancreatitis)

  • Clinical indications: (a) Acute STEMI (b) Acute massive VTE/DVT in patients who are hemodynamically unstable (c) Peripheral arterial thromboembolism (d) Trombosed hemodialysis solution
  • Precautions:

1. Previous treatments with streptokinase (take note if patient had previous MI)

*Previous streptokinase treatment or severe streptococcal infections (e.g. acute rheumatic fever, glomerulonephritis).

-Anti-streptokinase antibodies are likely to be present. Efficacy of streptokinase is likely to be reduced.

*If this occured between 5 days and 12 months ago, streptokinase contraindicated (risk of anaphylaxis)

*If used more than 12 months ago, consider alternative agents.

  • Adverse effects/Side effects:


*Hypotension (related to infusion rate)

  • Practice points

-Stop heparin before giving streptokinase. *Check APTT (should be less than twice the normal control value before beginning thrombolytic treatment and before reinstituting heparin)

-Give patients a record of use so the information is available in the event of future need for streptokinase.

-Hypotension usually responds to fluids and temporarily stopping streptokinase infusion.

5. Urokinase [Drug is not marketed in Australia but may be available through the SAS]

-Enzyme isolated from human urine

  • Clinical indications: (a) Thrombosed IV cannulae (b) Central venous catheters (c) Hemodialysis shunts (d) Peripheral arterial thromboembolis
  • Practice points:

*Stop heparin before giving urokinase.

*Check APTT (activated partial thromboplastin time should be less than twice the normal control value before beginning thrombolytic treatment and before reinstituting heparin)

*Comparative information


-Streptokinase, alteplase, reteplase and tenecteplase are used in ACUTE STEMI within 12 hours of onset of chest pain

-Earlier administration is of greater clinical benefit

-Weight-adjusted heparin is given routinely with alteplase, reteplase and tenecteplase.

-Heparin may be given with streptokinase in selected patients.

*Alteplase given as an accelerated infusion appears to be associated with a slightly greater reduction in mortality but slightly higher risk of cerebral hemorrhage than streptokinase in STEMI patients presenting within 6 hours of symptom onset.

*Reteplase and tenecteplase reduce mortality to a similar extent as alteplase with a similar incidence of adverse effects. Both are given as a bolus injection and are considered the preferred thrombolytics.

-Streptokinase should be avoided in ATSI (aboriginal and torres strait islander) people because of their frequent high levels of anti-streptococcal antibodies.

  • Venous thromboembolism/Deep Vein thrombosis

-Streptokinase is approved for treatment of deep vein thrombosis and pulmonary embolism

-Alteplase is approved for treatment of massive pulmonary embolism.

*Consider thrombolytics in patients with acute massive embolism who are hemodynamically unstable.

Note: Treatment always carries a high bleeding risk.

  • Peripheral arterial thrombosis

-Both streptokinase and urokinase have been used successfully.

However, there is little evidence to recommend thrombolysis over angioplasty or surgery.

  • Stroke

-Alteplase may be used for the treatment of acute ischemic stroke in selected patients within 4.5 hours of symptom onset (The earlier treatment is started, the greater the benefit)

It reduces disability at 3 months, despite an increased risk of symptomatic intracerebral hemorrhage.


Part 2———————————————————————————————————Anti-Coagulants (Very big class)————————————————————————————-


For treatment of venous thromboembolism (DVT):


Drug choice: Heparins or Low Molecular Weight Heparins (Enoxaparin)

Factor Xa Inhibitors

Warfarin (Discussed in detail here)


Prevention of venous thromboembolism (DVT):

Drug choice: Factor Xa inhibitors (Discussed in detail here)

-Low dose heparin

Direct Thrombin inhibitor (Discussed in detail here)

-Other preventive measures


Ischemic stroke and transient ischemic attack

Drug choice: Heparin (Discussed in detail here)




Part 3———————————————————————————————————Other drugs affected hemostasis——————————————————————————-

1. Protamine [Pro-coagulant due to inhibition of heparin]

Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential forsperm head condensation and DNA stabilization

  • Mechanism of action:

-Combines with heparin to form a stable inactive complex. Reversing its anticoagulant effect.

Thus, it is a drug that reverses the anticoagulant effects of heparin by binding to it.

  • Clinical Indications:

*Heparin, dalteparin or enoxaparin overdose in patients with/or at high risk of severe hemorrhage 

  • Precautions

-Consider the need for protamine and original reason for heparin as re-heparinisation may not be effective until the protamine has been eliminated

-Seek specialist hemorrhage advice or consult local protocols

*Give only when resuscitation facilities are available.

1. Fish Allergies-Increase risk of allergy

2. Previous protamine treatment (including protamine containing insulins)-Increases risk of allergy

3. Infertile men (including vasectomy)-May have protamine antibodies and an increased risk of allergy.

4. Pregnancy: CAT B2-AUS

5. Breastfeeding-Unlikely o be absorbed by child

  • Adverse effects/Side effects


1. Sensation of warmth

2. Flushing

3. Nausea

4. Vomitting

5. Tiredness

6. Allergy


Hypotension, bradycardia, dyspnea (especially if given rapidly), allergy, rebound bleeding with excessive doses


-Urticaria/Hives and severe hypersensitivity reactions including cardiovascular collapse. Bronchospasm and death have occured.

  • Administration advice

-IV maximum rate 5 mg/minute (too rapid administration may cause severe hypotension and anaphylactoid reactions)

  • Practice Points

-Protamine has an onset of action (OAA) of 5 mins.

-Withdrawal of heparin is usually sufficient to treat minor bleeding.

-Protamine is not recommended for danaparoid overdose

-Protamine can have an anti-coagulant effect in overdose or in the absence of heparin

-Transfusions may still be needed for severe hemorrhage.

2. Tranexamic acid [Anti-fibrolytic]

  • Mechanism of action: Inhibits breakdown of clots by blocking binding of plasminogen and plasmin to fibrin
  • Clinical indications: (a) Hereditary angioedema (b) Reduction of bleeding in minor surgery (dental surgery, cervical conisation, prostatectomy) in patients with mild to moderate coagulopathy (c) Reduces bleeding in heavy menstrual bleeding, traumatic hyphema, cardiac surgery or knee/hip arthroplsaty

*Coagulopathy refers to a condition in which the blood’s ability to clot is impaired

  • Precautions: 

1. Active intravascular clotting-CONTRAINDICATED

2. Predisposition to thrombosis-Increases risk of thrombotic adverse effects

3. Subarachnoid hemorrhage-May increase cerebral ischemic complications

4. Renal impaired

-Reduce dose in renal impairment

-In hematuria due to renal parenchymal disease, thrombosis may lead to intra-renal obstructoin.

5. Pregnancy

-Contact one of the pregnancy drug information centres. CAT B1-AUS

6. Breastfeeding-Appears safe

  • Adverse effects/Side effects:


1. Nausea

2. Vomitting

3. Diarrhea

Infrequent or rare

-Hypotension, thrombosis, allergic skin reactions, transient disturbance of colour vision

  • Practice points

-May be used as a mouthwash (e.g. in anti-coagulant treated or hemophiliac patients undergoing minor oral surgery)

-Recently marketing approval was given for IV tranexamic acid in cardiac surgery and knee or hip arthroplasty. However, there are shortcomings in the product information that AMH cannot provide

3. Vitamin K/ Pytomenadione [For coagulation]

  • Mechanism of action: Essential co-factor in the synthesis of blood clotting factors II, VII, IX and X and proteins C and S. Reverses effect of Vitamin K antagonists.


  • Clinical Indications: (a) Hemorrhage or threatened hemorrhage due to severe hypoprothrombinemia e.g. from excessive dose of vitamin K antagonist (b) Hypovitaminosis K (c) Prevention and treatment of hemorrhagic disease of the newborn
  • Precautions

1. Fat malabsorption syndromes, Biliary atresia, Pancreatic insufficiency-Impaired oral absorption

2. Elderly

Due to greater response to Vitamin K, dosage should be at the lower end of the recommended range.

3. Pregnancy

-Use if required, does not readily cross the placenta

-May be used from 36 weeks gestation in women taking liver enzyme inducing anti-epileptics (e.g. phenytoin and carbamazepine)

4. Breastfeeding-Safe to use

  • Adverse effects/Side effects


1. Pain

2. Tenderness

3. Erythema (IM injection)


-Allergic reactions including anaphylaxis (especially with rapid IV injection)


-Hemolytic anemia, Hyperbilirubinemia, Kernicterus (in neonates, especially if preterm)

  • Administration advice

-Give injection orally or by slow IV injection over 30s.

  • Practice Points

-Vitamin K may not be required in all cases of excessive anti-coagulation due to vitamin K antagonists

-Temporarily stopping the drug and re-adjustment of vitamin K antagonists dose may be all that is necessary

-Anti-coagulant of Vitamin K antagonist may be difficult to re-establish for several days to weeks after large doses of Vitamin K. *If intending to restart Vitamin K antagonist, use lowest possible dose of Vitamin K.

-IM administration is the preferred route for prevention of hemorrhagic disease of the newborn because of reliability of administration and level of compliance.

-Oral administration may be as effective as IM administration if there is full compliance with dosage schedule.

  • Extra information

-Sources of Vitamin K: Green leafy vegetables (supplies Vitamin K1-phylloquinone) and bacterial synthesis in the colon (supplies vitamin K2-menaquinone)

-After absorption into the bowel, Vitamin K is oxidized to form an inactive epoxide.

-Most Vitamin K comes from bacterial synthesis by colonic bacteria.

*To be catalytically active, Vitamin K synthesized must be reduced by epoxide reductase in the liver.

  • Vitamin K γ-carboxylates glutamate residues in the Vitamin K-dependent coagulation factors (Factor II/Prothrombin, VII, IX, and X + Protein C and S)
  • Vitamin K-dependent coagulation factors are synthesized in theliver in a non-functional state.
  • *When carboxylated in the liver by Vitamin K, these coagulation factors are able to bind to calcium which is essential to the formation of a fibrin clot.

Prothrombin time (PT)- This is a coagulation test that evaluates all of the vitamin K-dependent factors except factor IX and proteins C and S

Coumarin derivatives act as anti-coagulants by inhibiting the activity of epoxide reductase, hence the vitamin K-dependent coagulation factors are useless (cannot bind to calcium)

Summary of Vitamin K functions:

1. Assist in carboxylating Vit-K dependent coagulation factors which allows them to bind to calcium for the formation of clot.

2. Bone calcification: γ-carboxylatse glutamate residues in osteocalcin.

Vitamin K deficiency: Bleeding diathesis (GIT bleeding, ecchymoses-Subcutaneous purpura), prolonged PTT

  1. Rare but can be caused by use of broad-spectrum antibiotics, which destroys colonic bacterial synthesis of vitamin.
  2. Also caused by therapy with Coumarin (Warfarin) derivatives: Inhibits hepatic epoxide reductase.
  3. Fat malabsorption: Cannot reabsorb fat-soluble vitamins (e.g. Celiac disease)
  4. Newborns: Lack bacterial colonisation of the bowel and must receive an intra-muscular vitamin K injection at birth to prevent hemorrhagic disease

Vitamin K toxicity: Uncommon even due to excessive intake


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