Hemostasis and Clotting Processes

Hemostasis

• The process of stopping bleeding and forming a clot.
• Operates through positive feedback mechanisms.
• Injury to a blood vessel causes blood leakage, vasospasm, and exposure of collagen and other chemicals.

Clotting Processes

• Primary hemostasis involves platelet plug formation.
• Secondary hemostasis involves coagulation.

Primary Hemostasis: Platelet Plug Formation

• A damaged blood vessel exposes collagen.
• Chemicals cause platelets to adhere to the injury site, activate surrounding platelets, and aggregate to form a plug.

Secondary Hemostasis: Coagulation

• Coagulation forms fibrin through enzymatic reactions via clotting factors.
• Fibrin creates a meshwork to stabilize the platelet plug.
• Clotting factors are proteins made in the liver, circulating inactive until coagulation is activated.
• These factors instigate enzymatic reactions that result in fibrin formation.
• Fibrin threads create a meshwork, trapping blood constituents of the platelet plug, forming a clot.

Control of Coagulation

• The body inactivates stray clotting factors to prevent widespread coagulation.
• Antithrombin is a protein that inactivates clotting factors.

Fibrinolysis

• This is the clot removal process essential for healing.
• Fibrinolysis initiates within 24-48 hours after clot formation and continues until the clot dissolves.
• Plasmin is the main enzyme responsible for fibrinolysis.
• Plasmin starts dissolving the fibrin meshwork when blood vessel cells secrete tissue plasminogen activator (tPA).

D-dimer

• This is a major fibrin degradation product.
• Elevated plasma D-dimer concentrations indicate recent or ongoing intravascular coagulation and fibrinolysis.

Types of Hemostasis

• Primary hemostasis: Platelets adhere at the trauma site where they aggregate to create a blockage.
• Secondary hemostasis: Insoluble fibrin strands produce coagulation to reinforce this blockage.

Types of Thrombi

• A thrombus is a stationary clot within a blood vessel.
• An embolus is a thrombus fragment that breaks off and travels through the bloodstream.
• White thrombi (white clots) typically occur in arteries with fast blood flow, made mostly of platelets and fibrin.
• Red thrombi (red clots) typically occur in veins with slower blood flow, made mostly of RBCs and fibrin.

Hemostasis Measurement

• Complete Blood Count (CBC) measures platelet value.
• Prothrombin Time (PT) measures how long blood takes to clot, evaluating the extrinsic/common coagulation pathway, with a normal PT of 12 seconds.
• INR (International Normalized Ratio) is a PT ratio calculation to compare values across facilities, where Normal INR is 1.0; values presented as PT/INR.
• Activated Partial Thromboplastin Time (aPTT) measures how long blood takes to clot, evaluating intrinsic/common coagulation pathways, with normal aPTT at ~40 seconds.
• Anti-Factor Xa activity measures the effect of anticoagulants indirectly, and is calibrated for each specific anticoagulant.

Hemostasis Disorders

• Inability to Make Clots: Decreased platelets (thrombocytopenia) or clotting factor deficiencies from severe liver impairment/hemophilia.
• Clotting Problem: Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Myocardial Infarction, Ischemic Strokes.

Coagulation Disorders: Hemophilia

• It is a rare, inherited disorder where blood does not clot properly.
• It can result in spontaneous bleeding, severe bleeding after injury/surgery, or life-threatening internal bleeding.
• Hemophilia A (Classic) involves a lack/decrease in clotting factor VIII in 80% of cases.
• Treatment involves infusing the missing clotting factor.

Coagulation Disorders: Deep Vein Thrombosis (DVT)

• DVT: Thrombus in a major vein.
• Its Etiology: Venous stasis, endothelial damage, hypercoagulability of blood.
• Clinical Manifestations: Unilateral edema, warmth, redness, and tenderness.
• Treatment: Anticoagulation, prevent emboli formation/movement.
• Serious Complication: DVT leading to life-threatening Pulmonary Embolism (PE).

Pulmonary Embolism (PE) Clinical Manifestations

• Dyspnea
• Chest pain
• Sudden shortness of breath
• Tachycardia
• Tachypnea
• Hypotension
• Hemoptysis, cough
• Syncope

Overview of Hemostasis Modifiers

• Prevention of Clot Formation: Antiplatelets inhibit platelet action which decreases arterial thrombi (white clots), and Anticoagulants inhibit specific clotting factors to decrease arterial/venous thrombi (white/red clots).
• Removal of an Existing Clot: Thrombolytics (fibrinolytics) dissolve preexisting clots, and are fast-acting "clot busters" used in emergencies.

Rules of Thumb for Hemostasis Modifiers

• Medications prevent clot formation or dissolve existing clots by interfering with normal hemostasis processes.
• Contraindications: Avoid medications for patients with bleeding disorders or at risk of bleeding.
• Major Complication: Hemorrhage.
• Observe for bleeding gums, bruises, petechiae, epistaxis, tarry stools, hematuria, hematemesis, hematomas
• Increased heart rate, decreased blood pressure, abdominal pain
• Any multiple meds given with meds that increase bleeding (NSAIDs, steroids immunosuppressants, certain herbs, etc.), increases probability of hemorrhage.
• Medications altering hemostasis should be addressed before surgery/procedures.
• Any patient at risk of bleeding (disorder or taking medications) should be told to: avoid alcohol/OTC nonprescription medications (NSAIDs, aspirin), wear a medical alert bracelet, use a soft-bristled toothbrush/electric razor, and monitor clotting appropriately.
• Bleeding Herbs: Garlic Ginseng, Gingko biloba, Ginger Fish oil, St. John’s Wort, Dong Quai

Antiplatelet Medications

• These work on primary hemostasis to prevent platelet plug formation via Aspirin, ADP Receptor Antagonists, and GP IIb/IIIa Receptor Antagonists.
• It is used for acute treatment and/or prophylaxis of white clots for ischemic strokes, myocardial infarctions, peripheral atherosclerotic disease, cath lab procedures, and intermittent claudication.

Drug Class: Antiplatelet, Prototype: Aspirin

• Mechanism: Irreversibly inhibits cyclooxygenase 1 and 2 (COX-1, COX-2), decreasing platelet aggregation ("less sticky").
• Adverse: Hemorrhage, renal dysfunction, GI distress (use proton pump inhibitors or enteric-coated tablets), tinnitus.
• Contraindications: Hypersensitivity to NSAIDs, bleeding disorders/thrombocytopenia, viral infections in children/teenagers (<18 years), may be Reyes syndrome if fever is present.
• Route: Oral (immediate or enteric-coated).
• Clinical Considerations: Antipyretic, anti-inflammatory, analgesic properties, some platelet effects lasting 7 days. Administer immediate-release with food/water to minimize GI distress (do not crush enteric coated) and/or use DAPT = increased chances of bleeding.

Drug Class: Antiplatelet, Prototype: Clopidogrel

• The Mechanism is an irreversible blockade of platelet aggregation through ADP receptors.
• Adverse Effects: Hemorrhage, dyspepsia, BBW (reduced effect in CYP2C19 poor metabolizers), use CBC monitoring.
• Route: Oral.
• Clinical Considerations: Monitor CBC/signs of bleeding, where platelets gradually return to baseline at ~5-7 days after stopping.

Drug Class: Antiplatelet, Prototype: Eptifibatide

• The MOA is a reversible blockade of platelet GP IIb/IIIa receptors, via a glycoprotein inhibitor (most complete anti-platelet effect).
• Adverse Effects: Hemorrhage, hypotension and bradycardia.
• Clinical Considerations: Intravenous infusion, >90% inhibition attained within 10 mins, reversible effect, monitor vitals/CBC/bleeding.

Anticoagulant Medications

• These work by altering secondary hemostasis via decreasing the production of fibrin by interfering with the coagulation cascade.
• It is used for acute treatment and/or prophylaxis of red/white clots associated with Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Atrial Fibrillation, Acute Angina, Myocardial Infarctions, and Ischemic Strokes.

Parenteral Anticoagulants vs Oral Anticoagulants

• Parenteral Drugs: Unfractionated Heparin (UFH) enhances antithrombin which inactivates thrombin (IIa) and other clotting factors, and Low Molecular Weight Heparin (LMWH) inactivates thrombin (IIa) and Factor Xa.
• Oral Drugs: Warfarin reduces Vitamin-K dependent clotting factors (II, VII, IX, X) and Dabigatran is a direct thrombin inhibitor (IIa), and “-Xabans” (Apixaban, Betrixaban, Edoxaban, Rivaroxaban) are factor Xa inhibitors.

Drug Class: Parenteral Anticoagulant, Prototype: Unfractionated Heparin (UFH)

• Mechanism: Enhances antithrombin, inactivating thrombin (IIa) and other clotting factors.
• Adverse Effects: Hemorrhage; Heparin-induced thrombocytopenia (HIT).
• Contraindications: Thrombocytopenia, bleeding, lumbar puncture, regional anesthesia and/or following eye/brain/spinal surgery, do not administer IM because it could cause hematoma.
• Route: Intravenous infusion (acute) and Subcutaneous injection (DVT prophylaxis).

Key Details for Heparin

• Not absorbed orally, use parenteral administration, and is safe to use in breast feeding.
• Administer bolus, then adjust dose based on lab results.
• Confirm dose; distribution binds variability in plasma levels.
• Monitor aPTT (60-80 seconds) or Anti-Factor Xa levels (0.3-0.7 unit/ml); CBC daily (platelet count held if <100,000/mm3), and for hypersensitivity, hemorrhage, and renal/hepatic function.
• Reversal agent: protamine sulfate by slow IV injection, used for active bleeding or aPTT >150.

Heparin Induced Thrombocytopenia (HIT)

• It is a potentially fatal immune-mediated disorder (1-3% when heparin is used for 4+ days) where antibodies are developed against heparin-platelet complexes, activating platelets and damaging endothelium.
• Platelet counts rapidly and Thrombosis occurs despite adequate anticoagulation. STOP Heparin and give something other than heparin.

Drug Class: Parenteral Anticoagulant, Prototype: LMWH (Enoxaparin)

• Inactivates Factor Xa and thrombin.
• Lower incidence of hemorrhage and HIT than UFH.
• Contraindicated for active major bleeding and history of HIT.
• Route: Subcutaneous or IV.
• Monitor vitals and CBC (hold if platelets
• Advantages over UFH: it's as effective/easier to use, and does not require coagulation monitoring. Fixed-doses are given based on weight and renal function and can be administered at home. Disadvantages: cannot be quickly reversed or "turned off". It is partially reversed with protamine.

Key steps for LMWH (Enoxaparin) administration

• Subcutaneous administration; insert needle and do not expel air bubble; do not rub or aspirate; and carefully rotate injection sites.

Oral Anticoagulants

• Warfarin acts by altering secondary hemostasis to decreases production of fibrin.
• The direct-acting alternatives (DOACs) act through direct thrombin (Factor IIa) inhibitors (Dabigatran) or direct Factor Xa inhibitors "-Xabans".

Drug Class: Oral Anticoagulant, Prototype: Warfarin

• Mechanism of Action: Antagonizes Vitamin K (inhibits Vitamin K epoxide reductase), which reduces synthesis of clotting factors synthesized in the liver.
• At therapeutic warfarin inhibits vitamin K reduction, decreasing clotting factors by 30-50%. Therapeutic levels are only achieved after 3-5 days.
• Adverse Effects: Hemorrhage, fetal hemorrhage/teratogenesis discoloration of urine.
• Liver and Renal disease
• Contraindication: Uncontrolled bleeding, Thrombocytopenia
• The dose must be monitored by testing the INR.
• There are many Drug and Food interactions.
• Route: Oral.
• Monitor INR regularly for proper dosing compliance

Bridging Warfarin Therapy

• Warfarin as a delayed onset which requires consistent monitoring.
• Bridging is required with a short acting anticoagulant until INR is at the appropriate level.
• Monitor INR during therapy for compliance and appropriate dosing

Warfarin Counseling Points

• Carry alert card or bracelet, keep track of INR goal.
• Monitor for bleeding.
• Follow-up care with all health providers for warfarin administration.
• Only take recommended OTC medications.
• Strictly follow the pharmacy and dietary guidelines.
• Do not use Alcohol.

DOAC Drugs

• Direct acting oral anticoagulants (DOACs) can eliminate Vitamin K inhibitors
• Monitor for Hemorrhage, watch for renal dysfunction
• There are some reversal agents

Warfarin vs DOAC drugs

• Warfarin requires frequent INR monitoring vs the DOAC options.
• DOAC has to be accounted with renal or hepatic dysfuntion.
• Vitamin K is very important vs very little food consideration for the drug
• DOAC causes fewer interactions vs that MANY drug interaction

Fibrinolytics

• Function as Agents that break up the clot

Drugs Class and prototype, Thrombolytic and Alteplase (tPa)

• Should only be used severely by Restoring Patency ( opening blockage) by Ischemic type issues like ACS, PE and Strokes.
• Dissolves clots that degrades the fibrin matrix
• Super cautious with risk because you can cause risk of serious bleeding

Contradictions with thromboembolisms

• Recent Strokes must be accounted for.
• Time dependent
• Vitals signs could be an emergency.
• Reverse using an aminocaproic acid

Clinical Pearls

• All anticoagulants come with risk of Hemorrhage.
• INR will come in handy
• Clopidogrel should only be administered to a CYPC19 metabolism.
• Warfarin is great to use is the is no time sensitivity issues