Coagulation

Coagulation Cascade

Coagulation Labs

PT (Prothrombin Time): Thromboplastin (which contains Tissue Factor) is added to blood and the time needed to clot is recorded. Specifically analyzes the extrinsic pathway (factors II, V, VII, and X, and fibrinogen) ₍₁₎

INR (International Normalized Ratio): Because of variability in thromboplastin reagent mixtures around the world, the INR was developed to give a standardized number based on a ratio of the patient’s PT divided by a control PT using an internationally-accepted thromboplastin reagent. ₍₁₎

PTT (Partial Thromboplastin Time) aka aPTT (activated Partial Thromboplastin Time): Kaolin is added to a sample of the patient’s blood, which leads to activation of the intrinsic coagulation pathway. This test measures, collectively, all factors except VII and XIII ₍₂₎

Anticoagulants

Warfarin inhibits Vitamin K Epoxide Reductase Complex (VKORC), which inhibits this enzyme’s ability to recycle Vitamin K. This leads to a decrease in the number of Vitamin-K dependent coagulation factors, which are Factors II, VII, IX, X, and Proteins C and S. This prolongs the PT (in turn increasing the INR) and PTT

Heparin forms a complex with antithrombin III, which then inactivates thrombin and Factors IXa, Xa, and XIa. This prolongs the PTT, although many low-molecular weight heparins (such as enoxaparin) will not prolong the PT. Heparin should also, in theory, prolong the PT (in turn increasing the INR), however, most PT reagents contain heparin-binders, which remove heparin from the equation, allowing for a normal PT reading ₍₃₎

DOACs (Direct Oral Anticoagulants)

• Direct Thrombin Inhibitors: Dabigatran, argatroban, bivalirudin
• Factor Xa Inhibitors: Apixaban, rivaroxaban, edoxaban, betrixaban, fondaparinux

These agents may prolong the PT (and increase the INR) as well as prolong the PTT; however, patients who are anticoagulated therapeutically on these agents may still have normal studies. Therefore, routine monitoring of these labs is not recommended _{(4, 5, 6)}

Bleeding Disorders

Hemophilia A: Factor VIII deficiency ₍₇₎

• Inheritance: X-linked recessive
• PT/INR: normal, PTT: generally prolonged
• Diagnosis: Serum factor VIII levels
• Management: Depends on severity of disease. Desmopressin can stimulate endothelial cells to secrete Von Willebrand factor (VWF) which protects the limited amount of Factor VIII in the body

Hemophilia B (Factor IX deficiency) ₍₈₎

• Inheritance: X-linked recessive
• PT/INR: normal, PTT: generally prolonged
• Diagnosis: Serum factor IX levels
• Management: Recombinant factor IX prophylactically dosed twice per week or at a higher dose in acute bleeding events. Antifibrinolytic agents (Monoclonal antibodies (e.g., rituximab), tranexamic acid, and epsilon aminocaproic acid) can be used in cases of mucosal bleeding or dental extractions

Vitamin K Deficiency/Liver Disease

• Vitamin K deficits generally as a result of reduced dietary intake (or reduced absorption due to a biliary obstruction), diarrhea, or antibiotic use
• Vitamin K deficiency results in decreased synthesis of factors II, VII, IX, X, and proteins C and S. Liver disease results in decrease in production of all coagulation factors (except factor VIII)
• PT/INR: Elevated, PTT: Elevated
• Diagnosis: PT/INR, PTT, evidence of liver disease on routine laboratory studies (CMP)
• Management: PO or IV Vitamin K replacement; may also use fresh frozen plasma (FFP)

Von Willebrand Disease (VWD) ₍₉₎

• 3 sub-types
  • Type 1 (Autosomal Dominant) (most common): Deficiency of VWF
  • Type 2: (Autosomal Dominant) Abnormal, decreased functioning of VWF
  • Type 3: (Autosomal Recessive) Total or near-total absence of VWF
• PT/INR: normal, PTT: normal or elevated depending on severity of the disease (because of the subsequent deficiency of Factor VIII caused by low levels of VWF)
• Diagnosis: VWF Factor Antigen levels and VWF Factor Activity levels
• Management: DDAVP in minor bleeding episodes (generally only useful in Type 1 and Type 3). VWF can be replaced in major bleeding episodes that do not demonstrate a response to DDAVP.

Clotting Disorders

Factor V Leiden mutation ₍₁₀₎

• Most common inherited thrombophilia
• Mechanism: Point mutation in Factor V and Va prevents activated Protein C (aPC) from cleaving them, leading to increased thromboembolism risk
• Diagnosis: Mutation testing or Functional aPC resistance assays
• Management: Anticoagulation if the patient has a VTE, recommended for the same indications and duration as VTE in the general population

Antiphospholipid Antibody Syndrome ₍₁₁₎

• Autoantibodies against phospholipids and phospholipid-binding proteins, such as cardiolipin and β₂-glycoprotein I.
• Can be primary/idiopathic, or may be secondary to underlying autoimmune diseases, malignancy, or drugs
• Diagnosis:
  • Lupus anticoagulant: measures the effect that the antibody has on clotting time. Antiphospholipid antibodies bind to phospholipids in the blood sample, preventing clotting. The name is somewhat paradoxical – blood is prevented from clotting in the test tube, but at a higher risk of clotting in vivo.
  • Anticardiolipin antibody
  • Anti-Beta-2-glycoprotein-I antibody
• Treatment: Anticoagulation

Antithrombin III Deficiency ₍₁₂₎

• Antithrombin III normally functions to inhibit thrombin as well as factors Xa, IXa, and VIIa. Inherited or may be acquired in liver disease, nephrotic syndrome, DIC, sepsis, pre-eclampsia
• Type I: Quantitative defect
• Type II: Qualitative defect
• Diagnosis: Antithrombin III levels
• Management:
  • Anticoagulation for patients with a VTE. Prophylactic anticoagulation for pregnant women or patients who are to undergo surgery
  • Low-molecular weight heparin generally preferred, followed by warfarin or DOACs
  • Antithrombin III concentrate may be useful in patients with recurrent VTE despite anticoagulation, heparin-resistance, or patients on ECMO or hemodialysis

Protein C Deficiency ₍₁₃₎

• Protein C is vitamin K–dependent, converted into activated Protein C (aPC), which inactivates coagulation factors Va and VIIIa. Deficiency leads to increased risk of coagulation and thrombotic events
• Inheritance: Autosomal Dominant
• Diagnosis: Clotting assays, ELISA, and chromogenic tests to determine levels of protein C activity
• Management: Long-term Protein C replacement or anticoagulation with warfarin or low-molecular weight heparin

Paroxysmal Nocturnal Hemoglobinuria ₍₁₄₎

• Mutation of PIG-A gene, leading to paucity of several surface membrane proteins on RBCs, including CD55 and CD59. This leads to increased complement-mediated lysis of RBCs
• Hypercoagulability attributed mostly to increased complement-mediated activation of platelets
• Diagnosis: Flow cytometry
• Treatment: supportive treatment of hemolysis. Prophylactic anticoagulation remains controversial, however, management of thrombosis secondary to PNH with lifelong anticoagulation is generally accepted

Polycythemia Vera/Essential Thrombocytosis

• Can screen for with CBC

Oral Contraceptive use ₍₁₅₎

• Estrogen/progestins increase plasma fibrinogen levels, coagulation factor activity, and decrease antithrombin III levels, in addition to accelerating platelet aggregation
• Management: Discontinue oral contraceptives

References:

1. Yang, R. (2021, May 10). Prothrombin Time. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK544269/. 
2. Rountree, K. M. (2020, August 21). Partial Thromboplastin Time. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK507772/. 
3. DM;, F. (n.d.). Coagulation assays and anticoagulant monitoring. Hematology. American Society of Hematology. Education Program. https://pubmed.ncbi.nlm.nih.gov/23233620/. 
4. Kovacevic MP;Lupi KE;Wong A;Gilmore JF;Malloy R; (n.d.). Evaluation of the Effect of Apixaban on INR in the Inpatient Population. Journal of cardiovascular pharmacology and therapeutics. https://pubmed.ncbi.nlm.nih.gov/30905167/. 
5. Frans, G., Meeus, P., & Bailleul, E. (2019, June 12). Resolving DOAC interference on aPTT, PT, and lupus anticoagulant testing by the use of activated carbon. Wiley Online Library. https://onlinelibrary.wiley.com/doi/full/10.1111/jth.14488. 
6. Adcock, D. M., & Gosselin, R. C. (2017, April 26). The danger of relying on the APTT and PT in patients on DOAC therapy, a potential patient safety issue. Wiley Online Library. https://onlinelibrary.wiley.com/doi/full/10.1111/ijlh.12658. 
7. Centers for Disease Control and Prevention. (2020, July 17). Diagnosis of Hemophilia. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/hemophilia/diagnosis.html. 
8. Alshaikhli, A. (2021, February 6). Hemophilia B. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK560792/. 
9. Sabih, A. (2021, March 6). Von Willebrand Disease. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK459222/. 
10. Albagoush, S. A. (2021, March 1). Factor V Leiden Deficiency. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK534802/. 
11. Mezhov, V., Segan, J. D., Tran, H., & Cicuttini, F. M. (2019, July 4). Antiphospholipid syndrome: a clinical review. Wiley Online Library. https://onlinelibrary.wiley.com/doi/10.5694/mja2.50262. 
12. Găman, A. M., & Găman, G. D. (2014). Deficiency Of Antithrombin III (AT III) – Case Report and Review of the Literature. Current health sciences journal. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340457/. 
13. Gupta, A. (2021, January 29). Protein C Deficiency. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK542222/. 
14. Risitano, A. M., & Rotoli, B. (2008, June). Paroxysmal nocturnal hemoglobinuria: Pathophysiology, natural history and treatment options in the era of Biological Agents. Biologics : targets & therapy. Retrieved November 17, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721357/. 
15. J;, B. (n.d.). Coagulation effects of oral contraception. American journal of obstetrics and gynecology. Retrieved November 17, 2021, from https://pubmed.ncbi.nlm.nih.gov/2960241/.