Gabriela Soriano Hobbs and Gerald A. Soff
Clinical Scenarios Suggestive of Bleeding Disorders:
• 1° hemostasis: Mucocutaneous bleeding (Mucosal bleeding, menorrhagia, petechiae, & ecchymoses), suggests thrombocytopenia, plt dysfunction, vWD, or vascular causes.
• 2° hemostasis: Deep and/or delayed bleeding suggests factor deficiency.
Prothrombin Time (PT)
• Measures extrinsic pathway (factor VII) & common pathway (factors X, V, II, & fibrinogen(I)).
• INR compensates for differences in PT assays between labs: INR should ONLY be used for pts on warfarin Rx
Causes of Isolated Prolonged PT
• Vitamin K deficiency – needed for synthesis of factors II, VII, X, IX, & protein C & protein S; causes – poor nutrition, malabsorption & prolonged abx use; deficiency affects factor VII first. More sev. will affect PTT as well.
• Liver disease – clotting factors synthesized in liver. (Sev. liver disease affects PTT as well.)
• Medications
Warfarin – inhibits vitamin K-dependent gamma-carboxylation of coagulation factors
Other anticoagulants – rivaroxaban & apixaban inhibit Factor Xa & dabigatran inhibits thrombin
abx alter gut bacterial flora, interfering w/vitamin K absorption.
Activated Partial Thromboplastin Time (aPTT)
• Measures the intrinsic pathway (factors XII, XI, IX, VIII, prekallikrein, high molecular wt kininogen) & common pathway (factors X, V, II, & I).
Causes of Isolated Prolonged aPTT
• Factor deficiencies, particularly of intrinsic pathway
• Specific inhibitors – ie, VIII (hemophilia A) & IX (hemophilia B)
• Nonspecific inhibitors – antiphospholipid Ab, acquired inhibitors (MM, lymphoproliferative neoplasms), heparin
Combined Prolongation of PT and aPTT
• Deficiency or inhibition of factor(s) in common pathway or multiple factors, DIC, antiphospholipid Ab, adv liver disease (can affect all factors except VIII), dysfibrinogenemia, excessive warfarin anticoagulation or sev. vitamin K deficiency (Mayo Clin Proc 2007:864–873)
Fibrinogen
• Low – A/w bleeding. DIC (↑consumption of coagulation factors & plt), thrombolytic Rx, liver disease (↓synthesis), tx w/L-asparaginase (paradoxically a/w ↑ thrombosis, Leukemia 2012). (Note: Dabigatran & other direct thrombin inhibitors may falsely ↓ fibrinogen assay).
• High – ↑ age, pregnancy, oral contraceptives, disseminated malignancy
D-Dimer
• Product of plasmin-mediated lysis of cross-linked fibrin
• Current gen. of D-dimer assays is VERY specific biomarker indicating the presence of fibrin formation (ie, in vivo clot); sensitive, but not specific for presence of activation of the coagulation system in vivo.
• Negative D-dimer result is useful to R/O VTE (not to r/i).
Common Anticoagulants
Warfarin Reversal
• If no bleeding:
INR 6–10, observe or give vitamin 2.5 mg PO (better than SC or IV)
INR >10 vitamin K 5 mg
• If bleeding: Vitamin K 10 mg IV & FFP 2–4 units every 6–8 h (Annals Int Med 2009;150:293)
Additional Tests
• If w/unexplained high PT or PTT after ruling out causes of prolonged PT & PTT mentioned above, obtain thrombin time, if abnl then perform mixing study
• Mixing study (mixes pt plasma w/nl plasma): Correction = factor deficiency, no correction = inhibitor
• Types of inhibitors: (1) immediate acting inhibitors (often LA, contamination w/anticoagulants), (2) inhibitors requiring 37°C incubation for 60 min (suspect specific factor inhibitor), (3) follow up by ordering LA, specific factor assay, & specific factor inhibitor (Clin Lab Med 2009:229–252). Note: Weak inhibitor may be diluted by nl plasma leading to correction & an incorrect result
Bleeding Disorders With Normal PT/aPTT
• vWD: May have mild FVIII deficiency, not low enough to detect w/elevated aPTT
• Rare bleeding disorders may have nl PT/aPTT:
Factor XIII deficiency (insufficient fibrin cross-linking)
Deficiency of a2-antiplasmin (excessive fibrinolysis)