7.5 Coagulation Factor Disorders, Thrombophilia & Anticoagulant Reversal

ABIM Internal Medicine Exam

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1 Chapter 0: The ABIM Exam, Blueprint & Study Strategy

0.1 Exam Format, Question Types & the 2026 Blueprint 0.2 Eligibility, Registration, Fees & Exam-Day Logistics 0.3 Scoring, the Passing Standard & Score Reports 0.4 Building a Blueprint-Weighted Study Plan

2 Chapter 1: Cardiovascular Disease (14% of Exam)

1.1 Ischemic Heart Disease & Acute Coronary Syndromes 1.2 Antithrombotic Therapy, Secondary Prevention & Mechanical Complications of MI 1.3 Atrial Fibrillation, Atrial Flutter & Stroke Prevention 1.4 Supraventricular Tachycardias, Ventricular Arrhythmias & Bradycardias 1.5 Heart Failure: Classification, Staging & Guideline-Directed Medical Therapy 1.6 Device Therapy, HFpEF & the Cardiomyopathies 1.7 Valvular Heart Disease & Endocarditis Prophylaxis 1.8 Pericardial Disease & Acute Aortic Syndromes 1.9 Hypertension: Classification, Diagnosis & Secondary Causes 1.10 Hypertensive Crises & Dyslipidemia 1.11 Adult Congenital Heart Disease & Coarctation of the Aorta 1.12 Syncope: Reflex, Orthostatic & Cardiac Causes 1.13 Cardiac Physical Examination, Murmurs & Antithrombotic Selection

3 Chapter 2: Endocrinology, Diabetes & Metabolism (9% of Exam)

2.1 Diabetes Mellitus: Diagnosis, Glycemic Targets & Pharmacotherapy 2.2 Insulin Therapy, Hyperglycemic Emergencies & Chronic Complications 2.3 Thyroid Function Testing & Hypothyroidism 2.4 Thyrotoxicosis, Thyroid Storm & Thyroid Nodules 2.5 Adrenal & Pituitary Disorders 2.6 Hypercalcemia, Hypocalcemia & Disorders of Mineral Metabolism 2.7 Osteoporosis & Paget Disease of Bone 2.8 Ovarian, Testicular & Reproductive Endocrine Disorders 2.9 Hypoglycemia, Endocrine Tumors, Polyglandular Syndromes & Severe Hypertriglyceridemia

4 Chapter 3: Gastroenterology & Hepatology (9% of Exam)

3.1 Esophageal Disease 3.2 Stomach & Duodenal Disease and Gastrointestinal Hemorrhage 3.3 Inflammatory Bowel Disease 3.4 Celiac Disease & Irritable Bowel Syndrome 3.5 Diverticular Disease & Colorectal Cancer Screening 3.6 Viral Hepatitis, Steatotic & Alcohol-Associated Liver Disease 3.7 Cirrhosis & the Complications of Portal Hypertension 3.8 Acute Pancreatitis 3.9 Chronic Pancreatitis & Biliary Tract Disease 3.10 Inherited, Autoimmune & Drug-Induced Liver Disease 3.11 Small Intestinal Disease, Ischemia & Gastrointestinal Complications of HIV

5 Chapter 4: Infectious Disease (9% of Exam)

4.1 Lower Respiratory Tract Infections & Sepsis Syndromes 4.2 Viral Respiratory Pathogens & Tuberculosis 4.3 Central Nervous System Infections 4.4 Skin, Soft Tissue, Bone & Joint Infections 4.5 Infective Endocarditis & Cardiovascular Infection 4.6 Clostridioides difficile & Catheter-Related Bloodstream Infection 4.7 HIV Diagnosis, Antiretroviral Therapy & Prevention 4.8 Opportunistic Infections & Sexually Transmitted Infections 4.9 Fever of Unknown Origin, Neutropenic Fever & Toxic Shock 4.10 Travel-Related Illness, Vector-Borne Disease & Outbreaks 4.11 Infection Prevention, Nosocomial Infection & Postexposure Prophylaxis 4.12 Rheumatic Fever, Poststreptococcal Disease, Enteric & Hepatic Infections

6 Chapter 5: Pulmonary Disease (9% of Exam)

5.1 COPD: Diagnosis, GOLD Classification & Initial Pharmacotherapy 5.2 Interventions That Reduce COPD Mortality & Exacerbation Management 5.3 Asthma: Diagnosis, Stepwise Therapy & Status Asthmaticus 5.4 Interstitial Lung Disease & Idiopathic Pulmonary Fibrosis 5.5 Sarcoidosis, Hypersensitivity Pneumonitis & Occupational Lung Disease 5.6 Pulmonary Embolism: Diagnosis, Risk Stratification & Anticoagulation 5.7 Pulmonary Hypertension & Sleep-Disordered Breathing 5.8 Acute Respiratory Distress Syndrome & Mechanical Ventilation 5.9 Pleural Disease, Empyema & Pneumothorax 5.10 Bronchiectasis, Cystic Fibrosis & Restrictive Lung Disease 5.11 Evaluation of Cough, Dyspnea, Hemoptysis & the Solitary Pulmonary Nodule

7 Chapter 6: Rheumatology & Orthopedics (9% of Exam)

6.1 Rheumatoid Arthritis: Diagnosis & Systemic Manifestations 6.2 Antirheumatic Pharmacotherapy & the Spondyloarthropathies 6.3 Gout: Pathophysiology & Acute Management 6.4 Urate-Lowering Therapy & Calcium Pyrophosphate Deposition Disease 6.5 Osteoarthritis 6.6 Systemic Lupus Erythematosus 6.7 Systemic Sclerosis, Sjogren Syndrome & Inflammatory Myopathies 6.8 The Vasculitides 6.9 Regional Musculoskeletal Syndromes, Back Pain & Sports Injuries 6.10 Other Primary Rheumatic Disorders & Mixed Connective Tissue Disease 6.11 Osteonecrosis & Metabolic Bone Disease

8 Chapter 7: Hematology (6% of Exam)

7.1 Approach to Anemia & the Microcytic Anemias 7.2 Macrocytic, Normocytic & Hemolytic Anemias 7.3 Hemoglobinopathies, Thalassemias & Paroxysmal Nocturnal Hemoglobinuria 7.4 Platelet Disorders, Thrombocytopenia & the Bleeding Patient 7.5 Coagulation Factor Disorders, Thrombophilia & Anticoagulant Reversal 7.6 Acute Leukemias, Chronic Leukemias & Myeloproliferative Neoplasms 7.7 Lymphomas & Plasma Cell Disorders 7.8 Myelodysplastic Syndrome, Myeloproliferative Neoplasms & Porphyria 7.9 Transfusion Medicine & Late Complications of Transplantation

9 Chapter 8: Medical Oncology (6% of Exam)

8.1 Breast, Lung, Colorectal & Prostate Cancer 8.2 Oncologic Emergencies 8.3 Genitourinary & Gynecologic Malignancies 8.4 Head and Neck, Bone & Soft Tissue Cancer and Cancer of Unknown Primary 8.5 Complications of Cancer & Its Treatment 8.6 Cancer Prevention, Survivorship & Psychosocial Care

10 Chapter 9: Nephrology & Urology (6% of Exam)

9.1 Acute Kidney Injury: Staging, Etiology & Urine Microscopy 9.2 Glomerular Disorders & Nephrotic Syndrome 9.3 Nephritic Syndromes, RPGN & Indications for Renal Replacement Therapy 9.4 Chronic Kidney Disease: Staging & Progression Retardation 9.5 Complications of Chronic Kidney Disease: Anemia, CKD-MBD & Acidosis 9.6 Hyponatremia, Hypernatremia & Water Balance 9.7 Potassium Disorders & Systematic Acid-Base Analysis 9.8 Renal Tubular Acidosis & Nephrolithiasis 9.9 Prostate Disorders, Urinary Incontinence & Other Urologic Conditions 9.10 Cystic Kidney Disease, Obstructive Uropathy, Tubulointerstitial Disease & Hematuria

11 Chapter 10: Neurology (4% of Exam)

10.1 Acute Ischemic Stroke: Syndromes & Reperfusion 10.2 Transient Ischemic Attack, Secondary Prevention & Hemorrhagic Stroke 10.3 Headache & Facial Pain 10.4 Seizures, Epilepsy & Movement Disorders 10.5 Multiple Sclerosis & Neuromuscular Junction Disorders 10.6 Motor Neuron Disease & Acute Peripheral Neuropathy 10.7 Cranial Neuropathies & Neuro-Ophthalmology 10.8 Peripheral Neuropathies, CNS Tumors & Other Neurologic Disorders

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13 Chapter 12: Dermatology (3% of Exam)

12.1 Dermatitis, Papulosquamous & Inflammatory Dermatoses 12.2 Acne, Rosacea & Cutaneous Infections 12.3 Herpes Zoster & Autoimmune Blistering Diseases 12.4 Nodules, Tumors & Cutaneous Oncology 12.5 Dermatologic Emergencies & Severe Cutaneous Adverse Reactions 12.6 Pigment Disorders, Alopecia, Nail Disease & Photosensitivity 12.7 Vascular Dermatoses, Environmental Injury & Cutaneous Signs of Systemic Disease

14 Chapter 13: Obstetrics & Gynecology / Women's Health (3% of Exam)

13.1 Contraception, Preconception Care & Teratogenicity 13.2 Hypertensive Disorders of Pregnancy & Gestational Diabetes 13.3 Thyroid Disease & Venous Thromboembolism in Pregnancy 13.4 Menopause & Menopausal Hormone Therapy 13.5 Abnormal Uterine Bleeding, Endometrial Disease & Gynecologic Cancer Screening 13.6 Breast Disorders & Diseases of the Vulva and Vagina 13.7 Menstrual Disorders, Fibroids, Endometriosis & Early Pregnancy Complications

15 Chapter 14: Geriatric Syndromes (3% of Exam)

14.1 Comprehensive Geriatric Assessment & Frailty 14.2 Falls, Gait Assessment & Polypharmacy 14.3 Urinary Incontinence & Pressure Injuries in Older Adults 14.4 Mild Cognitive Impairment, Dementia & Its Subtypes 14.5 Delirium & the Pharmacotherapy of Cognitive Disorders 14.6 Palliative Care, Hospice & Advance Care Planning 14.7 Chronic Wounds, Nutrition, Swallowing, Constipation & Hip Fracture 14.8 Sensory Impairment, Dizziness, Elder Mistreatment & Care Settings

16 Chapter 15: Allergy & Immunology (2% of Exam)

15.1 Anaphylaxis: Recognition & Emergency Management 15.2 Urticaria & Angioedema 15.3 Drug Allergy, Desensitization & Adult Immunodeficiency 15.4 Food Allergy, Insect Venom Hypersensitivity, Serum Sickness & Contrast Reactions 15.5 Rhinitis, Conjunctivitis, Eosinophilic & Mast Cell Disorders

17 Chapter 16: Preventive Medicine, Immunization & Clinical Epidemiology

16.1 The USPSTF Framework & Evidence-Based Cancer Screening 16.2 Cardiovascular & Metabolic Screening and Primary Prevention 16.3 Adult Immunization & Vaccines in Special Populations 16.4 Clinical Epidemiology, Biostatistics & Study Design

18 Chapter 17: Miscellaneous - Ethics, Patient Safety & Quality Improvement (2% of Exam)

17.1 Principles of Bioethics & Decisional Capacity 17.2 Informed Consent, Treatment Refusal & Special Scenarios 17.3 Surrogate Decision-Making, Advance Directives & Confidentiality 17.4 Patient Safety Science, Medical Error & Diagnostic Reasoning 17.5 Quality Improvement Methods, Health Disparities & Health Equity

19 Chapter 18: Perioperative Medicine & Medical Consultation

18.1 Preoperative Cardiovascular Risk Assessment 18.2 Preoperative Pulmonary Risk & Perioperative Medication Management 18.3 Perioperative Anticoagulation, Bridging & Postoperative Complications

20 Chapter 19: Ophthalmology (1% of Exam)

19.1 The Acute Red Eye & Ophthalmic Emergencies 19.2 Painless Vision Loss & Chronic Ophthalmic Disease 19.3 Uveitis, Scleritis & Orbital Disease

21 Chapter 20: Otolaryngology & Dental Medicine (1% of Exam)

20.1 Dizziness, Vertigo & Epistaxis 20.2 Ear Disorders, Hearing Loss & Upper Respiratory Infections 20.3 Oral Cavity, Salivary Gland, Laryngeal & Taste and Smell Disorders

7.5 Coagulation Factor Disorders, Thrombophilia & Anticoagulant Reversal

Key Takeaways Explain This Topic AI

Coagulation factor deficiencies, primary hypercoagulable states, antiphospholipid antibody syndrome and undifferentiated thrombotic disorders are the enumerated topics.

A mixing study that corrects indicates factor deficiency, whereas failure to correct indicates an inhibitor such as a lupus anticoagulant or an acquired factor antibody.

Antiphospholipid syndrome requires a persistently positive antibody on two occasions at least twelve weeks apart together with thrombosis or pregnancy morbidity.

Warfarin rather than a direct oral anticoagulant is indicated in triple-positive antiphospholipid syndrome because of higher recurrent thrombosis rates with direct agents.

Four-factor prothrombin complex concentrate with vitamin K reverses warfarin in major bleeding, while idarucizumab reverses dabigatran and andexanet alfa reverses factor Xa inhibitors.

Last updated: August 2026

• 1. Coagulation Cascades & Mixing Studies
• Interpreting 1:1 Mixing Studies

A mixing study is performed when a patient has an unexplained prolongation of the activated partial thromboplastin time (aPTT) or prothrombin time (PT).

Patient plasma is mixed 1:1 with normal pooled plasma (which contains 100% activity of all clotting factors):

Correction of aPTT (Immediate & Incubated): The added normal plasma supplies the missing clotting factor. This confirms a Factor Deficiency (e.g., Factor VIII [Hemophilia A], Factor IX [Hemophilia B], Factor XI, or Factor XII deficiency).

Failure to Correct (or correction immediately that prolongs after 2-hour 37°C incubation): Indicates the presence of a circulating inhibitor:

Time/Temperature-Dependent Inhibitor: Acquired Factor VIII Inhibitor (autoantibody against FVIII; prolonged aPTT worsens after 2 hours at 37°C).

Immediate Inhibitor (Non-time-dependent): Lupus Anticoagulant (Antiphospholipid antibody) ; does not correct immediately or after incubation. Confirmed with Dilute Russell Viper Venom Time (dRVVT) showing neutralization with excess phospholipids.

Inherited & Acquired Bleeding Coagulopathies

Coagulopathy Genetics / Etiology Coagulation Profile Clinical Manifestations Definitive Treatment

Hemophilia A X-linked recessive; Factor VIII deficiency Isolated prolonged aPTT (corrects on 1:1 mix); normal PT/INR, normal platelets Recurrent hemarthroses, target joint arthropathy, deep muscle hematomas Recombinant/plasma-derived Factor VIII concentrate ; Emicizumab (bispecific antibody bridging FIXa and FX) for prophylaxis; DDAVP for mild disease

Hemophilia B X-linked recessive; Factor IX deficiency (Christmas disease) Isolated prolonged aPTT (corrects on 1:1 mix); normal PT/INR Identical clinical presentation to Hemophilia A Recombinant/plasma-derived Factor IX concentrate (DDAVP is ineffective)

Von Willebrand Disease (vWD) Autosomal dominant (Type 1 [70–80%, partial quantitative], Type 2 [qualitative]); Autosomal recessive (Type 3 [severe]) Prolonged PFA-100 closure time , normal or prolonged aPTT (if FVIII binding reduced), normal PT/INR Mucosal bleeding, menorrhagia, epistaxis, gingival hemorrhage, post-dental extraction bleeding Desmopressin (DDAVP) for Type 1 (induces endothelial Weibel-Palade release); vWF/Factor VIII concentrates (Humate-P) for Type 2/3 or surgery; Tranexamic acid

Acquired Factor VIII Inhibitor Acquired IgG autoantibody against FVIII (elderly, postpartum, autoimmune) Isolated prolonged aPTT that DOES NOT correct on incubated 1:1 mix; low FVIII activity Severe spontaneous soft tissue bleeding, extensive ecchymoses, hematomas (hemarthroses rare) Bypassing agents: Recombinant Factor VIIa ( rFVIIa ) or Activated Prothrombin Complex Concentrate ( FEIBA ); + Immunosuppression ( Prednisone + Cyclophosphamide / Rituximab )

Disseminated Intravascular Coagulation (DIC) Massive systemic tissue factor release (sepsis, trauma, obstetric emergencies, APL) Elevated PT/INR, elevated aPTT, low Fibrinogen (< 150 mg/dL), elevated D-dimer, low platelets Diffuse oozing from IV sites/wounds, petechiae, concurrent arterial/venous microthrombosis Treat underlying cause; Cryoprecipitate (to maintain fibrinogen > 150–200 mg/dL), Platelets (> 50k), Fresh Frozen Plasma (for active severe bleeding)

• 2. Thrombophilia & Hypercoagulable States
• Inherited Thrombophilias

Factor V Leiden (FVL) Mutation: Point mutation (G1691A) replacing arginine with glutamine at position 506 in the Factor V molecule, destroying the cleavage site for Activated Protein C ( Activated Protein C Resistance [APCR] ). Most common inherited thrombophilia in Caucasian populations (3–8% heterozygote prevalence). Heterozygotes have 3–5x increased risk of VTE; homozygotes have 50–80x increased risk.

Prothrombin G20210A Mutation: Gain-of-function mutation in the 3'-untranslated region of the prothrombin gene leading to elevated plasma prothrombin (Factor II) levels and 2–3x increased VTE risk.

Protein C and Protein S Deficiencies: Autosomal dominant deficiencies of Vitamin K-dependent natural anticoagulants. Predisposes to venous thromboembolism, purpura fulminans in neonates, and warfarin-induced skin necrosis during unbridged warfarin initiation.

Antithrombin (ATIII) Deficiency: Inherited or acquired (nephrotic syndrome with urinary ATIII wasting, cirrhosis, ECMO). Causes heparin resistance (inability to achieve therapeutic aPTT despite high doses of unfractionated heparin, because heparin requires antithrombin to exert its anticoagulant effect).

Acquired Thrombophilia: Antiphospholipid Syndrome (APLS)

Diagnostic Criteria (Sapporo / Sydney Criteria): Requires at least 1 clinical criterion AND at least 1 laboratory criterion documented on ≥ 2 occasions at least 12 weeks apart :

Clinical Criteria:

Vascular thrombosis: ≥ 1 episode of venous, arterial, or small-vessel thrombosis.

Pregnancy morbidity: ≥ 1 unexplained fetal death ≥ 10 weeks gestation, ≥ 3 consecutive unexplained spontaneous abortions < 10 weeks gestation, or ≥ 1 premature birth < 34 weeks due to severe preeclampsia/eclampsia or placental insufficiency.

Laboratory Criteria (Positive ≥ 12 weeks apart):

Lupus Anticoagulant (LA) detected via functional clotting assays (dRVVT).

Anticardiolipin Antibody (aCL) IgG or IgM (> 40 GPL/MPL or > 99th percentile).

Anti- β 2 \beta_2 β 2 ​ -Glycoprotein I Antibody IgG or IgM (> 99th percentile).

Anticoagulation Standard of Care:

For thrombotic APLS, lifelong anticoagulation with Warfarin (target INR 2.0–3.0) is the standard of care.

Direct Oral Anticoagulants (DOACs) are CONTRAINDICATED in thrombotic APLS (especially "triple-positive" patients) due to significantly higher rates of recurrent arterial thromboembolic events (stroke, myocardial infarction) compared to Warfarin (demonstrated in the randomized TRAPS and RAPID trials).

3. Anticoagulant Reversal Strategies

Anticoagulant Agent Mechanism of Action Monitoring Assay Specific Reversal Agent / Management

Warfarin Inhibits Vitamin K Epoxide Reductase (VKORC1); depletes active Factors II, VII, IX, X, Protein C, S PT / INR Life-Threatening Bleeding: 4-Factor Prothrombin Complex Concentrate (4F-PCC / Kcentra) weight-based (25–50 units/kg based on baseline INR) PLUS IV Vitamin K1 (Phytonadione 10 mg) slow infusion.; Urgent reversal without bleeding: Oral Vitamin K 2.5–5.0 mg.

Dabigatran (Pradaxa) Direct competitive Thrombin (Factor IIa) inhibitor Thrombin Time (TT), Dilute Thrombin Time, aPTT Idarucizumab (Praxbind) 5.0 g IV (two 2.5 g vials administered in rapid succession). Binds dabigatran with 350x higher affinity than thrombin.

Apixaban (Eliquis) / Rivaroxaban (Xarelto) Direct competitive Factor Xa inhibitors Anti-Factor Xa activity (calibrated) Andexanet alfa (Andexxa) : Recombinant modified decoy Factor Xa protein. High- or low-dose IV bolus followed by 2-hour infusion.; Alternative if unavailable: 4-Factor PCC (50 units/kg IV) .

Unfractionated Heparin (UFH) Binds Antithrombin III, potentiates inhibition of thrombin and Factor Xa aPTT (target 50–70s), Anti-Xa Protamine Sulfate : 1.0 mg IV per 100 units of UFH administered over preceding 2–3 hours (max dose 50 mg to avoid intrinsic anticoagulant toxicity).

Low-Molecular-Weight Heparin (Enoxaparin) Primarily inhibits Factor Xa via ATIII Anti-Factor Xa level Protamine Sulfate : 1.0 mg per 1.0 mg of Enoxaparin administered within preceding 8 hours (partially neutralizes ~60–75% of anti-Xa activity).