Hypercoagulable States

Inherited (non-modifiable) — mostly loss of anticoagulant braking or gain of procoagulant function

• Factor V Leiden: point mutation renders factor Va resistant to cleavage by activated protein C (APC resistance); by far the most common inherited thrombophilia in patients of European ancestry
• Prothrombin G20210A: 3' untranslated region variant increases prothrombin transcript stability, raising circulating factor II and thrombin generation
• Protein C, protein S, and antithrombin deficiency: loss of the physiologic inhibitors of factors Va/VIIIa (protein C/S) and of thrombin/factor Xa (antithrombin); antithrombin deficiency is the rarest but the most thrombogenic
• Homozygous homocystinuria / severe hyperhomocysteinemia: cystathionine β-synthase deficiency causes endothelial injury and both arterial and venous thrombosis
• Dysfibrinogenemia and elevated factor VIII (partly heritable, also an acute-phase reactant)

Acquired — grouped by Virchow's triad

• Hypercoagulability: malignancy (tissue factor and mucin release, Trousseau syndrome), antiphospholipid syndrome, myeloproliferative neoplasms with JAK2 V617F, paroxysmal nocturnal hemoglobinuria (GPI-anchor loss, CD55/CD59 deficiency), nephrotic syndrome (urinary antithrombin loss), heparin-induced thrombocytopenia, DIC, inflammatory bowel disease and other systemic inflammation
• Stasis: immobility, hospitalization, long-haul travel, casting, obesity, pregnancy (gravid uterus compressing the left iliac vein — hence left-leg predominance), heart failure, atrial fibrillation
• Endothelial injury: surgery (especially orthopedic), trauma, central venous catheters, indwelling hardware, smoking, prior DVT with residual valve damage

Modifiable exposures examiners plant in the stem

• Estrogen-containing contraceptives and hormone therapy: raise factors II, VII, X and fibrinogen while lowering protein S; risk is synergistic when layered on factor V Leiden, and combined pills are avoided in known thrombophilia per ACOG and CDC US Medical Eligibility Criteria guidance
• Pregnancy and the postpartum period: physiologic hypercoagulability peaks postpartum; ACOG recommends risk-based thromboprophylaxis rather than universal thrombophilia screening
• Tamoxifen, high-dose corticosteroids, and immunomodulators (thalidomide/lenalidomide with dexamethasone in myeloma) add measurable VTE risk
• Smoking, obesity, dehydration, and recent surgery or trauma are the modifiable levers; age, male sex, prior unprovoked VTE, and family history are not

• Alterations in coagulation factors: Gain-of-function mutations in factors V (Factor V Leiden), II (prothrombin G20210A), or elevated levels of factors VIII, IX, XI, and fibrinogen all increase thrombin generation and shift the coagulation cascade toward clot formation
• Deficiency of natural anticoagulants: Loss of protein C, protein S, or antithrombin removes critical negative feedback inhibitors, allowing unchecked thrombin generation and fibrin deposition
• Platelet hyperreactivity and increased platelet-derived procoagulants: Elevated phosphatidylserine exposure and microparticle release from platelets and endothelial cells provide additional surfaces for coagulation cascade amplification
• Abnormalities in fibrinolysis: Elevated plasminogen activator inhibitor-1 (PAI-1) or decreased tissue plasminogen activator (tPA) impair clot breakdown, prolonging clot persistence
• Endothelial dysfunction and altered blood flow: Atherosclerosis, antiphospholipid antibodies, or structural abnormalities damage the endothelial lining, exposing tissue factor and promoting platelet adhesion; stasis (immobility, atrial fibrillation, malignancy) slows blood flow and promotes local thrombin accumulation
• Hemoconcentration and increased blood viscosity: Seen in polycythemia, dehydration, and some myeloproliferative neoplasms; increases shear stress and platelet activation

Venous Thrombotic Events (most common)

• Deep vein thrombosis (DVT) presenting with unilateral leg swelling, erythema, warmth, and calf tenderness; may be asymptomatic (10-40% of cases discovered incidentally on imaging)
• Pulmonary embolism (PE) with dyspnea, pleuritic chest pain, tachycardia, and hemodynamic instability in severe cases; can present as sudden cardiac death in massive PE
• Recurrent or unprovoked thrombosis without clear precipitating factors (immobility, surgery, trauma); particularly suggestive of inherited thrombophilia
• Thrombosis in unusual locations (cerebral, mesenteric, portal, splenic, or renal veins) suggests consideration of hypercoagulable workup

Arterial Thrombotic Events

• Myocardial infarction or stroke in young patients (<50 years) without traditional atherosclerotic risk factors; particularly associated with antiphospholipid syndrome, homozygous factor V Leiden, or myeloproliferative neoplasms
• Recurrent pregnancy loss (antiphospholipid syndrome) or placental insufficiency manifesting as preeclampsia, intrauterine growth restriction, or preterm delivery

Important Clinical Pearls

• "Provoked" vs. "unprovoked" thrombosis: Provoked events (surgery, immobility, malignancy, trauma) have lower recurrence rates and may not warrant thrombophilia workup; unprovoked events warrant testing
• Age of onset matters: First thrombotic event before age 50, especially <30, raises suspicion for inherited thrombophilia
• Family history of early thrombosis or thrombophilia significantly increases pretest probability
• Superficial thrombophlebitis may be the presenting sign of occult malignancy (Trousseau syndrome), particularly with migratory or recurrent thrombosis

Initial Clinical Assessment

• Detailed history and physical exam: Age at first thrombotic event, provocation (surgery, immobility, pregnancy, oral contraceptives, recent travel), family history of VTE or thrombophilia, recurrence pattern, location of thrombosis, and associated malignancy symptoms
• Scoring systems: Wells' score (DVT/PE) or PERC rule help estimate pretest probability and guide imaging decisions

Confirmation of Thrombotic Event

• Compression ultrasound for DVT (95-98% sensitivity and specificity); standard imaging modality
• CT pulmonary angiography (CTPA) or ventilation-perfusion scan for PE diagnosis
• D-dimer (elevated in active thrombosis) has high negative predictive value but poor specificity; useful for ruling out VTE in low-probability patients

• Factor V Leiden mutation testing (DNA-based PCR): Most common inherited thrombophilia (~5% Caucasian prevalence); heterozygous = 3-8-fold increased risk, homozygous = 50-80-fold risk
• Prothrombin G20210A mutation (DNA-based): Second most common inherited thrombophilia (~2% prevalence); heterozygous = 2-3-fold increased risk
• Protein C activity (functional assay): Normal levels >70%; deficiency = 5-10-fold increased risk; Type I deficiency (quantitative) more common than Type II (qualitative)
• Protein S activity (functional assay): Free protein S (not total) is more clinically relevant; deficiency = 5-10-fold increased risk; remember estrogen reduces protein S, complicating interpretation in OCP/HRT users
• Antithrombin activity (functional heparin cofactor assay): Deficiency rare (~0.1% prevalence) but carries very high thrombotic risk (up to 25-fold); Type I (quantitative) and Type II (qualitative) variants exist
• Lupus anticoagulant, anticardiolipin antibodies, anti-β2 glycoprotein-I antibodies (antiphospholipid syndrome panel): Test in young patients with arterial or venous thrombosis, recurrent pregnancy loss, or thrombosis at unusual sites; requires mixing study and confirmatory testing (dilute Russell viper venom time)
• Factor VIII, IX, XI levels: Elevated levels (>90th percentile) associated with VTE risk; less commonly tested but part of comprehensive thrombophilia evaluation
• Fibrinogen level and fibrinolysis assays (PAI-1, tPA): Elevated fibrinogen and PAI-1 associated with increased thrombotic risk; less standardized testing

Important Diagnostic Considerations

• Timing is critical: Perform thrombophilia testing at least 2 weeks after stopping anticoagulation (warfarin, DOACs interfere with vitamin K-dependent factors; heparin may affect some assays); ideally wait 4-6 weeks for optimal results
• Acute phase response elevates factors V, VIII, IX, XI, and fibrinogen during acute thrombosis; retest after resolution if abnormal
• Estrogen use (OCPs, HRT) elevates factors II, VII, X, and fibrinogen while reducing protein S; may mask or worsen hypercoagulability
• Negative testing does not exclude thrombophilia: 10-20% of patients with unprovoked thrombosis have negative comprehensive thrombophilia workup (possible unidentified defects)
• Asymptomatic carriers of thrombophilic mutations do not require anticoagulation prophylaxis unless specific risk scenarios

Thrombotic complications of the disease

• Massive (high-risk) pulmonary embolism — EMERGENCY: clot burden raises RV afterload until the RV fails; hypotension, JVD, S1Q3T3 or right heart strain on echo, and elevated troponin/BNP. CHEST and AHA guidance support systemic thrombolysis (or catheter-directed therapy/embolectomy if bleeding risk is prohibitive) in hemodynamically unstable PE
• Phlegmasia cerulea dolens — EMERGENCY: near-total iliofemoral outflow occlusion produces a tense, cyanotic, painful limb with compartment syndrome and venous gangrene; requires urgent thrombus removal
• Catastrophic antiphospholipid syndrome — EMERGENCY: multi-organ small-vessel thrombosis over days with renal failure, ARDS, and thrombocytopenia; treated with anticoagulation plus glucocorticoids and plasma exchange/IVIG
• Cerebral venous sinus, mesenteric, portal, or hepatic vein (Budd-Chiari) thrombosis: unusual sites should trigger evaluation for myeloproliferative neoplasm (JAK2 V617F) or PNH
• Post-thrombotic syndrome: valvular destruction and ambulatory venous hypertension cause chronic edema, hyperpigmentation, and medial malleolar ulceration
• Chronic thromboembolic pulmonary hypertension: unresolved organized clot; persistent exertional dyspnea after PE — ventilation-perfusion scan, not CTPA, is the screening test of choice
• Obstetric morbidity in APS: placental thrombosis causing recurrent loss, preeclampsia, and growth restriction (ACOG: aspirin plus prophylactic heparin in obstetric APS)

Complications of treatment

• Major bleeding, including intracranial hemorrhage — EMERGENCY: reverse warfarin with 4-factor PCC plus IV vitamin K; dabigatran with idarucizumab; apixaban/rivaroxaban with andexanet alfa per ACC anticoagulant reversal guidance
• Heparin-induced thrombocytopenia — EMERGENCY: PF4-heparin IgG activates platelets; platelet count falls by more than half around days 5–10 with paradoxical thrombosis. Stop all heparin and start a non-heparin agent (argatroban, bivalirudin, or fondaparinux); ASH guidance warns against warfarin monotherapy or prophylactic platelet transfusion
• Warfarin-induced skin necrosis: rapid drop in short-half-life protein C before factors II/VII/IX/X fall, unmasking protein C deficiency; presents days after loading as breast/thigh/buttock necrosis
• Heparin osteoporosis and hyperkalemia (aldosterone suppression); warfarin embryopathy — nasal hypoplasia and stippled epiphyses, so LMWH is used in pregnancy

• Factor V Leiden is the most common inherited thrombophilia and the classic answer for a young patient with unprovoked DVT after starting combined oral contraceptives. Screening test is a functional activated protein C resistance assay; confirm with PCR genotyping — genotyping is the answer if the patient is already anticoagulated
• Warfarin-induced skin necrosis points to protein C deficiency: the buzzword is necrotic plaques over breast, buttock, or thigh a few days after starting warfarin without heparin overlap. Best next step is to stop warfarin, give vitamin K, and anticoagulate with heparin (protein C concentrate or FFP in severe cases). Prevention is bridging with a parenteral anticoagulant until the INR is therapeutic
• Failure of the aPTT to rise despite escalating heparin doses = antithrombin deficiency (heparin works by potentiating antithrombin). Treat with antithrombin concentrate or use a direct thrombin inhibitor
• Antiphospholipid syndrome gives a prolonged aPTT that fails to correct on mixing study — an in vitro anticoagulant with in vivo thrombosis — plus false-positive VDRL/RPR. Diagnosis requires a persistently positive antibody (lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein I) confirmed on repeat testing at least 12 weeks apart
• Triple-positive APS should be anticoagulated with warfarin, not a DOAC: randomized data showed excess thrombotic events with rivaroxaban, and ASH/ISTH guidance favors vitamin K antagonists in this group. This is the single most commonly missed management step on exams
• Unusual-site thrombosis has its own associations: hepatic/portal vein thrombosis with pancytopenia and hemolysis suggests paroxysmal nocturnal hemoglobinuria (flow cytometry for CD55/CD59); splanchnic thrombosis with erythrocytosis or thrombocytosis suggests a JAK2 V617F myeloproliferative neoplasm; nephrotic-range proteinuria plus flank pain and hematuria suggests renal vein thrombosis from membranous nephropathy
• **Migratory superficial thrombophlebitis (Trousseau syndrome) demands a malignancy search**, classically pancreatic adenocarcinoma; ASCO and ITAC guidance favor LMWH or an appropriate DOAC over warfarin in cancer-associated VTE
• Common distractor: ordering a thrombophilia panel during the acute event or while on anticoagulation. Acute thrombosis and anticoagulants distort protein C, protein S, and antithrombin levels, and a positive result rarely changes acute management