Blood & Lymphoreticular

Inherited thrombophilias: when to test and manage

Clinical Overview and When to Suspect Inherited Thrombophilia

— FVL heterozygosity: ~5% of Caucasians; most common inherited thrombophilia

— Prothrombin G20210A: ~2%

— Protein C, S, antithrombin deficiencies: rare (<1%) but high-penetrance

— Unprovoked VTE in a patient <45–50 years old

— Recurrent VTE, especially without identifiable triggers

— VTE at unusual sites (cerebral, splanchnic, mesenteric, portal, hepatic veins)

— Strong family history (first-degree relative with VTE <50)

— Warfarin-induced skin necrosis → suggests protein C deficiency

— Heparin resistance (need escalating doses to reach therapeutic aPTT) → suggests antithrombin deficiency

— Recurrent pregnancy loss, severe preeclampsia, IUGR, placental abruption

— Provoked VTE after surgery, trauma, immobilization, OCP/HRT, active cancer—management does not change

— Routine screening of asymptomatic family members (low yield, anxiety, insurance implications)

— During acute thrombosis or while on anticoagulation (alters levels)

Board pearl: Inherited thrombophilias are predominantly venous disease drivers. Arterial events (MI, stroke) are NOT a standard indication to test—if a stem pairs a young stroke with miscarriage, think antiphospholipid syndrome (acquired), not inherited thrombophilia.

Step 3 management: The single highest-yield testing principle: results rarely alter duration of anticoagulation in unprovoked VTE (most already get indefinite therapy if bleeding risk allows). Test only when the result will change management—pregnancy planning, hormonal contraception decisions, or family counseling in select cases.

Definition: Heritable conditions increasing venous thromboembolism (VTE) risk via either loss-of-function in natural anticoagulants (antithrombin, protein C, protein S deficiencies) or gain-of-function mutations (factor V Leiden [FVL], prothrombin G20210A).

Epidemiology in US adults:

When to suspect on Step 3:

When NOT to suspect/test:

Presentation Patterns and Key History

— DVT: unilateral leg swelling, calf tenderness, warmth, Homan sign (insensitive)

— PE: pleuritic chest pain, dyspnea, tachycardia, hemoptysis, syncope if massive

— Unusual-site thrombosis: cerebral venous sinus thrombosis (headache, papilledema, seizure), Budd-Chiari (RUQ pain, ascites, hepatomegaly), portal/mesenteric vein thrombosis (postprandial pain, bowel ischemia)

— Age at first VTE <45–50

— Recurrent events, particularly off anticoagulation

— Spontaneous (no surgery, trauma, immobilization, cancer, estrogen)

— Family history: parent/sibling with VTE, especially young or recurrent

— Obstetric history: ≥3 first-trimester losses, ≥1 second/third-trimester loss, severe preeclampsia, abruption, IUGR

— Warfarin skin necrosis on initiation → protein C or S deficiency (skin microvascular thrombosis before warfarin's anti–factor II/IX/X effect kicks in)

— Neonatal purpura fulminans → homozygous protein C deficiency

— Combined oral contraceptives, estrogen HRT, tamoxifen, raloxifene

— Recent surgery, trauma, prolonged immobility, long-haul travel

— Active malignancy or chemotherapy

— Pregnancy/postpartum (especially first 6 weeks)

— Smoking, obesity (BMI ≥30)

Key distinction: Provoked vs. unprovoked drives anticoagulation duration far more than thrombophilia status. Provoked by a transient major risk factor (surgery, trauma) → 3 months. Unprovoked or persistent risk → consider indefinite therapy based on bleeding risk and patient preference.

Board pearl: A 25-year-old woman with first-trimester miscarriage + DVT after starting OCPs is the prototypical FVL stem. Recurrent late losses + arterial events lean antiphospholipid, not inherited.

Classic VTE presentations:

History that should trigger thrombophilia consideration:

Medication and exposure history (critical):

Patient-reported triggers: Multiplicative risk—FVL heterozygote on OCPs increases VTE risk ~35-fold over baseline; this combination is a favorite stem.

Physical Exam Findings and Hemodynamic Assessment

— Unilateral calf or thigh swelling (>3 cm circumference difference at 10 cm below tibial tuberosity)

— Pitting edema, warmth, erythema, palpable cord

— Homan sign (calf pain on dorsiflexion): poorly sensitive/specific—do not rely on it

— Phlegmasia cerulea dolens: massive iliofemoral DVT with cyanosis, severe pain → limb-threatening, surgical/IR emergency

— Tachycardia, tachypnea, hypoxemia

— Loud P2, RV heave, JVD, S3—signs of RV strain

— Hypotension (SBP <90 or drop ≥40 mmHg for ≥15 min not explained otherwise) → massive PE

— Submassive PE: normotensive but with RV dysfunction on echo or elevated troponin/BNP

— Warfarin-induced skin necrosis: Painful erythematous patches → hemorrhagic bullae → necrosis, typically on breast, thigh, buttock, 3–10 days after warfarin start. Pathognomonic for protein C (or S) deficiency unmasking.

— Neonatal purpura fulminans: Diffuse purpura, DIC in newborn → homozygous protein C deficiency; emergency.

— Livedo reticularis: more often antiphospholipid syndrome than inherited thrombophilia

— Budd-Chiari: hepatomegaly, ascites, RUQ pain

— Cerebral venous sinus thrombosis: focal deficits, papilledema, seizures

— Mesenteric vein thrombosis: pain out of proportion to exam

Step 3 management: In suspected massive PE with hemodynamic instability, bedside echo is the rapid risk-stratifying tool—RV dilation, McConnell sign (apical sparing of RV free-wall hypokinesis), septal bowing. Don't delay thrombolytics waiting for CTPA if patient is crashing and PE is highly likely.

Board pearl: Warfarin skin necrosis is the visual hallmark question—always co-administer parenteral anticoagulation (heparin/LMWH) bridge until INR therapeutic for ≥24 hours and at least 5 days of overlap, especially in suspected protein C deficiency.

DVT exam:

PE exam and hemodynamics:

Skin and soft-tissue findings specific to thrombophilias:

Unusual-site clues:

Diagnostic Workup — Initial Labs and Imaging

— DVT: Compression ultrasound with Doppler is first-line; D-dimer useful for ruling out in low-pretest-probability patients (Wells score ≤1)

— PE: CT pulmonary angiography (CTPA) is gold standard; V/Q scan if contrast contraindicated (pregnancy, severe CKD, contrast allergy)

— Unusual sites: MR venography for cerebral sinus thrombosis; Doppler US/CT/MRI for splanchnic

— CBC (rule out HIT later if heparin-exposed, baseline platelets), PT/INR, aPTT, fibrinogen

— BMP (renal function—dictates anticoagulant choice and dosing)

— LFTs (hepatic function)

— Pregnancy test in reproductive-age women

— Troponin and BNP if PE confirmed → risk stratification

— Age- and sex-appropriate screening (mammography, colonoscopy, Pap, low-dose CT for smokers)

— H&P, CBC, CMP, urinalysis, chest imaging

— Do NOT do indiscriminate CT body scanning—no mortality benefit (SOME-PE trial reasoning)

— Start treatment empirically; don't delay anticoagulation to draw labs

— Acute thrombosis: consumes protein C, S, antithrombin → falsely low

— Heparin: lowers antithrombin levels

— Warfarin: lowers protein C and S (vitamin K-dependent)

— DOACs: interfere with lupus anticoagulant assays, dilute Russell viper venom time

— Ideal timing: ≥2 weeks off anticoagulation, ≥3 months after acute event; genetic tests (FVL, prothrombin gene) are unaffected by timing/drugs

CCS pearl: Order CBC, CMP, PT/INR, aPTT, type and screen, pregnancy test, then imaging (US for DVT, CTPA for PE), then anticoagulate. Defer thrombophilia panel to outpatient follow-up at 3 months if clinically indicated.

Confirm thrombosis first (always before thrombophilia testing):

Baseline labs at presentation:

Cancer screening for unprovoked VTE:

Initial anticoagulation BEFORE thrombophilia testing:

Why timing of thrombophilia testing matters:

Diagnostic Workup — Confirmatory Thrombophilia Studies

— Factor V Leiden: Activated protein C resistance assay (functional screen) → if abnormal, confirm with FVL genetic test

— Prothrombin G20210A: PCR-based genetic test

— Protein C activity: Functional assay (chromogenic preferred)

— Protein S activity: Free protein S antigen + functional assay

— Antithrombin activity: Functional (heparin cofactor) assay

— Antiphospholipid antibodies (acquired but always co-tested): lupus anticoagulant, anti–β2-glycoprotein I, anticardiolipin IgG/IgM × 2 separated by ≥12 weeks

— Pregnancy ↓ protein S (physiologic)

— OCPs/estrogen ↓ protein S, ↑ activated protein C resistance

— Acute thrombosis consumes antithrombin, protein C, protein S

— Liver disease ↓ all hepatically synthesized factors (protein C/S, antithrombin)

— Nephrotic syndrome ↓ antithrombin (urinary loss)

— DIC ↓ everything

— Unprovoked VTE in patient <45–50 with strong family history AND result will change management

— Recurrent unprovoked VTE

— Unusual-site thrombosis (cerebral sinus, splanchnic) in young patients

— Warfarin-induced skin necrosis (protein C/S)

— Heparin resistance (antithrombin)

— Recurrent pregnancy loss (combined with APS workup)

— Provoked VTE, asymptomatic relatives, arterial events, routine pre-OCP screening

Key distinction: Genetic tests (FVL, prothrombin G20210A) are time-independent and drug-independent. Functional assays (protein C/S, antithrombin) must be done off anticoagulation and ≥3 months after thrombosis, ideally not during pregnancy or estrogen use.

Board pearl: The American Society of Hematology Choosing Wisely list explicitly discourages thrombophilia testing in provoked VTE—high cost, low impact.

The thrombophilia panel (when truly indicated):

Confounders to remember:

When the panel is reasonable (selected scenarios):

When NOT to test:

Risk Stratification and Management Logic

— Provoked by major transient risk factor (surgery, major trauma, hospitalization ≥3 days): 3 months

— Provoked by minor transient factor (long travel, minor surgery, estrogen): 3–6 months, often 3

— Unprovoked VTE: minimum 3 months; then assess for indefinite therapy based on bleeding risk

— Active cancer-associated VTE: indefinite while cancer/treatment active

— Recurrent unprovoked VTE: indefinite

— Most heterozygous low-risk (FVL het, prothrombin het): do NOT change duration

— High-risk (homozygous FVL, homozygous prothrombin, compound heterozygotes, antithrombin deficiency, protein C/S deficiency): may favor indefinite anticoagulation, especially after unprovoked event

— Antiphospholipid syndrome (triple-positive): indefinite warfarin (DOACs inferior)

— HAS-BLED (originally afib) and VTE-BLEED scores guide judgment

— Risk factors: age >65, prior bleeding, renal/hepatic disease, antiplatelet use, alcohol, uncontrolled HTN

— Provoked VTE: ~3%/year off anticoagulation

— Unprovoked: ~10% first year, ~5%/year thereafter

— D-dimer at 1 month post-treatment, residual venous obstruction: refine risk

Step 3 management: A 38-year-old man with unprovoked PE and FVL heterozygosity: still complete 3 months, then make the indefinite-AC decision based on bleeding risk and patient preference—not the FVL result. The mutation does not independently mandate lifelong therapy.

Board pearl: "The decision to anticoagulate indefinitely is driven by event characteristics (provoked vs unprovoked, recurrence) and bleeding risk—not the thrombophilia panel."

Anticoagulation duration drivers (in priority order):

Where thrombophilia status fits in:

Bleeding risk assessment (annual mortality from major bleeding on AC ~1–3%):

Recurrence risk benchmarks:

HERDOO2 rule (women only): ≥2 of hyperpigmentation/edema/redness, D-dimer ≥250, BMI ≥30, age ≥65 → continue AC; 0–1 may stop after 3–6 months

Pharmacotherapy — First-Line Anticoagulation

— DOACs (preferred for most VTE):

— Apixaban: 10 mg BID × 7 days → 5 mg BID

— Rivaroxaban: 15 mg BID × 21 days → 20 mg daily with food

— Dabigatran and edoxaban: require 5–10 days of parenteral lead-in (LMWH)

— LMWH (enoxaparin 1 mg/kg SC BID or 1.5 mg/kg daily): preferred in cancer-associated VTE (or DOACs except for GI/GU cancers where bleeding risk higher), pregnancy, severe renal impairment requires caution

— Unfractionated heparin: preferred in CrCl <30, hemodynamic instability (titratable), planned thrombolysis/surgery

— Warfarin: target INR 2–3; requires LMWH/UFH bridge for ≥5 days AND until INR ≥2 for 24 hours

— Antithrombin deficiency: heparin requires antithrombin as cofactor → may need higher doses or antithrombin concentrate; DOACs or argatroban (direct thrombin inhibitor) reasonable alternatives

— Protein C/S deficiency: avoid warfarin monotherapy initiation—risk of skin necrosis; always bridge with heparin/LMWH; some experts prefer DOACs to avoid this risk entirely

— Antiphospholipid syndrome (triple-positive): warfarin preferred over DOACs (TRAPS trial showed worse outcomes with rivaroxaban)

— Apixaban 2.5 mg BID or rivaroxaban 10 mg daily—reduced-dose extended therapy reduces bleeding while preserving efficacy

— Warfarin: vitamin K + 4-factor PCC for major bleeding

— Dabigatran: idarucizumab

— Apixaban/rivaroxaban: andexanet alfa or 4-factor PCC

Board pearl: DOACs are first-line for most VTE including inherited thrombophilias, with two exceptions: antiphospholipid syndrome (use warfarin) and mechanical valves (warfarin only).

Initial/acute treatment options:

Thrombophilia-specific considerations:

Extended/secondary prevention dosing (after initial 6 months):

Reversal:

Special Situations and Adjunctive Management

— Massive PE (hemodynamic instability): systemic thrombolysis (alteplase 100 mg over 2 hours) unless contraindicated

— Submassive PE (RV dysfunction, elevated biomarkers, no hypotension): individualized—catheter-directed thrombolysis, surgical embolectomy, or anticoagulation alone

— Iliofemoral DVT with phlegmasia or significant symptoms in young patient with good functional status: consider catheter-directed thrombolysis to reduce post-thrombotic syndrome

— Acute VTE with absolute contraindication to anticoagulation (active bleeding, recent CNS hemorrhage)

— Recurrent PE despite therapeutic anticoagulation

— Retrievable filters preferred; remove as soon as anticoagulation can be initiated

— Do NOT place prophylactically in stable patients who can tolerate AC

— Prior intracranial hemorrhage

— Known intracranial neoplasm or AVM

— Ischemic stroke within 3 months (except acute)

— Suspected aortic dissection

— Active bleeding

— Recent major surgery or head trauma (<3 weeks)

— Routine use to prevent post-thrombotic syndrome no longer recommended (SOX trial)

— Use for symptom relief in PTS or chronic edema

— Bleeding precautions, medication adherence (DOACs short half-lives—missing doses = thrombosis risk), avoid NSAIDs

CCS pearl: In hemodynamically unstable PE with high suspicion: stabilize (IV fluids cautiously, norepinephrine for shock, oxygen), order CTPA if patient can tolerate, give heparin bolus, mobilize thrombolytics or interventional radiology. Advance simulated clock minutes, not hours.

Step 3 management: IVC filters are heavily over-ordered on board stems as distractors—anticoagulation is the answer unless there's a true absolute contraindication.

Massive/submassive PE:

Catheter-directed therapy:

IVC filter indications (narrow):

Thrombolysis contraindications (absolute):

Compression stockings:

Patient education during initiation:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher bleeding risk—falls, polypharmacy, CKD, frailty

— DOACs preferred over warfarin in most cases (less ICH risk)

— Apixaban has the most favorable bleeding profile in this group

— Apixaban dose reduction (2.5 mg BID) if ≥2 of: age ≥80, weight ≤60 kg, Cr ≥1.5

— Avoid concurrent NSAIDs, antiplatelets unless mandatory

— Reassess goals of care—indefinite anticoagulation requires shared decision-making

— CrCl <30: avoid dabigatran (80% renal); rivaroxaban not recommended <15; apixaban and edoxaban usable with caution—apixaban is preferred DOAC in advanced CKD

— CrCl <15 or dialysis: warfarin or apixaban (with cardiology/nephrology guidance); LMWH avoided due to accumulation—use UFH

— Always check baseline Cr and recheck periodically

— Child-Pugh B: caution with DOACs (rivaroxaban contraindicated in Child-Pugh B/C)

— Child-Pugh C: avoid all DOACs; warfarin difficult due to baseline INR elevation

— LMWH or UFH safer in advanced liver disease

— Coagulopathy of liver disease ≠ anticoagulation—patients can still clot

— Warfarin: amiodarone, TMP-SMX, fluconazole, fluoroquinolones (↑ INR); rifampin, carbamazepine (↓ INR)

— DOACs: strong CYP3A4/P-gp inhibitors (ketoconazole, HIV protease inhibitors) ↑ levels; rifampin, phenytoin ↓ levels

Board pearl: In a 78-year-old with new unprovoked PE and CrCl 35, apixaban is the cleanest choice—least renal clearance among DOACs, lowest major bleeding rate.

Key distinction: "Bleeding risk" alone doesn't justify withholding AC—quantify with HAS-BLED/VTE-BLEED, modify reversible factors (BP control, alcohol, concurrent antiplatelets), then proceed.

Elderly (≥75 years):

Renal impairment:

Hepatic impairment:

Drug interactions in elderly:

Fall risk: Not an absolute contraindication—data show 295 falls/year needed to outweigh AC benefit in AFib; similar logic for VTE.

Special Populations — Pregnancy, Pediatrics, and Postpartum

— 4–5-fold increased VTE risk during pregnancy; highest in postpartum (6 weeks)

— Inherited thrombophilia + pregnancy: synergistic risk

— LMWH is the anticoagulant of choice (does not cross placenta)

— Warfarin contraindicated (teratogenic—nasal hypoplasia, stippled epiphyses, CNS abnormalities) especially weeks 6–12

— DOACs contraindicated (limited data, placental crossing)

— UFH acceptable, especially peripartum (shorter half-life)

— High-risk thrombophilia (antithrombin deficiency, homozygous FVL, compound heterozygous FVL/prothrombin) + prior VTE: antepartum + 6 weeks postpartum prophylactic or therapeutic LMWH

— Low-risk thrombophilia (FVL het, prothrombin het) + no prior VTE: surveillance antepartum, postpartum prophylaxis 6 weeks

— Prior VTE without thrombophilia: postpartum prophylaxis at minimum

— Switch from LMWH to UFH at 36 weeks or hold LMWH 24 hours before planned delivery

— Neuraxial anesthesia requires 12 hours since prophylactic dose, 24 hours since therapeutic dose of LMWH

— Avoid estrogen-containing contraceptives in known thrombophilia or strong family history

— Progestin-only methods, copper IUD, levonorgestrel IUD are safe alternatives

— Homozygous protein C deficiency → neonatal purpura fulminans, DIC; emergency treatment with protein C concentrate, FFP, and lifelong anticoagulation

— Catheter-related VTE most common; provoked → 3 months

Step 3 management: Counsel reproductive-age women with FVL or prothrombin mutation to use non-estrogen contraception and discuss VTE risk before pregnancy planning—document this conversation.

Board pearl: Warfarin is safe in breastfeeding (not secreted in milk); LMWH and UFH also safe. DOACs not recommended during lactation.

Pregnancy-associated VTE:

Thromboprophylaxis in pregnancy with known thrombophilia:

Obstetric APS: LMWH + low-dose aspirin throughout pregnancy + 6 weeks postpartum

Delivery planning:

OCPs and inherited thrombophilia:

Pediatric considerations:

Complications and Adverse Outcomes

— Occurs in 20–50% of DVT patients within 2 years

— Chronic leg pain, edema, skin changes, venous ulcers

— Risk factors: proximal/iliofemoral DVT, recurrent ipsilateral DVT, inadequate initial AC

— Treatment: compression therapy, leg elevation, exercise; refractory cases → venous stenting

— Occurs in 2–4% post-PE

— Persistent dyspnea, RV dysfunction 3+ months after PE despite AC

— Workup: V/Q scan (preferred screen—more sensitive than CTPA for chronic disease), right heart catheterization, pulmonary angiography

— Treatment: pulmonary thromboendarterectomy (curative if operable); riociguat or balloon pulmonary angioplasty for inoperable

— Major bleeding ~2–3%/year; ICH 0.3–0.5%/year on warfarin, lower on DOACs

— GI bleeding more common with rivaroxaban, dabigatran 150 mg, edoxaban 60 mg

— Platelet drop >50% from baseline on day 5–10 of heparin exposure

— 4T score; confirm with serotonin release assay

— Stop heparin → bivalirudin, argatroban, fondaparinux

Board pearl: Persistent dyspnea ≥3 months after PE warrants CTEPH evaluation with V/Q scan first—this is a commonly missed Step 3 follow-up scenario.

Key distinction: PTS is venous (chronic limb swelling, brawny edema) vs. CTEPH which is pulmonary arterial hypertension from organized thromboemboli—two completely different complications of the same disease.

Post-thrombotic syndrome (PTS):

Chronic thromboembolic pulmonary hypertension (CTEPH):

Recurrent VTE: 10% in first year off AC after unprovoked event

Bleeding on anticoagulation:

Heparin-induced thrombocytopenia (HIT):

Warfarin-induced skin necrosis: Hours-to-days after warfarin start, especially without bridging; suspect protein C/S deficiency

Recurrent miscarriage in untreated thrombophilia (especially APS)

Cerebral venous sinus thrombosis sequelae: Increased ICP, seizures, residual focal deficits

When to Escalate Care — ICU, Consult, and Triage

— Massive PE with hemodynamic instability (SBP <90, vasopressor need)

— Right heart failure with end-organ hypoperfusion

— Hypoxemic respiratory failure requiring high-flow O2, NIV, or intubation

— Active major bleeding on anticoagulation requiring reversal and monitoring

— Post-thrombolysis monitoring

— Submassive PE with RV dysfunction, elevated troponin/BNP, normotensive

— Recent thrombolysis stable

— Bridging anticoagulation in high-risk patients with active comorbidities

— Hemodynamically stable, SaO2 >90% room air, no active bleeding, reliable follow-up, manageable comorbidities, social support

— Apixaban or rivaroxaban from day 1; no parenteral lead-in needed

— Hematology: complex thrombophilia evaluation, recurrent VTE, antiphospholipid syndrome, pregnancy planning with thrombophilia, considering protein C concentrate or antithrombin replacement

— Pulmonary critical care/PERT team (Pulmonary Embolism Response Team): intermediate/high-risk PE

— Interventional radiology/vascular surgery: catheter-directed thrombolysis, iliofemoral DVT, IVC filter

— Cardiothoracic surgery: surgical embolectomy candidates, CTEPH for pulmonary thromboendarterectomy

— Maternal-fetal medicine: pregnancy with thrombophilia or VTE

— Genetic counseling: family planning, asymptomatic relative testing decisions

— Anticoagulation errors are a top patient-safety event; medication reconciliation at every handoff is mandatory

— Clear written discharge instructions on DOAC dosing, missed-dose protocol, bleeding warnings

CCS pearl: For massive PE, simultaneously consult ICU, pulmonary, and the PERT team while ordering thrombolytics—don't sequentially page; parallel processing saves minutes.

Step 3 management: Low-risk PE patients meeting Hestia criteria can be discharged from the ED on apixaban with hematology follow-up in 1–2 weeks—a frequently tested ambulatory pathway.

ICU admission criteria:

Step-down/telemetry indications:

Outpatient management eligibility (HESTIA or PESI low-risk):

Consults to consider:

Transitions of care risk:

Key Differentials — Other Hypercoagulable States

— Antiphospholipid syndrome (APS): Lupus anticoagulant, anti-β2-GPI, anticardiolipin × 2 separated by 12 weeks. Clinical: arterial AND venous thrombosis, recurrent pregnancy loss, livedo, thrombocytopenia. Triple-positive APS warrants warfarin (not DOACs).

— Malignancy-associated: Trousseau syndrome (migratory superficial thrombophlebitis with pancreatic, gastric, lung adenocarcinomas). 20% of unprovoked VTE harbor occult cancer.

— Myeloproliferative neoplasms: JAK2 V617F → polycythemia vera, essential thrombocythemia. Splanchnic vein thrombosis is the classic presentation—always check JAK2 in Budd-Chiari or portal vein thrombosis.

— Paroxysmal nocturnal hemoglobinuria (PNH): Coombs-negative hemolytic anemia, pancytopenia, unusual-site venous thrombosis (hepatic, cerebral). Flow cytometry for CD55/CD59.

— Nephrotic syndrome: Urinary antithrombin loss → renal vein thrombosis classically with membranous nephropathy

— Heparin-induced thrombocytopenia (HIT): Paradoxical thrombosis with thrombocytopenia 5–10 days after heparin exposure

— Inflammatory bowel disease, Behçet disease, vasculitis: Inflammation-mediated hypercoagulability

— Estrogen-containing contraceptives, HRT, tamoxifen, raloxifene

— High-dose erythropoiesis-stimulating agents

— Major surgery, trauma, immobilization, hospitalization

— Long-haul travel (>4–6 hours)

Key distinction: Arterial event + venous event + miscarriage = think APS. Pure venous + family history = think inherited. Splanchnic vein + erythrocytosis = think JAK2/MPN.

Board pearl: Always order JAK2 V617F in splanchnic vein thrombosis (portal, hepatic, mesenteric, splenic)—up to 40% have an occult MPN.

Acquired thrombophilias (must rule out before labeling "inherited"):

Iatrogenic/situational:

Key Differentials — Non-Thrombotic Mimics

— Baker cyst (popliteal cyst rupture): Sudden calf pain, swelling—can mimic DVT exactly; US distinguishes

— Cellulitis/erysipelas: Erythema, warmth, fever, leukocytosis; portal of entry usually identifiable

— Lymphedema: Painless, non-pitting, bilateral often; Stemmer sign positive

— Chronic venous insufficiency: Bilateral, brawny, hyperpigmented, ulcers above medial malleolus

— Muscle hematoma/strain: Trauma history, ecchymosis

— Compartment syndrome: Pain out of proportion, paresthesias, pulselessness late—surgical emergency

— Acute coronary syndrome: ECG changes (ST/T), troponin elevation pattern, cath findings

— Pneumonia: Fever, productive cough, consolidation

— Pneumothorax: Decreased breath sounds, hyperresonance, tracheal deviation if tension

— Aortic dissection: Tearing chest/back pain, BP differential, widened mediastinum

— Pericarditis/tamponade: Diffuse ST elevation/PR depression; pulsus paradoxus

— Heart failure exacerbation: Bilateral findings, BNP elevation

— Anxiety/panic: Diagnosis of exclusion

— Budd-Chiari mimics: alcoholic hepatitis, cirrhosis, hepatic congestion

— Cerebral sinus thrombosis mimics: migraine, idiopathic intracranial hypertension, meningitis, subarachnoid hemorrhage

Step 3 management: A 35-year-old with sudden calf pain post-exercise and US showing a fluid collection without flow defect → Baker cyst rupture, not DVT—NSAIDs and reassurance, not anticoagulation. Don't anticoagulate without imaging confirmation.

Board pearl: Wells score helps stratify pretest probability, but it does NOT replace imaging in moderate-high probability—proceed directly to CTPA or US.

For DVT presentation (unilateral leg swelling):

For PE presentation (dyspnea, chest pain):

For unusual-site thrombosis:

Secondary Prevention and Long-Term Plan

— Provoked by major transient factor: 3 months

— Unprovoked VTE with low/moderate bleeding risk: indefinite, with annual reassessment

— Recurrent unprovoked VTE: indefinite

— Active cancer: indefinite while cancer/treatment active

— APS (especially triple-positive): indefinite warfarin

— Apixaban 2.5 mg BID OR rivaroxaban 10 mg daily—both reduce recurrence ~80% with bleeding rates approaching placebo

— Full-dose continuation also acceptable in higher-risk patients

— Aspirin 100 mg daily reduces recurrence ~30%—much less than AC but option if patient declines/cannot tolerate

— Weight loss if BMI ≥30 (obesity is independent VTE risk factor)

— Smoking cessation

— Hydration and mobility during long travel; mechanical prophylaxis (compression stockings) for prolonged flights in high-risk patients

— Avoid estrogen-containing contraceptives and HRT

— Discuss risk with first-degree relatives—but routine asymptomatic testing not recommended

— Specifically counsel reproductive-age female relatives about OCPs and pregnancy

— Provide written information about VTE symptoms

— Recommend medical alert bracelet/wallet card for known high-risk thrombophilia (antithrombin deficiency, homozygous mutations) and for chronic anticoagulation status

Step 3 management: After 6 months of full-dose apixaban for unprovoked PE, transition to apixaban 2.5 mg BID indefinitely in a patient with FVL homozygosity and low bleeding risk—document shared decision-making annually.

Board pearl: Indefinite ≠ permanent. Reassess bleeding risk and recurrence risk annually; the calculus can shift with new comorbidities, falls, age.

Anticoagulation duration after first VTE:

Extended-phase dosing (after initial 6 months):

Aspirin as bridge if AC stopped:

Lifestyle modifications:

Vaccinations: Routine immunizations as for general population; no specific contraindications from thrombophilia

Family counseling:

Medical alert identification:

Follow-Up, Monitoring, and Counseling

— 1–2 weeks: medication tolerance, adherence, side effects, education reinforcement

— 1 month: D-dimer (if planning to stop AC), symptom assessment

— 3 months: decision point—stop vs continue AC; thrombophilia testing if indicated

— 6 months: transition to extended-phase dosing if continuing

— Annually thereafter: bleeding/recurrence risk reassessment, medication reconciliation

— Warfarin: INR weekly until stable, then every 4–12 weeks

— DOACs: No routine coagulation monitoring; check CBC, Cr, LFTs at baseline, 3 months, then annually

— LMWH (long-term): Anti-Xa levels in obesity, renal impairment, pregnancy

— New leg swelling, pain, chest pain, dyspnea, hemoptysis → immediate evaluation

— Bleeding: hematochezia/melena, hematuria, prolonged epistaxis, severe headache, easy bruising, hematemesis

— Missed doses: take ASAP if same day; if not, skip and resume—never double dose

— Villalta score at follow-up visits

— Compression therapy if symptomatic (knee-high, 20–30 mmHg)

— Persistent dyspnea/exercise intolerance 3+ months post-PE → echo, then V/Q scan

— Pre-conception consultation for women with thrombophilia

— Postpartum prophylaxis 6 weeks

— Avoid estrogen contraceptives lifelong

— Post-VTE anxiety/PTSD common; screen and refer

CCS pearl: Schedule a 1-week post-discharge phone call or visit—anticoagulation transitions are a top patient-safety event tracked by CMS readmission metrics.

Board pearl: A patient on DOAC therapy needs annual CBC, Cr, LFTs—forgetting this is a common quality measure miss.

Follow-up cadence after VTE diagnosis:

Lab monitoring:

Symptom surveillance to teach patients:

Post-thrombotic syndrome screening:

CTEPH screening:

Reproductive counseling:

Mental health:

Ethical, Legal, and Patient Safety Considerations

— Genetic Information Nondiscrimination Act (GINA, 2008): Prohibits health insurance and employment discrimination based on genetic information

— Does NOT cover life insurance, disability insurance, long-term care insurance

— Counsel patients before genetic testing about these limits—a frequent Step 3 ethics scenario

— Generally NOT recommended for low-penetrance mutations (FVL, prothrombin het) in adults

— Even if positive, primary prophylaxis usually not given

— Pregnant or contraception-planning relatives may benefit from knowing status

— Children should generally not be tested—autonomy preserved for adulthood

— Document discussion of bleeding risks (major bleeding 2–3%/year, ICH 0.3–0.5%/year), recurrence risk off therapy, lifestyle implications, alternatives

— Special: women of reproductive age must understand contraception requirements and pregnancy risks

— Anticoagulants are on ISMP high-alert medication list

— Medication reconciliation at every transition (admission, discharge, level-of-care change)

— Written DOAC vs warfarin specific instructions, missed-dose protocol, INR clinic referral if warfarin

— Avoid duplicate anticoagulation (heparin drip overlap errors—watch DVT prophylaxis ordered simultaneously with therapeutic AC)

— Indefinite anticoagulation decisions are preference-sensitive; use decision aids

— Re-elicit preferences annually

Step 3 management: Before ordering a thrombophilia panel, discuss with the patient: cost (~$500–1500 out of pocket), implications for life/disability insurance, and the fact that results often do not change management. Document this conversation—this is a high-yield Step 3 ethics vignette.

Board pearl: GINA does NOT cover life insurance—a 28-year-old asking about FVL testing should know this before consenting.

Genetic information and insurance:

Testing asymptomatic family members:

Informed consent for anticoagulation:

Patient safety in transitions:

Shared decision-making:

Mandatory reporting: Not applicable to thrombophilia, but adverse drug events from anticoagulants reportable to FDA MedWatch if serious

High-Yield Associations and Rapid-Fire Facts

Board pearl: Memorize the "two warfarin exceptions to DOAC-first": mechanical valves and triple-positive antiphospholipid syndrome.

Key distinction: All thrombophilias predispose to venous events; APS adds arterial events and pregnancy morbidity—use this as your one-line trigger for APS workup.

Most common inherited thrombophilia: Factor V Leiden (5% of Caucasians)

Highest VTE risk per individual mutation: Antithrombin deficiency (>50% lifetime VTE risk)

Warfarin skin necrosis: Protein C deficiency > protein S

Heparin resistance: Antithrombin deficiency

Neonatal purpura fulminans: Homozygous protein C deficiency

Splanchnic vein thrombosis triad to test: JAK2 V617F (MPN), PNH flow cytometry, paroxysmal nocturnal hemoglobinuria; also Behçet

Cerebral venous sinus thrombosis: OCP use, postpartum, inherited thrombophilia, dehydration, head/neck infection

Pregnancy + thrombophilia + recurrent miscarriage: Think APS first

Activated protein C resistance: Screening test for FVL

Triple-positive APS treatment: Warfarin, NOT DOACs (TRAPS trial)

DOAC of choice in CKD with CrCl 15–30: Apixaban

DOAC contraindication: Mechanical valves, antiphospholipid syndrome (triple-positive), pregnancy, severe hepatic disease

Cancer-associated VTE treatment: Apixaban or edoxaban (or LMWH); avoid rivaroxaban in GI/GU malignancies

HIT treatment: Stop heparin, start argatroban or bivalirudin or fondaparinux

IVC filter indication: Absolute contraindication to AC, OR recurrent PE despite therapeutic AC

Long-haul travel VTE prophylaxis: Hydration, mobility, compression stockings in high-risk; no routine pharmacologic prophylaxis

HRT/OCP risk multiplier with FVL: 35-fold VTE risk

CTEPH screening: V/Q scan (more sensitive than CTPA for chronic disease)

PE risk stratification tools: PESI, sPESI, Hestia criteria

D-dimer use: Rule out VTE in low pretest probability only; not for confirmation, not in pregnancy/cancer/elderly without age-adjusted cutoff

Board Question Stem Patterns

— 45-year-old started on warfarin alone for DVT develops painful breast erythema → necrosis on day 4. Next step: stop warfarin, give vitamin K, start heparin/LMWH, evaluate protein C and S after recovery. Diagnosis: protein C deficiency unmasked by warfarin monotherapy.

— 24-year-old woman with calf swelling 3 months after starting OCP. Family history: mother had DVT at 30. Next: ultrasound → DVT. Start apixaban. Discontinue OCPs permanently, switch to non-estrogen contraception. Test FVL at outpatient follow-up if it will change counseling.

— Patient on heparin drip requires escalating doses, aPTT never therapeutic. Antithrombin level low. Diagnosis: antithrombin deficiency. Management: antithrombin concentrate or switch to argatroban/DOAC.

— 32-year-old with 3 first-trimester losses, prior DVT, now TIA. Labs: prolonged aPTT not corrected by mixing study, positive anti-β2-GPI. Diagnosis: antiphospholipid syndrome (NOT inherited thrombophilia). Treatment: warfarin, NOT DOAC.

— 45-year-old with abdominal pain, ascites, hepatomegaly. Doppler: hepatic vein thrombosis (Budd-Chiari). CBC: Hgb 18.5, platelets 600. Next test: JAK2 V617F mutation → polycythemia vera.

— 25-year-old healthy woman, sister has FVL, asks if she should be tested before starting OCP. Best answer: counsel about VTE risk regardless of testing; recommend non-estrogen contraception; testing not routinely indicated but may be considered for informed decision-making, with discussion of GINA limitations.

— Unprovoked PE in 50-year-old with FVL heterozygosity, low bleeding risk. After 3 months: continue indefinite AC based on unprovoked status, not FVL.

Step 3 management: Most board stems test the principle that clinical context (provoked vs unprovoked, recurrence, bleeding risk) drives management, not the thrombophilia panel itself.

Stem 1 — Warfarin skin necrosis:

Stem 2 — FVL + OCP:

Stem 3 — Heparin resistance:

Stem 4 — Recurrent miscarriage + DVT + arterial event:

Stem 5 — Splanchnic vein thrombosis:

Stem 6 — Asymptomatic relative testing:

Stem 7 — Anticoagulation duration:

One-Line Recap

Inherited thrombophilia testing should be done only when the result will change management—anticoagulation duration is driven by whether the VTE was provoked, recurrent, and the patient's bleeding risk, not by the mutation itself.

Board pearl: The mutation does not dictate duration—the event characteristics and bleeding risk do. Whenever a Step 3 stem hands you a thrombophilia result, ask first: "Was the VTE provoked? What's the bleeding risk? Does this finding change what I would do?" If the answer is no, the testing was likely unnecessary, and the management answer rests on standard VTE principles.

Test when result changes management: Unprovoked VTE in young patient with strong family history, warfarin skin necrosis (protein C/S), heparin resistance (antithrombin), unusual-site thrombosis, recurrent pregnancy loss, pre-pregnancy planning—and always after acute event resolved (≥3 months) and off anticoagulation (≥2 weeks for functional assays).

Anticoagulation choice: DOACs are first-line for most VTE including inherited thrombophilias; the two warfarin exceptions are mechanical valves and triple-positive antiphospholipid syndrome. LMWH is preferred in pregnancy and in some cancer-associated VTE.

Duration: Provoked by major transient factor → 3 months. Unprovoked or recurrent → indefinite with annual reassessment of bleeding risk; consider extended-phase low-dose (apixaban 2.5 mg BID or rivaroxaban 10 mg daily) after 6 months.

Counseling priorities: Avoid estrogen-containing contraceptives in women with known thrombophilia or strong family history; provide pre-pregnancy and postpartum prophylaxis planning with LMWH; discuss GINA limitations (no life/disability insurance protection) before genetic testing; document shared decision-making about indefinite anticoagulation.