Hematology, Oncology & Immunology · Topic 12 of 26

Hypercoagulable States

Hematology · thrombophilia

Hypercoagulable States

Test for thrombophilia only when the result changes management — and treat thrombotic antiphospholipid syndrome with warfarin, not a DOAC.

Key numbers

APS: thrombosis or pregnancy loss plus antibodiesrepeat ≥ 12 weeks

Thrombotic APS: warfarin INR 2–3, not DOACINR 2–3

Catastrophic APS: three or more organs failing≥ 3 organs

Khorana ≥ 2: consider outpatient thromboprophylaxisKhorana ≥ 2

Test after 3 months, not during acute clot≥ 3 months

01 · GiveThrombotic APS: warfarin INR 2–3, not DOAC

Treat thrombotic APS with indefinite warfarin, target INR 2–3. DOACs carry higher recurrence and are not used in high-risk APS — arterial thrombosis or triple-positive antibodies.

02 · CauseFactor V Leiden: most common inherited thrombophilia

Factor V Leiden, which makes factor V resistant to activated protein C, is the most common inherited thrombophilia (about 5% of White Americans); it raises venous but not arterial thrombosis risk.

03 · GiveCancer-associated VTE: oral Xa inhibitor over LMWH

For cancer-associated VTE, prefer an oral factor Xa inhibitor (apixaban, edoxaban or rivaroxaban) over LMWH for the first 3–6 months, and continue anticoagulation while the cancer remains active.

Causes & risk factors

Why it happens

Prothrombin 20210 mutation: venous clots onlyThe prothrombin G20210A mutation raises prothrombin levels and venous thrombosis risk but not arterial risk; it is diagnosed by genetic testing and treated with standard anticoagulants.

Antithrombin deficiency: about half develop VTEHeterozygous antithrombin deficiency (0.02–0.2% of people) leads to venous thrombosis in about half of carriers; because heparin acts through antithrombin, an activity (functional) assay is used to diagnose it.

Acquired risks: cancer, estrogen, surgery, immobilityAcquired hypercoagulable states include cancer, APS, HIT, sepsis, estrogen-containing contraceptives, pregnancy, surgery or trauma, and venous stasis (immobilization, heart failure, obesity); they often unmask an inherited defect.

Presentation

What you'll see

Lupus anticoagulant prolongs the PTT yet clotsLupus anticoagulant prolongs phospholipid-dependent tests (PTT, dilute Russell viper venom time) that do not correct with mixing but do correct with excess phospholipid — despite the long PTT, the patient is prothrombotic.

Diagnosis & monitoring

Work-up

APS: thrombosis or pregnancy loss plus antibodies must knowAntiphospholipid syndrome = venous, arterial or microvascular thrombosis or specific pregnancy morbidity plus persistently positive lupus anticoagulant, anticardiolipin or anti-β2-glycoprotein I antibodies, confirmed on repeat testing ≥ 12 weeks apart.

Management

Orders

APS in pregnancy: heparin plus low-dose aspirinIn pregnancy, APS is treated with unfractionated heparin or LMWH plus low-dose aspirin to prevent pregnancy loss, continuing heparin prophylaxis for 6 weeks after delivery.

Khorana ≥ 2: consider outpatient thromboprophylaxisScore VTE risk before chemotherapy with the Khorana score (stomach or pancreas cancer +2); at ≥ 2 without major bleeding risk, consider apixaban 2.5 mg twice daily, rivaroxaban 10 mg daily or LMWH.

Inherited thrombophilia: DOAC or warfarinVTE with factor V Leiden, prothrombin 20210, antithrombin, protein C or protein S deficiency is treated with standard agents (DOAC or warfarin); persistent thrombophilia favors indefinite anticoagulation with periodic risk–benefit review.

Unprovoked VTE: age-appropriate cancer screening onlyAfter unprovoked VTE, look for occult cancer with a history, examination, basic labs, chest x-ray and overdue age-appropriate screening; an extensive imaging search is low yield.

Red flags & don'ts

Avoid harm

Catastrophic APS: three or more organs failing complicationCatastrophic APS = widespread small-vessel thrombosis with dysfunction of ≥ 3 organs (AKI, encephalopathy, adrenal hemorrhage, skin necrosis); it mimics DIC, HIT and TMA. Treat with high-dose glucocorticoids, anticoagulation and plasma exchange and/or IVIG.

Protein C deficiency: warfarin skin necrosis complicationWarfarin lowers protein C before factors II and X: in protein C deficiency, skip warfarin loading and overlap heparin ≥ 5 days until INR ≥ 2 (or use a DOAC) to prevent skin necrosis.

The rules

Know these

Test for thrombophilia only if it changes management must knowMost patients with VTE need no thrombophilia testing. ASH 2023 suggests testing after VTE provoked by pregnancy, estrogen or a nonsurgical transient risk factor, not after unprovoked or surgery-provoked VTE.

Test after 3 months, not during acute clotAvoid false results: acute thrombosis and heparin lower antithrombin, warfarin lowers proteins C and S, and DOACs or heparin distort clot-based assays — test after ≥ 3 months of anticoagulation, off interfering drugs.

Factor V Leiden or antiphospholipid syndrome?

Commonly confused

Type	Inherited mutation
Clots	Venous only
Pregnancy loss	Not a defining feature
Diagnosis	APC-resistance assay, confirmed by DNA test
Long-term anticoagulant	DOAC or warfarin

Commonly confused

Tell apart

Low protein C, S, antithrombin: often acquiredProtein C, S and antithrombin fall in DIC and liver disease; warfarin lowers C and S, heparin and nephrotic syndrome lower antithrombin, estrogen lowers S — so a low level is not automatically inherited.

More detail

Reference

Show 7 reference facts

Estrogen-containing contraceptives raise venous thrombosis risk to about 3–9 per 10,000 users per year (vs 1–5 in nonusers), more so with a thrombophilia, smoking or age ≥ 35.

ASH 2023 recommends against screening the general population before combined oral contraceptives and suggests testing after cerebral or splanchnic vein thrombosis when anticoagulation would otherwise be stopped.

Factor V Leiden is screened with the activated protein C resistance assay and confirmed by DNA testing of the factor V gene; homozygotes carry higher risk than heterozygotes.

For APS with arterial thrombosis, some experts add aspirin to warfarin or target INR 3–4, but high-quality evidence for either approach is lacking.

Homozygous protein C (or protein S) deficiency causes neonatal purpura fulminans, a severe DIC-like state with venous and arterial thrombosis in the first days of life.

About 1–5% of patients with cancer develop VTE each year; the association is strongest for pancreatic, brain, hematologic, lung and ovarian cancers.

Heparin-induced thrombocytopenia is an acquired, antibody-mediated hypercoagulable state causing venous and arterial thrombosis; see the HIT sheet for the 4Ts score and non-heparin anticoagulants.

Pearl

Antiphospholipid syndrome is the exception to the DOAC era: high-risk APS gets warfarin, INR 2–3.