Hypercoagulable States, Thrombophilia Testing & Cancer-Associated VTE

Inherited thrombophilias

Gain-of-function mutations. Factor V Leiden (R506Q) makes factor Va resistant to cleavage by activated protein C (APC resistance). It is the most common inherited thrombophilia — about 5% of people of European ancestry are heterozygous — and carries a modest several-fold VTE risk in heterozygotes and far more in homozygotes. Prothrombin G20210A, a 3′-untranslated-region mutation that raises prothrombin levels by about 30%, is second. Both are diagnosed genetically, and estrogen (OCPs, pregnancy) multiplies the risk of each; carrying both mutations raises risk beyond either alone.

Loss of natural anticoagulants. Protein C, with its cofactor protein S, inactivates factors Va and VIIIa; antithrombin inactivates thrombin and Xa. These deficiencies are rarer, autosomal dominant, and more thrombogenic, with antithrombin deficiency the most potent.

Warfarin skin necrosis. Protein C has a half-life of about 8 hours, so warfarin started alone lowers it before factors II, IX, and X fall, creating a transient hypercoagulable state. Dermal microvascular thrombosis then necroses fatty areas — breasts, thighs, buttocks. Prevent it by overlapping heparin for at least 5 days and until the INR has been therapeutic for 24 hours; if it occurs, stop warfarin, give vitamin K, and anticoagulate with heparin.

Protein S. Free protein S also falls in pregnancy, with estrogen, warfarin, liver disease, acute thrombosis, and inflammation, so a single low value rarely proves an inherited defect.

Antithrombin. Heparin works only by accelerating antithrombin, so deficiency — inherited or acquired from nephrotic urinary loss, liver disease, DIC, or L-asparaginase — causes heparin resistance: escalating doses never reach a therapeutic aPTT or anti-Xa level. Switch to a direct thrombin inhibitor such as argatroban or give antithrombin concentrate; fondaparinux also depends on antithrombin.

Whom and when to test

Test only when the answer changes management. Reasonable candidates: VTE at a young age that is unprovoked or weakly provoked, especially with a strong family history; thrombosis at unusual sites such as the cerebral venous sinuses or splanchnic veins; and recurrent VTE. Skip testing after VTE provoked by surgery or major trauma, in the acute setting, and whenever the result will not alter anticoagulation duration or family counseling.

Timing. Acute clot consumes protein C, protein S, and antithrombin; heparin lowers antithrombin; warfarin lowers proteins C and S; and heparin and DOACs distort clot-based assays such as lupus anticoagulant and APC resistance. PCR for factor V Leiden and prothrombin G20210A is unaffected by any of these. Check functional levels at least 3 months after the event and off anticoagulation — never interrupt treatment of an acute clot just to test.

Genetic tests are valid anytime; functional assays sent during an acute clot or on anticoagulants generate false "deficiencies."

Acquired hypercoagulable states

• Malignancy — the most important acquired cause (below).
• Antiphospholipid syndrome — arterial or venous thrombosis or pregnancy loss with persistent lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein I on two tests at least 12 weeks apart; warfarin is preferred over DOACs in high-risk disease.
• JAK2-mutated MPN — Budd–Chiari, portal, and mesenteric vein thrombosis; test JAK2 even when counts are normal.
• PNH — hemolysis, cytopenias, and hepatic or cerebral vein thrombosis; flow cytometry for CD55/CD59.
• Nephrotic syndrome — urinary antithrombin loss; renal vein thrombosis, especially in membranous nephropathy (flank pain, hematuria, rising creatinine, left varicocele).
• Estrogen and pregnancy — OCPs, hormone therapy, pregnancy, and above all the postpartum period.
• Inflammatory bowel disease, particularly during flares; also surgery, immobility, obesity, and heparin-induced thrombocytopenia.

Occult cancer after unprovoked VTE. Take a history, examine the patient, and obtain a CBC, CMP (calcium, liver tests), urinalysis, chest x-ray, and up-to-date age-appropriate screening (colonoscopy, mammography, cervical screening, low-dose chest CT if eligible). Routine CT of the abdomen and pelvis, PET, or tumor markers add little and do not improve outcomes.

Cancer-associated VTE

Risk. VTE risk is highest with pancreatic, gastric, brain, and lung cancers, with metastatic disease, and in the first months after diagnosis. Chemotherapy, antiangiogenic drugs, thalidomide or lenalidomide, tamoxifen, ESAs, central venous catheters, and surgery add to it. Trousseau syndrome — migratory superficial thrombophlebitis — heralds an occult adenocarcinoma, classically pancreatic, and tends to recur on warfarin, so heparin is the traditional treatment.

Treatment. Apixaban, rivaroxaban, edoxaban (after at least 5 days of parenteral lead-in), or LMWH are all preferred over warfarin. Continue for at least 6 months and for as long as the cancer is active or under treatment. IVC filters are reserved for patients who cannot be anticoagulated.

Choosing the agent. DOACs suit most patients and are at least as effective as LMWH. Edoxaban and rivaroxaban caused more GI and GU bleeding in patients with unresected luminal GI or GU tumors, so LMWH or apixaban is preferred there. LMWH also sidesteps CYP3A4 and P-glycoprotein interactions with anticancer drugs and suits patients with vomiting or malabsorption.

In a patient with an unresected gastric, colorectal, or urothelial tumor, avoid edoxaban and rivaroxaban; choose LMWH or apixaban.