Hypercoagulable States Sheri Ziegler, DO

Virchow’s Triad Medication Acquired PICC line Hereditary Port –a-cath Cancer PICC line Port –a-cath Immobility

Forming a clot Platelets Clotting factors (I, II, V, VII, IX, X, XI, XII, XIII) Fibrin Thrombosis

Protein C, Protein S, Antithrombin III Coagulation Pathways Intrinsic Pathway Extrinsic Pathway IX Tissue Factor + VII Contact TF Pathway X XI TF-VIIa PL Common Pathway XIIa HKa Prothrombin XIa PL IXa VIIIa PL Xa XIII Va (Prothrombinase) Thrombin Protein C, Protein S, Antithrombin III XIIIa Fibrinogen Fibrin (weak) Fibrin (strong)

Case 1 35 yr old F presents with painful left leg x 1 week

History Trauma Medications Family History Personal History Immobility

Deep vein thrombosis Ultrasound

Acutely became short of breath What’s worse Lots of pain Little pain

Pulmonary embolism CT scan V/Q scan

Pulmonary Embolism

Cerebral vein thrombosis

Arterial Thrombosis  

Hypercoagulable States Definition Clinical situation wherein patients suffer from recurrent venous and/or arterial thrombotic problems or are predisposed to such problems

Hypercoagulable States Fine Balance in Hemostatic system "pro" hemostatic system (procoagulant) "anti" hemostatic system (anticoagulant) perturbations in either system can predispose to clotting or bleeding

Hypercoagulable States Acquired Hemostatic Abnormalities Lupus anticoagulant Nephrotic syndrome DIC Prior thrombosis Immobilization Malignancy TTP Heparin induced thrombocytopenia Myeloproliferative disorders Estrogens Prolonged travel

What patients with a thrombosis should you suspect as having a hereditary hypercoagulable state ?

Possible Hereditary Defects predisposing to Venous Thrombosis DVT < age 45 Positive family history Recur without precipitating factors Occurs at atypical site Idiopathic

Incidence of Hereditary Coagulation Defects

“Hypercoagulable work-up” Factor V Leiden mutation Genetic test for prothrombin gene mutation Functional assay of antithrombin III Functional assay of protein C Protein S assay Tests for antiphopholipid syndrome

Activated protein C Resistance MOST COMMON ETIOLOGY of hereditary venous thrombosis Variation among different populations 5% European or Caucasian population Rare in African Americans, native American Indians, Asians First described in 1994 Factor V Leiden mutation

Protein C, Protein S, Antithrombin III Cascade Intrinsic Pathway Extrinsic Pathway IX TF Pathway Tissue Factor + VII Contact X XI TF-VIIa PL Common Pathway XIIa HKa Prothrombin XIa PL (Tenase) IXa VIIIa PL Xa XIII Va (Prothrombinase) Thrombin Protein C, Protein S, Antithrombin III XIIIa Fibrinogen Fibrin (weak) Fibrin (strong)

Factor V Leiden Characteristics 15-20% of patients with venous thromboembolism Recurrent thrombosis, familial thrombosis, thrombosis assoc. with pregnancy or young patients

Factor V Leiden heterozygous First Episode of DVT Relative Risk Incidence/yr (%) Normal 1 0.008 Oral contraceptives 4 0.03 Factor V Leiden heterozygous 7 0.06 FVL + OCP 35 0.3 Factor V Leiden homozygous 80 0.5-1.0

Protein C/S and ATIII Deficiency All much higher risk of thrombosis Young age multiple VTE Usually life long anticoagulation

Protein C, Protein S, Antithrombin III Cascade Intrinsic Pathway Extrinsic Pathway IX TF Pathway Tissue Factor + VII Contact X XI TF-VIIa PL Common Pathway XIIa HKa Prothrombin XIa PL (Tenase) IXa VIIIa PL Xa XIII Va (Prothrombinase) Thrombin Protein C, Protein S, Antithrombin III XIIIa Fibrinogen Fibrin (weak) Fibrin (strong)

Prothrombin gene mutation First described in 1996 Mutation G20210A (guanine to adenine) Increased thrombosis Increased prothrombin levels 2.8 fold increased risk of thrombosis 0.02%/year risk of thrombosis

Protein C, Protein S, Antithrombin III Cascade Intrinsic Pathway Extrinsic Pathway IX TF Pathway Tissue Factor + VII Contact X XI TF-VIIa PL Common Pathway XIIa HKa Prothrombin XIa PL (Tenase) IXa VIIIa PL Xa XIII Va (Prothrombinase) Thrombin Protein C, Protein S, Antithrombin III XIIIa Fibrinogen Fibrin (weak) Fibrin (strong)

CASE 45 yr old F with acute pain in right foot. Rash located on arms and legs. History of recurrent fetal loss.

Arterial Thrombosis Evaluation Lupus anticoagulant Anticardiolipin antibody Homocysteine levels

Antiphospholipid syndrome A clinical diagnosis characterized by arterial and venous thrombosis and recurrent fetal loss Persistent lupus anticoagulant or anticardiolipin antibodies Thrombocytopenia and livedo reticularis

Lupus Anticoagulant Tests Dilute Russell Viper Venom Time (dRVVT) Elevated PTT Anticardiolipin antibody

CASE 80 yr old F with DVT. No previous hx of DVT/PE Not feeling well recently. Lost 15 pounds in 2 months but, increased abdominal girth.

Venous thrombosis in cancer Common (20%) of all patients with cancer Increased risk of recurrent VTE Increased risk bleeding with anticoagulation

DVT and Cancer Current evidence does not support extensive search for occult malignancy Pursue signs/symptoms Appropriate screening cancer tests

Cancer Screening CBC Chemistry panel Stool for occult blood/colonscopy PSA and digital rectal exam Mammogram Pelvic examination Urinalysis

Now you’ve diagnosed – how do you treat?

Therapy of DVT/PE Heparin Warfarin Thrombin inhibtors Unfractionated (IV) Low molecular weight (SQ) Fondaparinux (SQ) Warfarin Thrombin inhibtors Oral Factor Xa inhibitors Rivaroxaban Apixaban

LMWH Mainly Anti-Xa activity with some antithrombin activity Long duration of action More consistent therapeutic window Not reversible with protamine Included: Enoxaparin (Lovenox) Dalteparin (Fragmin) Tinzaparin (Innohep) Fondaparinux (Arixtra) – only anti-Xa activity

Coumadin

Warfarin—Mechanism of Action Vitamin K II Vitamin K Utilization Reduced VII IX X Warfarin

Effect of warfarin on clotting factors

Kaplan-Meier Estimates of the Probability of Symptomatic Recurrent Venous Thromboembolism among Patients with Cancer Lee, A. et al. N Engl J Med 2003;349:146-153

Warfarin—Contraindications Risk of hemorrhage is greater than benefits of therapy Pregnancy Hemorrhagic tendencies or blood dyscrasias Traumatic surgery with large open areas, recent or contemplated surgery of CNS or eye Bleeding tendencies with active ulceration or overt bleeding Lack of patient cooperation Spinal puncture and procedures with potential for uncontrollable bleeding

Long time coming….

Thrombin inhibitor Dabigatran (Pradaxa) Thrombin is key step in thrombosis Turns fibrinogen into clot Activates platelets Activates clotting factors

DVT treatment NEJM: 361:2342-2352, 2009

Bleeding

Oral Factor Xa inhibitors Rivaroxaban (Xarelto) Apixaba (Eliquis)

DVT treatment

Bleeding

Duration of Therapy First event with reversible or time limited risk factor 3-6 months Unprovoked VTE At least 6 months Special situations – life long Cancer – until resolved Antithrombin III, multiple genetic defects, antiphopholipid syndrome

Accept risk of recurrent disease 6 Months Coumadin INR = 2.0-3.0 Continue

Recurrent Venous Thrombosis Incidence of DVT (%) Years

D-dimer and Recurrent VTE (PREVENT) Patients with 1 prior VTE Patients with >1 prior VTE

Oral Direct Xa Inhibitor Xarelto (Rivaroxaban) Oral agent Do not need to check INR Can not be reversed

The End