Best Dx/Best Rx: Hypertension

Hypercoagulable State

Lawrence L. K. Leung, MD
Stanford University School of Medicine, Stanford, CA

Definition
Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition

Recurrent thrombosis attributable to either hereditary or acquired hypercoagulable risk factors
Pathophysiology: excessive clotting in combination with vascular inflammation, involving one or more elements
- Endothelial injury
- Decreased blood flow
- Inherited or acquired imbalance between procoagulant and anticoagulant factors

Key Clinical Features

Deep vein thrombosis of lower extremities with or without pulmonary embolism most common presentation
- Atypical site increases likelihood of underlying hypercoagulable state
Common triggers of thrombosis
- Surgery
- Trauma
- Pregnancy
- Malignancy
- Prolonged immobilization
- Infection
Mean age at first thrombosis 35–40 yr in inherited hypercoagulable states
Recurrent thrombosis suggests hypercoagulable state (inherited or acquired)
Thrombosis in patient who has had previous pregnancies or surgeries (especially orthopedic procedures) without thrombotic complications suggests acquired hypercoagulable state
Documented venous thromboembolism before 50 yr of age in a first-degree relative strongly suggests hereditary thrombotic disorder
Spontaneous, idiopathic thrombosis, especially in a younger person, strongly suggests hereditary hypercoagulable state
Relative risk of venous thrombosis and frequency of hypercoagulable states
- High risk
  - Antithrombin deficiency (1%–2%)
  - Protein C deficiency (3%–4%)
  - Protein S deficiency (2%–3%)
  - Antiphospholipid antibody syndrome (unknown)
  - Trousseau syndrome (NA)
- Modest risk
  - Factor V Leiden (20%–25%)
  - Prothrombin mutation G20210A (10%)
  - Hyperhomocysteinemia (10%)
  - Oral contraceptive use (NA)
- Combination of risk factors may have synergistic effect in increasing thrombosis risk

Differential Diagnosis

Inherited Hypercoagulable States

Resistance to activated protein C/factor V Leiden
Prothrombin gene mutation G20210A
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Hyperhomocysteinemia

Acquired Hypercoagulable States

Antiphospholipid antibody syndrome
Hypercoagulable state associated with physiologic or thrombogenic stimuli
- Advancing age
- Oral contraceptives
- Pregnancy
- Surgery
- Trauma
Hypercoagulable state associated with other clinical conditions
- Malignancy—Trousseau syndrome
- Heparin-induced thrombocytopenia with thrombosis
- Nephrotic syndrome
- Hyperviscosity (polycythemia vera, Waldenström macroglobulinemia, multiple myeloma)
- Myeloproliferative disorders (polycythemia vera, essential thrombocytopenia)
- Paroxysmal nocturnal hemoglobinemia
- Sickle cell anemia

Best Tests

For mild to moderate DVT of the lower extremities with an obvious provoking factor, a limited workup is appropriate. An extensive workup is generally warranted if the likelihood of a hypercoagulable state is high.

Venous Thrombosis

Resistance to protein C/factor V Leiden
- Factor V Leiden (DNA test)
- Clotting assay (unnecessary if DNA test is positive)
Prothrombin mutation G20210A (DNA test)
Antithrombin deficiency (functional assay)
Protein C deficiency (functional assay)
Protein S deficiency
- Functional assay
- Antigenic assay for free protein S
Postpone measurement of antithrombin, protein C, and protein S until resolution of acute thrombotic episode (e.g., ≥ 4 wk after termination of oral anticoagulation therapy)

Arterial Thrombosis

Antibodies associated with heparin-induced thrombocytopenia (in appropriate clinical settings)
Chronic disseminated intravascular coagulation (in appropriate clinical settings)
Lipoprotein(a)

Venous and/or Arterial Thrombosis

Homocysteine
- Fasting level
Antiphospholipid antibody
- Clotting assays for lupuslike anticoagulant
- Enzyme-linked immunosorbent assay (ELISA) for anticardiolipin antibodies IgG and IgM
Dysfibrinogenemia (if inherited hypercoagulable state is strongly suspected)
- Functional assay for fibrinogen level
- Thrombin time, reptilase time

Best Therapy*

Prophylaxis for Venous Thromboembolism with Underlying Risk Factors

Warfarin: international normalized ratio (INR) 2.0–3.0

High Risk

Lifelong oral anticoagulation therapy

Recurrent idiopathic thrombosis
One life-threatening thrombosis
One spontaneous thrombosis at an unusual site (e.g., mesenteric thrombosis)
One spontaneous thrombosis associated with antiphospholipid antibody syndrome
One thrombosis with two permanent risk factors
One thrombosis with Trousseau syndrome

Medium Risk

6 mo of oral anticoagulation therapy after first episode of thrombosis; vigorous prophylaxis in high-risk situations

One thrombosis with one permanent risk factor (except Trousseau syndrome and antiphospholipid antibody syndrome)
Idiopathic thrombosis with no identifiable risk factor

Low Risk

3 mo of oral anticoagulation therapy after first episode of thrombosis; vigorous prophylaxis in high-risk situations

One thrombosis with reversible risk factor

Best References

Cervera R, et al. Arthritis Rheum 2002;46:1019-27. [PMID 12777938]

Dalbäck B. Blood 2008;112:19-27. [PMID 18574041]

Gross PL, Weitz JI. Clin Pharmacol Ther 2009;86:139-46. [PMID 19553932]

Kearon C, et al. Chest 2008;133(6 Suppl):454S-545S. [PMID 18574272]

Miyakis S, et al. J Thromb Haemost 2006;4:295-306. [PMID 16420554]

Varki A. Blood 2007;110:1723-9. [PMID 17496204]

The author has no commercial relationships with manufacturers of products or providers of services discussed in this module.

* To obtain additional drug information, click on the DrugInfo tab in the left column, or click on the following link: http://search.medscape.com/drug-reference-search?queryText=

October 2010