Overview of Thrombotic Disorders

Genetic defects that increase the propensity for venous thromboembolism include:

• Factor V Leiden mutation, which causes resistance to activated protein C (APC)

• Prothrombin 20210 gene mutation

• Deficiency of protein C

• Deficiency of protein S

• Deficiency of protein Z

• Antithrombin deficiency

• Elevated factor VIII, IX, and XI levels

Protein Z, a vitamin K-dependent protein, helps inactivate coagulation factor Xa. Deficiency or dysfunction of protein Z predisposes to venous thrombosis (mainly in patients who also have other clotting abnormalities). The association of protein Z and thrombosis is an area of active investigation. A recent population-based analysis in the UK Biobank noted an association between loss of function variants of protein Z and stroke (1). However, measurement of its activity is not available in most laboratories.

Acquired defects also predispose to venous and arterial thrombosis (see table Acquired Causes of Thromboembolism).

Other disorders and environmental factors can increase the risk of thrombosis, especially if a genetic abnormality is also present.

Common manifestations of a thrombotic disorder include unexplained deep venous thrombosis (DVT) or pulmonary embolism (PE). Superficial thrombophlebitis can also develop. Other consequences may include arterial thrombosis (eg, causing stroke or mesenteric ischemia). Symptoms depend on the location of the clot, as in the following examples:

• Chest pain and shortness of breath: Possible PE or myocardial infarction

• Leg pain, warmth, erythema, and swelling: DVT

• Weakness/numbness of one side of the body, problems speaking, and problems with balance and walking: Possible ischemic stroke

• Abdominal pain: Possible splanchnic arterial or venous thrombosis

Most of the inherited disorders do not begin to cause an increased risk of clotting until young adulthood, although clots can form at any age. Women may have a history of multiple spontaneous abortions.

Diagnostic evaluations of thrombotic events that lead to deep venous thrombosis, pulmonary embolism, and ischemic stroke are discussed separately. Patients who have a thromboembolic event in the absence of an overt clinical explanation may have one of the genetic or acquired predisposing entities described below. It is often valuable to enlist the input of a hematologist to narrow the diagnostic possibilities.

The treatment of thrombotic events that lead to deep vein thrombosis, pulmonary embolism, and ischemic stroke are discussed in detail separately.

Anticoagulation is often required. For patients requiring hospitalization, anticoagulation typically is started with unfractionated heparin or low molecular weight heparin (Anticoagulation is often required. For patients requiring hospitalization, anticoagulation typically is started with unfractionated heparin or low molecular weight heparin (1, 2). For patients who can be treated as outpatients, direct oral anticoagulants (DOACs) or warfarin is used (). For patients who can be treated as outpatients, direct oral anticoagulants (DOACs) or warfarin is used (1, 2, 3).

DOACs include factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and the direct inhibitors (rivaroxaban, apixaban, edoxaban) and the directthrombin inhibitor dabigatran. Unlike warfarin, DOACs do not require regular laboratory monitoring, and some of these medications (inhibitor dabigatran. Unlike warfarin, DOACs do not require regular laboratory monitoring, and some of these medications (apixaban, rivaroxaban) can be used in acute treatment without initial parenteral anticoagulation. In contrast to warfarin, DOACs have fewer drug-drug interactions and their effectiveness is not influenced by diet.

In the event of life-threatening bleeding, reversal agents for DOACs include targeted antidotes (ie, idarucizumab for dabigatran; andexanet alfa for the In the event of life-threatening bleeding, reversal agents for DOACs include targeted antidotes (ie, idarucizumab for dabigatran; andexanet alfa for thefactor Xa inhibitors), as well as nonspecific prohemostatic agents such as prothrombin complex concentrates which contain factors VII, IX, X, and prothrombin (1, 4, 5). Warfarin is reversed with vitamin K and prothrombin complex concentrates. ). Warfarin is reversed with vitamin K and prothrombin complex concentrates.