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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2];Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Synonyms and Keywords: APC Resistance;

Overview

Activated protein C (APC) resistance occurs when APC fails to inactivate downstream coagulation factors, specifically Factor V and Factor VIII. This hemostatic disorder may be caused by either acquired, inherited, or a combination of both conditions. The factor V Leiden (FVL) mutation is the best known hereditary form accounts for more than 95 percent of cases of hereditary APC resistance, and acquired forms occur in the presence of elevated Factor VIII concentrations or conditions like hormone replacement therapy and pregnancy. These conditions contribute to the increased risk of hypercoagulable state and thrombosis.[1] It has been estimated that up to 64% of patients with venous thromboembolism might have activated protein C resistance.[2]

Historical Perspective

  • In the late 1980s, Dr. Dahlbäck a Swedish physician discovered activated protein C resistance associated with hypercoagulable condition.[3]
  • In 1993, Dr. Rogier Bertina and his colleagues identified that activated protein C (APC) resistance was primarily due to a mutation in the factor V gene (guanine to adenine substitution at nucleotide 1691, G1691A) resulting in the Factor V Leiden molecule.[4]

Classification

There is no established system for the classification of activated protein C resistance, however according to etiologic causes may be classified into inherited (primary), acquired (secondary), or a combination of both conditions.

Pathophysiology

  • Protein C is a vitamin K-dependent zymogen synthesized in the liver. Inactivated form of protein C is activated when it binds to thrombin, and the endothelial proteoglycan thrombomodulin.
  • Activated protein C (APC) functions an important role in regulating anticoagulation, and maintaining the permeability of blood vessel walls with negative feedback loop. Activated protein C anticoagulant activity operated by proteolytically inactivating proteins Factor Va and Factor VIIIa which are required for factor X activation and thrombin generation.
  • Protein C and S are natural anticoagulants which inhbit thrombin formation. Dysregulation in activated protein C (APC) can occur as either defects in the protein C or S molecule (Protein C and S deficiency) or as resistance to APC activity.[5]
  • Activated protein C resistance occurs when APC fails to inactivate downstream coagulation factors, specifically Factor V and Factor VIII.
  • The most common cause of activated protein C resistance is Factor V Leiden, which is a polymorphism of Factor V that is resistant to APC inactivation.[5]
  • In addition to the FVL mutation, a number of conditions which cause activated protein C resistance have been identified and are included: increased factor VIII, increased estrogen levels, antiphospholipid antibodies, and a variety of solid tumors and hematologic malignancies.

Figure: The Protein C Anticoagulant Pathway: Thrombin escaping from a site of vascular injury binds to its receptor thrombomodulin (TM) on the intact cell surface. As a result, thrombin loses its procoagulant properties and instead becomes a potent activator of protein C. Activated protein C (APC) functions as a circulating anticoagulant, which specifically degrades and inactivates the phospholipid-bound factors Va and VIIIa. This effectively down-regulates the coagulation cascade and limits clot formation to sites of vascular injury. T = Thrombin, PC= Protein C, Activated Protein C= APC, PS= Protein S

Causes

Activated protein C resistance may be caused by either inherited (primary), acquired(secondary), or a combination of both conditions.:

  • Inherited
  • Acquired
  • Mixed/Unknown
Activated Protein C Resistance
Inherited (Primary) Acquired (Secondary) Mixed
Factor V Leiden mutation Estrogen
Hormone replacement therapy
Factor V Cambridge Pregnancy Increased Factor VIII levels
Factor V Nara proteinuria Increased Factor XI levels
Factor V Liverpool elevated body mass Increased Factor IX levels
Factor V Bonn Myeloproliferative disorders (polycythemia vera, essential thrombocythemia, hyperviscosity)
Protein S deficiency Pregnancy
Antiphospholipid syndrome (APLS) or lupus anticoagulant

Activated protein C resistance may be caused by either acquired, inherited, or a combination of both conditions. Common inherited causes of activated protein C resistance include:

  • Factor V Leiden mutation: Factor V is a procoagulant which upon activation promotes the formation of thrombin. In 1994, Bertina and colleagues identified a single nucleotide polymorphism (guanine to adenine substitution in nucleotide 1691), which rendered factor V resistant to proteolytic inactivation by activated protein C (APC).
  • Protein S deficiency
  • Increased factor VIII: Increased levels of coagulation factor VIII can be associated with inflammatory disorders and pregnancy.
  • Estrogens: Increased estrogen levels during the use of oral contraceptives, hormone replacement therapy , and pregnancy
  • Antiphospholipid antibodies
  • Cancer: Certain solid tumors and advanced hematologic malignancies can cause aPC resistanceare

Differentiating Activated Protein C Resistance from Other Diseases

Activated protein C resistance must be differentiated from other diseases that cause recurrent thrombosis including deep venous thrombosis, pulmonary embolism or thrombosis at multiple sites, or unusual locations including in cerebral, hepatic, portal, mesenteric, and renal veins; in settings of family history of thrombosis, especially at an early age (< 45 years) such as:[6][5][7][8]

Epidemiology and Demographics

  • The prevalence of factor V Leiden mutation as the main cause of activated protein C resistance is approximately 5% between the general population and up to 18% in individuals with venous thromboembolism.[9][10]
  • Higher prevalence of the FVL mutation (12 to 14 percent) are reported in parts of Greece, Sweden, and Lebanon.[11]

Risk Factors

Common risk factors in the development of acquired activated protein C resistance include:

Common risk factors for the development of inherited activated protein C resistance are a family history of thrombosis at an early age or a family history of inherited thrombophilia.

Common genetic risk factors in the development of inherited activated protein C resistance is mutation in Factor V Leiden and Prothrombin G20210A.[6][5][12]

Screening

Natural History, Complications, and Prognosis

Natural History

Complications

The risk of future thrombosis in patients with activated protein C resistance:

Thrombophilic state Thrombotic risk[15]
Trauma/General surgery Modest
Age > 60 Modest
Immobilization Modest
Pregnancy Modest
Hormone therapies Modest
Factor V Leiden heterozygosity Modest
Prothrombin mutation Modest
Homocysteinemia Modest
Increased factor VIII levels Modest
Increased factor IX levels Modest
Increased factor XI levels Modest
Protein C and S deficiency Intermediate
Dysfibrogenemia Intermediate
Malignancy High
APLS/Lupus anticoagulant High
Myeloproliferative disorders/hyperviscosity High
PNH High
Orthopedic surgery High
Antithrombin deficiency High
Factor V Leiden homozygosity High

The effect of concurrent hormone exposure on incident thrombosis and thrombotic risk in patients with activated protein C resistance:

Thrombophilic state Annual Incidence (%) Relative Risk
Normal 0.008 1
Factor V Leiden heterozygous 0.06 3-10
Factor V Leiden homozygous 0.5-1 80
Prothrombin G20210A 0.02 1-5
Oral contraceptive (OCP) 0.03 4
OCP and factor V leiden heterozygous 0.3 35
OCP and factor V leiden homozygous 100
OCP and prothrombin G20210A 16
OCP and protein C/S, or antithrombin III deficiency 9.7
Pregnancy 7
Pregnancy and factor V leiden heterozygous 35
Cancer 5
History of venous thrombosis 50

Data were extracted from multiple sources.[15][20][21]

Prognosis

  • The prognosis depends on the underlying activated protein C resistance as each form has a different associated thrombotic risk. Patients who develop multiple or atypical clots, arterial thrombosis, or life-threatening thrombosis have worse prognosis.
  • Certain thrombophilic conditions are high risk and require consideration for lifelong anticoagulation. In these cases, expert consultation is recommended.
Possible indications for lifelong/prophylactic anticoagulation
Antiphospholipid syndrome
Paroxysmal nocturnal hemoglobinuria
Recurrent thrombosis regardless of underlying thrombophilia
History of life-threatening thrombosis or atypical locations
Malignancy with history of thrombosis

Diagnosis

Diagnostic Criteria

  • Suspicion of activated protein C resistance being the cause for any thrombotic event should be considered in a member of a thrombophilic family or in an individual with venous thromboembolism (VTE), especially VTE at a young age (eg, <50 years), VTE in an unusual location (eg, portal vein, cerebral vein), or recurrent VTE.
  • This disease can be diagnosed by watching the aPTT (the time it takes for blood to clot) as activated protein C is added. With a normal patient, adding aPC increases the APTT. In patients with factor V Leiden, adding aPC will barely affect the time it takes for blood to clot.
  • Functional coagulation test for aPC resistance using "second generation" aPC resistance assays.
  • Approximately 95% of cases is due to the Factor V Leiden [FVL] mutation –There is also a simple genetic test that can be done for this disorder. The mutation (a 1691G→A substitution) removes a cleavage site of the restriction endonuclease MnlI, so simple PCR, treatment with MnlI, and then DNA electrophoresis will give a quick diagnosis.
  • The FVL mutation can be detected directly by analyzing genomic DNA from peripheral blood cells. Since only a single mutation is involved, this testing is straightforward and relatively inexpensive to perform.

History and Symptoms

A positive family history of thrombosis and individual recurrent thrombosis history is suggestive of inherited thrombophilias. Thrombophilia screening may be beneficial in these scenarios.[22][6][5] A positive history of the following is suggestive of inherited thrombophilias:

Physical Examination

Physical examination of patients with thrombophilia is usually remarkable for:[5][6][23]

Laboratory Findings

  • The second generation for activated protein C resistance (APCR) assay, uses the ratio of aPTT with activated protein C (APC) and aPTT without APC. This functional assay is acceptably sensitive and specific for factor V Leiden, with significant differentiating between normal population and factor V Leiden heterozygous or homozygous patients.[24]
  • The normal reference range is ratio greater than 2.1. This range for heterozygous individuals with factor V Leiden is 1.5 -1.8, and for homozygous patients is less than 1.5.

Imaging Findings

  • There are no x-ray findings associated with thrombophilia. X-ray may be helpful in the diagnosis of thrombosis.

Treatment

Medical Therapy

Activated protein C resistance is a description for a condition which can be caused by either acquired, inherited, or a combination of both conditions etiologies. Most individuals with activated protein C resistance are asymptomatic. Up to 30% of patients who present with deep vein thrombosis (DVT) or pulmonary embolism (PE) have this condition.The initial treatment of venous thromboembolism (VTE) in individuals with activated protein C resistance is the same as that of the general population, with anticoagulation unless there is a contraindication. The mainstay of therapy for thrombophilia is anticoagulation with either warfarin, low molecular weight heparin, direct Xa inhibitors, or direct thrombin inhibitors. Treatment should be tailored to the individual patient. The risks and benefits, required monitoring, and costs associated with each form of anticoagulation should be discussed with the patient prior to initiation of therapy. All patients on anticoagulation should be monitored for bleeding.

Important exceptions include:
  • Pregnancy[26]
  • Renal insufficiency
  • Malignancy[27]
  • Low molecular weight heparin (LMWH) is recommended for anticoagulation for the following acquired thrombophilias:
    • Post-surgery prophylaxis[28][29][30]
      • The duration of anticoagulation after surgery is variable. Most clinical trials have evaluated anticoagulation for 10-35 days
      • General recommendations for thrombophrophylaxis is 7-10 days for standard risk patients and 10-35 days for higher risk patients as described in the algorithims below and for patients undergoing abdominal and pelvic surgeries for gynecologic malginancies[31]
      • DOACs may be considered as agents for extended thromboprophylaxis after total hip replacement and total knee replacement.
    • Pregnancy and postpartum[26]
      • Patients who develop acute thrombosis during pregnancy should be anticoagulated for the remainder of the their pregnancy and 6 weeks postpartum for a minimum of 3 months
      • A similar duration of anticoagulation is recommended for patients with high risk thrombophilias as described in the algorithims below
    • Malignancy[27]
  • Alternative agents include Warfarin and Fondaparinux
    • Warfarin is the agent of choice for prophylactic anticoagulation in patients with nephrotic syndrome, as there are no studies evaluating DOACs and LMWH for this clinical indication. Refer to the treatment algorithim below. It is important to note that the recommendations for prophylactic anticoagulation in patients with nephrotic syndrome are not based on expert consensus guidelines.[32][33]

Surgery

Surgery is not required for treatment for thrombophilia. IVC filter placement may be indicated if the patient has contraindications to or complications from anticoagulation, recurrent thrombosis on anticoagulation, or failure to achieve therapeutic anticoagulation levels.[34]

Primary Prevention

Thromboprophylaxis with anticoagulation may be recommended for primary prevention of acute thrombosis in high risk acquired and inherited thrombophilias.[23][6][5][28][29][30]

Secondary Prevention

Thromboprophylaxis with anticoagulation may be recommended for secondary prevention of acute thrombosis in high risk acquired and inherited thrombophilias:[25][23][6][5][28][29][30]

References

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  2. D. R. Sheppard (2000). "Activated protein C resistance: the most common risk factor for venous thromboembolism". The Journal of the American Board of Family Practice. 13 (2): 111–115. PMID 10764192. Unknown parameter |month= ignored (help)
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