Thrombophilia due to protein C deficiency

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: PROC (HGNC:9451)
• Literature Search: 05/09/2017
• Curation Status: In Preparation (0.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
PROC	thrombophilia due to protein C deficiency, autosomal dominant (0008316)	176860	Assertion Pending
PROC	thrombophilia due to protein C deficiency, autosomal recessive (0012860)	612304	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
No scores were found.

Severity of Outcome

Prevalence of the Genetic Condition

Partial protein C (PROC) deficiency (heterozygous forms) is present in 0.2-0.5% of the general population and 3% of patients with thrombosis. Prevalence of severe PROC deficiency (homozygous or compound heterozygous forms) is estimated as 1/500,000.

Clinical Features (Signs / symptoms)

PROC deficiency is associated with reduced or absent levels of PROC activity, where PROC is a natural inhibitor of coagulation. Partial PROC deficiency (heterozygous forms) is associated with an increased risk of venous thromboembolism (VTE). VTE most commonly occurs in the form of a deep vein thrombosis (DVT) of the lower limbs with or without pulmonary embolism (PE). Cerebral venous thrombosis (CVT) may occur as well. Beyond the acute sequelae, VTE may result in chronic conditions, including post-thrombotic syndrome, venous insufficiency, and pulmonary hypertension.Patients with severe PROC deficiency (homozygous or compound heterozygous forms with undetectable PROC levels) typically manifest several hours to days after birth and may develop purpura fulminans, a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues. Prognosis is severe for these patients. Patients with homozygous or compound heterozygous PROC deficiency with low but detectable PROC levels have milder symptoms similar to those of heterozygous individuals.

Natural History (Important subgroups & survival / recovery)

Heterozygotes are usually asymptomatic until adulthood. VTE events are mainly provoked by other risk factors such as surgery, pregnancy, immobilization, or exogenous hormone use. Additional risk factors for VTE include a first-degree relative with an VTE event before age 50, personal history of VTE, obesity, and certain comorbidities (e.g., cancer, heart or respiratory failure). The annual VTE incidence is 1-2% for PROC deficiency. In general, prognosis is good for heterozygous patients, though mortality may result from PE. With adequate treatment and monitoring, the risk of VTE is markedly reduced. Men and women are equally affected.Women with PROC deficiency are at an increased risk of VTE during pregnancy, with an estimated VTE risk of 0.1-0.8% per pregnancy without a prior VTE and 4-17% with a prior VTE. Among those with a family history of VTE, the risk in pregnancy has been reported as 2-7%. However, it is currently controversial whether there is an association between inherited thrombophilias and pregnancy complications such as uteroplacental thrombosis that can lead to adverse pregnancy outcomes such as fetal loss, preeclampsia, fetal growth restriction, and placental abruption.

Likelihood of Outcome

Mode of Inheritance

Prevalence of Genetic Variants

Unknown

The prevalence of mutations associated with PROC deficiency were not identified.

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

PROC deficiency is associated with a reduced penetrance of VTE and specific estimates are not available. In general, individuals are at an annual risk of 0.4-1.0 VTEs (%/year).

Tier 3

Unknown

Women with PROC deficiency have a VTE risk of is estimated as 0.1-0.8% per pregnancy without a prior VTE and 4-17% with a prior VTE compared to a background VTE incidence of ~0.1%.

Tier 3

Unknown

Although individuals with a PROC deficiency have a greater relative risk of VTE during pregnancy (estimated from case-control odds ratios), given the background incidence of VTE during pregnancy ~1/1000 deliveries, the absolute risk of in women without a prior event or family history remains low (0.7%; 95% CI: 0.3-1.5%).

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

The risk of VTE has been estimated from a meta-analysis of case-control and cohort studies which estimated both an increased risk of first VTE (OR=7.5; 95% CI: 3.2-17.5) and VTE recurrence (OR=2.9; 95% CI: 1.4-6.0) associated with PROC deficiency compared to controls.

Tier 1

Unknown

PROC deficiency was not found to be associated with recurrent fetal loss (pooled OR: 1.6; 95% CI: 0.2–10.5) or non-recurrent fetal loss (pooled OR: 1.4, 95% CI: 1.0-2.1).

Tier 1

Expressivity

There is not a clear correlation between residual enzyme activity and clinical thrombosis. Clinical variability among individuals with homozygous PROC deficiency, including relatives, suggested that other factors need to interact for full clinical penetrance of the defect.

Tier 3

Intervention Effectiveness

Patient Management

There is very little evidence to guide management of asymptomatic people with hereditary thrombophilias (including PROC deficiency) for the primary prevention of stroke. Evidence that most VTE events occurred during periods of high risk periods (such as surgery, trauma, or pregnancy) suggest that antithrombotic prophylaxis would likely be effective. However, the effect of this prophylaxis on the incidence of stroke or transient ischemic attack is unknown.

Tier 2

Following a CVT or cerebral venous and sinus thrombosis (CVST), there is an increased risk of recurrence (estimated from 2-5%; adjusted HR=4.71, 95% CI: 1.34-16.5) and recurrence tends to occur within the first year of the index CVT. The recurrent event is more often a VTE than a CVT. Indefinite anticoagulation may be considered in patients with PROC deficiency at the first CVT or CVST. However, there are no secondary-prevention trials of duration of anticoagulation in adults with CVT and guidelines are based solely on observational data.

Tier 2

Perioperative VTE prophylaxis is recommended for patients with PROC deficiency undergoing gynecological surgery. Prophylaxis may include low-dose unfractionated heparin (UFH) or low molecular weight heparin (LMWH) with or without intermittent pneumatic compression devices or graduated compression stockings. Continuing prophylaxis may be considered for 2-4 weeks after discharge. Data from two randomized trials and a large retrospective series in the general population have found that the incidence of VTE in patients undergoing prophylaxis following gynecologic surgery with one of the above modalities was 1-6.5% compared with 15-40% reported in an untreated population.

Tier 2

Based on the increased risk of VTE, all pregnant women with an inherited thrombophilia should be referred to a local expert and undergo individualized risk assessment which may modify pregnancy management decisions. The decision to treat with thromboprophylaxis, anticoagulation therapy, or no pharmacological treatment is influenced by VTE history, severity of inherited thrombophilia, and additional risk factors (e.g., cesarean delivery, prolonged immobility, obesity, and family history of VTE). Thromboprophylaxis may include LMWH or UFH. Surveillance includes clinical vigilance and appropriate objective investigation of women with symptoms suspicious of VTE.

• Women without a prior VTE are recommended to undergo antepartum and postpartum surveillance without thromboprophylaxis. Guidelines differ on whether postpartum thromboprophylaxis is recommended among all women or only in the presence of other risk factors (e.g., family history of VTE).

• Women with a prior VTE who are not receiving long-term anticoagulation therapy may undergo either antepartum surveillance without anticoagulation therapy or with prophylactic or intermediate-dose LMWH/UFH, but are recommended postpartum thromboprophylaxis.

• Pneumatic compression boots or elastic stockings should be considered during the intrapartum period until the patient is ambulatory postpartum.

• LMWH is estimated to reduce the risk of VTE from 20 VTEs per 1000 to 13 fewer VTEs per 1000 among individuals with PROC deficiency. However, evidence about the relative effects of treatment is taken from a meta-analysis of thromboprophylaxis in patients undergoing hip arthroplasty and is rated by the guideline authors to be of low quality due to the indirectness of the population and imprecision in the baseline risk estimates for women with thrombophilias.

Tier 2

Circumstances to Avoid

Thrombophilic disorders (including PROC deficiency) are contraindications for the use of estrogen containing prescription drugs approved for the prevention of postmenopausal osteoporosis.

Tier 2

Nature of Intervention

Nature of Intervention

The primary intervention proposed for patients with PROC deficiency is the use of injectable heparin in situations of stress that may increase the risk of VTE. Neither UFH nor LMWH crosses the placenta and both are considered safe in pregnancy. During pregnancy, both UFH and LMWH have shorter half-lives and lower peak plasma concentrations, usually necessitating higher doses and more frequent administration in order to maintain effective concentrations. However, bleeding complications can arise from administration of UFH or LMWH, and this complication should be considered before initiating anticoagulation therapy. UFH, which is associated with increased bruising at the injection sites, also has been associated with other skin reactions and serious allergic reactions.

Context: Adult

Chance to Escape Clinical Detection

Screening for PROC deficiency is not routinely recommended. VTE may be the first manifestation of the disease.

Context: Adult

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			PROC			176860	0008316	0019145
PROC			612304	0012860	0019145

References List

American College of Obstetricians and Gynecologists Women's Health Care Physicians. (2013) ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstetrics and gynecology. 122(3):706-17.

Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. (2012) VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 141(2 Suppl):e691S-736S.

Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL, Howard VJ, Lichtman JH, Lisabeth LD, Pina IL, Reeves MJ, Rexrode KM, Saposnik G, Singh V, Towfighi A, Vaccarino V, Walters MR. (2014) Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 45(5):1545-88.

Committee on Practice Bulletins--Gynecology, American College of Obstetricians and Gynecologists. (2007) ACOG Practice Bulletin No. 84: Prevention of deep vein thrombosis and pulmonary embolism. Obstetrics and gynecology. 110(2 Pt 1):429-40.

Committee on Practice Bulletins-Gynecology, The American College of Obstetricians and Gynecologists. (2012) ACOG Practice Bulletin N. 129. Osteoporosis. Obstetrics and gynecology. 120(3):718-34.

Di Minno MN, Ambrosino P, Ageno W, Rosendaal F, Di Minno G, Dentali F. (2015) Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thrombosis research. 135(5):923-32.

Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuunemann HJ. (2012) Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 141(2 Suppl):7S-47S.

Hereditary thrombophilia due to congenital protein C deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=745

James A. (2011) Practice bulletin no. 123: thromboembolism in pregnancy. Obstetrics and gynecology. 118(3):718-29.

Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, Creager MA, Eckel RH, Elkind MS, Fornage M, Goldstein LB, Greenberg SM, Horvath SE, Iadecola C, Jauch EC, Moore WS, Wilson JA. (2014) Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 45(12):3754-832.

National Clinical Guideline Centre for Acute and Chronic Conditions. Venous thromboembolic diseases: diagnosis, management, and thrombophilia testing. Clinical guideline no. 144. (2012) URL: https://www.nice.org.uk/guidance/cg144

Rey E, Kahn SR, David M, Shrier I. (2003) Thrombophilic disorders and fetal loss: a meta-analysis. Lancet (London, England). 361(9361):901-8.

Royal Collge of Obstetrics and Gynaecologists (RCOG). Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline No. 37a.. (2015) URL: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.pdf

Scottish Intercollegiate Guidelines Network (SIGN). SIGN publication no. 122. Prevention and management of venous thromboembolism. (2010) URL: http://www.sign.ac.uk

THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT; THPH3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 176860, (2016) World Wide Web URL: http://omim.org/

THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE; THPH4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 612304, (2017) World Wide Web URL: http://omim.org/

Varga EA, Kujovich JL. (2012) Management of inherited thrombophilia: guide for genetics professionals. Clinical genetics. 81(1):7-17.