INTRODUCTION — Protein C deficiency is associated with a small percentage of cases of inherited thrombophilia, as well as the even more uncommon findings of warfarin-induced skin necrosis and neonatal purpura fulminans, and a possible weak association with pregnancy loss. However, establishing a diagnosis of hereditary protein C deficiency can be difficult, as many clinical states can lead to acquired protein C deficiency.
This topic review discusses the diagnosis and management of protein C deficiency (inherited and acquired).
Separate topic reviews address the appropriate use of thrombophilia testing in various clinical settings:
●Children – (See "Thrombophilia testing in children and adolescents".)
●Patients with VTE – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)
●Patients with stroke – (See "Overview of the evaluation of stroke", section on 'Blood tests'.)
●Patients with pregnancy loss – (See "Inherited thrombophilias in pregnancy", section on 'Selection of patients for screening'.)
●Asymptomatic patients with a positive family history – (See "Screening for inherited thrombophilia in asymptomatic adults".)
PATHOPHYSIOLOGY
Biology of protein C — Protein C is a vitamin K-dependent anticoagulant protein synthesized in the liver. It has a molecular weight of about 62 kilodaltons (kD) and consists of two chains connected by a disulfide bridge.
Protein C circulates as a zymogen and exerts its anticoagulant function after activation to activated protein C (aPC), a serine protease [1]. This process occurs when thrombin is bound to thrombomodulin, a specific receptor on vascular endothelium (figure 1). Synthesis of gamma-carboxyglutamic acid (Gla) in protein C requires vitamin K. The Gla domain binds calcium, leading to a structural change that facilitates phospholipid binding, which is important for protein C function.
The primary role of aPC is to inactivate coagulation factors Va and VIIIa, which are necessary for efficient thrombin generation and factor X activation, respectively [1]. The inhibitory effect of aPC is enhanced by protein S, another vitamin K-dependent anticoagulant protein. Inherited deficiency of protein C can lead to thrombophilia (increased tendency toward thrombosis). (See "Overview of hemostasis", section on 'Control mechanisms and termination of clotting'.)
In addition to its anticoagulant function in the coagulation pathway, aPC has a role in counteracting inflammation. By binding to the endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR1), aPC exerts cytoprotective effects on cells, including antiinflammatory activity and endothelial barrier protection [2,3].
After birth, levels of protein C take some time to reach normal adult levels. Preterm infants have protein C levels of approximately 7 to 18 percent of normal, while full term newborns have protein C levels of 20 to 40 percent of normal [4-7]. Neonates with significant thrombosis can have extremely low levels (low enough to suggest homozygous deficiency) that normalize upon recovery from the event [8]. Protein C levels increase during normal aging [9].
Genetics — Most patients with inherited protein C deficiency are heterozygous. Over 160 different mutations in the protein C gene (PROC) have been described [10-12]. The gene is located on chromosome 2 (2q13-14) [13,14].
Inherited protein C deficiency can be subdivided according to whether the deficient activity is due to reduced protein levels (type I) or to reduced protein function (type II). Type I deficiency is more common than type II deficiency; there do not appear to be clinical differences between type I and type II protein C deficiencies.
●Type I – Type I deficiency (reduced protein C antigen and activity levels) is most commonly caused by a missense or nonsense mutation (encoding an alternate amino acid or a premature stop codon, respectively) [11,12,15]. Other types of mutations have also been described, including promoter mutations, splice site abnormalities, in-frame deletions, frameshift deletions, in-frame insertions, and frameshift insertions [11]. These defects can reduce the production of protein C or accelerate its destruction. The plasma protein C level is approximately 50 percent of normal, as measured in immunologic and functional assays [11]. Despite the similar protein C activity level in most patients with type I deficiency, there is marked phenotypic variability among patients. Similar mutations have been found among symptomatic and asymptomatic individuals, implying that the nature of the protein C gene defect alone does not explain the phenotypic variability [12,16,17].
●Type II – Type II deficiency (reduced protein C function with normal antigen levels) is caused by mutations that affect the amino acid sequence of protein C and in turn inhibit the ability of protein C to carry out its anticoagulant function. A variety of different point mutations affecting protein function have been described [11,18].
Although less common than the heterozygous state, some individuals are homozygous or compound heterozygous for mutations in the protein C gene; this is due to inheritance of a mutant allele from both parents. Severe deficiency of protein C (ie, level <1 percent) can lead to neonatal purpura fulminans at birth. (See 'Neonatal purpura fulminans management' below.)
This was demonstrated in a 2017 series of 22 individuals who were homozygous or compound heterozygous for a protein C mutation, in which 16 (73 percent) presented with neonatal purpura fulminans, intracranial thromboembolism, or both [19]. Six others with a higher plasma protein C level (approximately 30 percent) developed thrombosis after age 15. Other individuals can have mutations leading to protein C levels under 20 percent of normal; they are at risk for more severe phenotypes than heterozygotes. These mutants are collated in various mutation databases [11,20,21]. (See 'Clinical features' below.)
The coinheritance of protein C deficiency and another thrombophilic defect such as the factor V Leiden mutation is also occasionally seen and increases thromboembolic risk, although high quality evidence is lacking regarding the magnitude of the combined effect. (See 'Venous thromboembolism' below.)
Control of protein C levels
Normal levels — Protein C circulates in human plasma at an average concentration of 4 mcg/mL. The concentrations of protein C are normally distributed in healthy adults with 95 percent of the values ranging between 70 to 140 percent of normal [9]. There is no significant sex difference.
Causes of reduced protein C — In addition to the role of protein C gene mutations, circulating levels of protein C may be reduced in a number of conditions that affect protein C synthesis (typically, acute insults to the liver such as right heart failure with hepatic congestion, severe liver disease, or disseminated intravascular coagulation [DIC]) [6,22]. Protein C levels are also generally lower than normal in the setting of acute inflammation, which may explain reduced levels in trauma/surgery or acute respiratory distress syndrome. There is little evidence that acute thrombosis by itself lowers protein C levels. As noted above, neonates have lower-than-normal levels of protein C, and protein C levels increase modestly during normal aging. (See 'Biology of protein C' above.)
●DIC – Patients with DIC have ongoing consumption of coagulation factors and natural anticoagulants.
●Liver disease – Patients with severe liver disease have reduced circulating levels of all of the natural anticoagulants produced by the liver, including protein C [23]. However, these changes are counterbalanced by corresponding changes in procoagulant factors, leading to a state of "rebalanced" hemostasis. (See "Hemostatic abnormalities in patients with liver disease".)
●Infection – Protein C levels are not generally affected by infection. However, a particularly severe form of acquired protein C deficiency has been described in certain patients with acute viral, bacterial, and other infections (eg, malaria) [24]. Meningococcemia is probably the best characterized of these [25,26]. In these cases administration of protein C concentrate may be helpful, similar to the management of neonatal purpura fulminans [25,27,28]. (See "Neonatal thrombosis: Management and outcome", section on 'Neonatal purpura fulminans'.)
●Uremia – Most uremic patients have low levels of protein C anticoagulant activity despite normal levels of protein C amidolytic activity and protein levels [29]. This is thought to be due to a dialyzable substance in uremic plasma that interferes with most clotting assays for protein C activity [29].
●Cancer or cancer therapy – A syndrome of venous limb ischemia with gangrene has been described in 10 patients with cancer who were treated with warfarin [30]. The affected individuals had evidence of reduced coagulation factor VII and protein C activity.
Some cancer chemotherapeutic agents such as asparaginase cause reductions in protein C levels. Hormonal agents have also been reported to alter protein C levels, though studies are less consistent with respect to the observed effects.
●Vitamin K antagonists – Vitamin K antagonist (VKA) anticoagulants (eg, warfarin) interfere with protein C production and maturation, as well as protein S. This has implications for diagnostic testing and patient management:
•Diagnostic testing – Testing for protein C deficiency generally should not be performed if the patient is receiving a VKA anticoagulant, regardless of the type of assay. (See 'Timing/effects of anticoagulants' below.)
•Management – The reduction of protein C levels by warfarin produces a transient procoagulant state, since protein C has a shorter half-life than the other vitamin K-dependent factors (except for factor VII) and thus is depleted more rapidly. This is of no clinical consequence to the vast majority of patients. However, it is responsible for the increased risk of the rare complication of warfarin-induced skin necrosis in individuals with hereditary protein C deficiency; this provides the rationale for administration of a source of protein C (either with Fresh Frozen Plasma [FFP] or protein C concentrate) to patients suspected of having this thrombotic complication. (See 'Management' below.)
In contrast to reduced protein C levels with vitamin K antagonists, other anticoagulants such as heparin, direct thrombin inhibitors, direct oral factor Xa inhibitors, and fondaparinux do not affect circulating protein C levels. However, as noted below, the direct oral anticoagulants may interfere in assays for protein C activity with clotting endpoints. (See 'Timing/effects of anticoagulants' below.)
●Vitamin K deficiency – Patients with vitamin K deficiency have a defect that resembles the use of a VKA anticoagulant. Common causes of deficiency include severe malnutrition and antibiotic use. (See "Overview of vitamin K", section on 'Vitamin K deficiency'.)
●Autoantibodies – A case of an acquired inhibitor of protein C has been reported in an Australian patient [31]. This individual had a bleeding diathesis for several years and developed purpura fulminans before his death. Autopsy revealed arterial and venous thrombi in many organs. The IgG fraction of the patient's plasma completely inhibited the functional anticoagulant activity of activated protein C.
Although these conditions can transiently reduce protein C levels, the reduction is typically modest, and these patients generally should not be considered to have protein C deficiency for diagnostic or therapeutic purposes (ie, we do not consider them to be in the same category as individuals with inherited protein C deficiency with respect to their risk of thrombosis). An exception is a patient with severe clinical manifestations such as purpura fulminans and DIC in acute meningococcemia; in such cases administration of protein C concentrate may be beneficial. (See "Neonatal thrombosis: Management and outcome", section on 'Neonatal purpura fulminans'.)
Despite the reduced levels of protein C seen in acute inflammatory states, administration of activated protein C was shown to be ineffective for the treatment of sepsis, as discussed separately. (See "Investigational and ineffective therapies for sepsis".)
Causes of increased protein C — Protein C levels may be increased in the following settings; these increases generally do not affect patient management but are worth noting if the level is slightly above the threshold for deficiency:
●Nephrotic syndrome – Patients with nephrotic syndrome often have elevated levels of protein C [32-34]. It appears the hypercoagulable state is due to effects on other hemostatic factors. (See "Hypercoagulability in nephrotic syndrome".)
●Hyperlipidemia – Patients with hyperlipidemia may have increased protein C levels. In one study of 150 adults, mean levels of protein C activity rose approximately 25 percent as total cholesterol and triglyceride levels increased from the 5th to the 95th percentile [35].
●Normal aging – Normal aging is associated with modest increases in protein C levels (by approximately 4 percent per decade).
EPIDEMIOLOGY — The incidence of inherited protein C deficiency varies depending on the population (table 1):
●Healthy individuals in the general population – Approximately 0.2 to 0.5 percent [9,36].
●Individuals with venous thromboembolism (VTE) – Approximately 2 to 5 percent [37-39].
Data from which these incidence numbers were derived include the following:
●General healthy population – In two series of healthy adults (eg, blood donors, volunteers), protein C deficiency was documented in 10 of 5422 (0.18 percent; 1 in 555) and in 14 of 9854 (0.14 percent; 1 in 714) [9,36]. Both studies noted that there is not a strict cutoff between heterozygotes and unaffected individuals, so the true number of heterozygotes could be higher or lower. Additionally, the larger study noted that protein C levels fluctuated over time and between readings such that individuals with borderline levels sometimes met criteria for protein C deficiency and sometimes did not [36]. None of the protein C-deficient individuals identified by population screening had a clinical history of VTE. Also of note, some of the individuals with true protein C deficiency in the larger study had genetic testing and family studies performed and were identified as the index case of a new genetic defect [36].
●Patients with VTE – In a series of 2132 consecutive individuals presenting with VTE in Spain, 68 (3.2 percent) had protein C deficiency [37]. In another series of 277 outpatients who presented with an acute VTE, nine (3.3 percent) had protein C deficiency [39]. In both of these series, protein C deficiency was more common than antithrombin (AT) deficiency; protein C deficiency was slightly more common than protein S deficiency in one and slightly less common than protein S deficiency in the other. The frequency of the factor V Leiden mutation in these cohorts, which is now known to be much more common than these deficiencies, was not evaluated.
CLINICAL FEATURES — There is considerable phenotypic variability among individuals with protein C deficiency with respect to the development of symptomatic venous thrombosis. The overall relative risk of thrombosis with heterozygous protein C deficiency is approximately seven times that of individuals without an inherited thrombophilia (table 1) [40,41]. It has also been suggested that there is an association of protein C deficiency with arterial thromboembolism (eg, stroke).
Venous thromboembolism — Individuals with protein C deficiency can develop venous thromboembolism (VTE) at any site; thrombosis in the deep veins of the leg (DVT), mesenteric veins, and pulmonary embolism (PE) are the most common. VTE can also affect other sites including cerebral veins, portal vein, superficial or other unusual sites [40,42-44]. As noted above, the risk of thrombosis with heterozygous protein C deficiency is increased approximately seven-fold (table 1) [40,41].
The absolute risk of VTE in a patient with protein C deficiency is difficult to estimate because other modifying factors also contribute to risk; family history of VTE or other clinical events is the best predictor. Among thrombophilic families, the risk of thrombosis in individuals with protein C deficiency is similar to that of protein S deficiency and antithrombin (AT) deficiency (approximately 1 thrombosis per 100 patient-years), and higher than individuals with the factor V Leiden mutation (approximately 0.3 thromboses per 100 patient-years) [40].
●The absolute risk of VTE in individuals with a positive family history may be as high as 75 percent in severely affected families and closer to 30 percent in other families [40,42,45,46]. In a series that included 46 protein C-deficient individuals, there were 13 thromboses (28 percent), compared with five thromboses in 138 unaffected relatives (4 percent) [47].
●Regardless of family history, the risk of VTE in individuals with protein C deficiency is expected to be increased by additional inherited or acquired VTE risk factors (eg, factor V Leiden mutation, prolonged immobility, surgery, oral hormonal contraceptive use) [44,48-50]. In one series that included 15 individuals with protein C deficiency, six (40 percent) also had the factor V Leiden mutation, a higher proportion than would be expected in the general population [49]. Compared with the individuals with isolated protein C deficiency, those with combined protein C deficiency and factor V Leiden mutation had an earlier onset of thrombosis (mean age of onset, 32 versus 18 years) and a greater risk of thrombosis. Other uncharacterized genetic modifiers may also increase VTE risk.
●The initial episode of VTE in patients with protein C deficiency is apparently spontaneous in approximately two-thirds of cases, and the remaining third have the usual risk factors (eg, pregnancy, parturition, oral contraceptives, surgery, or trauma). In a series of 22 patients with protein C deficiency, 15 (68 percent) had a history of VTE.
●The age of a first thromboembolic event can be in young adulthood. Individuals with a positive family history are more likely to have a first VTE in their 20s to 30s, while individuals without a family history of thrombophilia are more likely to have a first VTE in their 30s to 40s [49,51].
●The risk of recurrent thrombosis depends on the clinical setting but is thought to be approximately 60 percent in patients from thrombophilic families without prophylactic anticoagulation [52].
Warfarin-induced skin necrosis — Warfarin-induced skin necrosis is a complication of warfarin therapy in which the patient develops demarcated areas of purpura and necrosis due to vascular occlusion. The appearance may be similar to that of neonatal purpura fulminans and may affect one or more areas of skin including the extremities, breasts, trunk, or penis (picture 1 and picture 2 and picture 3).
The mechanism of warfarin-induced skin necrosis involves a transient hypercoagulable state during initial warfarin administration that in turn leads to vascular occlusion and tissue infarction followed by extravasation of blood. (See "Approach to the patient with retiform (angulated) purpura", section on 'Thrombotic and coagulopathic disorders'.)
The half-lives vary among the vitamin K-dependent coagulation factors (factors II, VII, IX, and X) and natural anticoagulants (protein S and protein C), and as a result, the factors with the shorter half-lives (half-lives for factor VII and protein C of 8 and 14 hours, respectively) are depleted more rapidly than the others (figure 2) [53]. Laboratory studies of thrombin generation using an assay for the activation of prothrombin using the generation of fragment F1+2 have suggested that effects on protein C (ie, a procoagulant effect) predominate over effects on factor VII in vivo [54].
The skin lesions in warfarin-induced skin necrosis typically form during the first few days of warfarin therapy, often in the setting of large loading doses of 10 or more milligrams of warfarin per day [55-57]. If the patient is receiving heparin and warfarin therapy, the lesions may appear upon discontinuation of the heparin [58]. Lesions appear in the absence of heparin because the early effect of warfarin is procoagulant.
The lesions typically marginate over a period of hours from an initial central erythematous macule, similar to neonatal purpura fulminans. If a product containing protein C is not rapidly administered, the affected cutaneous areas become edematous, develop central purpuric zones, and ultimately become necrotic. Biopsy of the lesions is not generally performed, but if a biopsy is obtained it may show diffuse microthrombi within dermal and subcutaneous capillaries, venules, and deep veins, with endothelial cell damage, resulting in ischemic skin necrosis and marked red blood cell extravasation [59]. These findings are indistinguishable from other thrombotic skin lesions including antiphospholipid syndrome (APS), disseminated intravascular coagulation (DIC), and heparin-induced thrombocytopenia (HIT).
The incidence of warfarin-induced skin necrosis in individuals with protein C deficiency is unknown, as most descriptions are in the form of case reports. Warfarin-induced skin necrosis is not pathognomonic for protein C deficiency; it has been described in individuals with other inherited thrombophilias (factor V Leiden mutation, protein S deficiency) and transient reductions of protein C levels (eg, in the setting of cancer) (see 'Causes of reduced protein C' above) [60-62].
As noted, immediate interventions should include the discontinuation of warfarin and the administration of intravenous vitamin K to reverse warfarin as well as a source of protein C (either Fresh Frozen Plasma [FFP] or protein C concentrate) in order to minimize the extent of skin necrosis. (See 'Management' below.)
Neonatal purpura fulminans — Purpura fulminans in newborns is a rare, life-threatening condition characterized by disseminated intravascular coagulation (DIC), extensive venous and arterial thrombosis, and hemorrhagic skin necrosis. It usually is caused by a homozygous or compound heterozygous deficiency in protein C, as discussed above (see 'Genetics' above). Laboratory testing reveals evidence of disseminated intravascular coagulation and extremely low protein C levels of under 1 percent of normal. Diagnosis and management of this disorder, including the use of protein C concentrate, are discussed in detail separately. (See "Neonatal thrombosis: Clinical features and diagnosis", section on 'Purpura fulminans' and "Neonatal thrombosis: Management and outcome", section on 'Neonatal purpura fulminans'.)
Arterial thrombosis/stroke — The risk of arterial thrombosis in patients with protein C deficiency may be increased slightly, but high quality data are lacking to support or refute an association. Ischemic stroke has been reported in young adults (heterozygotes) with hereditary protein C deficiency [63-65]. It is difficult to establish whether the rate of stroke is actually increased in individuals with protein C deficiency. Larger studies have not convincingly demonstrated that protein C deficiency is a risk factor for the development of arterial thrombosis [66-68]. In one series, for example, antithrombin, protein C, and protein S levels were measured in 127 consecutive patients with a mean age of 34 years admitted for an ischemic stroke [66]. Abnormal anticoagulant protein levels were found in nine patients. However, seven of these patients had an acquired cause of deficiency, such as pregnancy or estrogen administration, and the other two patients had transiently low levels in the absence of an obvious acquired cause.
Fetal loss — Protein C deficiency has been linked to fetal loss, but thrombophilia is not thought to be a major factor in most adverse pregnancy outcomes (miscarriage, fetal loss, preeclampsia, fetal growth impairment) [69-71]. (See "Inherited thrombophilias in pregnancy", section on 'Adverse pregnancy outcome risk'.)
In a report from the European Prospective Cohort on Thrombophilia that compared pregnancies in 843 women with thrombophilia and 541 controls (unaffected partners of men in the cohort), the risk of fetal loss (miscarriage or stillbirth) was slightly increased in the thrombophilic women (odds ratio [OR] 1.35; 95% CI 1.01-1.82) [69]. The highest risk for stillbirth was in women with more than one thrombophilic defect. For the 162 women in this cohort with protein C deficiency, the numbers were too small to reach statistical significance (OR 1.4; 95% CI 0.9-2.2). The role (or lack thereof) of prophylactic anticoagulation to prevent pregnancy complications, as well as increased fetal surveillance and timing of delivery, are discussed separately. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of pregnancy complications'.)
However, it is important to note that pregnancy increases the risk of VTE due to a number of physiologic and anatomic changes, and prophylactic anticoagulation during pregnancy and the postpartum period to reduce the risk of VTE is appropriate for certain individuals with protein C deficiency. This subject is discussed in detail separately. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE' and "Use of anticoagulants during pregnancy and postpartum".)
DIAGNOSTIC EVALUATION
Overview of diagnosis — The diagnosis of protein C deficiency may be suspected in a patient with recurrent venous thrombosis, thrombosis in an unusual vascular bed (eg, portal, hepatic, mesenteric, cerebral), thrombosis at a young age (eg, <50 years), strong family history of venous thromboembolism (VTE), and/or warfarin-induced skin necrosis.
The diagnosis of protein C deficiency is established by documenting low protein C levels. In most cases, levels are approximately 50 percent of normal. However, the absolute threshold for deficiency is not clear. In a series of 28 individuals identified as members of a protein C-deficient family for whom pedigree analysis established that they personally inherited the familial defect, the range of protein C values was wide (median activity level 53 percent, range 19 to 82 percent; median antigen level 54 percent, range 22 to 89 percent) [72]. Most laboratories set the threshold for deficiency below 65 to 70 percent of normal [47]. (Related Lab Interpretation Monograph(s): "Low protein C in adults".)
Individuals with a protein C level below 55 percent of normal are very likely to have a genetic abnormality, while levels from 55 to 65 percent are consistent with either a deficiency state or the lower end of the normal distribution [9].
Measures to improve the usefulness and accuracy of laboratory testing include the following:
●Testing ideally should be done after the patient has recovered from an acute event such a severe inflammatory illness. If the result was obtained at the time of one of these events, it is prudent to repeat the testing. (See 'Causes of reduced protein C' above.)
●The possible interference from an anticoagulant, especially warfarin, should be taken into account when ordering protein C testing, based on the medication list and the patient’s prothrombin time (PT) and international normalized ratio (INR). (See 'Assays' below and 'Timing/effects of anticoagulants' below.)
●Age-appropriate and laboratory-specific normal values should be consulted for infants and young children because protein C levels are lower at birth and take time to reach adult levels. (See 'Biology of protein C' above.)
In contrast to patients with a personal or family history of VTE before age 50, we do not routinely suspect protein C deficiency in an individual ≥50 years of age with a first episode of VTE in a typical location (eg, deep vein of the leg, pulmonary embolism) unless there is a strong family history of thrombophilia.
Assays — A variety of assay methods has been developed to measure protein C activity or protein levels in plasma samples. The preferred method is a functional assay, because a functional assay will detect reduced protein levels as well as defective protein C function with normal protein levels (type I and type II defects). (See 'Genetics' above.)
●Available functional assays for protein C include an aPTT-based assay, a factor Xa-based assay, or an enzymatic assay using a chromogenic substrate (eg, amidolytic cleavage of a synthetic peptide substrate). The venom of a copperhead snake Agkistrodon contortrix (Protac) is used to activate protein C, although other activators such as thrombin or thrombin-thrombomodulin have also been used [53,73,74]. Amidolytic assays are frequently preferred by hospital laboratories because they have better performance characteristics than clotting assays.
●The procedures for protein C antigen determination include various types of immunoassays [75]. The use of such assays will assist in characterizing patients as having a type I (reduced protein level and function) or type II (normal protein level, reduced function) defect; however, as noted above, this is not necessary for clinical management. (See 'Genetics' above.)
As a general rule, the clotting-based assays (aPTT or factor Xa-based) may be affected by anticoagulants including heparins, whereas the chromogenic assays generally are unaffected by anticoagulants, with the exception of vitamin K antagonists, which can lower activity in any assay. Clotting-based assays may occasionally identify a type II defect that was missed by an amidolytic assay. (See 'Timing/effects of anticoagulants' below.)
As with all coagulation testing, the test must be done using plasma (not serum). (See "Clinical use of coagulation tests", section on 'Ensuring accuracy'.)
If a functional assay does not reveal reduced protein function but clinical suspicion is extremely high, it may be worthwhile to use an alternative type of functional assay.
●Several individuals have been described with normal protein C antigen measurements who have substantial reductions in protein C anticoagulant activity, but normal or near normal amidolytic activity [53]. These defects may reflect a reduced ability of activated protein C to interact with platelet membranes or its substrates such as factor V and factor VIII. The molecular abnormality in one of these families has been determined and is characterized by two gamma-carboxyglutamic acid (Gla) domain mutations (Glu20 to Ala and Val34 to Met) [76]. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid", section on 'Function of gamma-carboxyglutamic acid'.)
●Other patients have abnormal protein C molecules that are normally activated by the thrombin-thrombomodulin complex, but fail to exhibit proteolytic activity as measured by amidolytic or anticoagulant assays [77,78]. These patients may have mutations near the active site of the protein.
Timing/effects of anticoagulants — As noted above, an important consideration in laboratory testing for protein C deficiency is the possibility of erroneous diagnosis due to interference of an anticoagulant or an acute thrombosis or other illness. (See 'Overview of diagnosis' above.)
●Warfarin – Warfarin (or other vitamin K antagonist [VKA]) reduces functional and, to a lesser extent, antigenic measures of protein C [45,53,73,79,80]. In practice, it is preferable to perform testing at least two weeks after the last dose of the VKA. If it is not possible to discontinue the VKA for clinical reasons, it may be possible to transition the patient to heparin or low molecular weight (LMW) heparin prior to testing. However, if the protein C level is tested and found to be normal during warfarin therapy, this effectively excludes protein C deficiency.
●Heparins – Heparins (unfractionated or LMW) may interfere with clotting-based protein C assays.
●Fondaparinux – Fondaparinux may interfere with clotting-based protein C assays.
●Direct thrombin inhibitors – Direct thrombin inhibitors (DTIs; eg, argatroban, dabigatran) do not cause abnormal results of functional assays using snake venom to activate protein C and a chromogenic substrate to measure enzymatic activity. However, DTIs may interfere with functional assays using a clotting-based endpoint (eg, aPTT-based assays). DTIs do not interfere with antigenic assays of protein C.
●Direct factor Xa inhibitors – Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) do not cause abnormal results of functional assays using snake venom to activate protein C and a chromogenic substrate to measure enzymatic activity. However, these agents may interfere with functional assays using a clotting-based endpoint (eg, aPTT-based assays). These agents do not interfere with antigenic assays of protein C.
Consultation with the testing laboratory regarding the types of tests used (and available alternatives) is advised.
Several research laboratories have used a reduced ratio of protein C antigen to prothrombin or factor X antigen to identify patients with a type I deficiency state [45,80]. However, this approach can only be used in individuals who are in a stable phase of anticoagulation, and the diagnostic criteria for the disorder vary with the intensity of warfarin therapy [80]. Other groups have successfully used protein C activity assays in conjunction with functional and antigenic measurements of factor VII, a vitamin K-dependent factor with a similar plasma half-life to protein C [81-83].
Genetic testing — Genetic testing for mutations and other defects in the PROC gene, which encodes protein C, is not available for routine clinical use. A listing of research laboratories that perform this testing is available through the Genetic Testing Registry.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of venous thromboembolism (VTE) includes other inherited thrombophilias and acquired risk factors for thrombosis. The differential diagnosis of skin necrosis includes vascular lesions and heparin-induced thrombocytopenia (HIT).
●Other inherited thrombophilias – Other inherited thrombophilias include factor V Leiden mutation, protein S deficiency, antithrombin (AT) deficiency, and prothrombin G20210A mutation (table 1); of these, factor V Leiden is the most common. Like protein C deficiency, patients may present with a positive personal or family history of VTE, warfarin-induced skin necrosis, or other thromboembolic complications and often are treated with indefinite anticoagulation if one of these clinical events occurs. Unlike protein C deficiency, individuals with these other inherited thrombophilias will have laboratory evidence of the other specific defect and will have normal protein C levels, unless tested in the setting of acute illness or interfering anticoagulant. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)
●Acquired VTE risk factors – A number of acquired risk factors for VTE have been described, including immobility, surgery, trauma, cancer or myeloproliferative neoplasms (MPN), certain drugs, the antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria (PNH), disseminated intravascular coagulation (DIC), and hormonal changes including hormonal contraceptives, pregnancy, and the postpartum period. Like protein C deficiency, these patients may have VTE in typical or atypical locations. Unlike protein C deficiency, these acquired risk factors are often obvious from other features of the patient history and physical examination, and the family history typically does not reveal thrombophilia in these acquired disorders. (See "Overview of the causes of venous thrombosis", section on 'Acquired risk factors'.)
●Other causes of skin necrosis – Skin necrosis (or a similar-appearing finding) can occur in the setting of a number of vascular lesions including cryoglobulinemia, vasculitis, septic or cholesterol emboli, levamisole-contaminated cocaine, and calciphylaxis; or with other anticoagulants such as heparin. Like protein C deficiency, these other disorders may occur in a hospitalized patient who may be receiving an anticoagulant and may be associated with dramatic and life-threatening infarction in the skin and internal organs. Unlike patients with protein C deficiency, individuals with other forms of skin necrosis often have other findings of vasculitis or other clinical or skin biopsy findings of vascular inflammation, organ damage, or infection. Unlike patients with protein C deficiency, individuals with HIT usually have thrombocytopenia and a clear temporal relationship with heparin exposure, and individuals with calciphylaxis typically have end-stage kidney disease and bilateral skin findings in the upper extremities. (See "Approach to the patient with retiform (angulated) purpura" and "Calciphylaxis (calcific uremic arteriolopathy)" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)
MANAGEMENT
Thromboembolism management — Anticoagulation is appropriate for individuals with protein C deficiency who develop a thromboembolic event (algorithm 1). Management is similar to other individuals with a thromboembolism, with the possible exception of measures to reduce the risk of warfarin-induced skin necrosis. These measures may include the use of an anticoagulant other than warfarin, judicious use of warfarin with a lower-than-average starting dose, and/or longer duration of overlapping heparin/low molecular weight (LMW) heparin administration. (See 'Warfarin-induced skin necrosis (management and prevention)' below.)
The choice between a direct oral anticoagulant (DOAC) versus warfarin is individualized based on a number of factors including the severity of thrombosis, patient preference, adherence to therapy, and potential drug and dietary interactions. We are more likely to use a DOAC for individuals with typical venous thromboembolism (VTE) presentations, and we are more likely to use LMW heparin for an extended period or warfarin for individuals with concerns about adherence or severe clinical presentations such as hypoxemia/shock or proximal deep vein thrombosis (DVT) with an extensive clot burden.
The duration of anticoagulation is individualized according to the age of the patient, site and clinical significance of the thromboembolism, and whether the thromboembolism was provoked or unprovoked. Indefinite anticoagulation is recommended for many patients with an unprovoked thromboembolic event, regardless of whether an inherited thrombophilia is identified; the documentation of protein C deficiency may strengthen the case for indefinite anticoagulation particularly if there is a strong family history of VTE. Factors to consider in deciding on the duration of anticoagulation are discussed in more detail separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)
If it is decided to use a DOAC for the long-term prevention of recurrent VTE, we generally continue a higher dose regimen (eg, rivaroxaban 20 mg once daily or apixaban 5 mg twice daily rather than rivaroxaban 10 mg once daily or apixaban 2.5 mg twice daily), assuming the individual's bleeding risk is not excessive. This is because protein C deficiency is one of the more thrombophilic of the hereditary thrombophilias. The prescribing physician and patient should understand that evidence for the optimal dose in such patients is lacking.
Warfarin-induced skin necrosis (management and prevention) — As noted above, warfarin-induced skin necrosis is a potential complication of warfarin therapy in patients with protein C deficiency caused by transient hypercoagulability during warfarin initiation. (See 'Warfarin-induced skin necrosis' above.)
●Acute treatment – It is important to establish that skin necrosis is due to protein C deficiency rather than another cause such as vasculitis, calciphylaxis, or heparin-induced thrombocytopenia (HIT) (see 'Differential diagnosis' above). In patients with known protein C deficiency (or a known family history of protein C deficiency) and skin necrosis, a presumptive diagnosis of warfarin-induced skin necrosis can be made while protein C levels are being obtained. In patients without a known personal or family history of protein C deficiency, consultation with a specialist with expertise in thrombophilia may help in determining the likelihood of protein C deficiency.
Once the diagnosis is made, immediate intervention is required to prevent rapid progression and to minimize complications. The following should be done without delay:
•Discontinue warfarin.
•Administer vitamin K intravenously.
•Administer unfractionated heparin (therapeutic dose) (see "Heparin and LMW heparin: Dosing and adverse effects").
•Administer a source of protein C such as protein C concentrate (eg, Ceprotin, not available in all centers) or Fresh Frozen Plasma (FFP) [84,85]. The required volume of FFP may be great depending on the patient’s baseline protein C activity level.
In some cases, skin lesions may continue to progress despite these interventions due to tissue infarction. The therapies should be continued; involvement of a dermatologist and/or surgeon may also be required.
●Prevention – Patients with protein C deficiency who require an anticoagulant have several options for reducing the risk of warfarin-induced skin necrosis. Interventions may be individualized depending on clinical factors and patient values and preferences. If warfarin is administered, it should be started at a low dose (eg, 2 mg daily for the first three days followed by gradually increasing increments of an additional 2 to 3 mg until therapeutic anticoagulation is achieved).
Additional options include:
•Use of an anticoagulant other than warfarin (eg, a DOAC such as dabigatran, rivaroxaban, apixaban, or edoxaban)
•Overlapping of heparin with warfarin during the first several days of warfarin administration
●Retreatment with warfarin – Patients with a history of warfarin-induced skin necrosis have been successfully retreated with warfarin after an episode of warfarin-induced skin necrosis; in such cases, protein C concentrate should be used until a stable level of anticoagulation is established [56,86]. However, use of a DOAC would circumvent these issues. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)
Of note, protein C concentrate is different from recombinant activated protein C, a product that was tested and found to be ineffective in the treatment of sepsis. As discussed below, prophylactic protein C concentrate may also be appropriate for prophylaxis in other settings (eg, perioperative, peripartum) in especially high-risk individuals. Additional information about protein C concentrate is provided separately. (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Protein C'.)
Neonatal purpura fulminans management — This subject is discussed separately. (See "Neonatal thrombosis: Management and outcome", section on 'Neonatal purpura fulminans'.)
Patients without thrombosis (eg, obstetrical/surgical management) — Individuals with protein C deficiency who have not had a thromboembolic event may benefit from avoiding conditions that increase thrombotic risk (eg, estrogen-containing contraceptives, prolonged immobility) and from the judicious use of prophylactic anticoagulation in certain settings (algorithm 1). In addition, some individuals with an especially high risk of thrombosis (eg, individuals with severe thrombotic phenotypes, homozygosity for a protein C defect) may be treated with prophylactic protein C concentrate (Ceprotin) around the time of surgery or delivery. Close consultation with a specialist who has expertise in the management of inherited thrombophilias is advised.
Recommendations for alternative contraceptives and for anticoagulation in high-risk settings are presented in separate topic reviews:
●Contraception – (See "Contraception: Counseling for women with inherited thrombophilias".)
●Pregnancy – (See "Inherited thrombophilias in pregnancy", section on 'Adverse pregnancy outcome risk'.)
●Surgery – Protein C deficiency confers three points on the modified Caprini score (table 2). (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
●Acute medical illness – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
Testing of first degree relatives — The testing of asymptomatic first degree relatives can be delayed until after puberty and is generally most helpful in settings in which the risk of thrombosis is increased, such as initiation of oral hormonal contraceptives or pregnancy. This subject is discussed in more detail separately. (See "Screening for inherited thrombophilia in asymptomatic adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)
SUMMARY AND RECOMMENDATIONS
●Causes – Protein C is a vitamin K-dependent anticoagulant protein synthesized in the liver. Upon activation, protein C inactivates coagulation factors Va and VIIIa, which are necessary for thrombin generation and factor X activation (figure 1). Most patients with inherited protein C deficiency are heterozygous for a genetic defect that reduces protein C levels, activity, or both (ie, transmission is autosomal dominant). A number of acquired conditions also can reduce protein C levels, including disseminated intravascular coagulation (DIC), liver disease, vitamin K antagonist (VKA) anticoagulants, meningococcal infection, and others. (See 'Pathophysiology' above.)
●Prevalence – The prevalence of inherited protein C deficiency is approximately 0.2 to 0.5 percent in the general population and 2 to 5 percent in individuals with venous thromboembolism (VTE) (table 1). (See 'Epidemiology' above.)
●Presentation – Individuals with hereditary protein C deficiency lack the natural anticoagulant function of activated protein C and are at risk for clinical phenotypes associated with increased thrombotic risk including VTE, warfarin-induced skin necrosis, and (in homozygotes) neonatal purpura fulminans. There may also be an association with stroke although this risk is likely to be small. Individuals identified by population screening may have no other clinical manifestations besides low protein C activity levels. (See 'Clinical features' above.)
●Diagnosis – The diagnosis of protein C deficiency may be suspected in a patient with recurrent venous thrombosis, thrombosis in an unusual vascular bed (eg, portal, hepatic, mesenteric, cerebral), thrombosis at a young age (eg, <50 years), strong family history of VTE, and/or warfarin-induced skin necrosis. The diagnosis is established by laboratory testing that reveals protein C activity below the lower limit of normal in the laboratory performing the testing. Typical values in heterozygotes are approximately 50 percent of normal. A number of assays are available; none of the available assays will be accurate during warfarin therapy, and some clotting-based assays may also be affected by other anticoagulants. Consultation with the testing laboratory may be advisable. (See 'Diagnostic evaluation' above.)
Appropriate settings in which to test for protein C deficiency are presented separately:
•Children – (See "Thrombophilia testing in children and adolescents".)
•Pregnancy – (See "Inherited thrombophilias in pregnancy".)
•Patients with VTE – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)
•Patients with stroke – (See "Overview of the evaluation of stroke", section on 'Blood tests'.)
•Patients without thrombosis – (See "Screening for inherited thrombophilia in asymptomatic adults".)
●Differential diagnosis – The differential diagnosis of protein C deficiency includes other inherited and acquired thrombophilias and other causes of skin necrosis such as vasculitis and heparin-induced thrombocytopenia. (See 'Differential diagnosis' above.)
●Treatment
•VTE – Anticoagulation is appropriate for individuals with protein C deficiency who develop a thromboembolic event, similar to all patients with a thrombosis; this should be continued indefinitely in most patients with an unprovoked VTE unless there is a reason not to do so (algorithm 1). The choice between a direct oral anticoagulant (DOAC) versus warfarin is based on a number of factors including the severity of thrombosis, patient preference, adherence to therapy, and potential drug and dietary interactions. (See 'Thromboembolism management' above and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)
•Skin necrosis – For warfarin-induced skin necrosis, immediate intervention is required to prevent rapid progression and to minimize complications. Warfarin should be discontinued, vitamin K and therapeutic heparin anticoagulation administered, and protein C concentrate or Fresh Frozen Plasma (FFP) given. Options for prevention include use of an alternative anticoagulant, heparin coverage, or protein C concentrate prophylaxis. (See 'Warfarin-induced skin necrosis (management and prevention)' above.)
•Purpura fulminans – Management of neonatal purpura fulminans is presented separately. (See "Neonatal thrombosis: Management and outcome", section on 'Neonatal purpura fulminans'.)
●Prevention – Patients without a personal history of thrombosis may benefit from avoiding conditions that increase thrombotic risk and from the judicious use of prophylactic anticoagulation in certain settings (algorithm 1). In addition, some individuals with an especially high risk of thrombosis may be treated with prophylactic protein C concentrate perioperatively and in the peripartum period. Close consultation with a specialist who has expertise in the management of inherited thrombophilias is advised. (See 'Patients without thrombosis (eg, obstetrical/surgical management)' above.)
