AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Protein C deficiency, a deficiency of the anticoagulant protein C, is associated with a variably increased risk of thrombosis. In the rare inherited homozygous or compound heterozygous state, protein C deficiency is associated with severe life-threatening neonatal purpura fulminans or massive venous thrombosis. The inherited heterozygous state of protein C deficiency most frequently is associated with deep venous thrombosis of the lower limb but also may manifest in other venous locations. A significant percentage of patients with protein C deficiency remain asymptomatic. A family history is essential in assessing the association of a patient's deficiency with the patient's risk of thrombotic disease. Acquired protein C deficiency occurs in certain clinical scenarios, but this most often is associated with a transient predisposing factor.

Protein C is a 62-kD glycoprotein, synthesized in the liver as a zymogen, which circulates in the blood at a concentration of 4 mcg/mL. Activation of protein C requires conversion of the single-chain zymogen into a 2-chain serine-protease–like enzyme required for catalytic activity. Physiologically, this activation occurs on phospholipid cell surfaces by the action of thrombin when bound to the endothelial cell proteoglycan, thrombomodulin.

Additionally, endothelial cell protein C receptor, primarily located in major blood vessels, augments thrombin/thrombomodulin activity. Once activated, activated protein C (APC) binds to the cell-surface–bound anticoagulant cofactor, protein S. The APC/protein S complex then proteolyses activated procoagulant cofactors factor VIII and factor V, thereby retarding fibrin formation by preventing activation of procoagulant proteins, factor X and prothrombin.

Pathophysiology

The hemostatic system is comprised of multiple procoagulant and anticoagulant plasma proteins that interact with platelets, along with cellular phospholipids to promote physiological coagulation. The formation of a fibrin clot depends on thrombin generation, the key regulator in the hemostatic process. Protein C inhibits thrombin generation through its proteolysis of key cofactors required in procoagulant enzymatic complexes.

Anticoagulant proteins are particularly important in areas where there may be prolonged exposure of procoagulant factors and platelet phospholipids to the vessel wall, which predisposes to thrombotic disease, largely due to this prolonged exposure. Deficiencies of anticoagulant proteins thus place a patient at increased risk for thrombosis in the slowly flowing venous circulation. In the rapidly flowing arterial circulation, laminar flow largely prevents prolonged interaction between platelets and vessel walls. However, occasional reports of protein C deficiency document an increased incidence of arterial thrombosis, particularly in pediatric patients.

Protein C also plays profibrinolytic, anti-inflammatory, and anti-ischemic roles. Additionally, in patients with severe sepsis, a decrease in the generation of APC contributes to the dysregulation of physiological clot formation.

Frequency

United States

The frequency in the United States is similar to that found internationally.

International

Incidence of protein C deficiency by plasma levels alone is between 1 in 200 and 1 in 500 persons in the general asymptomatic population. Incidence of symptomatic protein C deficiency is approximately 1 in 16,000 to 1 in 32,000 persons. Frequency of protein C deficiency in patients with hypercoagulability and venous thrombosis is approximately 5%. Incidence of severe protein C deficiency occurs in approximately 1 in 500,000 to 1 in 750,000 live births.

Mortality/Morbidity

Despite the morbidity of thrombosis associated with homozygous protein C deficiency, overall mortality in families with heterozygous protein C deficiency is similar to that of the general population. Morbidity in protein C deficiency greatly increases with advancing age, when patients are at greater risk for thrombotic events.

• Deep venous thrombosis is the most common symptomatic manifestation of protein C deficiency. Pulmonary embolism and postphlebitic syndrome may occur subsequent to deep venous thrombosis. Mortality in protein C deficiency most often is due to pulmonary embolism subsequent to deep venous thrombosis.
• Morbidity and mortality in homozygous or compound heterozygous protein C deficiency include neonatal purpura fulminans and massive thrombosis. Blindness secondary to vitreous hemorrhages may occur in patients with these severe conditions. Morbidity and mortality in acquired protein C deficiency usually are related to the inciting agent of the deficiency. However, treatment of the acquired protein C deficiency can greatly aid other therapeutic measures.
• Complications secondary to anticoagulant therapy also represent a significant cause of both morbidity and mortality. Anticoagulation exposes the individual to significant risk of major and/or fatal hemorrhage. Warfarin-induced skin necrosis may occur in protein C deficiency subsequent to initiation of oral anticoagulant therapy. Precautions can be taken by administering heparin prior to or concomitantly with oral anticoagulants.

Race

Protein C deficiency is recognized as a significant cause of thrombophilia in most populations. However, APC resistance, briefly discussed in Lab Studies, is very frequent in whites (incidence of approximately 5%) but rare in Asian and African populations (incidence of <1%).

Sex

Incidence of protein C deficiency is similar in men and women. However, pregnancy and postpartum periods increase the risk of thrombosis in patients with protein C deficiency, although the protein C levels are not further decreased during these times.

Age

The median age of onset of thrombosis in heterozygous protein C deficiency is 30-40 years. Homozygous or compound heterozygous deficiency usually manifests several hours to days after birth, with purpura fulminans or massive venous thrombosis. However, some patients with inherited homozygous or compound heterozygous deficiency with low protein C levels (<20%) present during childhood or early adulthood.

Preterm infants, neonates, and adolescents have protein C levels approximately 10-15%, 35%, and 80%, respectively, of normal adult levels. Protein C levels increase approximately 4% per decade in adulthood. Despite the lower protein C levels during childhood, thrombosis associated with heterozygous protein C deficiency is uncommon in individuals younger than 20 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients with heterozygous protein C deficiency usually are asymptomatic until after puberty. At this time, patients may experience spontaneous thrombosis or thrombosis subsequent to a predisposing risk factor. The frequency and extent of thrombosis are highly variable, and a careful family history of thrombotic disease is essential whenever possible. Familial studies of sequelae in protein C deficiency reveal that individuals likely experienced undiagnosed thrombotic events.

• Personal history of venous thrombosis
• • Query the patient about prior thrombotic problems and history of thromboembolic events (eg, deep venous thrombosis, pulmonary embolus, superficial thrombophlebitis, cerebral vein thrombosis, ophthalmic vein thrombosis, mesenteric vein thrombosis), particularly during periods of increased risk factors (eg, surgery, immobilization, trauma, pregnancy, peripartum period, oral contraceptive use).
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  • Ascertain the severity and location of a person's thrombotic events because these factors are important in deciding whether anticoagulant therapy is necessary.
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  • Also question the patient about arterial thrombotic events (eg, myocardial infarction, cerebrovascular accident), particularly if such events happened prematurely.
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  • Obtain a thorough bleeding history and a platelet-type bleeding history (eg, nose bleeds, bruising, menses, mucosal bleeding).
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  • Also inquire about symptomatology of bleeding associated with a deficiency of coagulation factors (eg, joint bleeds, retroperitoneal bleeds).
  
  
• Family history of thrombosis
• • Ask patients about the history of thrombosis in biological family members.
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  • The age, sex, and risk factors associated with thrombotic events are important.
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  • If a relative has been placed on anticoagulant therapy, the health care worker should inquire about the relative's response to this therapy.
  
  
• Prior history of abnormal laboratory coagulation tests
• • Question patients concerning prior coagulation laboratory results.
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  • When abnormalities have been found previously, attempt to find the specific laboratory where these abnormal results were observed because diagnostic laboratories may differ in their methods of testing.
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  • Likewise, if a patient's current laboratory tests reveal protein C deficiency but prior testing failed to show this diagnosis, attempt to correlate these results.

Physical

• Patients present with physical sequelae of thrombotic disease in the affected organ.
• • Deep venous thrombosis in the leg is the most common manifestation of thrombotic disease. Compare the extremities with each other with regard to circumference, color, and tenderness.
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  • Pulmonary embolism is a possible complication of deep venous thrombosis, particularly when the thrombosis occurs in a proximal leg vein. Signs and symptoms of pulmonary embolism include elevated heart rate, elevated respiratory rate, and difficulty breathing.
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  • Postphlebitic syndrome is a chronic complication of venous thrombosis. It is thought to occur in approximately 50% of patients with proximal vein thrombosis and in 30% of patients with calf-vein thrombosis. Symptomatology may include pain, swelling, and possible skin ulceration and/or induration in the leg.
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  • Superficial thrombophlebitis is primarily a clinical diagnosis, with symptoms of swelling, redness, and tenderness along a superficial vein.
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  • Mesenteric vein thrombosis is unusual but characteristic of an anticoagulant deficiency. Clinical presentation usually results in abdominal progressive pain that is greater than would seem indicated by physical examination findings. Vomiting, distension, melena, and fever may occur with more advanced disease. The thrombosis may result in hemorrhagic bowel infarction.
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  • Patients with cerebral venous thrombosis present with symptomatology depending on the specific area of neurologic dysfunction. Manifestations include headache, pseudotumor cerebri syndrome, focal neurologic deficits, decreased consciousness, meningeal signs, and possible seizures (focal or generalized).
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  • Warfarin-induced skin necrosis occurs in the feet, buttocks, thighs, breasts, upper extremities, and genitalia. The lesions usually begin as maculopapular lesions several days after initiation of warfarin and progress into bullous, hemorrhagic, necrotic lesions. Patients with protein C deficiency are at high risk for warfarin-induced skin necrosis during initiation of therapy with warfarin. Approximately one third of patients with warfarin-induced skin necrosis have protein C deficiency.

Causes

• Inherited disease has been reported to be due to more than 160 distinct mutations in the protein C gene on chromosome 2.
• • Heterozygous deficiency is inherited in an autosomal dominant manner. Many patients with protein C values in the deficient range are asymptomatic.
  • The coexistence of a deficiency of anticoagulant proteins, antithrombin, or protein S, or the presence of APC resistance, factor V Leiden, prothrombin G20210A; or an unknown recessively transmitted factor greatly increases the risk of symptomatic disease.
  • Inheritance of severe deficiency presenting in the neonatal period is autosomal recessive.

• Acquired protein C deficiency may occur in a number of clinical scenarios.
• • Such scenarios include meningococcal septic shock; disseminated intravascular coagulation; liver disease; ill preterm infants; acute inflammation; acute thrombosis; and administration of L-asparaginase, warfarin, or chemotherapy (eg, cyclophosphamide, methotrexate, and 5-fluorouracil or cisplatinum-Navelbine).
  • In severe sepsis, deficiencies of activated protein C may be pronounced due to the combination of multiple events that decrease protein C levels and dysregulate the functions of thrombomodulin and endothelial protein C receptor.

• Cases also have been reported associated with an anti-APC antibody, bone marrow transplantation, long-term hemodialysis, inflammatory bowel disease, post-Fontan procedure for congenital heart disease, acute myelogenous leukemia, and hepatocellular carcinoma.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Activated protein C resistance
Factor V Leiden
Prothrombin G20210A mutation
Cancer-related thrombosis
Homocystinuria

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• A decreased protein C activity level is required to make the laboratory diagnosis of protein C deficiency.
• Normal functional protein C levels range from approximately 60-130% of the level of pooled plasma from 20 nonpregnant nonclotting individuals who are not taking medications known to affect the protein C level (ie, warfarin).
• • Immunological levels frequently have a higher threshold of the normal range (70-130%).
  • Normal ranges should be established at each laboratory performing protein C level determinations.

• Protein C deficiencies are classified as type I or type II deficiencies. This can only be distinguished by comparing the functional protein C (activity) level with an immunologic protein C level.
• • Type I deficiencies, the most common type of inherited disease, are quantitative deficiencies in which the activity and antigenic levels are comparable, which illustrates that the defect is associated with a decreased concentration of protein.
  • Type II deficiencies are qualitative due to the presence of a dysfunctional protein and often are due to a missense mutation in the coding region of the protein C gene. The activity level is disproportionately decreased compared to the immunological level in type II deficiencies.

• Numerous variables may alter the protein C level. Thus, a patient's clinical scenario must be considered carefully before diagnosing a patient with inherited protein C deficiency.
• • A decreased activity level should be repeated on a separate specimen to ensure that the decreased level truly is associated with a low patient plasma level and not a result of a preanalytical variable.
  • Active clotting causes consumption of procoagulant and anticoagulant proteins and may result in a decreased protein C level.
  • Warfarin administration causes decreased protein C activity and a variably normal to decreased immunological protein C level. Assessing protein C levels while a patient is on warfarin therapy is suboptimal; however, if protein C must be assessed during such therapy, a comparison should be made between the protein C activity and that of another vitamin K–dependent protein, such as factor VII or protein S. Additionally, an immunological level should be performed.
  • In a patient who is pregnant and has borderline levels of protein C, the diagnosis of protein C deficiency should not be definitively ruled out.

  • Because of the low levels of protein C during childhood, a definitive diagnosis of inherited deficiency of heterozygous disease should not be made on the basis of plasma levels until an individual reaches maturity. Alternatively, family studies, which greatly aid in making the correct diagnosis, may be performed.

• The laboratory workup for a patient with suspected protein C deficiency should include tests that help assess a patient's hemostatic parameters, which are necessary in properly evaluating any laboratory value in the coagulation system. These include an activated partial prothrombin time (aPTT), a prothrombin time (PT), a fibrinogen level, and a D-dimer test.
• • If a patient has a decreased protein C level and the PT is elevated, further testing of procoagulant proteins helps assess if the low protein C is due to vitamin K deficiency (low II, VII, IX, and X but normal factor V) or low protein C associated with liver disease (low II, VII, IX, and X; deficient and low factor V).

  • A fibrin degradation product (FDP), D-dimer, fragment 1.2, or a thrombin-antithrombin complex test also helps to determine if a patient is actively clotting, which could cause a decreased protein C level.

• Perform other tests to assess the concurrent presence of other thrombotic risk factors.
• • These tests include an antithrombin level, free protein S level, a plasma-based test for APC resistance, or a genetic test for factor V Leiden and prothrombin G20210A. Tests for plasminogen and a dysfibrinogenemia also may be helpful. Perform these additional tests if the protein C deficiency is suspected but findings are negative. Likewise, in a patient found to be deficient in protein C, these laboratory tests help indicate thrombotic risks and guide therapeutic intervention.
  • APC resistance is a resistance to the anticoagulant function of APC. By far the most common cause of APC resistance is a genetic mutation referred to as factor V Leiden. Factor V Leiden results from a mutation in the factor V gene that causes resistance to degradation of the activated factor V cofactor (factor Va). Because one of the principal anticoagulant functions of APC is the degradation of factor Va, this mutation results in a gain of function of a procoagulant protein, very different from a functional deficiency of the anticoagulant protein C molecule.
  • Tests for a lupus anticoagulant and an anticardiolipin antibody may be indicated because some antibodies may cause an increased risk of clotting.
  • Recent studies also indicate an increased risk of thrombosis associated with elevations in factor VIII levels. Evaluation of these procoagulant protein levels in the nonacute stage may provide additional information to assess a patient's risk of thrombotic disease.

• As laboratory tests improve for quantitating D-dimer, a degradation product of cross-linked fibrin, this laboratory test has become increasingly popular as a test to help in the diagnosis of acute thromboembolic disease.

Imaging Studies

• Imaging studies are appropriate for assessing the presence of thrombotic disease in a particular vessel.
• • Duplex ultrasonography: Real-time B-mode venous ultrasonography is the method of choice for evaluating a deep venous thrombosis. In symptomatic patients, the sensitivity and specificity of ultrasound imaging for proximal deep venous thrombosis is 97% and 94%, respectively. However, the sensitivity for isolated calf venous thrombosis is much less, approximately 73%.
  • Venography: Contrast venography performed by injecting a radiopaque contrast material into the venous system allows direct visualization of the deep veins.
  • Magnetic resonance imaging: Currently, this is not performed in the standard workup for the diagnosis of deep venous thrombosis, although studies now suggest it may be helpful in difficult cases. This technique may be used for diagnosis of thrombotic vessels in areas inaccessible by ultrasound.
  • Ventilation/perfusion (V/Q) scan: A V/Q scan is performed routinely for the diagnosis of pulmonary embolism, a possible symptomatic manifestation of protein C deficiency. Patients classified in a non–high-probability scan often require further testing to rule out the diagnosis of a pulmonary embolus.
  • Spiral CT scan: This new diagnostic modality for directly visualizing the pulmonary arterial circulation may be a helpful adjunct to the V/Q scan for the diagnosis of pulmonary embolism. However, currently, availability of this diagnostic technique is limited.
  • Pulmonary angiography: Pulmonary angiography is considered the criterion standard for the diagnosis of a pulmonary embolus. However, because of the invasiveness of the procedure, pulmonary angiography is only performed when other diagnostic measures have failed.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Medical care for patients with protein C deficiency depends largely on a particular patient's disease manifestations.
  
  
  • In asymptomatic patients found to have protein C levels in the deficiency range, no specific therapeutic intervention is usually required. However, consider possible prophylactic intervention during times of increased risk, such as peripartum, perioperatively during periods of prolonged immobilization (including significantly long air travel). Additionally, the potential increased risk of thrombotic disease during oral contraceptive therapy should be considered.
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  • Patients who have experienced one thrombotic episode should be treated with anticoagulant therapy for a period of 3 months to 1 year to prevent further thrombotic episodes. The clinician should consider the risks of hemorrhage against the risk of further thrombotic disease in each particular patient depending on individual physical demands and risks of thrombosis.
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  • Patients who experience recurrent thrombotic disease and/or have a strong positive family history of thrombotic disease may be placed on long-term anticoagulant therapy, again weighing the risks of thrombotic disease against hemorrhagic disease.
  • 
    
  • Patients with severe homozygous or compound heterozygous protein C deficiency must be rigorously treated due to the high risk of thrombosis in these patients.
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  • Patients with acquired protein C deficiency associated with medical problems may be treated with protein C concentrate in some circumstances. Conditions in which this has been found to be helpful include disseminated intravascular coagulation due to meningococcemia.
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  • A recombinant version of activated protein C has been approved by the FDA for the treatment of acquired protein C deficiency, which frequently occurs during sepsis, as defined as a systematic inflammatory response due to infection. Human protein C concentrate (Ceprotin) has recently been designated as an orphan drug for congential protein C deficiency.

Surgical Care

• Surgical treatment associated with protein C deficiency is indicated in association with symptomatic disease and preventive measures. Surgical treatment may be appropriate in some circumstances of a thrombotic lesion that could be excised surgically.
• A vena caval filter may be indicated in certain circumstances, as with recurrent or proximal deep venous thrombosis, to prevent the development of a pulmonary embolism.
• Liver transplantation may be considered in severely affected patients with life-threatening disease.
• Surgical procedures predispose patients to an increased risk of thrombotic complications. Thus, patients with protein C deficiency, even those with asymptomatic disease, may require additional anticoagulant prophylaxis and observation beyond that normally required for patients undergoing a given surgical procedure.
• • In particular, avoid immobilization to the greatest extent possible, and careful prophylactic management is necessary.
  • Compression stockings and pneumatic compression devices are helpful in decreasing the risk of postsurgical deep venous thrombosis.

Consultations

Consultation with a specialist in hematology is warranted for the care of a patient with protein C deficiency.

Consultation with a critical care specialist is necessary for possible treatment with APC during sepsis.

• Monitor pregnancy carefully because patients are at increased risk for the development of venous thrombosis. Additionally, paternal levels should be assessed, when possible, to screen for the possibility of severe recessive disease in the neonate.
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• Patients on oral contraceptives are also at increased risk for venous thrombosis, including cerebral venous thrombosis. Careful discussion of the risk of contraceptives should be addressed.
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• Patients in intensive care units may benefit from administration of the recombinant version of APC.

Diet

Diet is particularly important in patients on warfarin anticoagulant therapy.

• The diet should provide a relatively constant amount of vitamin K because fluctuating levels of vitamin K alter the efficacy of warfarin and can predispose the patient to hemorrhagic complications. Foods high in vitamin K include green leafy vegetables, oils, and green tea.
• It also is wise for patients to follow the dietary guidelines for those with increased cardiovascular risk.

Activity

• Immobilization increases the risk of thrombosis in patients with protein C deficiency. Advise patients to punctuate periods of long inactivity, including extended car and airplane travel, with intermittent walks and leg exercises to prevent venous stasis.
• Patients on anticoagulant therapy are at increased risk of hemorrhagic complications, including intracranial hemorrhage. Thus, instruct patients taking anticoagulants to avoid excessive activity that may pose significant risk. Prompt medical attention should be sought when hemorrhagic sequelae are suspected.
• Remind patients to avoid aspirin and other nonsteroidal anti-inflammatory drugs that might further increase the risk of bleeding.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical treatment of protein C deficiency depends on the symptomatic expression of disease in a given patient. Prevention of thrombotic disease must be carefully balanced with exposing a patient to the increased risk of hemorrhage with anticoagulant therapy. Per year, the risk of fatal hemorrhage is 0.3-0.6% and the risk of major hemorrhage associated with oral anticoagulant therapy is 1-3%. Patients with heterozygous protein C deficiency rarely require treatment before puberty. Physicians normally wait until a patient experiences thrombotic disease before administering anticoagulant therapy. The extent of disease and the likelihood of recurrence must be carefully assessed before placing a patient on long-term anticoagulant treatment. However, short-term therapy of 3 months to 1 year is warranted subsequent to a thrombotic incident.

Patients with severe homozygous or compound heterozygous disease must be treated with anticoagulant therapy and/or protein concentrate.

Drug Category: Anticoagulant therapies

Protein C deficiency causes a lack of inhibition of the procoagulant pathways. Anticoagulant therapy reduces the factors normally promoting clot formation.

Drug Category: Blood products

Plasma blood products contain protein C. Thus, plasma products can be given to directly supply the missing protein.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Treat the acute thrombotic event that brought the patient to the hospital. Patients should not be discharged before the risks associated with pulmonary embolism have been addressed.
• Establish a strategy to stabilize anticoagulant therapy in a therapeutic range to be taken as an outpatient treatment for patients presenting with an acute thrombotic event.

Further Outpatient Care

• Assess protein C levels.
• • Repeat protein C values when the patient is not experiencing an acute event.
  • Counsel and perform laboratory tests on biological relatives if indicated.

• Monitor anticoagulant therapy with appropriate laboratory tests (ie, PT).

In/Out Patient Meds

• Order anticoagulant medication, usually warfarin or LMWH, to be given to patients who present with an acute clotting event.

Deterrence/Prevention

• Advise patients to be careful in situations of prolonged immobilization and/or stasis, such as during a lengthy period of travel.
• Advise women of increased thrombotic risks associated with pregnancy and oral contraceptive pills.

Complications

• Forewarn patients of possible hemorrhagic complications secondary to anticoagulant therapy.
• Postphlebitic syndrome frequently occurs after thrombotic events.

Prognosis

• The relative risk of thrombosis for a patient with heterozygous protein C deficiency is approximately 7 times higher than for a patient without a defined hypercoagulable state.
• By the fifth decade, approximately 50% of patients with heterozygous protein C deficiency have experienced a thromboembolic event.
• Patients with heterozygous protein C deficiency have an incidence of spontaneous thrombosis of approximately 0.4-2.5% per year. Approximately 50-70% of thromboses are spontaneous.
• When patients with protein C deficiency are carefully monitored and given appropriate prophylaxis during high-risk periods (eg, surgery, trauma, immobilization, pregnancy, postpartum period), the risk of thromboembolic disease is markedly reduced.
• In most patients, the risk of major hemorrhage associated with anticoagulant therapy is higher than the risk of thrombosis. Therefore, unless a patient has recently experienced a thromboembolic event or is in a high-risk clinical scenario, anticoagulant medications usually are not recommended. However, the specific clinical scenario must be carefully evaluated for each patient.

Patient Education

• Advise patients of the symptomatology of clotting so that patients present for medical care early for the treatment of a clot.
• Advise patients to speak with a physician for possible prophylactic therapy during higher risk periods of surgery, trauma, immobilization, pregnancy, postpartum period, and oral contraceptive therapy.
• Forewarn patients of possible problems with anticoagulant therapy and with an irregular diet and their potential effects on warfarin dosage.
• For excellent patient education resources, visit eMedicine's Circulatory Problems Center. Also, see eMedicine's patient education article Blood Clot in the Legs.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Anticoagulant therapy may be particularly problematic in patients with protein C deficiency because medical therapy demands carefully juggling thrombotic and hemorrhagic risks in a particular patient. The proportions of these risks change with clinical scenario, age, and hormonal influences. However, predicting exactly when the risk of thrombosis outweighs the risk of bleeding, warranting medical management, is difficult.
• Careful monitoring of warfarin dosage is necessary on a frequent basis, and adjustment of medical therapy should be considered when the international normalized ratio (INR), the index of drug warfarin therapy, is outside the therapeutic range.
• Pulmonary embolism poses a high risk of fatality. Thus, measures should be taken to avoid this complication when the risk of the development of pulmonary embolism outweighs the risks of anticoagulant therapy or vena caval filter placement. Carefully document consideration of the risks and benefits of therapy.

Special Concerns

• Women with protein C deficiency are at higher risk for thrombosis during pregnancy. Additionally, some studies show an increased association with other complications during pregnancy for patients with anticoagulant deficiencies.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bates SM, Hirsh J. Treatment of venous thromboembolism. Thromb Haemost. Aug 1999;82(2):870-7. [Medline].
• Bucciarelli P, Rosendaal FR, Tripodi A, et al. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study. Arterioscler Thromb Vasc Biol. Apr 1999;19(4):1026-33. [Medline].
• Dahlback B, Villoutreix BO. The anticoagulant protein C pathway. FEBS Lett. Jun 13 2005;579(15):3310-6. [Medline].
• Drews RE. Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients. Clin Chest Med. Dec 2003;24(4):607-22. [Medline].
• Emmerich J, Vossen CY, Callas PW, et al. Chronic venous abnormalities in symptomatic and asymptomatic protein C deficiency. J Thromb Haemost. Jul 2005;3(7):1428-31.
• Koster T, Rosendaal FR, Briet E, et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood. May 15 1995;85(10):2756-61. [Medline].
• Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: Part 1. Thromb Haemost. Nov 1996;76(5):651-62. [Medline].
• Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: Part 2 [published erratum appears in Thromb Haemost 1997 May;77(5):1047]. Thromb Haemost. Dec 1996;76(6):824-34. [Medline].
• Macias WL, Nelson DR. Severe protein C deficiency predicts early death in severe sepsis. Crit Care Med. May 2004;32(5 Suppl):S223-8. [Medline].
• Macias WL, Yan SB, Williams MD, et al. New insights into the protein C pathway: potential implications for the biological activities of drotrecogin alfa (activated). Crit Care. 2005;9 Suppl 4:S38-45.
• Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med. Oct 15 1987;317(16):991-6. [Medline].
• Rivard GE, David M, Farrell C, et al. Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr. Apr 1995;126(4):646-52. [Medline].
• Rohrer MJ, Andrew M, Michelson AD. Hemorrhage, thrombosis, and antithrombotic therapy in children. In: Loscalzo J, Schafer AI, eds. Thrombosis and Hemorrhage. 2nd ed. Boston, Mass: Blackwell Scientific; 1998:. 1027-63.
• Sanz-Rodriguez C, Gil-Fernandez JJ, Zapater P, et al. Long-term management of homozygous protein C deficiency: replacement therapy with subcutaneous purified protein C concentrate. Thromb Haemost. Jun 1999;81(6):887-90. [Medline].

Article Last Updated: Jun 30, 2006