Some Critical Notices Should Knowing When Using Warfarin

June 30, 2017 Anticoagulant Therapy, Hematology, Laboratory Medicine No comments , , , , , , , , , , , ,

PT/INR and Anticoagulation Status

For the vast majority of patients        , monitoring is done using the prothrombin time with international normalized ratio (PT/INR), which reflects the degree of anticoagulation due to depletion of vitamin K-dependent coagulation. However, attention must be paid that the PT/INR in a patient on warfarin may note reflect the total anticoagulation status of the patient in certain settings:

  • First few day of warfarin initiation

The initial prolongation of the PT/INR during the first one to three days of warfarin initiation does not reflect full anticoagulation, because only the factor with the shortest half-life is initially depleted; other functional vitamin K-dependent factors with longer half-lives (e.g., prothrombin) continues to circulate. The full anticoagulation effect of a VKA generally occurs within approximately one week after the initiation of therapy and results in equilibrium levels of functional factors II, IX, and X at approximately 10 to 35 percent of normal.

  • Liver disease

Individuals with liver disease frequently have abnormalities in routine laboratory tests of coagulation, including prolongation of the PT, INR, and aPTT, along with mild thrombocytopenia, elevated D-dimer, especially when liver synthetic function is more significantly impaired and portal pressures are increased. However, these tests are very poor at predicting the risk of bleeding in individuals with liver disease because they only reflect changes in procoagulant factors.

  • Baseline prolonged PT/INR

Some patients with the antiphospholipid antibody syndrome (APS) have marked fluctuations in the INR that make monitoring of the degree of anticoagulation difficult.

Time in the Therapeutic Range (TTR)

For patients who are stably anticoagulated with a VKA, the percentage of time in the therapeutic range (TTR) is often used as a measure of the quality of anticoagulation control. TTR can be calculated using a variety of methods. The TTR reported depends on the method of calculation as well as the INR range considered β€œtherapeutic.” A TTR of 65 to 70 percent is considered to be a reasonable and achievable degree of INR control in most settings.

Factors Affecting the Dose-Response Relationship Between Warfarin and INR

  • Nutritional status, including vitamin K intake
  • Medication Adherence
  • Genetic variation
  • Drug interactions
  • Smoking and alcohol use
  • Renal, hepatic, and cardiac function
  • Hypermetabolic states

In addition, female sex, increased age, and previous INR instability or hemorrhage have been associated with a greater sensitivity to warfarin and/or an increased risk of bleeding.

Dietary Factors

Vitamin K intake – Individuals anti coagulated with warfarin generally are sensitive to fluctuations in vitamin K intake, and adequate INR control requires close attention to the amount of vitamin K ingested from dietary and other sources. The goal of monitoring vitamin K intake is to maintain a moderate, constant level of intake rather than to eliminate vitamin K from the diet. Specific guidance from anticoagulation clinics may vary, but a general principle is that maintaining a consistent level of vitamin K intake should not interfere with a nutritious diet. Patients taking warfarin may wish to be familiar with possible sources of vitamin K (in order to avoid inconsistency).

Of note, intestinal microflora produce vitamin K2, and one of the ways antibiotics contribute to variability in the prothrombin time/INR is by reducing intestinal vitamin K synthesis.

Cranberry juice and grapefruit juice have very low vitamin K content but have been reported to affect VKA anticoagulation in some studies, and some anticoagulation clinics advise patients to limit their intake to one or two servings (or less) per day.

Medication Adherence

Medication adherence for vitamin K antagonists can be challenging due to the need for frequent monitoring and dose adjustments, dietary restrictions, medication interactions, and, in some cases, use of different medication doses on different days to achieve the optimal weekly intake. Reducing the number of medications prescribed may be helpful, if this can be done safely.

Drug Interactions

A large number of drugs interact with vitamin K antagonists by a variety of mechanisms, and additional interacting drugs continue to be introduced. Determine clinically important drug interactions is challenging because the evidence substantiating claims for some drug is very limited; in other cases, the evidence is strong but the magnitude of effect is small. Patients should be advised to discuss any new medication or over-the-counter supplement with the clinician managing their anticoagulation, and clinicians are advised to confirm whether a clinically important drug-drug interaction has been reported when introducing a new medication in a patient anticoagulated with a VKA.

Smoking and Excess Alcohol

The effect of chronic cigarette smoking on warfarin metabolism was evaluated in a systematic review and that included 13 studies involving over 3000 patients. A meta-analysis of the studies that evaluated warfarin dose requirement found that smoking increased the dose requirement by 12 percent, corresponding to a requirement of 2.26 additional mg of warfarin per week. However, two studies that evaluated the effect of chronic smoking on INR control found equivalent control in smokers and non-smokers.

The mechanisms by which cigarette smoking interacts with warfarin metabolism is by causing enhanced drug clearance through induction of hepatic cytochrome P-450 activity by polycyclic aromatic hydrocarbons in cigarette smoke. Nicotine itself is not thought to alter warfarin metabolism.

The interaction between excess alcohol use and warfarin anticoagulation was evaluated in a case-control study that compared alcohol use in 265 individuals receiving warfarin who had major bleeding with 305 controls from the same cohort receiving warfarin who did not have major bleeding. The risk of major bleeding was increased with moderate to severe alcohol use and with heavy episodic drinking.

Mechanism by which alcohol use interacts with warfarin anticoagulation are many, and the contribution of various factors depends greatly on the amount of intake and the severity of associated liver disease. Excess alcohol consumption may interfere with warfarin metabolism. Severe liver disease may also be associated with coagulopathy, thrombocytopenia, and/or gastrointestinal varices, all of which increase bleeding risk independent of effects on warfarin metabolism.


The major comorbidities that affect anticoagulation control are hepatic disease, renal dysfunction, and heart failure. In addition, other comorbidities such as metastatic cancer, diabetes, or uncontrolled hyperthyroidism may also play a role.

The liver is the predominant site of warfarin metabolism. It is also the source of the majority of coagulation factors. Thus, liver disease can affect warfarin dosage, INR control, and coagulation in general. Importantly, individuals with severe liver disease are not β€œauto-anticoagulated,” because they often have a combination of abnormalities that both impair hemostasis and increase thrombotic risk.

Warfarin undergoes partial excretion in the kidney. Patients with kidney disease can receive warfarin, and management is generally similar to the population without renal impairment; however, dose requirement may be lower.

Heart failure has been shown to interfere with INR stabilization.

Acute illnesses may alter anticoagulation through effects on vitamin K intake, VKA metabolism, and medication interactions, especially infections and gastrointestinal illnesses.

Genetic Factors

Genetic polymorphisms have been implicated in altered sensitivity to warfarin and other vitamin K antagonists.

[Hemostasis] General – Diagnostic Approach to the Bleeding Disorders

November 21, 2016 Clinical Skills, Hematology No comments , , , , , , , , , , , , , ,

screen-shot-2016-10-10-at-10-38-16-amClinical Presentations and Clinical Distinction Between Platelet- or Vessel-Induced Bleeding and Coagulation-Induced Bleeding

Certain signs and symptoms are virtually diagnostic of disordered hemostasis. They can be divided arbitrarily into two groups: those seen more often in disorders of blood coagulation and those most commonly noted in disorders of the vessels and platelets. The latter group is often called purpuric disorders because cutaneous and mucosal bleeding usually are prominent. The clinical findings that are most valuable in distinguishing between these two broad categories are summarized in Table 45.1. Although these criteria are relative, they provide valuable clues to the probable diagnosis if they are applied to the predominant clinical features in a given patient.

Bleeding into Skin and Soft Tissues

Petechiae are characteristic of an abnormality of the vessels or the platelets and are exceedingly rare in the coagulation disorders. These lesions are small capillary hemorrhages ranging from the size of a pinhead to much larger. They characteristically develop and regress in crops and are most conspicuous in areas of increased venous pressure, such as the dependent parts of the body and areas subjected to pressure or constriction from girdles or stockings. Petechiae must be distinguished from small telangiectasias and angiomas. Vascular structures such as telangiectasias or angiomas blanch with pressure, whereas petechiae do not.


Hemorrhage into synovial joints is virtually diagnostic of a severe inherited coagulation disorder, most commonly hemophilia A or hemophilia B, and is rare in disorders of the vessels and platelets or in acquired coagulation disorders. This disabling problem often develops with pain and swelling as chief symptoms but without discoloration or other external evidence of bleeding. Subperiosteal hemorrhages in children with scurvy and swollen painful joints that may developin some patients with allergic purpura occasionally may be confused with hemarthrosis.

Traumatic Bleeding

The unavoidable traumas of daily life and even minor surgical procedures are a greater challenge to hemostasis than any test yet developed in the laboratory. In contrast to "spontaneous" bleeding manifestations, bleeding after trauma in a person with a hemorrhagic diathesis differs in a quantitative way from that which would normally be expected in terms of the amount, duration, and magnitude of the inciting trauma. Such variables are extremely difficult to assess accurately by taking the patient's history. The need for transfusions and the number administered may serve as a rough guide. The patient's statement concerning the duration of bleeding is more reliable.

In individuals with a coagulation disorder, the onset of bleeding after trauma often is delayed. For example, bleeding after a tooth extraction may stop completely, only to recur in a matter of hours and to persist despite the use of styptics, vasoconstrictors, and packing. The temporary hemostatic adequacy of the platelet plug despite defective blood coagulation may explain this phenomenon of delayed bleeding, as well as the fact that patients with coagulation disorders seldom bleed abnormally from small superficial cuts scuh as razor nicks. In contrast, posttraumatic or postoperative surgical bleeding in thrombocytopenic patients usually is immediate in onset, as a rule responds to local measures, and rarely is as rapid or voluminous as that encountered in patients with coagulation disorders. However, it may persist for hours or days after surprisingly small injuries.

Anyway, the response to trauma is an excellent screening test for the presence of an inherited hemorrhagic disorder, and a history of surgical procedures or significant injury without abnormal bleeding is equally good evidence against the presence of such a disorder.

Clinical Features of Inherited and Acquired Bleeding Disorders

An inherited bleeding disorder is suggested by the 1) onset of bleeding symptoms in infancy and childhood, 2) a positive family history (particularly if it reveals a consistent genetic pattern), and 3) laboratory evidence of a single or isolated abnormality, most commonly the deficiency of a single coagulation factor.

Birth and the neonatal period provide unique challenges to the hemostatic mechanism, and bleeding during the first month of life often is the first evidence of an inherited disorder of hemostasis. Small cephalohematomas and petechiae are common in tne newborn as a result of the trauma of delivery. Large cephalohematomas that progressively increase in size may result from hemophilia but are more common in association with acquired bleeding disorders such as hemorrhagic disease of the newborn. Bleeding from the umbilical stump and after circumcision is common in the acquired coagulation disorders, and it also occurs in the inherited coagulation disorders, with the exception of hypofibrinogenemia, dysfibrinogenemia, and factor XIII deficiency. The onset of bleeding from the umbilical cord may be delayed in these latter disorders. In the evaluation of bleeding in the neonate, the clinician should remember that hematochezia and hematemesis may originate from swallowed blood of maternal origin. Simple tests to distinguish such maternal blood from fetal blood have been described. It must be paid attention that manuy infants with inherited coagulation disorders do not bleed significantluy in the neonatal period. In such patients, the disorder may become clinically silent for a time. Hematomas may first be seen only when the child becomes active. Hemarthrosis commonly does not develop until a child is 3 or 4 years of age.

The family history is of great importance in the evaluation of bleeding disorders. In disorders inherited as autosomal dominant traits with characteristic symptoms and high penetrance, such as hereditary hemorrhagic telangiectasia, an accurate pedigree spanning several generations can often be obtained. The presence of typical bleeding manifestations in male siblings and maternal uncles is virtually diagnostic of X-linked recessive inheritance, which characterizes hemophilia A and hemophilia B. But, the limitations of the family history, however, are greater than is commonly realized. Hearsay history is difficult to evaluate, and it is often impossible to assess the significance of easy bruising or to differentiate between manifestations of a generalized bleeding disorder and more common localized lesions, such as peptic ulcer and uterine leiomyomas. A negative family history is of no value in excluding an inherited coagulation disorder in an individual patient. As many as 30% to 40% of patients with hemophilia A have a negative family history. The family history usually is negative in the autosomal recessive traits, and consanguinity, which is commonly prsent in these kindreds, is notoriously difficult to document or exclude.

Approach to the Patient W/ Excessive Bleeding

Excessive bleeding may occur in both male and female patients of all ages and ethnicities. Symptoms can begin as early as the immediate newborn period (uncommonly even in utero) or anytime or anytime thereafter. The bleeding symptoms experienced are related in large part to the specific factor and level of deficiency.

  • [Spontaneous or induced] Bleeding can be spontaneous; that is, without an identified trigger, or may occur after a hemostatic challenge, such as delivery, injury, trauma, surgery, or the onset of menstruation.
  • [Anatomic location(s)] Furthermore, bleeding symptoms may be confined to specific anatomic sites or may occur in multiple sites.
  • [Family history] Finally, bleeding symptoms may be present in multiple family members or may occur in the absence of a family history. All of this information is important to arrive at a correct diagnosis rapidly and with minimal yet correctly sequenced laboratory testing.

Thus, a detail patient and family history is a vital component of the approach to each patient with a potential bleeding disorder.


Obtaining a detail patient and family history is crucial regardless of prior laboratory testing. The history includes a detailed discussion of specific bleeding and clinical symptoms. Information regarding bleeding symptoms should include location, frequency, and pattern as well as duration both in terms of age of onset and time required for cessation.


The location may suggest the part of the hemostatic system affected; patients with disorders of primary hemostasis (platelets and vWF) often experience mucocutaneous bleeding, including easy bruising, epistaxis, heavy menstrual bleeding, and postpartum hemorrhage in women of child-bearing age; whereas patients with disorders of secondary hemostasis (coagulation factor deficiencies) may experience deep-tissue bleeding, including the joints, muscles, and central nervous system.

Pattern and Duration

The bleeding pattern and duration of each episode, particularly for mucus membrane bleeding, assist in the determination of the likelihood of the presence of an underlying bleeding disorder.


The onset of symptoms can suggest the presence of a congential versus acquired disorder. Although congenital conditions can present at any age, it is more likely that patients with a long history of symptoms or symptoms that begin in childhood have a congenital condition, whereas patients whose onset occurs at an older age are more likely to have an acquired condition. Congenital clotting factor deficiencies that do not present until later in life do occur and include mild factor deficiencies and coagulation factor deficiencies associated with variable bleeding patterns, most notably FXI deficiency.


Additional important information to be collected includes the current use of medications and herbal supplements, as these may affect the hemostatic system; the presence or absence of a family history of bleeding; a history of hemostatic challenges, including surgery, dental procedures, and trauma; and a menstrual history in females.

The goal at the end of the history is to establish the likelihood of a bleeding disorder, as this will guide the direction of the laboratory investigation. Quantification of clinical bleeding is a challenge, particularly in the outpatient setting. In recent years, several bleeding assessment tools (BAT) have been developed to more accurately differentiate bleeding phenotypes in healthy individuals and in patients with bleeding disorders. These tools, which were originally designed for assessing bleeding in von Willebrand disease (vWD) do not appear to be diagnostic and are in the process of being validated for the ability to screen other bleeding disorders. However, it is increasingly clear that a normal bleeding score rules out the presence of a bleeding disorder. Therefore, if the bleeding score is indicative of excessive bleeding, it should be followed by an evaluation of a hematologist to evaluate the need for further laboratory tests.

Screening Tests

  • Platelet count, PT, aPTT

The laboratory evaluation for bleeding includes performance of initial screening tests. The most common screening tests utilized include the platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT). When the PT or aPTT is prolonged, mixing studies are required via a one-to-one mix of patient plasma with known normal standard plasma. Test correction in the mixing study indicates a deficiency state, whereas lack of correction indicates an inhibitor, either one directed against a specific factor or a a global inhibitor as best exemplified by a lupus anticoagulant. Specific factor analyses are performed after mixing studies reveal a correction of prolonged coagulation screening test(s) indicative of a deficiency state or in the face of normal screening tests with a positive history. Screening tests are not sensitive and do not evaluate all abnormalities associated with bleeding including vWF, FXIII, PAI-1, and 𝛼2AP deficiencies and may be insensitive to mild FVIII and FIX deficiencies; therefore, a patient history strongly suggestive of a bleeding disorder may warrant testing for such deficiencies, including rare abnormalities regardless of screening test results. The most common screening tests utilized include the platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT). When the PT or aPTT is prolonged >10 seconds, mixing studies are required via a one-to-one mix of patient plasma with known normal standard plasma. Test correction in the mixing study indicates a deficiency state, whereas lack of correction indicates an inhibitor.

  • Platelet function

Screen tests also are utilized to identify individuals with a high likelihood of vWD or platelet disorders. The bleeding time, once widely used, has become obsolete because of the lack of sensitivity and specificity. The PFA-100 (platelet function analyzer) has been proposed to have a role in screening individuals with suspected platelet dysfunction or vWD. Initial studies demonstrated the efficacy of the PFA-100 in the evaluation of patients with known severe platelet disorders or vWD. The PFA-100 induces high shear stress and simulates primary hemostasis by flowing whole blood through an aperture with a membrane coated with collagen and either ADP or epinephrine. Platelets adhere to the collagen-coated surface and aggregate forming a platelet plug that enlarges until it occludes the aperture, causing cessation of blood flow. The time to cessation of flow is recorded as closure time (CT). The sensitivity and spcificity of the CT of the PFA-100 were reported as 90% for severe platelet dysfunction or vWD, with vWD plasma levels below 25%. The utility of the PFA-100 as a screening tool, however, has been challenged based on the reported low sensitivity (24%-41%) of the device in individuals with mild platelet secretion defect, mild vWD or storage pool disorders. Additionally, a significant limitation of the PFA-100 is the fact that the platelet count and hemoglobin levels affect the CT. The CT will be abnormal if the platelet count is less than 100,000/πœ‡L and the hemoglobin is <10 g/dL.