Drugs Used in Disorders of Coagulation

Question 1

Regulation of Hemostasis

Answer 1

After vascular injury, anticoagulant factors are secreted by the endothelium: prostacyclin (PGI2), antithrombin III, proteins C and S, tissue factor pathway inhibitor (TFPI), and tissue-type plasminogen activator (t-PA).

PGI2 is an eicosanoid synthesized and secreted by the endothelium. PGI2 increases cAMP levels within platelets and thereby inhibits platelet activation. PGI2 is also a vasodilator: it relaxes vascular smooth muscle by increasing cAMP levels within the vascular smooth muscle cells.

Antithrombin III inactivates thrombin and other coagulation factors (IXa, Xa, XIa, and XIIa) by forming a complex with them.

Protein C is a vitamin K-dependent serine protease that is activated by thrombin. The activated form (with protein S as a cofactor) degrades factors Va and VIIIa.

Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). TFPI prevents excessive TF-mediated activation of factors IX and X.

Plasmin proteolytically degrades fibrin (fibrinolysis). Plasmin is generated by the proteolytic cleavage of plasminogen, a plasma protein that is synthesized in the liver. The proteolytic cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized and secreted by the endothelium.

Question 2

Drugs Used in Disorders of Coagulation

Answer 2

DRUGS USED TO REDUCE CLOTTING

PLATELET AGGREGATION INHIBITORS

ANTICOAGULANTS

THROMBOLYTICS

DRUGS USED TO TREAT BLEEDING

PLASMINOGEN ACTIVATION INHIBITORS

PROTAMINE SULFATE

VITAMIN K

PLASMA FRACTIONS

Question 3

Aspirin

Answer 3

PLATELET AGGREGATION INHIBITORS

CYCLOOXYGENASE INHIBITORS

ASPIRIN

Thromboxane A2 causes platelets to change shape, to release their granules and to aggregate. Drugs that antagonize thromboxane A2 synthesis interfere with platelet aggregation and prolong bleeding time. Aspirin is the prototype of this class of drugs. Aspirin inhibits TXA2 synthesis by irreversible acetylation of the enzyme COX.

Because the anuclear platelet can’t synthesize new proteins, it can’t synthesize new enzyme during its 10-day lifetime.

Other salicylates and other NSAIDs also inhibit COX but have shorter duration of action because they can’t acetylate COX, ie, their action is reversible.

USES

Aspirin is used in the prophylactic treatment of transient cerebral ischemia, to reduce the incidence of recurrent myocardial infarction and to decrease mortality in postmyocardial infarction patients.

Question 4

Name the 2 ADP Receptor Blockers and their Uses

Answer 4

PLATELET AGGREGATION INHIBITORS

ADP RECEPTOR BLOCKERS

CLOPIDOGREL & TICLOPIDINE

Clopidogrel and ticlopidine irreversibly inhibit P2Y12, one of the two subtypes of ADP receptor on the platelet surface. As a consequence, they reduce platelet aggregation by irreversibly inhibiting ADP binding.

Both drugs are effective in preventing cerebrovascular and cardiovascular as well as peripheral vascular disease.

Like aspirin, they are irreversible platelet inhibitors, increasing the risk of bleeding for 5-7 days after drug cessation. Both drugs can cause prolonged bleeding for which there is no antidote.

The most serious side effect of ticlopidine is neutropenia.

Thrombocytopenic purpura has been reported for both drugs.

Both drugs inhibit cytochrome P450 and can therefore interfere with the metabolism

of other drugs if taken concomitantly.

Clopidogrel has fewer adverse effects than ticlopidine and is rarely associated with neutropenia. Because of its superior side effect profile and dosing requirements, clopidogrel has largely replaced ticlopidine.

Clopidogrel is a prodrug converted to an active metabolite, mainly by CYP2C19. Patients who are CYP2C19 poor metabolizers have lower plasma levels of the active metabolite.

CYP2C19 poor metabolizers with acute coronary syndrome, or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Alternative treatments should be considered for CYP2C19 poor metabolizers

Metabolism of clopidogrel to its active metabolite can also be impaired by concomitant drugs that interfere with CYP2C19. The concomitant use of clopidogrel and CYP2C19 inhibitors should be avoided. Omeprazole, a moderate CYP2C19 inhibitor, reduces plasma levels of the active metabolite of clopidogrel. The concurrent use of clopidogrel and omeprazole should be avoided.

USES

Clopidogrel is indicated to reduce the rate of stroke, MI, and death in patients with recent MI or stroke, established peripheral arterial disease, or acute coronary syndrome.

Question 5

Name the 2 Phosphodiesterase Inhibitors and their Uses

Answer 5

DIPYRIDAMOLE

A coronary vasodilator. Employed to prophylactically treat angina pectoris.

Dipyridamole increases cAMP levels by inhibiting phosphodiesterase and/or by blocking uptake of adenosine, which acts at A2 receptors to activate platelet adenylyl cyclase.

Dipyridamole by itself has little or no beneficial effect.

Indicated as an adjunct to warfarin in the prevention of postoperative thromboembolic complications of cardiac valve replacement.

A combination of aspirin and extended-release dipyridamole is available for secondary prophylaxis of cerebrovascular disease.

CILOSTAZOL

Phosphodiesterase inhibitor.

Promotes vasodilation and inhibition of platelet aggregation.

Used to treat intermittent claudication.

Question 6

BLOCKERS OF PLATELET GP IIb/IIIA RECEPTORS

Name the 3 and their Uses

Answer 6

Used to reduce the rate of thrombotic cardiovascular events in patients with non-ST elevation acute coronary syndrome (NSTE-ACS), and also as adjuncts to percutaneous coronary intervention (PCI) for the prevention of cardiac ischemic complications.

Given parenterally.

The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin, but also for fibronectin and von Willebrand factor. Activation of this receptor is the final common pathway for platelet aggregation. Persons lacking this receptor have a bleeding disorder called Glanzmann’s thrombasthenia.

ABCIXIMAB

Chimeric mouse–human monoclonal antibody directed against the human GPIIb/IIIa receptor. The binding of abciximab to GPIIb/IIIa is essentially irreversible, with a dissociation half-time of 18 to 24 hours.

EPTIFIBATIDE

Cyclic peptide reversible antagonist of the GPIIb/IIIa receptor.

TIROFIBAN

Nonpeptide tyrosine analogue. Reversible antagonist of the GPIIb/IIIa receptor.

Question 7

UNFRACTIONATED & LOW-MOLECULAR-WEIGHT HEPARINS

Name the 3 LMWHs

Answer 7

Heparin is an injectable, rapidly acting anticoagulant often used acutely to interfere with formation of thrombi.

Heparin is a heterogeneous mixture of straight-chain, sulfated mucopolysaccharides, isolated from bovine lung or porcine intestinal mucosa. Heparin normally occurs as a macromolecule complexed with histamine in mast cells where its physiologic role is unknown. Unfractionated (standard) heparin (UFH) has a molecular weight range of 5,000 -30,000.

Low-Molecular-Weight Heparins (LMWH) (enoxaparin, dalteparin and tinzaparin) are produced by chemical or enzymatic depolymerization of UFH. Their molecular weights range from 1,000 – 5,000. LMWHs are free of some of the drawbacks associated with UFH; therefore they are replacing UFH in many clinical situations. LMWHs have equal efficacy to UFH, superior bioavailability, longer half- life, and less frequent dosing requirements (once or twice daily is sufficient).

Question 8

Mechanism of Action of Heparin

Answer 8

Heparin’s anticoagulant effect is a consequence of binding to antithrombin III. Antithrombin III is an α-globulin. It inhibits clotting factor proteases, especially thrombin, IXa and Xa, by forming equimolar stable complexes with them. In the absence of heparin, these reactions are slow. In the presence of heparin, antithrombin III undergoes a conformation change which allows it to interact more rapidly with the proteases.

A critical sequence of five carbohydrate residues in heparin is required for binding to antithrombin III. The binding of heparin to antithrombin III leads to a 1000-fold acceleration in the process. Heparin functions as a cofactor for the antithrombin- protease reaction without being consumed. Once the antithrombin-protease complex is formed, heparin is released intact.

Heparins of different molecular weights have different anticoagulant activities. To catalize most efficiently the inactivation of thrombin by antithrombin III a molecule of heparin must bind simultaneously to both thrombin and antithrombin, forming a ternary complex. In contrast, to catalize the inactivation of of factor Xa by antithrombin III the heparin molecule must bind only to antithrombin. As a result, LMWH efficently inhibit Xa but have less effect on thrombin, because the majority of LMWH molecules are of insufficient length to form the ternary complex and thus catalyze inhibition of thrombin. In contrast, UFH efficiently inactivates both thrombin and factor Xa.

Question 9

Monitoring of Heparin Levels and its Uses

Answer 9

MONITORING OF HEPARIN LEVELS

Monitoring of unfractionated heparin therapy is important for maintaining the anticoagulant effect within the therapeutic range and prevent bleeding. Monitoring is usually performed with the activated partial thromboplastin time (aPTT) assay. The aPTT is a test of the integrity of the intrinsic and common pathways of coagulation. The aPTT evaluates the coagulation factors XII, XI, IX, VIII, X, V, II, and fibrinogen. The patient’s plasma is added to an excess of phospholipid, and the time for formation of a fibrin clot is measured. Increasing amounts of heparin in the plasma prolong the time required for the formation of a fibrin clot.

Weight-based dosing of LMWH results in predictable plasma levels in patients with normal renal function. For this reason, it is generally not necessary to monitor blood activity levels of LMWH, except in the setting of renal insufficiency, obesity and pregnancy. The potency of LMWH can be assessed with anti-factor Xa assays. Because LMW heparins are excreted by the kidneys, care should be taken to avoid excessive anticoagulation in patients with renal insufficiency.

USES

UFH and LMWH are used to initiate treatment of venous thrombosis and pulmonary embolism. Warfarin is usually started concurrently, and the heparin is continued for at least 5 days to allow warfarin to achieve its full therapeutic effect.

UFH and LMWH are used in the initial management of patients with unstable angina or acute myocardial infarction.

UFH and LMWH are used during coronary balloon angioplasty to prevent thrombosis.

In contrast to warfarin, UFH, LMWH, and fondaparinux do not cross the placenta and have not been associated with fetal malformations; therefore, these are the drugs of choice for anticoagulation during pregnancy.

Question 10

Adverse Effects and Reversal of Heparin Action

Answer 10

ADVERSE EFFECTS

Bleeding

Hypersensitivity reactions

Heparin-induced Thrombocytopenia (HIT). Two types have been identified. Type I is common and involves a mild decrease in platelet number due to nonimmunologic mechanisms. Usually occurs within the first 5 days of treatment and is not serious. Type II is a systemic hypercoagulable state that occurs in 1 – 4% of individuals treated with UFH for a minimum of 7 days. The risk is lower in individuals treated exclusively with LMWH. It is caused by antibodies that recognize complexes of heparin and a platelet protein, Platelet Factor 4 (PF4). IgG binds to the PF4/heparin complex forming immune complexes. Then IgG binds to the Fc receptor on platelets.

Fc activation leads to platelet degranulation & aggregation. The activated platelets release more PF4. New immune complexes form. This can result in thrombocytopenia (due to platelet consumption) and thrombosis that range from mild to life-threatening. The result can be deep vein thrombosis, pulmonary embolism, or even a heart attack or stroke. Platelet counts can drop 50% or more. Patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor or fondaparinux.

Other Toxicities

Mild elevations of liver transaminases in plasma.

Osteoporosis can occur in patients who receive full therapeutic doses of heparin for extended periods. The risk of osteoporosis is lower with LMWHs or fondaparinux than it is with heparin.

REVERSAL OF HEPARIN ACTION

Excessive anticoagulant action of heparin is treated by discontinuance of the drug.
If bleeding occurs, administration of a specific antagonist such as protamine sulfate is indicated. Note: Protamine will not reverse the effect of fondaparinux.

Question 11

Fondaparinux

Answer 11

Synthetic pentasaccharide that contains the sequence of five carbohydrates necessary for binding to antithrombin III and inducing the conformational change in antithrombin required for its binding to factor Xa.

Fondaparinux is a selective, indirect, inhibitor of factor Xa, with negligible antithrombin activity.

Indicated for prophylaxis and treatment of deep vein thrombosis.

Available as once-daily SC injection.

The potency of fondaparinux also is assessed with an anti-Xa assay.

Question 12

Direct Thrombin Inhibitors (DTIs)

Answer 12

DIRECT THROMBIN INHIBITORS (DTIs)

They exert their anticoagulant effect by directly binding to the active site of thrombin.

Question 13

PARENTERAL DIRECT THROMBIN INHIBITORS

Name the 3 and their Uses

Answer 13

LEPIRUDIN

Hirudin is a powerful and specific thrombin inhibitor from the leech. Now available in recombinant form as lepirudin, a 65-amino acid peptide.

Its action is independent from antithrombin III, therefore lepirudin can reach and inactivate both free and fibrin-bound thrombin in developing clots.

Excreted by the kidney. Should be used with great caution in patients with renal insufficiency as no antidote exists.

Indicated for use in patients with HIT in order to prevent further thromboembolic complications.

Given parenterally. Monitored by the aPTT.

BIVALIRUDIN

Synthetic congener of the naturally occurring drug hirudin. Bivalent inhibitor of thrombin. Given IV. Also inhibits platelet activation. Monitored by the aPTT.

Indicated for use in patients undergoing percutaneous coronary intervention (PCI).

ARGATROBAN

Small molecule thrombin inhibitor.

Indicated for prophylaxis or treatment of thrombosis in patients with HIT.

Indicated in patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).

Given IV. Monitored by aPTT.

Question 14

ORAL DIRECT THROMBIN INHIBITORS

Answer 14

DABIGATRAN ETEXILATE

Prodrug rapidly converted to dabigatran, which reversibly blocks the active site of thrombin.

Dabigatran produces a predictable anticoagulant response, therefore routine monitoring is unnecessary.

Dabigatran is not metabolized by liver enzymes and is excreted mainly in urine.

Approved for prevention of thromboembolic stroke in patients with non-valvular atrial fibrillation.

Dabigatran has no antidote, but it is dialyzable.

Question 15

DIRECT FACTOR Xa INHIBITORS

Name the 2

Answer 15

APIXABAN & RIVAROXABAN

Oral direct factor Xa inhibitors.

Like dabigatran, they do not require coagulation monitoring.

There is no antidote to reverse their anticoagulant effect.

Question 16

Warfarin

Mechanism of Action

Answer 16

THE COUMARIN ANTICOAGULANTS: WARFARIN

This group of drugs is often called oral anticoagulants, because unlike heparin, they are administered orally. The coumarin anticoagulants, act by antagonizing the cofactor function of vitamin K. Initially used as a rodenticide, warfarin is widely used clinically as an oral anticoagulant.

MECHANISM OF ACTION

As stated before, factors II, VII, IX and X undergo a vitamin K-dependent post- translational modification, whereby a number of their glutamic acid residues are carboxylated to form γ-carboxy-glutamic acid residues. Warfarin inhibits vitamin K epoxide reductase. Treatment with warfarin results in the production of inactive clotting factors, because they lack the γ-carboxyglutamyl side chains.

The coagulation factors involved have half-lives ranging from 6 hours (factor VII) to 60 hours (factor II), therefore several hours are required before an effect is seen. A therapeutic anticoagulant effect is usually apparent within 24 hours of warfarin administration. However, peak anticoagulant effect may take 72 to 96 hours. The duration of action of a single dose of warfarin is 2 to 5 days.

Warfarin has no direct effect on an established thrombus, and it does not reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.

The anticoagulant effects of warfarin can be overcome by the administration of vitamin K. However, reversal following administration of vitamin K takes approximately 24 hours.

Question 17

Monitoring of Warfarin Levels

and Uses

Answer 17

Warfarin has a narrow therapeutic index and participates in numerous drug–drug interactions, therefore the effects of warfarin therapy must be monitored regularly (every 2 - 4 weeks). Monitoring is performed with the prothrombin time (PT). This is a test of the integrity of the extrinsic and common pathways of coagulation. In this test, the patient’s plasma is added to a crude preparation of tissue factor (thromboplastin), and the time for formation of a fibrin clot is measured.

The PT is prolonged when the functional levels of fibrinogen, factor V, or the vitamin K- dependent factors II, VII, or X are decreased. Reduced levels of factor IX or proteins C or S have no effect on the PT.

Measurement of the PT is standardized, and is expressed as the International Normalized Ratio (INR) of the prothrombin time in the patient sample to that in a control sample, normalized for the international sensitivity index (ISI) of the laboratory’s thromboplastin preparation compared to the World Health Organization’s reference thromboplastin preparation.

USES

Warfarin is used to prevent the progression or recurrence of acute DVT or pulmonary embolism following an initial course of heparin.

Warfarin is effective in preventing venous thromboembolism in patients undergoing orthopedic or gynecological surgery, recurrent coronary ischemia in patients with acute myocardial infarction, and systemic embolization in patients with prosthetic heart valves or chronic atrial fibrillation.

For treatment of acute venous thromboembolism, heparin, LMWH, or fondaparinux usually is continued for at least 5 days after warfarin therapy is begun, and until the INR is in the therapeutic range on 2 consecutive days. This overlap allows for adequate depletion of the vitamin K-dependent coagulation factors with long half-life, especially factor II.

Question 18

Adverse Effects and Drug Interactions of Warfarin

Answer 18

ADVERSE EFFECTS

The principal untoward reaction caused by warfarin is hemorrhage. It is important to frequently monitor and adjust the anticoagulant effect. Minor bleeding may be treated by withdrawal of the drug and administration of oral vitamin K1. Severe bleeding requires that greater doses of vitamin K1 be given IV. Whole blood, frozen plasma or plasma concentrates of blood factors may also be employed to arrest hemorrhaging.

Cutaneous necrosis due to reduced activity of protein C sometimes occurs during the first weeks of therapy. The pathological lesion associated with the hemorrhagic infarction is venous thrombosis.

Warfarin crosses the placenta readily and can cause a hemorrhagic disorder in the fetus. Furthermore, fetal proteins with γ-carboxyglutamate residues found in bone and blood may be affected by warfarin. The drug can cause a serious birth defect characterized by abnormal bone formation. Thus, warfarin should never be administered during pregnancy. Warfarin is pregnancy category X.

DRUG INTERACTIONS

DRUGS THAT INHIBIT WARFARIN METABOLISM (THUS POTENTIATING ANTICOAGULATION)

Cimetidine
Chloramphenicol
Disulfiram
Fluconazole
Metronidazole
Phenylbutazone
Sulfinpyrazone Trimethoprim-Sulfamethoxazole

DRUGS THAT STIMULATE WARFARIN METABOLISM (THUS REDUCING ANTICOAGULATION)

Barbiturates, Carbamazepine, Phenytoin, Rifampin

Question 19

THROMBOLYTIC (fibrinolytic) DRUGS

Answer 19

Although warfarin, unfractionated and low molecular weight heparins, selective factor Xa inhibitors, and direct thrombin inhibitors are effective in preventing the formation and propagation of thrombi, these agents are generally ineffective against pre- existing clots.

Thrombolytic drugs are used to lyse blood clots and thereby to restore the patency of an obstructed vessel before distal tissue necrosis occurs.

Blood clots can occur in any vascular bed; however, when they occur in coronary, cerebral or pulmonary vessels, they can be immediately life-threatening: coronary thrombi are the cause of myocardial infarctions, cerebrovascular thrombi cause strokes, and pulmonary thromboemboli can lead to respiratory and cardiac failure.

Thrombolytic agents act by converting the inactive zymogen plasminogen to the active protease plasmin. Plasmin is a relatively nonspecific protease that digests fibrin.

Unfortunately, thrombolytic therapy has the potential to dissolve not only pathologic thrombi, but also physiologically appropriate fibrin clots that have formed in response to vascular injury. Thus, the use of thrombolytic agents can lead to hemorrhage of varying severity.

Thrombolytics are contraindicated in patients with healing wounds, pregnancy, history of cerebrovascular accident or metastatic cancer.

Thrombolytic drugs are helpful for unclotting catheters and shunts by lysing clots causing occlusions. They are also used to dissolve clots that cause strokes.

Question 20

Streptokinase

Answer 20

Protein (not enzyme) produced by β-hemolytic streptococci. Combines with plasminogen. This complex catalyzes conversion of plasminogen into plasmin.
The complex also catalyzes the degradation of fibrinogen as well as clotting factors V and VII.

Approved for use in acute myocardial infarction, acute pulmonary embolism, arterial thrombosis and occluded access shunts. It is rarely used clinically for fibrinolysis since the advent of newer agents.

Question 21

Urokinase

Answer 21

Human enzyme synthesized by the kidney and found in the urine. Obtained from human neonatal kidney cells grown in tissue culture. Directly converts plasminogen into plasmin. Approved for lysis of pulmonary emboli.

Question 22

ALTEPLASE, RETEPLASE & TENECTEPLASE

Answer 22

Tissue plasminogen activator (t-Pa) is a serine protease produced by human endothelial cells. t-Pa is a poor plasminogen activator of free plasminogen in plasma, but it rapidly activates plasminogen bound to fibrin in a thrombus or a hemostatic plug. t-Pa is said to be “fibrin selective” (unlike streptokinase and urokinase, which are non-fibrin- selective). Under physiological conditions (low t-Pa concentrations), the selectivity of t- Pa for fibrin limits systemic formation of plasmin and the induction of a systemic lytic state. During therapeutic infusions of t-Pa, however, the higher concentrations of t- Pa may lead to activation of circulating plasminogen, leading to hemorrhage.

ALTEPLASE

Recombinant DNA technology has allowed the production of recombinant t-PA, generically referred to as alteplase. The biological half-life of alteplase is 3-6 min.

Alteplase is indicated for the management of acute myocardial infarction, and acute ischemic stroke. Alteplase should be given within 4.5 hours after the onset of stroke symptoms.

RETEPLASE

Reteplase is modified recombinant human t-PA (some amino acids have been deleted). Reteplase is less fibrin-specific than t-Pa. The half-life is 14-18 min. Because of its longer half-life, reteplase can be given as a “double bolus” (two boluses, 30 minutes apart). Reteplase is indicated for the management of acute myocardial infarction.

TENECTEPLASE

Mutant form of t-Pa that has a longer half-life (20-24 min), and thus it can be given as a single IV bolus. Tenecteplase is slightly more fibrin-specific than t-Pa. It is indicated for the management of acute myocardial infarction.

Question 23

AMINOCAPROIC ACID & TRANEXAMIC ACID

Answer 23

PLASMINOGEN ACTIVATION INHIBITORS (Used to treat bleeding)

Synthetic inhibitors of fibrinolysis. Competitively inhibit plasminogen activation. Can be given orally or IV. Excreted in the urine.

Uses include: adjunctive therapy in hemophilia, and therapy for bleeding from fibrinolytic therapy

A potential adverse effect is intravascular thrombosis.

Question 24

Protamine Sulfate

Answer 24

Low molecular weight protein; chemical antagonist of heparin. High in arginine content. The positively charged protein interacts with negatively charged heparin to form a stable complex with no anticoagulant activity.

Given IV to reverse the effects of heparin in situations of life-threatening hemorrhage or great heparin excess. Protamine is most active against UFH and it can partially reverse the anticoagulant effects of LMWHs. Inactive against fondaparinux.

Can interfere in coagulation when given in absence of heparin, since the basic protein interacts with platelets and fibrinogen. Adverse effects include hypersensitivity, dyspnea, flushing, bradycardia and hypotension.

Question 25

Vitamin K and Plasma Fractions

Answer 25

VITAMIN K

Vitamin K is used therapeutically to correct the bleeding tendency or hemorrhage associated with its deficiency.

Vitamin K deficiency can result from inadequate intake, absorption, or utilization of the vitamin, or as a consequence of the action of a vitamin K antagonist, such as warfarin.

THERAPEUTIC USES

DRUG-INDUCED HYPOPROTHROMBINEMIA

Warfarin interferes with the hepatic biosynthesis of γ-carboxy glutamate-containing clotting factors.

Vitamin K is available clinically in oral and parenteral forms. Onset of effect is delayed for 6 hours but the effect is complete by 24 hours when treating depression of prothrombin activity by excess warfarin or vitamin K deficiency.

If immediate hemostasis is required, fresh-frozen plasma should be infused.

Vitamin K repletion is best achieved with intravenous or oral administration, because its bioavailability after subcutaneous administration is erratic.

PREVENTION OF VITAMIN K DEFICIENCY BLEEDING IN NEWBORNS

There is general consensus that all babies should receive vitamin K. Standard treatment is with vitamin K1 IM administered at birth.

PLASMA FRACTIONS

Deficiencies in plasma coagulation factors can cause bleeding. Spontaneous bleeding occurs when factor activity is less than 5 – 10% of normal. Factor VIII deficiency (classic hemophilia, or hemophilia A) and factor IX deficiency (Christmas disease or hemophilia B) account for most of the heritable coagulation defects.