NSAIDs easy on platelets
100 mg/kg q6h (max 5 gm) IV
4-5 gm (16-20cc) in 250 / 1h, then CIV @ 1gm (4cc)/h x 8h or until bleeding controlled (up to 24-48h)
PO: 5 gm (Ten 500mg tabs or 20cc = 4tsp) then 1 gm/hr x 8 hr
Max dose: 24 gm/d (decreases platelet function at higher doses)
(Note: same dose po/iv)
Elixir: 250 mg/cc = 1.25 gm/tsp
-Do NOT give if evidence of DIC (may worsen)
-Adjust for renal failure
-Avoid if hematuria: may cause clots
-Rarely --> rhabdomyolysis
IV: 10 mg/kg slow IV ( 1mg/min) TID-QID
Supplied: 10cc ampules @ 100mg/cc
PO: 25 mg/kg TID-QID
Supplied: 500mg tabs
Topical: apply IV solution directly
Tox: GI, BP if injected too fast
** Adjust for renal failure **
A selective inhibitor of FXa produced by leech.
A naturally occurring protease inhibitor usually used in conjunction with cardiac bypass surgery. The precise mechanism by which aprotinin minimizes perioperative bleeding associated with CABG surgery is unclear but appears to involve effects on platelet function as well as on coagulation and fibrinolysis. It may preserve platelet membrane glycoproteins that maintain the adhesive and aggregative capacity of platelets. It also inhibits fibrinolysis through inhibition of plasmin and kallikreins. The effect on kallikreins in turn activation of the intrinsic clotting system.
After an initial bolus it is rapidly distributed into the total extracellular space with a rapid drop in plasma concentrations. This is followed by a phase with a half life of about 150 minutes (2.5 hrs), with a terminal elimination phase half-life of 10 hours.
Dosing: First give a test dose: 10,000 units (1.4 mg) IV. If no adverse effect in 10 minutes, then give a loading dose of 2 million units (280 mg) IV/20-30 minutes while the patient is supine, after induction of anesthesia but before sternotomy. Then infuse at 500,000 units/hr (70 mg/hr). Watch for hypersensitivity reactions. Contraindicated in patients allergic to beef.
Aprotinin may falsely prolong the PTT and Activated Clotting Time because of its inhibition of contact activation. It may also alter liver tests and block the acute hypotensive effect of Captopril. It may cause elevation of creatinine (renal failure).
Antithrombin (AT, formerly AT3, also called "heparin cofactor") is a glycoprotein that is a major inhibitor of thrombin and other clotting factors. It is not dependent upon vitamin-K.
AT slowly inactivates thrombin in the absence of heparin. In the presence of heparin, AT rapidly inactivates thrombin. When heparin binds to the heparin-binding site on AT, it leads to a conformational change in AT which accelerates the inactivating process by 4000 fold. In other words, heparin catalyzes the action of AT on thrombin.
Acquired AT Deficiency
Can be caused by:
Accelerated consumption -- acute thrombosis, DIC, major surgery (nadir
around third post-op day with increase to normal by day 5), pregnancy, induced
HBP, pre-eclampsia, eclampsia.
Reduced synthesis -- liver disease
excretion -- nephrotic syndrome. (Nephrotic syndrome is a hypercoagulable
4. Drugs -- estrogens, L-asparaginase, heparin,
Hereditary AT Deficiency
Both types are autosomal dominant.
Type I Deficiency - Due to reduced production of AT, so see reduced antigen and activity. In the heterozygote, it is about 50%.
Type II Deficiency - produced by a discrete molecular defect within the protein. See normal antigen level, but reduced activity.
Of the second type, there are variants:
1. Heparin binding site defect --> reduced heparin cofactor activity. Patients do not usually clot spontaneously, but they do not respond well to heparin.
2. Thrombin binding site defect - These patients have thrombophilia because thrombin cannot be inactivated.
3. Pleiotropic defects - cause variety of clinical effects.
Severe thrombotic disease is most common in patients with Type I deficiency and Type II with thrombin binding site mutation. Thrombophilia is less common in patients with heparin binding-site defect.
Treatment: Patients may require larger-than-usual doses of heparin. In patients who have unusually severe thrombosis or history of recurrent DVTs, or in patients who cannot be adequately anticoagulated, AT concentrates may be needed.
AT concentrate: 50 u/kg dose will usually result in a 120% level in a patient with congenital deficiency with a baseline level of 50% (see Dose). Administer 60% of initial dose at 24 hrs to maintain inhibitor levels in the normal range. Monitor levels to maintain above 80%.1/2 life is 60-90 hrs (~3 days).
Use of AT concentrate as adjunctive therapy or as an alternative to heparin in patients with ATA deficiency and venous thromboembolism has not been studied in controlled trials.
See Blood 75(1): 33-39, Jan 1990
Dose in Units = (PercentDesired - PercentMeasured)*Kg/1.4
Initial dose should be calculated to raise ATIII levels to 120%. Measure post-infusion (peak) dose and trough levels. Monitor levels q12h.
Maintain in 80-120% range by giving 60% of loading dose q24h.
Supplied: 500u/10cc vial, 1000u/20cc vial
APC RATIO: PTT with APC added divided by PTT without APC added [(PTT+APC)/(PTT-APC) = ratio]. Adding APC should prolong the PTT --> an increased ratio. Therefore a lower ratio suggests APC resistance because the numerator is not prolonged.
Lupus Anticoagulants: 3 step test:
1) screening tests: kaolin clotting time, dilute APTT, dilute PT, and dilute RVVT.
2) Tests repeated in a 1:1 mix with normal plasma.
3) Positive tests confirmed with same reagent in presence of excess phospholipids.
To be considered LA+, had to have positive in all three steps.
To see which Profile to order Click Here
Presence of both Acquired APC resistance and LA's was associated with increased risk of thromboembolism in kids with SLE. THIS MAY BE THE MECHANISM BY WHICH LAs LEAD TO INCREASED RISK FOR THROMBOSIS, i.e., by causing APC resistance. There was no increased risk associated with anticardiolipin antibodies (ACA) and APCR. That is, ACAs that do not behave as LA’s do not seem to carry increased risk. (Blood 97:844, 2/01)
Platelet factor 3 deficiency
Factor XIII deficiency
Induces a complex coagulopathy characterized by:
- activation of platelets -> release of granular contents -> storage pool disorder
- activation of fibrinolytic system -> degradation of GP Ib receptor by plasmin
Although ddAVP (desmopressin) has been reported to decrease blood loss in patients on prolonged bypass, other studies have not confirmed any in operative bleeding.
Aprotinin, a plasmin inhibitor, reduces significant bleeding by 50%. It decreases activation of fibrinolysis leading to decreased consumption of clotting factors causing decreased bleeding.
Plasmin has 3 anti-clotting actions:
1. degrades fibrin
2. degrades GP Ib
3. degrades F 5, F 8, vWF
All clotting factors except vWF are made in the liver. Site of F 8 synthesis is unknown, but level does NOT decrease with liver disease.
* = Vit K dependent, W = molecular wt, P = plasma concentration (mcg/ml), H = half-life
Fibrinogen (I): W = 340,000, P= 3,000, H =72-120 hr
*Prothrombin (II): W = 72,000, P = 100, H = ~72 hr
Factor III (Tissue Thromboplastin)
Factor V: W = 330,000, P = 10, H = ~12 hr
*Factor VII: W = 50,000, P = 0.5, H = 3-6 hr
Factor VIII: W = 330,000, P = 0.1, H = 8-12 hr
*Factor IX: W = 56,000, P = 5, H = 24 hr
*Factor X: W = 56,000, P = 10, H = 36 hr
Factor XI: W = 160,000, P = 5, H = 72 hr
Factor XII: W = 80,000, P = 30, H = 48 hr
Factor XIII: W = 320,000, P = 6, H = 200 hr
*Protein C: W = 62,000, P = 4, H = 6-16 hr
*Protein S: W = 80,000, P = 25, H = ?
vWF: W = 225,0000 x n, P = 10, H = 20 hr
Tissue factor: W = 37,000, P = 0.0, H = ?
AT-III: W = 65,000, P = 140, H = 48
-Factors 11,9,10,2 inhibited by antithrombin
-Factors 8,5 inhibited by Protein C&S
-TF and Factor 7 inhibited by TFPI/Xa
- Surface contact factors (Intrinsic pathway): Prekallekrein (Fletcher factor), and HMWK (Fitzgerald factor)
FACTOR [Inheritance Pattern] [Prevalence] [Min. Desired Level] [Replacement Source]
Afibrinogenemia [AutoR] [<200 reported]
Hypofibrin [AutoD or R] [Very rare]
Dysfibrino [AutoD or R] [Rare (>200 types)]
PROTHROMBIN (II) [AutoD or R] [25 kindreds] [30%] [FFP/FIX complex]
FACTOR V [AutoR] [1/1,000,000] [25%] [FFP (10cc/kg)]
FACTOR VII [AutoR] [1/500,000] [25%] [FFP/FIX complex, FVII conc.]
FACTOR VIII [X-link] [1/5,000 males] [80-100% for major bleeding or surgery, 50% for significant bleed, 30% for minor bleed]
FACTOR IX [X-link] [1/30,000 males] [25-50%] [FIX complex or concentrate]
FACTOR X [AutoR] [1/500,000] [10-25%] [FFP/FIX complex]
FACTOR XI [AutoD] [4% Ashk Jews] [20-40%] [FFP]
FACTOR XII [AutoR] [Rare] [None required]
FACTOR XIII [AutoR] [1/sev million] [5%] [FFP/Cryo]
PREKALLIK (Fletcher)[AutoR] [Rare] [None required]
HMWK (Fitzg) [AutoR] [None required]
vWF [AutoD] [1/100] [50%] [DDAVP (except IIB), Cryo, Impure conc.]
· Warfarin takes 4-7 days to have its optimum antithrombotic effect. (It lowers Factor 7 levels more quickly, but takes about 4 days to lower the other vitamin K-dependent factors.)
· Large loading doses do not markedly shorten the time to achieve a full therapeutic effect but cause rapid falls in the level of Protein C, which may precipitate paradoxical thrombosis in the first few days of warfarin therapy.
· Usual starting dose should be 4-5 mg QD, and this dose can often be started without worry about skin necrosis.
· Initiate therapy with the estimated daily maintenance dose (2-5 mg).
· Elderly or debilitated patients often require low daily doses (2-4 mg)
· Patients are confused by alternating daily doses (ie, 7.5 mg and 5 mg)
· Significant changes in INR can usually be achieved by small changes in the dose (15% or less).
· 4-5 days are required after any dose change or any new diet or drug interaction to reach the new antithrombotic steady state.
CONDITION [Minimally Effective] [Recommended INR] [Target INR]
DVT Prevention [1.5-2.5] [2.0-3.0] [2.5]
DVT Treatment [ 2.0-2.3] [2.0-3.0] [2.5]
Recurrent DVT ( >2)  [2.5-4] 
Prevention of stroke [2.0] [2.0-3.0] [2.5]
Prevent recurrence [2.7-4.5] [3.0-4.5]
Decrease mortality [2.7-4.5] [3.0-4.5]
PERIPH ARTERIAL DISEASE
Prevent death  [2.6-4.5]
Prevent systemic emboli [1.5-2.5] [2.0-3.0] [2.5]
CARDIAC VALVE REPLACE
Tissue valves [2.0-2.3] [2.0-3.0] [2.5]
Mechanical valves [1.9-3.6] [3.0-4.5] [3.5]
CEREBRAL EMBOLISM Not evaluated
NATIVE VALVULAR HT DISEASE Not evaluated
Preop Coumadin started 2 weeks prior to hip surgery  [2-3] [2.5]
Start with 4-5 mg on Days 1-2 (or lower in the elderly or infirm).
Day 3 INR < 1.5 give
1.5-1.9 2.5-5 mg
2-3 0-5 mg
Day 4 INR < 1.5 give 10 mg
1.5-1.9 5-7.5 mg
2-3 0-5 mg
Day 5 INR < 1.5 give 10 mg
1.5-1.9 7.5-10 mg
2-3 0-5 mg
Day 6 INR < 1.5 give 7.5 -12.5 mg
1.5-1.9 5-10 mg
2-3 0-7.5 mg
> 10 Stop Coumadin. Contact
patient for exam.
7-10 Stop Coumadin x 2 days. Decrease weekly dose by 25% or by 1 mg/day for next week. Repeat PT in 1 week.
4.5-7 Decrease weekly dose by 15% or by 1 mg/day x 5 days. Repeat PT in 1 week.
3-4.5 Decrease weekly dose by 10% or by 1 mg/day x 3 days of next week. Next PT 1 week.
2-3 No change.
1.5-2.5 Increase weekly dose by 10% or by 1 mg/day x 3 days next week. Next PT one week.
< 1.5 Increase weekly dose by 15% or by 1 mg/day x 5 days of next week. Next PT one week.
Low risk: 6 weeks or until risk gone
Intermediate risk: 6 months
High risk (History of more than 1 venous embolism, APC with Factor V Leiden mutation, or prosthetic valve) Duration = indefinite
INR < 5 : Hold next dose of Coumadin. Decrease dose.
INR 5-9 : Hold 1-2 doses. When INR therapeutic, resume at lower dose. If necessary, can give 1-2.5 mg oral vitamin K1.
INR > 9 : Give 3-5 mg oral vitamin K1. If INR not decreased by 48 hours, may repeat vitamin K1. When INR therapeutic, resume at lower dose.Bleeding or INR > 12:
Give 10 mg vitamin K1 IV. May give q 12h if necessary. Use FFP if quick correction needed.
FFP - contains all clotting factors except V and VIII (but levels of these don't usually drop below 50% with massive transfusion). Dose FFP = 5-15cc/kg
Cryoprecipitate - Each unit is made from 1 unit of whole blood; the volume varies from 5-20 ml/bag.
Each unit contains:
VIII (80-100 u/bag)
Dose: 1 unit/10kg. A "dose" is usually made by pooling 10 bags of cryoprecipitate which should raise the fibrinogen by 75 mg/dl in a 70 kg adult.
From venom of Malayan pit viper.
Acts like thrombin to convert fibrinogen to fibrin. However, it cleaves fibrinopeptide A without activating F XIII. This leads to a defective fibrin that gets eaten up by fibrinolysis rather than getting cross-linked. Nevertheless, ancrod is not a good drug to use in HIT, where thrombin generation is the main problem, because it does not lower thrombin levels.
Dose: 1-2 u/kg SQ/IV over 24h until fibrinogen falls to 50-100.
[Blood 78:2194, 1991]
A mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate. It has predominantly anti-factor Xa activity and is effective in most patients with HIT. It has a half-life of 25 hours which is good if one plans to eventually switch to oral anticoagulation, but a disadvantage if surgery or invasive procedures are planned. Another potential problem is that 10-40% of HIT patients will still cross-react in vitro. This is not necessarily clinically significant, but some physicians are reluctant to use this agent for this reason.
Prophylactic dose 750 u q12h
For DVT in HIT: 2000u IV, then 2000u SQ q12h
Comes in 750u pre-filled syringes.
400u x 3hr
300u x 3hr
then 150-200u/hr. AIM for Anti-Xa 0.5-0.8
CAROTID ENDARTERECTOMY (70kg)
5000u IV Preop +/- 750mg BID Post-op
Flush solution: RML 1250u in 1L inadequate. UK flush of 250,000u in 1L worked especially & LMD flush at end to coat
CARDIAC TRANSPLANT OR CAB
8750u IV pre CPB
7500u to prime pump
If > 2hr procedure, 1500u q 2hr
150-250u/hr, 6-12hr support
2500u bolus (if <90kg)
3750u bolus (> 90kg)
2500u bolus (do not repeat if cath), then 150-200u/hr x 1-2days
The most sensitive single test for DIC is the platelet count.
DIC is due to increased activity of both thrombin (which activates platelet aggregation and clotting) and plasmin (which activates fibrinolysis).
Give cryoprecipitate to keep fibrinogen > 150 mg% (Usual dose: 1 unit/10kg)
Give FFP to keep PT < 15 sec (Usual dose: 10 ml/kg)
Give Platelets to keep platelet count > 20K
Antithrombin: Restoration of antithrombin levels to 150% using antithrombin concentrates has been reported. (Sem Hema 31:(2) Suppl 1 pp60-64, 4/94). An antithrombin level of <50% was associated with fatal outcome with a specificity of 96% and sensitivity of 76% (Fourrier Chest 101:816, 92)
- Low dose infusion (10 u/kg/hr) may be helpful, especially if clotting is more predominant than bleeding. May also be used as stop gap (eg, while inducing APL). Lower doses used: 50U/kg bolus, then 400-750 U/hr CIV). Adjust to platelet count and fibrinogen concentrations.
- Rarely, may encounter heparin resistance due to decreased antithrombin. In such cases replenish antithrombin.
- Heparin is especially useful in Chronic DIC such as Trousseau's syndrome (which is frequently resistant to warfarin).
Antifibrinolytics (such as aminocaproic acid or tranexamic acid):
- Since increased fibrinolysis is a major part of the problem, use of antifibrinolytics is controversial because of the potential to exacerbate the thrombotic component by inhibiting fibrinolysis. Have been used successfully in APL.
Minor: Load: none, then 10-15 u/kg
Major: Load: 30-40 u/kg then 30-40 u/kg q12h for 2-4 days
Minor: Load: 20-30 u/kg, then 15 u/kg q 24h
Major: Maint: 60-70 u/kg, then 20-40 u/kg q 24h x 2-4 days
MILD BLEEDING (early hemarthrosis, hematoma, epistaxis, hematuria, gingival or dental bleeding unresponsive to EACA) Factor 8: 15u/kg (30%) Factor 9: 20u/kg (20%)
MAJOR BLEEDING (joint with pain/swelling, potential airway obstruction, head trauma without neurological deficit, severe phys trauma without bleeding, severe abdominal pain, GI bleeding) Factor 8: 25u/kg (50%) Factor 9: 40 u/kg (40%)
LIFE-THREATENING BLEED (CNS bleed, major trauma w bleed, surgery) Factor 8: 40-50u/kg (80-100%) Factor 9: 60u/kg (60%)
The principles are:
· For FVIII, the dose is one half the level you want to achieve times the wt in kg.
· For F IX, the dose is the desired level times the weight in kg (because the volume of distribution is twice that of F VIII. Other Difference: 1/2 life of IX is twice as long, so only have to give once a day rather than every 12h for F VIII.
· For surgery, keep levels at highest level initially, then at medium level for several days, then low level for 7-10 days. Orthopedic surgery may require longer periods.
Numbers in () represent levels required for Hemostasis
FACTOR I (Fibrinogen) (100mg/ml)
FACTOR II (Prothrombin) (20-40%)
Rarest congenital deficiency (55 cases reported). Sometimes decreased in amyloidosis (along with other K-dep factors. Factor X is most common)
FACTOR V (<25%)
AutoR. Hereditary homozygous FV def very rare. Also called parahemophilia. Synthesized by liver and megakaryocytes --> prolongation of both PT and PTT.
Factor 5 deficiency can cause a prolonged bleeding time if due to decreased platelet factor V.
Factor 5 is particularly lowered by cardiopulmonary bypass if thrombin glue is used. (Bovine thrombin contains small amounts of Factor 5 causing the production of antibodies to Factor 5.)
Ddx: combined FV and VIII (see FMFD below)
FACTOR VII (10-20%)
AutoR (chrom 13)
Sometimes decreased in amyloidosis
Variable amounts of bleeding, does NOT correlate with factor level
Ddx: liver disease, warfarin intox, vitK
TX: F VII concentrates
Although 1/2 life only 3-4hr, replacement needed q12-24. Major surgery has been done with levels as low as 10%.
FACTOR X (10-20%) (Stuart-Prower Factor)
Sometimes decreased in amyloidosis (most common).
Umbilical and mucus membrane hemorrhage. Both PT/PTT abnormal.
Ddx: vitK def, liver disease, warfarin
TX: FFP (15-25cc/kg) q12h. Can also use prothrombin complexes that contain F X
FACTOR XI (15-25%)
One of the "contact factors" along with
XII, PK, HMWK
Is the only contact factor whose deficiency can --> bleeding. Almost exclusively Ashkenazi Jews.
Incomplete AutoR (chrom 4)
When symptomatic, see mild-mod bleeding after trauma or surgery
Bleeding does NOT correlate with level. Only 50% with deficiency actually bleed
TX: FFP. Not known what level to achieve, but >50% probably
FACTOR XII (Not associated with bleeding. May actually have some risk for thrombosis, but this is unproven)
PREKALLIKREIN (Fletcher factor)
--> abnormal PTT but not bleeding
Ddx: just need specific assay to distinguish from each other
Tx: None needed
FACTOR XIII (25-50%)
Acquired: leukemia, UC, Chron's, DIC
F XIII also seems to contribute to wound healing. There is an increased incidence of keloids.
Umbilical stump bleeding
High incidence of CNS bleeding
Clinically similar to fibrinogen problems
Normal screening tests
Abnormal clot formation --> more easily dissolved clot (ie clot is soluble in urea or acetic acid)
Tx: Cryoprecipitate, FFP (5cc/kg)
Type [Factor Deficiencies] [Pathogenesis]
I [V, VII] [Unknown]
II [VIII, IX] [Unknown]
III [II,VII,IX,X] [decreased gamma-carboxylation]
IV [VII,VIII] [Unknown]
V [VIII,IX,XI] [Unknown]
VI [IX,XI] [Unknown]
Product [Company] [Purity] [Method] [Activity]
Monoclate P [Armour] [High] [Pasteur] [5-10U/mg]
Hemofil M [Baxter-Hyland] [High] [Detergent] [2-11]
Koate HP [Miles-Cutter] [Interm] [Solv deterg] [9-22]
Humate P [Armour] [Interm] [Pasteur] [1-2]
Also contains 2.09 u vWF per unit F VIII.
Usu dose is 20-40 u vWF/kg once daily.
Ie, 10-20u Humate-P/kg once/day
AlphaNine [Alpha Therapeu] [Heat/sol] 
AlphaNine SD [Alpha Therapeu] [Sol deterg] 
Mononine 7M [Armour] [Ultrafilter] 
F IX COMPLEX CONCENTRATES
Konyne 80 [Miles-Cutter] [Dry heat] [1.3]
Proplex T [Baxter-Hyland] [Dry heat] 
Profilnine HT [Alpha Therapeu] [Heat/solv] 
Bebulin [Immuno] [Vapor heat] 
ACTIVATED F IX COMPLEX CONCENTRATES
NOTE: The use of these products has decreased now that recombinant Factor 7 is available. See Factor 7
Autoplex T [Baxter-Hyland] [Dry heat] 
FEIBA [Immuno] [Vapor heat] [0.8]
Dose of either Autoplex or Feiba: 75U/kg q 8h
Porcine F VIII [Porton] [None] [>50]
Recombinate [Baxter] [Recomb None] [2.5]
Kogenate [Miles-Cutter] [Recomb None] [8-30]
Fragments A&B demonstrate the activation of fibrinogen (conversion of fibrinogen to fibrin)
D Dimer: produced from cross-linking of fibrin clot, so demonstrates that clotting has actually occurred (such as in DIC)
Administration and therapeutic monitoring. Before beginning thrombolytic therapy the prothrombin time, partial thromboplastin time, thrombin time, fibrinogen, and platelet count should be determined to assess hemostatic competence and to serve as a guideline for subsequent therapy. Concurrent use of antiplatelet drugs or anticoagulants is to be avoided. Both streptokinase and urokinase should be administered by continuous intravenous infusion via a constant-infusion pump. No medications should be added to the lines containing streptokinase or urokinase. The usual loading dose of streptokinase is 250,000 units given intravenously over 30 minutes followed by an infusion of 100,000 units/hr for 24-72 hours. The initial loading dose for urokinase is 4400 units/kg given over 10 minutes followed by an infusion of 4400 units/kg/hr for 12 hours. Optimal duration of therapy is uncertain. For pulmonary embolism, equivalent results have been obtained with 12 or 24 hours of urokinase or with 24 hours of streptokinase. Most studies have utilized 72 hours of streptokinase therapy for deep venous thrombosis although considerable thrombolysis may be achieved with as little as 12 hours of therapy. Only streptokinase has been approved for treatment of deep venous thrombosis. Recombinant t-PA has been successfully used in the treatment of angiographically documented pulmonary embolism. The drug was infused through a peripheral vein over 2 hours (25 mg/hour); if immediate repeat angiography showed no clot lysis, an additional 40 mg of t-PA was given over the ensuing 4 hours. Angiographic evidence of clot lysis was marked in the majority of patients, but there was considerable bleeding morbidity. A recent trial compared 100 mg of t-PA infused over 2 hours with a 24-hour-regimen of urokinase for the treatment of patients with acute pulmonary embolism. In the doses used, t-PA resulted in more rapid hemodynamic improvement and clot lysis than did urokinase. However, use of t-PA for the treatment of acute pulmonary embolism remains investigational. For occluded catheters or arteriovenous cannulae, two 250,000 unit instillations of streptokinase (wait 2 hours after instillation before aspiration and flushing) or 1-2 5000 unit instillations of urokinase (wait 30-60 minutes before aspiration) have been recommended.
Laboratory tests are used to ascertain that a lytic state has been achieved. If the thrombin time is more than twice the control value 3 hours after initiation of therapy, there is usually adequate activation of the fibrinolytic system. A decrease in serum fibrinogen and the appearance of fibrinogen-fibrin degradation products provide additional indications of systemic lysis. An effective level of fibrinolytic activity is produced in about 95% of patients; if after 3 hours laboratory tests fail to indicate systemic lysis, treatment should be immediately reevaluated. Failure to achieve a lytic state, despite a second loading dose and repeated laboratory assessment after another 3-4 hours of infusion, mandates cessation of fibrinolytic therapy and prompt administration of heparin. Because of its antigenicity and the potential for high circulating titers of streptococcal antibodies, streptokinase should not be used for 6-12 months after a course of treatment; urokinase can be used in its stead. Laboratory monitoring does not predict the extent of clot lysis and the risk of bleeding is not correlated with the degree of change in fibrinolytic laboratory parameters. Dose alterations, once a lytic state has been achieved, do not enhance the extent of thrombolysis nor decrease the risk of hemorrhage. After thrombolytic therapy has been completed, the partial thromboplastin time should be monitored; when this value falls to approximately twice the control level, heparin infusion should be initiated without a loading dose for 5-10 days followed by oral anticoagulants.
Complications and contraindications to thrombolytic therapy. During thrombolytic therapy patients should be kept at bed rest, handling of the patient should be minimized, and invasive procedures should be avoided. All parenteral medications should be discontinued. Absolute contraindications to thrombolytic therapy include a recent (within 3 months) cerebrovascular accident, an intracranial neoplasm, recent (10 days) cranial surgery or trauma, severe uncontrolled hypertension, major surgery within 10 days, active internal bleeding, or a recent history of prolonged cardiopulmonary resuscitation. Nine percent of patients in the Urokinase Pulmonary Embolism Trial experienced hemorrhage that necessitated transfusion or cessation of treatment. Intracranial hemorrhage has been reported to occur in about 1% of patients treated with thrombolytic agents for 12 or more hours but in only 0.2% of patients receiving a 1-hour intravenous infusion of streptokinase after acute myocardial infarction. More commonly, light bleeding or oozing may occur from venipuncture or arteriotomy sites and can usually be controlled by mechanical compression. Arterial blood gas samples should be obtained only if absolutely necessary and should be taken from the upper extremity, followed by digital compression on the puncture site for 30 minutes. Serious hemorrhage may require discontinuation of treatment. Cryoprecipitate can be administered for severe (less than 100 mg/dl) hypofibrinogenemia (each bag of cryoprecipitate contains about 400 mg of fibrinogen). For uncontrollable bleeding epsilon-aminocaproic acid can be administered either orally or intravenously as a 4 gm loading dose, followed by 1 gm/hr for 2-4 hours. Mild allergic reactions occur in up to 15% of patients treated with streptokinase and include urticaria, pruritus, flushing, nausea, vomiting, headaches, and musculoskeletal pain. These reactions occur much less frequently in patients treated with urokinase. Rare instances of bronchospasm and angioneurotic edema have also been reported. Hydrocortisone (100 mg IV before beginning therapy and then 100 mg every 12-24 hrs for the duration of the infusion) can be used prophylactically to minimize allergic reactions in patients receiving streptokinase. Mild febrile reactions may be observed in up to one-third of patients receiving streptokinase and in a smaller number of patients treated with urokinase. Embolic phenomena may be precipitated by thrombolytic therapy: Clinically significant pulmonary embolization occurring during thrombolytic therapy for deep venous thrombosis is probably very infrequent, although pulmonary reperfusion edema may occur after rapid lysis of massive pulmonary emboli. Distal embolization of arterial thromboemboli during induced thrombolysis is a more common occurrence and may contribute to tissue ischemia.
Heparin binds to antithrombin, which in turn binds to Xa and thrombin (IIa). When heparin binds to antithrombin, it causes the activity of antithrombin on thrombin to increase 4000 fold. Potentiates the action of antithrombin III and thereby inactivates thrombin (as well as activated coagulation factors IX, X, XI, XII, and plasmin) and prevents the conversion of fibrinogen to fibrin; heparin also stimulates release of lipoprotein lipase (lipoprotein lipase hydrolyzes triglycerides to glycerol and free fatty acids)
LMWH also exerts its effect on Xa through binding to antithrombin, but the molecules are too short to also bind to thrombin.
Some LMWH’s have longer molecules (more than 18 kilodaltons) in the mixture, so there may be some antithrombin activity. The purity of the LMWH is expressed in terms of the ratio of anti-Xa activity to anti-IIa. Heparin would be 1:1 since both factors are affected equally. Most LMWH’s are in the range of 4:1 because they affect FXa more than IIa.
1. Make calculation based on actual weight.
2. Bolus: 80 u/kg
3. Initial infusion: 18 u/kg/hr (mix 100 u/ml)
4. Lab: PTT in 6 hrs, CBC q 3 days
PTT < 50: Bolus 80 u/kg and increase rate by 4 u/kg/hr. Next PTT in 6 hrs.
PTT 50-69: Bolus 40 u/kg and increase rate by 2 u/kg/hr. Next PTT in 6 hrs.
PTT 70-104: no change. Next PTT in 24 hrs.
PTT 105-135: Decrease rate by 2 u/kg/hr. Next PTT in 6 hrs.
PTT > 135: Stop infusion for 1 hr, then resume at 3 u/kg/hr less than previous rate. Next PTT in 2 hrs. Call if still > 135.
Round doses to nearest ml/hr (nearest 100 units/hr)
LMWH for DVT (Levine NEJM 334:677 3/96)
Enoxaparin 1 mg/kg SQ BID (100 mg/cc vials) or 1.5 mg/kg SQ QD.
Coumadin started on day 1-2
Patients treated until PT therapeutic x 2 days (or minimum of 4-5 days)
LMWH FOR KNEE ARTHROPLASTY (AIM 7:619 4/96)
Enoxaparin 30mg SQ BID x 14 days.
Was more effective than Coumadin in reducing incidence of DVT overall. No difference seen in incidence of proximal DVT or bleeding.
Hyperhomocysteinemia is due to mutation in the gene that codes for 5,10-methylene tetrahydrofolate reductase (MTHFR) which catalyzes the remethylation of homocysteine into methionine. Abnormalities lead to increased levels of homocysteine and decreased levels of folate.
30-50% of Americans are carriers (heterozygotes) of this mutation (C677T). 11% are homozygotes with homocysteine levels 20-40 times normal. Other gene mutations that code for enzymes in homocysteine metabolism have been identified, and combined heterozygous deficiencies may result in the same net effect as homozygous mutations of this single gene.
Homocysteine seems to exert its thrombotic effect primarily through injury to the blood vessel walls as the sharp crystals rub against the epithelium. This injury leads to platelet activation which, in turn, initiates the formation of fibrin.
The treatment for thromboembolism in the setting of hyperhomocysteinemia is the same as thrombosis in anyone else. However, correction of the underlying condition should also be addressed. Dietary supplementation with folate, vitamin B6 and vitamin B12 have all been advocated though long-term studies have not yet proved whether such interventions really make a difference.
Treatment: Folate 5mg TIW (some give QD). Some also add vitamin B6 300 mg QD and vitamin B12 1000 mcg weekly
Liver makes all clotting factors except VIII. Includes PK & HMWK.
Also makes plasminogen, a2-antiplasmin, proteins C&S, and AT-III.
vWF is made by endothelial cells and megakaryocytes.
Endothelial cells also make thrombomodulin and TFPI.
Complex problems may develop in liver disease because it makes coagulants and anticoagulants. Moreover, get defective clearance of plasminogen activator--> hyperplasminemia -->destruction of circulating fibrinogen. (This type of bleeding may be particularly prominent after portacaval shunt.)
DIC-like picture often seen. Usually it is not truly DIC, but occasionally it is.
FFP-has all factors, but need large volume
Prothrombin complex concentrates (aFIX concentrates). These have some inherent procoagulant properties, so must be careful. Giving FFP (which contains AT-III) along with FIX concentrates may help reduce risk.
Antifibrinolytic agents-ONLY if no evidence of DIC (contraindicated in DIC). DIC unlikely if VIII:C normal or high, FDPs normal or only slightly elevated.
Use of heparin in liver disease is controversial. Usually NOT recommended.
Indicated for prevention of DVT in patients following hip or knee replacement therapy. NOT recommended for protection in patients with artificial heart valves. Not known what effects might be in pregnancy.
Dose: Adults - 30mg SQ BID starting 12-24hrs post-op.
Average duration is 7-10 days, but can give until risk for DVT is over. Should not be given IM.
For TREATMENT of DVT:
1mg/kg q12h OR
1.5 mg/kg once daily. (Equal efficacy). Either is as good as standard heparin (AIM 134:191 2/01)
Prevention: 2500u SQ 1-2h preop, then QD x 5-10d
Treatment: 200u/kg SQ QD x at least 5d, starting Coumadin on day 1. (Confirm this dose & sched b4 using)
LAs are antiphospholipid antibodies (APLA). So are anticardiolipin abs (ACA). LA's are more predictive of thrombotic events than are ACA's.
LAs interfere with the phospholipids used to perform the PT /PTT by limiting the quantity of phospholipid available to support coagulation reactions, thus prolonging the coagulation times.
There are some considerations concerning the diagnosis of LAs:
1) The effect of LAs on phospholipid-dependent coag assays depends on the diligent removal of platelets and platelet fragments from plasma
2) The sens and spec of "confirmatory" assays varies, and each is capable of detecting only subpopulations of abs. Thus can get discrepant results if different labs used.
3) A normal PTT is not enough to exclude a LA. So if suspect one, need to do additional screens such as kaolin clotting time or DRVVT.
4) Evaluation of pt with prolonged PTT needs to consider clinical setting as well as lab values. Some patients may have deficiencies of or inhibitors to specific clotting factors in the extrinsic pathway. For example, marked discrepancies in Factor 12 levels have been noted in patients with LAs. Also, consider the possibility that when APLA's are present, they may have an infectious etiology such as syphilis, Lyme disease, HIV, or hepatitis C. They may also be seen with certain medications (e.g., antipsychotics)
PTT -- Repeating the PTT using a reagent that is not
sensitive to LA's should lead to normalization of the PTT. Also note the effect
with warming: factor inhibitors will tend to correct the PTT initially, but get
longer with warming. LA's tend not to correct initially, and they do not
generally get worse with warming.
Also note that LA's may result in artifactual decreases in factor levels since they are based on the aPTT. These patients can be misdiagnosed as having multiple coagulation factor deficiencies. Progressive dilution will result in improved coagulation factor levels (because the LA gets diluted).
DRVVT -- Considered to be one of the most sensitive of LA tests. Performed by using RVV in a system containing limiting quantities of dilute rabbit brain phospholipid. The RVV directly activates Factor X --> formation of a fibrin clot. LA's prolong the DRVVT by interfering with the assembly of the prothrombinase complex. To ensure that the prolongation is not due to a factor deficiency, the method uses mixtures of patient and control plasmas. The presence of the LA may be confirmed by adding an excess of phospholipid which will correct the prolongation. (Esoterix reports the difference between the PTT and the DRVVT, so an elevated number means there was correction. Ie, high number is consistent with presence of LA.)
Kaolin Clotting Time -- This assay depends upon the ability of APLA's to block the availability of trace quantities of phospholipid present in centrifuged plasma from participation in coagulation reactions.
Platelet Neutralization Procedure (PNP) -- Uses fresh washed platelets as the source of phospholipid. Doing this will normalize the PTT when LA's are present. (Esoterix reports the difference between the PTT and the PNP, so an elevated number means there was correction. Ie, high number is consistent with presence of LA.)
Hexagonal Phase Phospholipids -- Incubation of plasma with the hexagonal phase of phosphatidyl ethanolamine (LA’s don’t bind to the lamellar phase) should absorb the LA antibodies, if present, and therefore normalize the PTT. (Esoterix reports the difference between the PTT and the Hex, so an elevated number means there was correction. Ie, high number is consistent with presence of LA.)
OK to use Trilisate (is non-acetylated salicylate that does not poison platelets)
Dose: 750mg BID-TID. Can give up to 3000 mg/day
LOW RISK FOR THROMBOEMBOLISM (eg, A Fib)
Stop Coumadin 3-5 days before op. Restart when concern for bleeding is gone.
HIGHER RISK (eg, recent PE or DVT)
Stop Coumadin & put on full-dose heparin.
Stop heparin at least 6h prior to surgery.
Restart heparin when no longer worried about bleeding.
Vit K will shorten time to normalization of INR preop, but will complicate reinstitution of warfarin postop.
MINOR SURGERY (Dental extraction, cataracts)
Do not need to stop Coumadin.
Just lower INR to 1.5.
No clear guidelines. Some just stop Coumadin 1-5 days preop. Others put on heparin. Depends on perceived risk of thromboembolus.
Controversial whether it is ok to do LPs or epidurals while anticoagulated. Should avoid central line placement.
INDICATION [Preop] [Postop]
Month 1 [IV Hep*] [IV Hep]
Months 2-3 [No change+] [IV Hep]
RECURRENT DVT** [No change] [SC Hep]
ACUTE ARTERIAL EMBOLISM (Mon 1) [IV Hep] [IV Hep++]
MECH HT VALVE [No change] [SC Hep]
NONVALV AFIB [No change] [SC Hep]
*IV Hep at therapeutic doses. SC Hep means LMWH at preventive doses.
+If patients already hospitalized, can start SC Hep, but don't hospitalize solely for this purpose.
**Refers to patients whose last episode occurred >3mon before evaluation but who require long-term anticoagulation because of high risk for recurrence.
++Use IV Heparin postop only if risk for bleeding is low.
PT < 14.5
PTT < 34
MECHANISM: Natural hirudin is a specific inhibitor of thrombin. Comes from the leech, Hirudo medicinalis. Recombinant form of hirudin made from yeast. Binds to the active site of thrombin and to the exosite at which thrombin binds to fibrinogen. (This is a different site than where heparin binds.) In contrast to heparin, hirudin does not require AT-III to interact with thrombin. It can also inhibit thrombin that is bound to fibrin. Hirudin, and its synthetic analogue, hirulog, provide effective anticoagulation without inducing bleeding in animals. It is a good drug for HIT syndrome because thrombin generation, more than platelet aggregation, is actually the problem in HIT syndrome.
Its half-life is ~1hr. No known antidotes. Does not seem to affect platelets (which distinguishes it from argatroban, which does inhibit platelet aggregation).
Refludan affects all the clotting assays, including the prothrombin time. (If trying to convert to Coumadin, see instructions for argatroban.). Also note that the ACT (activated clotting time), which the cardiologists like to use, does not correlate well with plasma lepirudin levels.
ANTIBODIES: 40-70% of patients on Refludan for more than 5-7 days develop antibodies. These antibodies do NOT inhibit function, but may actually facilitate the action of the drug. Thus the PTT needs to be checked daily to ensure that a downward dose adjustment is not required.
For treatment of thrombosis (acute HIT): 0.4 mg/kg bolus, then 0.15 mg/kg/hr
For treatment with thrombolysis (acute HIT plus thrombolytic therapy): 0.2 mg/kg bolus, then 0.1 mg/kg/hr
For prophylaxis (isolated HIT without thrombosis): No bolus. Just 0.1 mg/kg/hr infusion
The package insert says to follow the PTT aiming to keep the PTT ratio 1.5-2.5. However, this confuses nurses, so use the guidelines below (adapted from heparin protocol).
Sample Orders (based on BSA heparin sliding scale, low-risk protocol):
For more conservative dosing based on BSA’s current PTT normals, click here.
- Give bolus (see above for dose)
over 15-20 seconds, then start infusion.
- Check first PTT 4 hrs after bolus.
- Adjust as follows:
PTT < 50: Increase by 20%. Next PTT in 4 hours.
PTT 50-69: Increase by 10%. Next PTT in 4 hours.
PTT 70-104: No change in dose. Next PTT in the AM.
PTT 105-135: Decrease rate by 10%. Next PTT in 4 hours.
PTT > 135: Stop infusion x 2 hours. Resume at 1/2 previous rate. Next PTT in 4 hours.
Max infusion rate no greater than 0.21 mg/kg/hr.
CAUTION: Renal excretion, so be careful in renal disease. For patients on dialysis, AVOID INFUSION. Dose is 0.1-0.2 mg/kg, bolus only, QD or QOD.
Notes on surgery: Refludan has been used during bypass surgery in patients with HIT. Doses from 0.25 mg/kg to 50 mg (total) have been used to prime the heart/lung machine, then additional boluses given to maintain lepirudin plasma levels above 2.0-2.5 mcg/ml. Depending on the type of surgery, lepirudin infusion rates ranged from 0.04 to 0.23 mcg/kg/hr. Monitoring is generally done using the ecarin clotting time (ECT) to monitor lepirudin levels during cardiac surgery. (The activated clotting time (ACT) and aPTT both correlate poorly with plasma lepirudin levels.)
Indication [% risk without treatment] [% Risk Reduction with treatment]
Month 1  
Months 2-3  
(Risk is 100x greater with surgery)
RECURRENT VENOUS TE [15%/yr] 
NONVALVULAR ATRIAL FIB [5%/yr] 
NONVALV AFIB & PREVIOUS EMBOL [12%/yr] 
MECHANICAL HT VALVE [8%/yr] 
ACUTE ARTERIAL EMBOLISM  
Converts fibrinogen to fibrin
Activates factor 13 which --> cross-linking of fibrin
Activates factor 11 --> helps generate 9
Activates factors 5 and 8 --> cofactors
Induces platelet aggregation
Activates Protein C (which inactivates Va and VIIIa)
Stimulates endothelium to release prostacyclin --> vasodilatation and platelet aggregation --> PDGF and PAI-1 --> blocks t-PA activation of plasminogen to plasmin
Binds to thrombomodulin thereby reducing thrombin’s procoagulant properties and enhancing its activation of Protein C.
Chemotactic for monocytes/macrophages
- Massive PE
- DVT of upper extremity
- DVT proximal leg
- Peripheral art occlusion
- CVA, CNS trauma or surgery within past 2 months
- Brain or spinal cord neoplasms (including metastases)
Within Past 10 Days:
- Major surgery
- Arterial procedure not accessible to compression
- Biopsy " " " "
- History GI bleeding secondary to anticoagulation (not ASA)
- LV thrombus
- Uncontrolled HBP
- Pregnancy or delivery within past 10 days
- SK and UK better at dissolving big venous clots than tPA.
- SK very antigenic, inducing production of anti-streptococcal Abs. May not be able to use again for 6 months.
- TPA best for peripheral art clots, in which case intra-arterial infusion best.
- Premed: Hydrocortisone, Tylenol, Benadryl
- DVT: 250,000 u IV/30min, then 100,000 u/hr x 72hr. Local or systemic administration.
- PE : Same as DVT for 12-24hr. No advantage local vs systemic.
- Perip A Occ: Same as PE for systemic. Local infusion dose 10,000 u/hr x 12-72hr.
- MI : 1.5 million u IV/1hr for systemic. 3000 u/min for up to 2hr for local admin.
- DVT: 4000 u/kg IV/10-30min, then 4000u/kg/hr x 24-72hr. Local or systemic
- PE : As for DVT. No advantage of 24 vs 12hr or local vs systemic.
- Peripheral Arterial Occlusion: As for DVT for systemic x 12-72hr. Local infusion at 4000 u/min until flow re-established, then 1000-2000 u/min until thrombus totally dissolved over 12-18hr
- MI : Up to 3 million u IV/1hr for systemic. 10,000 u/min for up to 2hr for intracoronary.
No premed needed
- DVT: no proven efficacy
- PE : 100mg IV/2hr. Systemic preferred.
- Periph A Occ: Under study
- MI : 100mg IV/3h, then 6mg bolus, then 54mg iv/1hr, then 40mg over 2hr. Systemic preferred.
For most clinicians, a hypercoagulable state describes a person at risk of developing clinical thromboses in settings where normal persons are not.
Virchow postulated that the causes of thromboembolism could be placed into three major categories: (1) blood flow, (2) inflammation of or near vessels, or (3) alterations in the blood itself. Science has confirmed the first two, but the third is more difficult to demonstrate.
If low levels of clotting factors cause bleeding, maybe higher levels, such as fibrinogen and VIII, cause clotting. Research has not borne this out, however. Increased levels of activated factors are thrombogenic, but only when abetted by other circumstances such as stasis or impaired hepatic clearance of activated factors.
Research tests that demonstrate a hypercoagulable state but that fail to
prove cause-effect include:
Fibrinopeptide A by RIA (evidence of thrombin acting on fibrinogen)
Prothrombin fragments F1+2 (the small peptides released when Xa acts on prothrombin)
Increased PF4 (incr levels imply platelet activation)
Increased beta-thromboglobulin (released from platelet granules)
Increased thromboxane B2
Coagulation is counterbalanced and regulated by 4 recognized anticoagulants acting as partners to limit and localize clot formation. They are AT-III, the protein C system, TFPI, and the fibrinolytic system.
Produced by gene on chrom 1. Type I: Decreased production. Type II: normal level when measured immunologically, but Decreased function.
Deficiency is inherited as an Auto-D trait although there are variations. Sometimes have normal levels of dysfunctional protein. Heterozygotes with levels 25-50% are predisposed to recurrent DVTs, PEs, and clotting in unusual sites such as mesenteric veins. Severity may vary within families and does not correlate well with AT-III levels. Onset at any age, but usually in 20s.
Diagnosis: demonstrate low functional level.
Tx: Heparin, usually requiring very high doses, followed by lifelong oral anticoagulation.
Treatment of asymptomatic patients controversial, but should be considered in patients at risk for clotting (pregnancy, post-op, immobility, etc).
AT-III concentrates available from Baxter-Hyland and Miles. Terminal 1/2 life of infused AT-III is 61-90 hrs! Try to maintain at 80% level in those patients who require infusion.
Protein C System
Auto D. Gene on chrom 2.
Partial deficiency found in 1/200-300 asymptomatic patients. However, heterozygous def that --> thromboses found in only 1/1000. Thus 15% of heterozygous patients may have normal functional Protein C levels. Type I: in antigen & functional Protein. Type II: normal immunologic levels, but function. Type III: normal immunologic and functional levels when measured in chromogenic assay, but activity when measured in phospholipid-dependent clotting assay. Due to dysfunction of Gla domain --> binding of Protein C to phospholipid.
Venous thromboses similar to AT-3 def, usu when levels are <50%.
Warfarin-induced skin necrosis: pathognomonic for Protein-C def. Occurs because 1/2 life of Protein C (5-6hrs) is short, and anticoagulation is blocked before coagulation --> microvascular thrombi in skin.
Purpura fulminans: Infants homozygous for protein C def. Treatment with Protein C concentrate.
Protein S deficiency: levels < 60% may --> clotting similar to AT-3 or Protein C def.
Tissue Factor Pathway Inhibitor
Deficiency has not yet been demonstrated to --> thrombosis.
Defects here are not really hypercoagulability because they do not represent excessive clot formation, but rather, defective clot lysis.
- plasminogen activity (with nl amt)
- levels of plasminogen
- Defective release of plasminogen activator from vascular endothelium
Dx: sophisticated tests. Prolonged whole blood clot lysis time may give a clue.
Plasminogen activator inhibitors (PAIs): Incr levels of PAI-1 have been linked to thrombophilia. However, have to be careful about ordering esoteric & expensive tests that may be non-diagnostic.
ELEVATED FACTOR VIII
Factor 8 (levels above 150 assoc with 4X risk of venous thrombosis. This pertains to chronically elevated levels, not acute phase rx. Mechanism unclear-may be genetic.)
Usu --> bleeding, but occ --> venous thrombosis. May be due to formation of rigid fibrin gels that are resistant to removal by plasmin.
Incr levels --> arterial and venous clotting.
Cystadane (betaine), an orphan drug, has recently been marketed for treating
this. It is derived from choline and is a substrate in the alternate recycling
pathway of homocysteine to methionine. Usu dose 3gm bid, up to 20gm QD. Minimal
side effects. See Med Ltr 39(993):12,
Results in venous clotting.
Currently, patients with thrombophilia are found to have low levels of AT-3 or Proteins C/S in <20% of all cases. Resistance to activated protein C seems to be 5-10 times more common in such patients. APC resistance is AutoD. The abnormality appears to be a defect in Factor V that allows FV to function normally as a procoagulant, but that makes it resistant to natural anticoagulation by APC.
Tx: warfarin, keeping INR ~4
Acquired AT-3 deficiency due to urinary loss in nephrotic syndrome
Acquired Protein S deficiency
Levels are physiologically decreased in pregnant women and in those taking BCPs. Also see levels in some cases of HIV of long duration.
Factor V Leiden
Prothrombin G20210A mutation
Factor 8 (levels above 150 assoc with 4-fold risk of venous thrombosis. This pertains to chronically elevated levels, not acute phase reaction. Mechanism unclear: may be genetic.)
Arterial: the above plus
Methylene THF reductase mutations (C677T and A1298C). (Heterozygosity for either does not confer increased risk, but double heterozygosity increases risk for coronary artery disease by 1.7 times; cerebrovascular disease 2.5x; DVT by 2.5x; and peripheral vascular disease 6.8 times.
Only if strongly suspect:
Protein C & S, AT III
Note: Protein S may cause arterial thrombi; the assoc is not solid.
TX: If 2+ events, APLA, or any life threatening event
Chronic thrombotic DIC assoc with solid visceral tumors.
Frequently resistant to warfarin and requires heparin.
Experimental: MoAbs against TNF (which may be what triggers the process)
In uremia get abnormal vWF binding. This could be due to production of abnl multimers or due to accumulation of interfering substances such as guanidinosuccinic acid.
1. ddAVP 0.3 mcg/kg IV/20-30min (70% RR)
2. vWF (in Humate-P)
4. Conjugated estrogens (but variable and delayed effect)
5. Keep Hct 26-35% (forces migration of platelets toward vessel walls)
Vitamin K is a cofactor for the enzyme that carboxylates the glutamic acid residues of factors 2,7,9,10 and Proteins C and S. Coumadin (warfarin) blocks two enzymes in the vitamin K recycling system, vitamin K epoxide reductase (major) and vitamin K reductase (minor). Vitamin K is needed for the final post-ribosomal carboxylation of coagulation factors 2,7,9 and 10, as well as Proteins C & S.
In vitamin K deficiency, the liver synthesizes bogus molecules that are collectively termed PIVKA (proteins induced by vitamin K absence or antagonists), also called des-carboxylated factors. They have no coagulant activity.
Administration of warfarin also --> production of PIVKA. People obtain Vitamin K from the diet (green leafy veggies, casein, vegetable oils) and from synthesis by gut bacterial flora. Humans cannot store Vitamin K.
Causes of Vitamin K deficiency:
1. supply - with intake and antibiotics can develop factors, especially FVII in a few days.
2. Impaired absorption - obstructive jaundice--> bile salts, steatorrhea (sprue, Crohn's, cystic fibrosis)
3. Surreptitious ingestion of warfarin
Lab features: PT becomes prolonged, first due to FVII, then other factors. PTT is normal at first due to longer 1/2 lives of FIX and FX. It may also prolong later.
Vitamin K 15mg SQ. Failure to correct PT in 24hr suggests other etiology.
If serious bleeding is occurring, 5-10 mg may be given very slowly IV. May be given IM, but could--> hematoma if severe deficiency.
Type I: dec levels
Type 2: abnl multimers (2B is bad)
Type 3: absent levels
DDAVP: 0.3 mcg/kg in 50-100cc NS IV/30 min. (Restrict water to avoid hyponatremia.). The dose may be repeated q 8h if necessary.
Stimate® Nasal Spray: 150 mcg/ml: Prior to surgery or if bleeding: one spray in each nostril (300 mcg dose) for adults. Kids use less. (Aventis’ ddAVP comes as 10 mcg/ml which is better for dosing small kids.)
Contra: Type IIB (causes decreased platelets & thrombosis) or Platelet-type vWD, Epilepsy (can cause seizures, especially kid), Careful in elderly (angina & CVA caused by thrombosis due to release of ultra-large multimers).
- Works best in patients w baseline levels of 10-20 IU/dL (usu Type I pt w nl platelet count). Will raise levels to 3-5 x baseline in about 30 min. Effect lasts about 8-10 hr. May repeat in 12-24h. Can be used in pregnancy (little or no oxytocic activity).
HUMATE P: F VIII concentrate that has 2.09u per unit F VIII.
Usu dose is 20-40 u vWF/kg q12h. (Although it contains vWF:FVIII 2:1, most assume 1:1. Half-life is similar to FVIII, so dose q12h.
Recommendations from Blood 4/01:
- Major surgery: 40-60 u once QD. Maintain F8 level >50 until healing complete. (Measure q12h day of surgery, then QD)
- Minor surgery: 30-50 u once QD or QOD. Keep F8 > 30 until healing complete.
- Dental extractions: 20-30 u once. Goal: F8 > 30 for at least 12h.
- Spontaneous Bleed: same as dental.
If doesn’t seem to be working, give platelets, especially in type 3. These may help transport the vWF to sites of injury.
Recommendations from company:
TYPE I vWD
Mild (RCof >30): DDAVP for minor bleeding. For MAJOR: Load 40-60 u/kg then 40-50 q8hr x 3 days to keep nadir RCof >50%, then 40-50 u/kg QD x 7d
MOD OR SEVERE vWD: Minor bleed: 40-50 u/kg x 1-2 doses. Major Bleed(GI, CNS, Joint, trauma): 50-75 u/kg, then 40-60 u/kg q8h q8-12h x 3 days to keep nadir RCof > 50%, then 40-60 u/kg QD x 7days
TYPE II and III
Minor: 40-50 u/kg x 1-2 doses. Major: 60-80 u/kg, then 40-60 u/kg q8-12h x 3days to keep nadir level > 50%, then 40-60 u/kg QD x 7days
CRYOPRECIPITATE: Each bag has 80-100u. Give q12-24h. Risk of infx because cant use virucidal methods like other factors/products.
-----old data below---------
For major surgery, replace so that vWF activity level is 80-100, and trough is >40 for 2-3 days. Then maintain FVIII level >40 for another 4-5 days.
This usually means:
30-40u/kg bolus then 15-20u/kg q12h to maintain vWF >40-50 for 3 days, then DDAVP once daily x 3-7d. In patients who do not respond, continue Humate-P 15-25 u/kg QD for 3-7d (Coleman & Hirsh 3rd Ed. p 160)
For minor surgery: DDAVP once QD x 1-2days. If not responsive, Humate-P 15-20 u/kg x 1 dose.
Antifibrinolytics: recommended for oral surgery, mucosal bleeding (including GI), mennorhagia.
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Entire molecule above is VIII Ag (not a functional assay)
1) VIII:vWF= ristocetin cofactor (missing in vWF)
2) "C" = coagulation: missing in hemophilia (functional assay)
VWD Profile: Esoterix Profile 300910
Note: Factor 8 concentrates containing VWF are now preferred to cryoprecipitate because they have higher concentrations of VWF and are viral inactivated. Cryoprecipitate cannot be viral inactivated.
vWF has 2 roles: mediates platelet adhesion to site of endothelial injury (via GP Ib-vWF), and acts as a courier protein for F8
Defects in vWF can cause bleeding by decreased platelet adhesion and decreased clotting
vWD caused by defect in vWF gene on chromosome 12 (Auto D). Occurs in 1% of general population.
No specific gene mutation.
Due to quantitative decrease in all multimers, especially large and intermediate (IB)
Proportional decrease in vWF antigen and activity (Ristocetin cofactor)
F VIII levels may vary.
TX: ddAVP 0.3 mcg/kg IV over 15-30 minutes. Can give as often as q8h, but because of tachyphylaxis, may try to limit to q 24h or so.
Due to genetic defect that results either in (1)
decreased assembly of large multimers or (2) enhanced clearance (sometimes due
to increased sensitivity to ADAMTS13, the metalloproteinase that normally
degrades vWF multimers).
Therefore, get qualitative decrease in intermediate and large multimers
vWF activity tends to be disproportionately lower than antigen
Unpredictable response to DDAVP, so must test first. Also, responses tend not to last as long as in Type I.
TX: ddAVP if responsive and minor problem. Otherwise preferred treatment is Humate-P (a Factor 8 concentrate that contains vWF).
(Usual dose of Humate-P for vWD is 20-40 u/kg once QD)
Due to genetic defect that results in abnormally increased binding to platelets, leading
to enhanced clearance of large multimers and platelets (can cause
Gets worse with stress, infection, and pregnancy.
Multimers present are hyper-reactive to ristocetin, and react at levels that normal patients will not. (Increased sensitivity to RIPA [ristocetin-induced platelet aggregation])
Multimer pattern is normal, though levels decreased.
Indistinguishable from pseudo-vWD which is due to abnormal GP Ib-IX-V on platelets (causing increased binding to vWF).
ddAVP --> release of more abnormal multimers which may --> platelet aggregation and thrombosis. DON'T USE!
TYPE 2M (“multimer”)
Due to genetic defect that results in impaired
binding of vWF to platelets.
Disproportionate decrease in activity compared to Ag level
Normal multimer pattern
TX: Can sometimes respond to ddAVP, like Type 2A, but usually use Humate-P if bleeding
TYPE 2N (“Normandy”)
Due to genetic defect that impairs binding of vWF
to F VIII leading to very low F VIII levels.
Normal platelet binding
Normal vWF antigen level, but prolonged PTT
Consider if: (1) factor 8 inhibitor is ruled out, (2) X-linked inheritance is not clear, (3) initial therapy with factor 8 concentrate doesn’t work well.
TX: must use factor 8 concentrate that contains vWF (Humate-P)
Severely decreased functional multimers
DDAVP not helpful because no multimers to release
Problem is not vWF, but rather, abnormal GPIb
protein on platelet.
The abnormal GPIb is hyper-reactive even to normal vWF, and platelets may aggregate spontaneously.
May be difficult to distinguish from Type 2B
TX: Platelet transfusion. NOT cryoprecipitate because platelets will aggregate (this is diff from type IIB)
Can see in conditions that lower vWF levels, such as lymphoproliferative disorders or monoclonal gammopathies with antibody activity against VWF. Can also see in conditions with increased platelet counts (myeloproliferative disorders) that bind circulating VWF (enhanced clearance).
Mechanism: A synthetic antithrombin (derived from L-arginine) that is highly selective for thrombin. Reversibly binds to the active thrombin site of free and clot-associated thrombin. It directly inhibits the action of thrombin, thus inhibiting activation of factors 5, 8, and 13, protein C, and platelet aggregation.
Elimination half-life is 39-51 minutes (except in hepatic impairment: > 3hrs)
Onset of action is ~20 minutes
Time to peak steady state: 1-3 hrs
Duration of action is ~2 hours.
Initial dose: 2 mcg/kg/minute (note that this is minute, not hour like heparin or Refludan)
Maintenance dose: Measure aPTT after 2 hours, adjust dose until the steady-state aPTT is 1.5-3.0 times the initial baseline value, not exceeding 100 seconds; dosage should not exceed 10 mcg/kg/minute
- Start infusion at 2 mcg/kg/min
- Check first PTT after 2 hrs. Adjust as follows:
PTT < 50: Increase by 20%. Next PTT in 2 hours.
PTT 50-69: Increase by 10%. Next PTT in 2 hours.
PTT 70-100: No change in dose. Next PTT in the AM.
PTT 101-135: Decrease rate by 10%. Next PTT in 2 hours.
PTT > 135: Stop infusion and check PTT q 2hrs until < 100, then resume infusion at 1/2 previous rate. Next PTT in 2 hours.
If required dose would exceed 10 mcg/kg/min, notify physician.
Conversion to oral anticoagulant: Because there may be a combined effect on the INR when argatroban is combined with warfarin, loading doses of warfarin should not be used. Warfarin therapy should be started at the expected daily dose.
Patients receiving 2 mcg/kg/minute of argatroban: Argatroban therapy can be stopped when the combined INR on warfarin and argatroban is >4; repeat INR measurement in 4-6 hours; if INR is below therapeutic level, argatroban therapy may be restarted. Repeat procedure daily until desired INR on warfarin alone is obtained.
Patients receiving >2 mcg/kg/minute of argatroban: Reduce dose of argatroban to 2 mcg/kg/minute; measure INR for argatroban and warfarin 4-6 hours after dose reduction; argatroban therapy can be stopped when the combined INR on warfarin and argatroban is >4. Repeat INR measurement in 4-6 hours; if INR is below therapeutic level, argatroban therapy may be restarted. Repeat procedure daily until desired INR on warfarin alone is obtained.
Initial: Begin infusion of 25 mcg/kg/minute and administer bolus dose of 350 mcg/kg (over 3-5 minutes). ACT should be checked 5-10 minutes after bolus infusion; proceed with procedure if ACT >300 seconds.
Following initial bolus:
ACT <300 seconds: Give an additional 150 mcg/kg bolus, and increase infusion rate to 30 mcg/kg/minute (recheck ACT in 5-10 minutes)
ACT 300-450 seconds: Continue infusion at current dose for the duration of the procedure.
ACT >450 seconds: Decrease infusion rate to 15 mcg/kg/minute (recheck ACT in 5-10 minutes)
Impending abrupt vessel closure, thrombus formation during PCI, or inability to achieve ACT >300 sec: An additional bolus of 150 mcg/kg, followed by an increase in infusion rate to 40 mcg/kg/minute may be administered.
Dosage adjustment in hepatic impairment: Decreased clearance and increased elimination half-life are seen with hepatic impairment; dose should be reduced. Initial dose for moderate hepatic impairment is 0.5 mcg/kg/minute. Note: During PCI, avoid use in patients with elevations of ALT/AST (>3 x ULN); the use of argatroban in these patients has not been evaluated.
Elderly: No adjustment is necessary for patients with normal liver function
MONITORING PARAMETERS — Obtain baseline aPTT prior to start of therapy. Check aPTT 2 hours after start of therapy to adjust dose, keeping the steady-state aPTT 1.5-3 times the initial baseline value (not exceeding 100 seconds). Monitor hemoglobin, hematocrit, signs and symptoms of bleeding. Argatroban produces dose-dependent effects on PT, INR, ACT, and TT, however, therapeutic ranges are not established. The PiCT (prothrombinase-induced clotting time) is probably the most sensitive and best test for monitoring the direct thrombin inhibitors, once it becomes available.
ADMINISTRATION — Solution must be diluted to 1 mg/mL prior to administration. May be mixed with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection. To prepare solution for I.V. administration, dilute each 250 mg vial with 250 mL of diluent (500 mg with 500 mL of diluent). Mix by repeated inversion for one minute. A slight but brief haziness may occur prior to mixing. Do not mix with other medications. The prepared solution is stable for 24 hours at 25ºC (77ºF) in ambient indoor light. Do not expose to direct sunlight. Prepared solutions are stable for 48 hours at 2ºC to 8ºC when stored in the dark.
Rise in liver-dependent clotting factors: Fibrinogen, 2, 7, 9, 10 and vWF
Decrease in Protein C and S
Note: If the Factor 8 level is low, remember to consider occult von Willebrand’s in addition to an acquired Factor 8 inhibitor as the possible cause.
Recombinant coagulation factor VIIa (rFVIIa) (Novoseven), is a Vitamin K-dependent glycoprotein recently licensed by the FDA for treatment of bleeding in individuals with hemophilia A and B inhibitors, acquired inhibitors (e.g. anti-VIII), and congenital factor VII deficiency.
Produced in baby hamster kidney (BHK) cells transfected with the FVII gene, secreted rFVII is rapidly activated in cell culture to its active form, rFVIIa during chromatographic purification. Because the culture medium contains newborn calf serum, the final product contains trace mouse IgG and BHK protein. The observed half-life of the product in pharmacokinetic studies is 2-3 hours. The site of action of rFVIIa is the extrinsic coagulation cascade, specifically complexing to tissue factor, with which promotes activation of factor X to Xa, factor IX to IXa, and factor II (prothrombin) to IIa (thrombin). The clot promoting activity of this product through the extrinsic pathway, bypassing the intrinsic pathway (factors VIII and FIX), makes it potentially beneficial in patients with acquired inhibitors to factor VIII or IX, who no longer respond to factor VIII or IX concentrates, and patients with congenital factor VII deficiency. Factor VIIa efficacy demonstrated in the Wessler rabbit stasis model have shown that FVIIa promotes clot formation and hemostasis at the site of injury with no evidence of activation of the coagulation system, e.g. decreased in platelets, fibrin split products, or fibrin monomer.
rFVIIa has been shown to be safe and effective for acute bleeding, life and limb-threatening hemorrhage, and in the surgical setting. In a study by Lusher et al carried out in 78 hemophilia A and B patients with severe or moderately severe disease, with FVIII:C or IX:C < 0.02 U/ml, 66 with inhibitors, the product was found to be safe and effective during treatment for 179 hemorrhages. The clinical response to the higher of two tested treatment doses, 70 vs.35 m g/kg, was somewhat higher, 69% vs. 53%. Only mild adverse events were reported in 22%.
rFVIIa has been evaluated in nearly 300 patients for 2,000 hemorrhages and appears to be safer and more effective than currently available treatment for patients with inhibitors (plasma-derived FEIBA, Autoplex) or congenital factor VII deficiency (plasma). Specifically, rFVIIa avoids the major risk associated with FEIBA and Autoplex, thrombosis, and it avoids the major risk associated with plasma, e.g. blood-borne virus transmission and other pathogens, as well as plasma-derived product shortages. There has been no evidence of allergic reaction or activation of coagulation, thrombocytopenia, or disseminated intravascular coagulation. A drawback is the short half-life of rFVII, which requires frequent dosing and results in high cost. Continuous infusion may be a potential approach, although local thrombophlebitis is a major complication, possibly related to the high concentration of rVIIa in peripheral veins. Until more information is available on rFVIIa stability and local thrombophlebitis, continuous infusion is not recommended.
The major effect of rFVIIa is to shorten the prothrombin time (PT), that is, the time from vessel injury to clot formation via the tissue factor pathway. The extent of PT shortening, however, does not specifically correlate with clinical efficacy of rFVIIa. Thus, patients treated with rFVIIa should be monitored for blood loss, transfusion requirement, and hemoglobin.
The initial recommended dose of rFVIIa is 90 mcg/kg, continued every 2-3 hours, and once bleeding and hemoglobin have stabilized, tapered to every 6-8 hours, then every 12-24 hours, and stopped. Dosing in children may differ from that in adults, given the shorter half-life observed in pharmacokinetic studies of pediatric patients.
Tissue or cell defect à activates F7
F7 + F3( tissue thromboplastin) à activates F10
Surface contact / collagen / F12 activator à activates F12
F12a + Ca à activates F11 (F12a enhances F7 activation, and F7a enhances F11 activation)
F11a + Ca à activates F9 (enhanced by thrombin)
F9a + F8a + PF3 + Ca à activates F10 (Thrombin activates F8)
F10a + F5a + Ca à converts Prothrombin to Thrombin (Thrombin activates F5)
Thrombin à converts Fibrinogen to Fibrin monomers (yielding fibrinopeptides 1,2)
Fibrin monomers à form polymers
F13a à crosslinks polymers (F13 activated by thrombin) (yielding D-dimers)
Plasminogen converted to Plasmin by (TPA, streptokinase, F12a, urokinase, HMWK, kallikrein) à FDPs
Activated Protein C à inhibits thrombin and F8 activation of F8 and F12
Antithrombin à blocks activation of F12, F11, and F9, but especially F10 and thrombin. (Thus effect of unfractionated heparin is primarily on F10 and thrombin.)
PTT – intrinsic and common pathways – time to form fibrin
PT – extrinsic and common pathways
Thrombin time – conversion of fibrinogen to fibrin
Reptilase time – same as PTT, but not affected by heparin (so will be normal if heparin is cause of prolonged PTT)
Activated Protein C [drotrecogin alpha] (Xigris - Lily) (NEJM 344:699 3/01)
Dose: 24 mcg/kg/hr IV x 96 hrs.
Stop infusion for 1 hr before any invasive procedures. Resume 1 hr after percutaneous procedures, or 12 hrs after major surgery.
Not clearly better than placebo except in certain subgroups:
Reduced relative risk of death by 19% and absolute risk by 6%.
Approved for patients at high risk for death from sepsis.
NOT yet considered standard of care. (NEJM 347:1027, 9/02)